Handbook on the Neuropsychologyof Aging and Dementia

Clinical Handbooks in Neuropsychology Ravdin · Katzen Eds. Clinical Handbooks in Neuropsychology Lisa D. Ravdin · Heather L. Katzen Editors Handbook on the Neuropsychology of Aging and Dementia

As the population of older adults increases, so does the incidence of age related cognitive disorders such as dementia. Alzheimer’s disease is the most common form of dementia, yet there are many other conditions associated with neuropsychological impairment in older adults. Th e conscientious clinician must be able not only to diff erentiate between normal age-related cognitive decline and early signs of dementing disorders, but also accurately identify diff erential diagnoses for possible causes of dementia. Th e Handbook on the Neuropsychology of Aging and Dementia off ers practitioners a hands-on guide to these bedrock clinical tasks. Th e fi rst half of the Lisa D. Ravdin volume addresses special considerations for conducting neuropsychological assessments of older adults, such as disease management issues, sleep concerns, Heather L. Katzen Editors and ethical matters. Th e second section illuminates symptoms and issues associated with specifi c disorders and their relationship to functional impairments. Information is presented in a practitioner friendly format with sample cases, test battery recommendations, and “clinical pearls” from recognized experts in the fi eld. Among the Handbook’s topics: 1 • Serial assessments in dementia. Handbook on the • Considerations for neuropsychological evaluations with older minority Handbook on the Neuropsychology patients. of Aging and Dementia • Impact of medications on cognition. • Assessing depression and anxiety in older adults. Neuropsychology • Prevention of cognitive decline. • Plus in-depth chapters on late-life cognitive impairment resulting from Alzheimer’s disease, vascular cognitive impairment, cancer, stroke, epilepsy, and a variety of other conditions. Useful and informative well beyond its immediate specialty, the Handbook on of Aging the Neuropsychology of Aging and Dementia is a singular reference for neuropsychologists, neurologists, primary care physicians (geriatricians, internists, family doctors), health psychologists, clinical psychologists, and clinical social workers. and Dementia

Psychology ISBN 978-1-4614-3105-3

9 781461 431053 Clinical Handbooks in Neuropsychology

Series Editor William B. Barr New York University New York, NY, USA

For further volumes: http://www.springer.com/series/8438

Lisa D. Ravdin • Heather L. Katzen Editors

Handbook on the Neuropsychology of Aging and Dementia Editors Lisa D. Ravdin Heather L. Katzen Department of Neurology Division of Neuropsychology & Neuroscience Department of Neurology Weill Cornell Neuropsychology Service University of Miami Miller Weill Medical College of Cornell School of Medicine University Miami, FL, USA New York Presbyterian Hospital New York, NY, USA

ISBN 978-1-4614-3105-3 ISBN 978-1-4614-3106-0 (eBook) DOI 10.1007/978-1-4614-3106-0 Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 2012937655

© Springer Science+Business Media, LLC 2013 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on micro fi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied speci fi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a speci fi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com) Preface

The Clinical Handbooks in Neuropsychology series was designed to be a departure from typical texts by focusing on concrete clinical descriptions and detailed instructions regarding how neuropsychologists evaluate various patient conditions. This particular book was created with the knowledge that older adults are the fastest growing segment of the population, and neuropsychologists are increasingly being called upon to evaluate seniors in a variety of contexts. Many predict that 15Ð20% of the baby-boomer generation will develop some form of cognitive decline over the course of their lifetime, with estimates escalating to up to 50% in those achieving advanced age. Although much attention has been directed at Alzheimer’s disease, the most common form of dementia, it is estimated that nearly one-third of those cases of cognitive decline result from other neuropathological mechanisms. Handbook on the Neuropsychology of Aging and Dementia is a unique work that provides clinicians with expert guidance and a hands-on approach to neuropsychological practice with older adults. The authors of each chapter are expert practitioners, recognized by their peers as opinion leaders on their chosen chapter topics. The book is divided into two parts: the fi rst addresses special considerations for the evaluation of older adults, and the second focuses on common referral questions likely to be encountered when working with this age group. In many chapters, case examples are provided to highlight common issues that may arise when a particular disorder is considered in the differential diagnosis. Suggested test batteries are also provided in many cases, and each chapter concludes with a user-friendly list of Clinical Pearls, items extracted from the text that include expert tips and key take-home messages on each topical area. The fi eld of neuropsychology has played a critical role in developing methods for early identifi cation of late life cognitive disorders as well as the differential diagnosis of dementia. Each chapter in this work reinforces the notion that neuropsychological measures provide the clinician with sensitive tools to differentiate normal age-related cognitive decline from disease-associated impairment, aid in differential diagnosis of cognitive dysfunction in older adults, as well as identify cognitive defi cits most likely to translate into functional impairments in everyday life. Our contributing authors embraced the approach of providing insightful commentary and useful strategies gained from their clinical experience, and we are grateful to them for generously giving their time and expertise to this

v vi Preface project. We appreciate the support of Janice Stern, Springer’s senior editor for health and behavior, and Bill Barr, series editor, who together were the driving force behind this project. Finally, a special thanks to Brooke Schiowitz and James Maniscalco, who were extraordinarily helpful with administrative aspects of preparing this work.

New York, NY, USA Lisa D. Ravdin Miami, FL, USA Heather L. Katzen Contents

Part I Assessment of Older Adults: Special Considerations

1 Special Considerations for the Neuropsychological Interview with Older Adults ...... 3 Stephanie Assuras and Bonnie Levin 2 Consideration of Cognitive Reserve ...... 11 Stephanie Cosentino and Yaakov Stern 3 Considerations for the Neuropsychological Evaluation of Older Ethnic Minority Populations ...... 25 Monica Rivera Mindt, Alyssa Arentoft, Kelly Coulehan, and Desiree Byrd 4 The Assessment of Change: Serial Assessments in Dementia Evaluations ...... 43 Gordon J. Chelune and Kevin Duff 5 After the Diagnosis of Dementia: Considerations in Disease Management ...... 59 Steven Hoover and Mary Sano 6 Sleep and Aging ...... 79 Matthew R. Ebben 7 Medications and Cognition in Older Adults ...... 89 Gregg L. Caporaso 8 Assessment of Depression and Anxiety in Older Adults ...... 109 Dimitris N. Kiosses 9 Neuropsychological Assessment and Management of Older Adults with Multiple Somatic Symptoms ...... 121 Greg J. Lamberty and Kimberly K. Bares 10 Driving Evaluation in Older Adults ...... 135 Kevin J. Manning and Maria T. Schultheis 11 Environmental Design for Cognitive Decline ...... 153 Rosemary Bakker

vii viii Contents

12 Prevention of Cognitive Decline ...... 167 Jose Gutierrez and Richard S. Isaacson 13 Clinical Neuropsychology Practice and the Medicare Patient ...... 193 Edward A. Peck III, Lucien W. Roberts III, and Joy M. O’Grady 14 Professional Competence as the Foundation for Ethical Neuropsychological Practice with Older Adults ..... 217 Arthur C. Russo, Shane S. Bush, and Donna Rasin-Waters 15 Ethical Considerations in the Neuropsychological Assessment of Older Adults ...... 225 Arthur C. Russo, Shane S. Bush, and Donna Rasin-Waters

Part II Late Life Cognitive Disorders

16 Mild Cognitive Impairment and Normal Aging...... 239 Lauren A. Rog and Joseph W. Fink 17 Differential Diagnosis of Depression and Dementia ...... 257 Linas A. Bieliauskas and Lauren L. Drag 18 Assessment of Alzheimer’s Disease ...... 271 David Loewenstein 19 Vascular Cognitive Impairment ...... 281 Robert Paul, Elizabeth Lane, and Angela Jefferson 20 Assessment in Acute Stroke Rehabilitation ...... 295 George M. Cuesta 21 Accurate Assessment of Behavioral Variant Frontotemporal Dementia ...... 313 Amanda K. LaMarre and Joel H. Kramer 22 Movement Disorders with Dementia in Older Adults ...... 333 Alexander I. Tröster and Nina Browner 23 Neuropsychological Considerations for Parkinson’s Disease Patients Being Considered for Surgical Intervention with Deep Brain Stimulation...... 363 Paul J. Mattis, Chaya B. Gopin, and Kathryn Lombardi Mirra 24 Idiopathic Normal Pressure Hydrocephalus ...... 385 Lisa D. Ravdin and Heather L. Katzen 25 Episodic and Semantic Memory Disorders ...... 401 Taylor Kuhn and Russell M. Bauer 26 Epilepsy and Aging ...... 421 Brian D. Bell and Anna Rita Giovagnoli Contents ix

27 Neuropsychological Assessment of Older Adults with a History of Cancer ...... 443 Mariana E. Witgert and Jeffrey S. Wefel 28 Evaluating Cognition in Patients with Chronic Obstructive Pulmonary Disease ...... 455 Elizabeth Kozora and Karin F. Hoth 29 Hepatic Encephalopathy ...... 467 Robin C. Hilsabeck and Amy L. Webb 30 Late-Onset Schizophrenia ...... 487 Tracy D. Vannorsdall and David J. Schretlen 31 Capacity Evaluations in Older Adults: Neuropsychological Perspectives ...... 501 Joel E. Morgan and Bernice A. Marcopulos

Index ...... 511

Contributors

Alyssa Arentoft Department of Psychology , Fordham University , New York , NY , USA Stephanie Assuras Department of Psychiatry , Harvard Medical School , Massachusetts General Hospital , Boston, MA, USA Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA Rosemary Bakker Division of Geriatrics, Department of Medicine , Weill Cornell Medical College , New York , NY , USA Kimberly K. Bares Minneapolis VA Health Care System , Minneapolis , MN , USA Russell M. Bauer Department of Clinical and Health Psychology , University of Florida , Gainesville , FL , USA Brian D. Bell Charles Matthews Neuropsychology Laboratory, Department of Neurology , University of Wisconsin School of Medicine and Public Health , Madison , WI , USA W.S. Middleton Memorial Veterans Hospital , Madison , WI , USA Linas A. Bieliauskas Neuropsychology Section, Department of Psychiatry , Mental Health Service, Ann Arbor VA Healthcare System, University of Michigan Healthcare System , Ann Arbor , MI , USA Nina Browner Department of Neurology (CB 7025) , University of North Carolina School of Medicine , Chapel Hill , NC , USA Shane S. Bush VA New York Harbor Healthcare System , New York , NY , USA Desiree Byrd Departments of Pathology and Psychiatry , The Mount Sinai School of Medicine , New York , NY , USA Gregg L. Caporaso Division of Neurology, W estchester Health Associates , Yorktown Heights , NY , USA Gordon J. Chelune Department of Neurology, Center for Alzheimer’s Care, Imaging and Research , University of Utah School of Medicine , Salt Lake City , UT , USA

xi xii Contributors

Stephanie Cosentino Cognitive Neuroscience Division of the Gertrude H. Sergievsky Center, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, and Department of Neurology , Columbia University Medical Center , New York , NY , USA Kelly Coulehan Department of Psychology , Fordham University , New York , NY , USA George M. Cuesta Burke Rehabilitation Hospital , Weill Cornell Medical College , White Plains , NY , USA Department of Veterans Affairs, Manhattan Vet Center, Readjustment Counseling Service, Veterans Health Administration , Manhattan , NY , USA Lauren L. Drag Neuropsychology Section, Department of Psychiatry , University of Michigan Healthcare System , Sunnyvale , CA , USA Kevin Duff Department of Neurology, Center for Alzheimer’s Care, Imaging and Research , University of Utah School of Medicine , Salt Lake City , UT , USA Matthew R. Ebben Department of Neurology and Neuroscience, Center for Sleep Medicine , New York Presbyterian Hospital, Weill Cornell Medical College , New York , NY , USA Joseph W. Fink Department of Psychiatry and Behavioral Neuroscience , University of Chicago , Chicago , IL , USA Anna Rita Giovagnoli Department of Clinical Neurosciences, Neuropsychology Laboratory, Carlo Besta Neurological Institute, Milan, Italy Chaya B. Gopin Department of Neurology , North Shore University Hospital , Manhasset , NY , USA Department of Psychiatry , The Zucker Hillside Hospital , Glen Oaks , NY , USA Jose Gutierrez Department of Neurology, Neurological Institute , Columbia University , New York , NY , USA Robin C. Hilsabeck Psychology Service, South Texas Veterans Health Care System , San Antonio , TX , USA Department of Psychiatry , University of Texas Health Science Center at San Antonio , San Antonio , TX , USA Department of Psychiatry , University of California, San Diego , San Diego , CA , USA Steven Hoover Department of Psychiatry , Mount Sinai School of Medicine , Elmwood Park , NJ , USA Karin F. Hoth Division of Psychosocial Medicine, Department of Medicine , National Jewish Health , Denver , CO , USA Departments of Psychiatry and Neurology , University of Colorado Denver , Aurora , CO , USA Department of Medicine , National Jewish Health , Denver , CO , USA Contributors xiii

Richard S. Isaacson Department of Neurology, Univ ersity of Miami Miller School of Medicine , Miami , FL , USA Angela Jefferson Vanderbilt Memory & Alzheimer’s Center , Department of Neurology, Vanderbilt University Medical Center , Nashville , TN, USA Heather L. Katzen Division of Neuropsychology, Department of Neurology , University of Miami Miller School of Medicine , Miami , FL , USA Dimitris N. Kiosses Department of Psychiatry, Weill Cornell Institute of Geriatric Psychiatry , Weill Medical College of Cornell University , White Plains , New York, NY , USA Elizabeth Kozora Department of Medicine , National Jewish Health , Denver , CO , USA Departments of Psychiatry and Neurology , University of Colorado Medical School , Aurora , CO, USA Joel H. Kramer Memory and Aging Center , University of California , San Francisco , CA , USA Taylor Kuhn Department of Clinical and Health Psychology , University of Florida , Gainesville , FL , USA Greg J. Lamberty Minneapolis VA Health Care System , Minneapolis , MN , USA Amanda K. LaMarre Memory and Aging Center, University of California, San Francisco , CA , USA Elizabeth Lane Department of Psychology, Division of Behavioral Neurosciences, University of Missouri, St. Louis , MO , USA Bonnie Levin Division of Neuropsychology, Department of Neurology , University of Miami Miller School of Medicine , Miami , FL , USA David Loewenstein Department of Psychiatry and Behavioral Sciences , Miller School of Medicine, University of Miami Miller School of Medicine , Miami , FL , USA Kevin J. Manning Department of Psychology , Drexel University , Philadelphia , PA , USA Bernice A. Marcopulos Department of Graduate Psychology , James Madison University , Harrisonburg , VA , USA Paul J. Mattis Center for Neurosciences , The Feinstein Institute for Medical Research , Manhasset , NY , USA Department of Neurology , North Shore University Hospital , Manhasset , NY , USA Movement Disorders Center , Great Neck , NY , USA xiv Contributors

Monica Rivera Mindt Department of Psychology , Fordham University , New York , NY , USA Departments of Pathology and Psychiatry, The Mount Sinai School of Medicine, New York, NY, USA Kathryn Lombardi Mirra Department of Neurology , North Shore University Hospital , Manhasset , NY , USA Department of Psychiatry , The Zucker Hillside Hospital , Glen Oaks , NY , USA Joel E. Morgan Department of Neurology and Neurosciences , UMDNJ—New Jersey Medical School , Madison , NJ , USA Joy M. O’Grady Neuropsychological Services of Virginia Inc, , Richmond , VA , USA Robert Paul Department of Psychology, Division of Behavioral Neurosciences , University of Missouri , St. Louis, MO , USA Edward A. Peck III Neuropsychological Services of Virginia Inc, , Richmond , VA , USA Donna Rasin-Waters VA New York Harbor Healthcare System, New York, NY , USA Lisa D. Ravdin Department of Neurology & Neuroscience, Weill Cornell Neuropsychology Service , Weill Medical College of Cornell University, New York Presbyterian Hospital , New York , NY , USA Lucien W. Roberts III Neuropsychological Services of Virginia Inc , Richmond , VA , USA Lauren A. Rog Illinois Institute of Technology , Chicago , IL , USA Arthur C. Russo Psychology Department, VA New York Harbor Healthcare System , Brooklyn , NY , USA Fordham University , New York , NY , USA Mary Sano Department of Psychiatry , Mount Sinai School of Medicine , New York , NY , USA James J Peters Veterans Administration Medical Center , Bronx , NY , USA David J. Schretlen Department of Psychiatry and Behavioral Sciences , Johns Hopkins University School of Medicine , Baltimore , MD , USA Russell H. Morgan Department of Radiology and Radiological Science , Johns Hopkins University School of Medicine , Baltimore , MD , USA Maria T. Schultheis Department of Psychology , Drexel University , Philadelphia , PA , USA Department of Biomedical Engineering , Drexel University , Philadelphia , PA , USA Contributors xv

Yaakov Stern Cognitive Neuroscience Division of the Gertrude H. Sergievsky Center, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, and Department of Neurology , Columbia University Medical Center , New York , NY , USA Alexander I. Tröster Barrow Neurological Institute, Phoenix, USA Tracy D. Vannorsdall Department of Psychiatry and Behavioral Sciences , Johns Hopkins University School of Medicine , Baltimore , MD , USA Amy L. Webb Psychology Service, South Texas Veterans Health Care System, San Antonio, TX, USA Hepatology Clinic, South Texas Veterans Health Care System , San Antonio , TX , USA Department of Medicine , University of Texas Health Science Center at San Antonio , San Antonio , TX , USA Jeffrey S. Wefel Section of Neuropsychology, Department of Neuro-Oncology , University of Texas M.D. Anderson Cancer Center , Houston , TX , USA Mariana E. Witgert Section of Neuropsychology, Department of Neuro-Oncology, University of Texas M. D. Anderson Cancer Center, Houston , TX , USA

Part I Assessment of Older Adults: Special Considerations Special Considerations for the Neuropsychological Interview 1 with Older Adults

Stephanie Assuras and Bonnie Levin

Abstract The clinical interview is an essential part of a neuropsychological evaluation for any age, but particularly among older adults because of the myriad of physical, cognitive, psychological and social changes associated with the normative aging process. This essential data can be used to guide the testing process, assist in formulating a differential diagnosis, and informing recommendations. This chapter provides guidelines for developing an interview designed to provide a level of insight and understanding of a patient’s presentation that cannot be obtained from psychometric testing, and is speciﬁ c to the presenting concerns of older adults.

Keywords Neuropsychological interview • Cognitive complaints • Somatic/sensory/ motor symptoms • Emotional functioning • Activities of daily living • Functional capacity • Collateral information • Medical history • Social history

The neuropsychological interview presents a in formulating a differential diagnosis. A compre- unique opportunity to gather essential data that hensive interview not only provides important can be used to guide the testing process and assist background information that cannot be obtained from psychometric testing but it also offers an opportunity for the examiner to gather critical S. Assuras , Ph.D. () Department of Psychiatry, Harvard Medical School , behavioral observations that are often witnessed Massachusetts General Hospital , One Bowdoin Square, only in a less-structured setting. Although inter- 7th Floor , Boston , MA 02114, USA views vary in their focus and depth, they provide Department of Neurology, Brigham and Women’s a framework from which examiners can assess Hospital , Boston , MA , USA demographic and referral information, data e-mail: [email protected] pertaining to presenting complaints and symptom B. Levin , Ph.D. progression, information regarding activities of Division of Neuropsychology, Department of Neurology , daily living, pertinent environmental risk factors, University of Miami Miller School of Medicine , 1120 NW 14th Street, Room 1337 , Miami , FL 33136 , USA and relevant background information regarding e-mail: [email protected] past medical, developmental, educational, and

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 3 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_1, © Springer Science+Business Media, LLC 2013 4 S. Assuras and B. Levin psychosocial history. The interview also offers interviewing techniques such as having patients the opportunity to assess the caregiver’s perspec- verbally describe their chief concerns and then tive of the patient’s cognitive status, additional following up with a more structured series of stressors, and available resources that can be used questions or having the examiner administer a to guide the treatment recommendations. formal questionnaire before testing begins and then reviewing each item with the patient and caregiver during the interview. Demographic and Referral Information Physical Symptoms The fi rst questions posed by the examiner will set the tone for the rest of the interview. Asking a The most common noncognitive neurologic com- patient to provide demographic information can be a plaints reported by older adults are headache, good way to begin establishing rapport. In addition dizziness, numbness/tingling, visual changes, and to essential information such as one’s name, date problems with balance. Generally speaking, physical of birth, handedness, gender, educational level, complaints can be grouped into motor, sensory, and living arrangement, patients should also and somatic functions. Important areas to address explain in their own words, whenever possible, with regard to motor changes include weakness, who referred them for testing and the reason for gait and balance dif fi culties (such as shuf fl ing and the referral. This is really the fi rst opportunity smaller steps), motor slowing, the presence of that the examiner will have to assess the level of tremor, stiffness, numbness, dif fi culty pronounc- insight and ability to formulate one’s thoughts. ing words clearly, and diffi culty with eye move- Other important questions that should be ments (e.g., upward gaze). Some motor symptoms addressed before testing begins are medication such as tremor and motor slowing may be obvious, regimen, their primary language and, when appli- but others such as weakness or stiffness are more cable, secondary language, and whether the subtle and would be missed unless the patient is patient requires glasses, hearing assistive devices, directly questioned. It is also important to follow and/or ambulatory assistance. up individual questions with further inquiry. For example, when the patient confi rms that he or she has balance diffi culties, it is important to ask about Physical, Cognitive, and Emotional a history of falls. Keeping in mind that falls are the Complaints most common reason for hospitalization among older adults [1 ] , this line of questioning will not One goal of the interview is to document the only provide information with regard to a past specifi cs of the complaints and the time course of history of possible traumatic injury or the presence symptoms to determine the severity level and to of a movement disorder but it will also alert the assess whether there has been a change from a clinician to possible safety concerns. premorbid condition. There are several different Sensory complaints are subjective and require approaches used to evaluate current physical, that patients be able to express their concerns. cognitive, and emotional complaints. These Typical sensory complaints include pain, visual include (1) having the patient or caregiver fi ll out and auditory changes, appetite change (e.g., a structured questionnaire, (2) asking the patient increased consumption of sweets), changes in to elaborate on each of his or her concerns and smell and odor detection, dizziness, and heart the examiner records the complaints verbatim, or palpitations. Somatic complaints, which can be (3) start the interview using a structured format diffi cult to disentangle from sensory symptoms, where the examiner systematically reviews a pre- are frequent and include an array of gastrointestinal determined list of possible symptoms. The best problems (bowel and bladder), constipation, head- approach usually involves a combination of these aches and arthritic pain, and sleep disturbances. 1 Special Considerations for the Neuropsychological Interview with Older Adults 5

Table 1.1 Examples of question topics for interviewing older adults Cognitive symptoms Physical symptoms Emotional symptoms Dif fi culty remembering conversations Dif fi culty pronouncing words clearly Lack of interest in activities Unsure of previous day’s activities Visual or auditory changes Reduced initiation Repeating questions Dif fi culty with eye movements Apathy (e.g., upward gaze) Forgetting why you walked into a room Changes in smell and odor detection Irritability or what you need at the store Dif fi culty coming up with the right Gait changes (e.g., shuf fl ing, smaller Restlessness word or remembering people’s names steps, slowing) Poor attention/concentration when Reduced balance, increased falls Depressed mood reading or watching television Slower thinking and problem solving Urinary changes (frequency, urgency, Hallucinations (describe incontinence) content, quality, e.g., if they elicit fear) Dif fi culty planning and organizing tasks Constipation Inappropriate behavior (e.g., approaching strangers, making inappropriate comments) Inability to complete multiple steps Dizziness/heart palpitations Increased nervousness or worry Dif fi culty performing routine tasks, Numbness, weakness, or tremor Fatigue or reduced energy such as making coffee Appetite changes, increase or decrease Past or present suicidal ideation (e.g., increased consumption of sweets) Sleep changes

Since sensory complaints have been linked to (NPH) [ 4 ] . Additionally, somatic symptoms depression [2 ] , this area should be carefully related to autonomic function, such as impotence addressed with older adult patients. Sleep quality and dizziness or hypotension, may be relevant plays an important role in alertness, attention, when a movement disorder such as multiple and overall cognitive functioning, and is often a system atrophy or other Parkinson’s plus disor- contributing factor to cognitive decline [ 3 ] . Given der is on the list of differentials (see Table 1.1 the high prevalence of sleep disorders in this age for examples to guide questioning of various group, clinicians should be aware of common symptoms) [5 ] . complaints such as diffi culty falling or staying asleep, sleep-disordered breathing, frequent awakening, snoring, awakening to a choking sen- Cognitive Symptoms sation, use of sleep aids, feelings of daytime fatigue and napping. If a family member reports The most common cognitive complaint among unusual behaviors during sleep such as dream older adults is memory [ 6] . It has been esti- enactment (shouting out loud, punching a bed mated that subjective memory complaints are as partner, or other forms of acting out a dream), high as 56% in community-based samples [ 7 ] . they should be noted and explored in greater Typical memory complaints are diffi culty recalling detail for possible REM sleep behavior disorder, names, faces, and appointments, problems recall- a condition associated with parkinsonism. ing numbers such as phone numbers, repeating Questions regarding urinary function are important questions, word- fi nding dif fi culties, misplacing and should extend beyond asking about frank personal items, disorientation while traveling, incontinence to include inquiries regarding urinary and losing one’s train of thought [ 8 ] . urgency and frequency, since these may be early It is not uncommon for a patient to report features of normal pressure hydrocephalus memory diffi culties when, in fact, the problem 6 S. Assuras and B. Levin actually stems from a different etiology, but one aimed at undercovering the seriousness of intent that impacts memory. For example, upon closer and the necessity for intervention. questioning, the clinician may fi nd that the prob- Personality changes are often the fi rst symp- lem is actually diffi culty fi nding words or attend- tom of a degenerative disease. In older adults, ing to task demands and may signify de fi cits in behavioral symptoms are the presenting feature aspects of cognition other than memory, language, in frontotemporal lobar degeneration, behavioral or attention. Another common cognitive com- variant, various cortical dementias including plaint is executive dysfunction [ 9 ] , the category Alzheimer’s disease, early stages of Parkinson’s of skills involved in sustaining attention, goal and Parkinson’s plus syndromes such as pro- setting, problem solving, planning, organization, gressive supranuclear palsy, Wilson’s disease, and decision making. The executive functions Huntington’s disease, and myasthenia gravis have been shown to be a major determinant of [13– 17] . Symptoms may include inappropriate one’s ability to perform instrumental activities laughing or crying, apathy, and social withdrawal. of daily living such as fi nancial decision making Although observed more frequently in younger and medication management, and they also adults, the effect of autoimmune illnesses such as predict onset and progression of instrumental systemic lupus erythematosus and multiple scle- functional decline [10 ] . Since patients with rosis can present with psychiatric symptoms, executive dysfunction are frequently not aware of including psychosis [ 18, 19] . Furthermore, their diffi culties, examiners should ask directed patients with endocrine and metabolic disor- questions during the interview that relate to ders, such as hypoparathyroidism and hypercorti- specifi c executive abilities. Topics from which to solism, can present with both cognitive decline draw interview questions are listed in Table 1.1 . and psychosis, as well as personality changes [20 ] . Third, a careful intake of mood and personality change is especially important in formu- Emotional Symptoms lating recommendations, which may include pharmacologic treatment, behavioral interven- Careful questioning regarding mood and person- tion, or psychotherapy. ality change is an important part of the interview. First, depression and anxiety complaints, especially at the subsyndromal level, are common Functional Capacity among older adults [11 ] . A recent survey published by the Centers for Disease Control indi- An individual’s ability to perform basic and cated that 16% of suicide deaths were among complex activities of daily living (ADL) is a those 65 years of age and older, higher than the measure of one’s functional status. This is an rate of 11 per 100,000 in the general population especially important area to address in the older [ 12 ] . Depression in older adults often goes adult because impairment in social and/or occu- untreated as the symptoms, which may present as pational function is a key component to a diag- somatic or cognitive complaints (e.g., memory nosis of dementia. A patient’s functional capacity problems, confusion, social withdrawal, loss of should be comprehensively examined, focusing appetite, weight loss, and irritability), are not on basic and instrumental ADLs. Basic ADLs recognized as such. Furthermore, symptoms of include questions pertaining to independence in depression are often mistaken as signs of dementia bathing, dressing, and feeding, whereas instru- (see Chap. 8 ). It is essential that the interviewer mental ADLs involve higher-order abilities such take the time to question an individual about past as one’s ability to pay bills, shop for food and and present suicidal ideation and attempts to self- prepare a meal, manage fi nances, and manage a harm. Any mention of suicidal thoughts or behav- medication schedule. In some cases, it is hard to ior should be carefully followed up with questions tell whether an individual who lives in a supportive 1 Special Considerations for the Neuropsychological Interview with Older Adults 7

Table 1.2 Assessing functional independence/activities cardiovascular diseases (e.g., heart disease, of daily living (ADL) stroke), surgeries, especially those involving Basic ADLs general anesthesia, alcohol and substance use, Personal hygiene prior head trauma, with particular attention to Toileting (the ability to use a restroom) those involving concussion and/or loss of con- Dressing sciousness, periods of confusion, infectious dis- Feeding oneself ease (Hepatitis C, HIV), and unusual dietary or Instrumental ADLs sleep patterns. How the patient manages these Managing fi nances/paying bills conditions (e.g., checking blood sugar, compli- Looking up phone numbers ance with blood pressure medication, dietary Doing housework practices, exercise regimen, etc.) will provide Using computer Shopping valuable information with regard to an individ- Cooking ual’s ability to participate in self-care and man- Making appointments age oneself independently. In addition, specifi c Driving/traveling questions should address patient’s medication, Medication management prescribed and over-the-counter. Past medication and prior hospitalizations should also be addressed with the patient and/or caregiver. environment (a spouse pays the bills, the staff in Finally, the patient’s family medical history the assisted-living facility prepares the meals and should be carefully assessed in order to under- makes sure patients take their medication) has stand relevant genetic risk factors. This is likely actually changed or whether the patient has to become an increasingly important area to retained the skill but relies on others as a matter address given that family health history re fl ects of convenience. In this case, it is important to inherited genetic susceptibility for a large inquire about speci fi c operational skills such as number of neurologic diseases. whether the patient is capable of carrying out emergency procedures if left alone, following a recipe if necessary, balancing a check book to Social History pay bills, using email, etc. (see Table 1.2 ). A comprehensive interview should include a careful assessment of one’s past social experiences, Taking a History educational attainment, and occupation. There are many ways to assess this information, but Medical History most of the time, it is best to probe beyond a simple question. For example, questions pertaining Documenting a patient’s medical history is to level of education should always be fol- necessary in order to formulate a differential lowed up with inquiries pertaining to past his- diagnosis and to make treatment recommenda- tory of learning dif fi culties, school failure, and tions. A patient’s ability to convey this informa- other issues relating to academic performance, as tion can be as informative as the history itself. well as occupational achievement. This can be a Commonly reported cardiometabolic risk factors challenging area to assess with older adults because known to impact cognition include hyperten- societal mores and educational opportunities were sion, hypercholesterolemia, type 2 diabetes, and different decades ago. Yet, establishing if the heart disease and vascular conditions associated patient has a longstanding and developmental with ischemia or kidney disease. Clinicians vulnerability in cognitive function is critical to should address past illnesses, surgeries, injuries, understanding if a current level of impairment and treatments, including metastatic cancer, represents a decline. 8 S. Assuras and B. Levin

• Do not rely solely on behavioral observations Conclusion without further probing. For example, motor symptoms such as tremor or paralysis are visible, The interview is an essential part of a neuropsy- but other motor abnormalities such as weakness chological evaluation for any age, but particularly or stiffness are more subtle and would be missed among older adults, because of the myriad of unless the patient is directly questioned. physical, cognitive, psychological, and social • Not all complaints should be taken at face value. changes associated with the normative aging pro- It is important to ask the patient to give exam- cess. These normative changes are further com- ples of the type of cognitive problems they are pounded by the onset of a disease. A carefully experiencing. While memory complaints are the conducted interview will play a critical role in most common, the de fi cits may actually be in establishing a diagnosis and generating treatment language (e.g., diffi culty fi nding words) or recommendations. In addition, it provides an attention (e.g., attending to task demands). opportunity to observe and document informa- • Personality changes are often the fi rst symptom tion that cannot be obtained from psychometric of a degenerative disease. Therefore, careful testing. The interview also creates a forum for assessment of emotional and behavioral establishing rapport with the patient and allows changes is critical. Since patients frequently the clinician to verify important demographic lack insight into their own behavior, a collat- and historical information from a caregiver. This eral source should be consulted. chapter has provided guidelines for developing • It can be challenging to determine whether an an interview designed to provide a level of insight individual who lives in a supportive environ- and understanding of a patient’s presentation, ment has experienced a decline in functional which cannot be obtained through other means. independence. Every interview should inquire about specifi c functional abilities and give examples of instrumental activities of daily Clinical Pearls living. Knowledge of safety procedures should also be routinely assessed. • The clinical interview provides a level of insight and understanding of a patient’s presentation, which cannot be obtained References through other means . • A patient’s ability to convey his/her history 1. Milat AJ, et al. Prevalence, circumstances and conse- during the interview session can be as informa- quences of falls among community-dwelling older peo- tive as the history itself. Observations regarding ple: results of the 2009 NSW Falls Prevention Baseline Survey. N S W Public Health Bull. 2011;22(3–4):43–8. a patient’s expressive and receptive language, 2. Chakraborty K, et al. Psychological and clinical cor- level of insight, and ability to formulate thoughts relates of functional somatic complaints in depres- are as valuable as the test data and scores. sion. Int J Soc Psychiatry. 2012;58(1):87–95. • Use of a combination of interviewing techniques, 3. Kronholm E, et al. Self-reported sleep duration and cognitive functioning in the general population. such as verbal description of complaints, a J Sleep Res. 2009;18(4):436–46. structured series of questions, and a formal 4. Tsakanikas D, Relkin N. Normal pressure hydroceph- review of each item with the patient and care- alus. Semin Neurol. 2007;27(1):58–65. giver, is ideal. Using a questionnaire to gather 5. Gilman S, et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci. background information can be useful, but this 1999;163(1):94–8. information should always be reviewed with 6. Minett TS, et al. Subjective memory complaints in an the patient and follow-up questions should be elderly sample: a cross-sectional study. Int J Geriatr asked. Patients typically elaborate and provide Psychiatry. 2008;23(1):49–54. 7. Reid LM, Maclullich AM. Subjective memory com- much more detailed information when ques- plaints and cognitive impairment in older people. tions are asked verbally. Dement Geriatr Cogn Disord. 2006;22(5–6):471–85. 1 Special Considerations for the Neuropsychological Interview with Older Adults 9

8. Ahmed S, et al. Memory complaints in mild cognitive 15. Aarsland D, Litvan I, Larsen JP. Neuropsychiatric impairment, worried well, and semantic dementia patients. symptoms of patients with progressive supranuclear Alzheimer Dis Assoc Disord. 2008;22(3):227–35. palsy and Parkinson’s disease. J Neuropsychiatry Clin 9. Hirschman KB, et al. Cognitive impairment among Neurosci. 2001;13(1):42–9. older adults in the emergency department. West 16. Marchello V, Boczko F, Shelkey M. Progressive J Emerg Med. 2011;12(1):56–62. dementia: strategies to manage new problem behav- 10. Carlson MC, et al. Association between executive iors. Geriatrics. 1995;50(3):40–3. quiz 44–5. attention and physical functional performance in 17. Musha M, Tanaka F, Ohuti M. Psychoses in three community-dwelling older women. J Gerontol B cases with myasthenia gravis and thymoma— Psychol Sci Soc Sci. 1999;54(5):S262–70. proposal of a paraneoplastic autoimmune neuropsy- 11. Wilkins CH, Mathews J, Sheline YI. Late life depres- chiatric syndrome. Tohoku J Exp Med. 1993;169(4): sion with cognitive impairment: evaluation and 335–44. treatment. Clin Interv Aging. 2009;4:51–7. 18. Aggarwal A, et al. Acute psychosis as the initial pre- 12. Centers for Disease Control and Prevention, sentation of MS: a case report. Int MS J. 2011;17(2): N.C.f.I.P.a.C. Web-based injury statistics query and 54–7. reporting system. 2005. 19. Wright MT. Neuropsychiatric illness in systemic 13. Akil M, Brewer GJ. Psychiatric and behavioral abnor- lupus erythematosus: insights from a patient with ero- malities in Wilson’s disease. Adv Neurol. 1995;65: tomania and Geschwind’s syndrome. Am J Psychiatry. 171–8. 2010;167(5):502–7. 14. Cummings JL. Behavioral and psychiatric symptoms 20. Ghosh A. Endocrine, metabolic, nutritional, and toxic associated with Huntington’s disease. Adv Neurol. disorders leading to dementia. Ann Indian Acad 1995;65:179–86. Neurol. 2010;13 Suppl 2:S63–8. Consideration of Cognitive Reserve 2 Stephanie Cosentino and Yaakov Stern

Abstract This chapter reviews the concept of cognitive reserve, including relevant theoretical issues, various means of characterizing this construct, and its clinical implications. We begin with a broad overview of the epidemiological evidence in support of the concept of cognitive reserve, and review neuroimaging studies that contribute to our understanding of this construct. We then review several theoretical issues surrounding the mechanisms by which cognitive reserve confers its beneﬁ ts, and outline the advantages and disadvantages of various methods of estimating reserve. We conclude by discussing the clinical implications of cognitive reserve and listing several speciﬁ c recommendations for the application of cognitive reserve in clinical practice.

Keywords Cognitive reserve ¥ Dementia ¥ Cognition ¥ Aging ¥ Assessment ¥ Diagnosis

brain pathology or damage and the clinical Introduction to Cognitive Reserve manifestation of that damage. For example, Katzman and colleagues described ten cases of The idea of reserve against brain damage cognitively normal elderly women who were dis- stems from the repeated observation that there covered to have advanced Alzheimer’s disease is not a direct relationship between degree of (AD) pathology in their brains at death [ 1 ] . In more recent cohort studies, it has been estimated that approximately 25% of individuals who have S. Cosentino , Ph.D. () ¥ Y. Stern , Ph.D. Cognitive Neuroscience Division of the Gertrude postmortem neuropathological evidence of AD H. Sergievsky Center, Taub Institute for Research are not demented during their lives [ 2 ] . This dis- on Alzheimer’s Disease and the Aging Brain, crepancy raises the question of how brain func- and Department of Neurology, Columbia University tion and structure become decoupled and whether Medical Center , New York , NY , USA e-mail: [email protected] ; certain person-speci ﬁ c variables provide reserve [email protected] against the clinical effects of pathological brain

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 11 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_2, © Springer Science+Business Media, LLC 2013 12 S. Cosentino and Y. Stern changes. Several theoretical models have been elderly in New York [9 ] . During follow-up, put forth to address this issue. subjects who engaged in more of these activities The cognitive reserve (CR) model suggests that had 38% less risk of developing dementia. the brain actively attempts to cope with brain Interestingly, speci fi c classi fi cations of leisure damage by using preexisting cognitive pro- activity (such as purely intellectual activities) cessing approaches or by enlisting compensatory did not provide better prediction then a simple approaches [3, 4 ] . Individuals with high CR would summation of all the considered activities. be more successful at coping with the same amount A meta-analysis examining cohort studies of of brain damage than those with low CR. In this the effects of education, occupation, premorbid scenario, brain function rather than brain size is IQ, and mental activities on dementia risk over the relevant variable. This characteristic distin- approximately 7 years revealed that 25 of 33 guishes the CR model from the brain reserve datasets demonstrated a signifi cant protective model in which reserve derives from brain size or effect of these variables [ 11 ] . The summary over- neuronal count [ 5] . According to the CR model, all risk of incident dementia for individuals with the same amount of brain damage or pathology high levels of the protective variable as compared will have different effects on different people, even to low was 0.54, a decreased risk of 46%. There when brain size is held constant. is also evidence for the role of education in age- Epidemiological studies have helped to shape related cognitive decline, with many studies of our understanding of the nature of cognitive reserve normal aging reporting slower cognitive and and the person-specifi c variables which appear to functional decline in individuals with higher edu- enhance reserve. Many studies have demonstrated cational attainment [12Ð 19 ] . These studies sug- the benefi cial effects of education [ 6 ] , occupation gest that the same factors that delay the onset [7 ] , leisure [8, 9 ] , and intellectual ability [10 ] on of dementia also allow individuals to cope dementia incidence. In 1994, Stern and colleagues more effectively with brain changes encountered reported incident dementia data from a follow-up in normal aging. The concept of CR provides study of 593 community-based, non-demented a ready explanation for the manner in which individuals aged 60 years or older [ 7 ] . After intellectual functioning, education, and other 1Ð4 years of follow-up, 106 became demented with life experiences may allow individuals to sustain all but fi ve meeting research criteria for AD. The greater burdens of brain pathology or age-related risk of dementia was increased in subjects with low changes before demonstrating cognitive and education, such that the relative risk (RR) of devel- functional de fi cits. oping dementia over the follow-up period was 2.2 Neuroimaging studies have also provided times higher in individuals with less than 8 years of evidence in support of cognitive reserve and have education as compared to those with more years of contributed to our conceptualization of this phe- education. Similarly, risk of incident dementia was nomenon. Our original functional imaging study increased in those with low lifetime occupational found that in patients matched for overall severity attainment (RR = 2.25) and greatest for subjects of dementia (i.e., clinical expression of disease), with both low education and low lifetime occupa- the parietotemporal cerebral fl ow defi cit was tional attainment (RR = 2.87). greater in those with more years of education To the extent that aspects of educational and [20 ] . This observation was con fi rmed in a later occupational attainment re fl ect lifetime expo- PET study in which higher education correlated sures that would increase CR, it would be logical negatively with cerebral metabolism in prefrontal, to expect that environmental exposures later in premotor, and left superior parietal association life would also be bene fi cial. In a subsequent areas after controlling for clinical dementia sever- study, the same group assessed participation in ity [21 ] . Similar observations have been made a variety of leisure activities characterized as for occupational attainment [22 ] and leisure intellectual (e.g., reading, playing games, going activities [23 ] and across multiple markers of to classes) or social (e.g., visiting with friends or pathology including white matter abnormalities relatives) in a population sample of non-demented [24 ] and amyloid deposition [ 25 ] . The negative 2 Consideration of Cognitive Reserve 13

Fig. 2.1 Effect of cognitive reserve on dementia onset higher cognitive reserve can tolerate more AD pathology, and course memory function will begin to be affected later in time, Note: Figure 2.1 illustrates the way in which cognitive after more pathology has accumulated, pushing back the reserve may mediate the relationship between AD pathol- “point of infl ection.” Therefore, all other things being ogy and its clinical expression. We assume that AD equal, dementia should emerge later in people with higher pathology slowly increases over time, and this is graphed cognitive reserve. This leads to the prediction that the rate on the x -axis. The y -axis represents cognitive function, in of incident dementia should be lower in individuals with this case memory performance. AD pathology begins to higher cognitive reserve. An assumption of this model is develop many years before the disease is expressed clini- that at some point, AD pathology must become too severe cally and slowly becomes more severe. At some point, to support the processes that mediate either cognitive this developing pathology will begin to produce the initial reserve or memory function. The timing of this fi nal com- cognitive changes associated with dementia. This is mon endpoint will be the same in all patients, regardless labeled as the point of infl ection in the fi gure. The pathol- of their level of cognitive reserve. It then follows that the ogy will subsequently result in symptoms of suf fi cient time between the point of in fl ection and this common end- severity to allow the clinical diagnosis of AD (indicated point will be shorter in patients with higher cognitive by the dotted line labeled Incident Dementia). The cogni- reserve. This leads to the prediction that memory decline tive reserve (CR) model predicts that because there are after the infl ection point must be more rapid in patients individual differences in reserve capacity, there will be with higher cognitive reserve. Although this trajectory individual differences in the amount of pathology required might appear counterintuitive at fi rst, its theoretical basis for the initial expression of clinical symptoms and the is illustrated in this fi gure, and it has been supported by subsequent diagnosis of disease. Because people with multiple epidemiological studies

correlations between the exposures of interest tia in life [ 27] . These studies converge nicely and pathology are consistent with the CR hypoth- with epidemiological evidence that supports that esis’ prediction that at any given level of clinical higher levels of education, occupational attain- disease severity, those with higher CR should ment, and leisure activity reduce dementia inci- have greater pathology (see Fig. 2.1 ). dence, and suggest that these variables in fl uence Results and interpretations of these studies dementia risk by enhancing cognitive reserve. have been further supported by prospective projects with subsequent neuropathological analysis. Specifi cally, education has been found to modify Theoretical Issues the association between AD pathology and levels of cognitive function. With brain pathology held Despite the wealth of information that has accumu- constant, higher education was associated with lated in support of the concept of cognitive reserve, better cognitive function [26 ] and less likelihood there are many aspects of this construct that have of having received a clinical diagnosis of demen- yet to be fully elaborated. It is important to 14 S. Cosentino and Y. Stern highlight these issues prior to discussing the vari- and not simply cognitive properties. Evidence for ous means of characterizing reserve and consider- this possibility comes from two recent studies, ing the clinical implications of cognitive reserve. one of which found reduced rate of hippocampal The intent of the current chapter is not to fully atrophy over 3 years in individuals with higher explore these theoretical issues but simply to raise levels of complex mental activity across the the reader’s awareness of the unanswered questions lifespan [28 ] , and the second which found micro- surrounding the construct of cognitive reserve. structural differences in the hippocampus as a First, the precise manner in which cognitive function of education [29 ] . Additionally, the child reserve affords protection from pathology is not developmental literature suggests that not only do understood. As discussed above, we know that individuals with higher IQ have larger brain vol- across individuals, there is a discrepancy ume [30, 31] but that cognitively stimulating between brain changes or pathology and cognitive aspects of life experience may also be associated change such that in some individuals, cognitive with increased brain volume. It is also now clear function remains relatively preserved in the face of that stimulating environments and exercise pro- pathological markers. As such, individuals with mote neurogenesis in the dentate gyrus [ 32, 33 ] . high cognitive reserve are not necessarily pro- Both exercise and cognitive stimulation regulate tected from developing pathology, but rather factors that increase neuronal plasticity (such as that they are spared the clinical effects of such brain derived neurotrophic factor) and resistance pathology. Thus, when we refer to the preserva- to cell death. Finally, there is some evidence to tion of a cognitive function such as memory in suggest that environmental enrichment might act the sections below, we are in fact talking only directly to prevent or slow the accumulation of about memory itself and not the integrity of the AD pathology [34 ] . brain areas underlying that cognitive function In sum, there appears to be growing evidence (e.g., hippocampus). Indeed, the concept of cog- that the experiences that provide cognitive reserve nitive reserve only applies when considering may indeed refl ect not only a cognitive advantage variability in cognitive functioning (i.e., memory) but a structural advantage as well. Thus, brain in the face of changes in brain integrity (i.e., reserve and cognitive reserve concepts are not hippocampal volume). mutually exclusive, and it is likely that both are This raises one of the puzzling questions involved in providing reserve against brain dam- surrounding reserve: memory and hippocampal age. A complete model of cognitive reserve will integrity are intimately related and the mecha- have to integrate the complex interactions nisms underlying the decoupling of structure between genetics, the environmental infl uences and function are not clear. From a strict point of on brain reserve and pathology, and the ability to view, the differences in cognitive processing actively compensate for the effects of pathology. envisioned by the CR model must also have a Setting aside the question of brain integrity, physiologic basis, in that the brain must ulti- and considering cognitive reserve only, we return mately mediate all cognitive function. The differ- to the question of why insult to brain structure ence is in terms of the level of analysis. does not invariably affect cognition. We have Presumably, the physiologic variability subsumed observed that individuals with higher cognitive by cognitive reserve is at the level of variability reserve (de fi ned using a literacy measure) have less in synaptic organization or in relative utilization rapid memory decline over time than those with of specifi c brain regions. Thus, cognitive reserve lower literacy levels [ 35 ] . However, the manner implies anatomic variability at the level of brain in which this memory advantage is conferred is networks, while brain reserve implies differences unknown. It may be that preserved memory in the quantity of available neural substrate. refl ects preservation of the memory networks per Moreover, we must acknowledge the possibil- se or use of alternative and supportive skills such ity that life exposures that are associated with as enhanced organizational strategies [36 ] . Stern reserve also affect brain structure or brain pathology and colleagues have described these two potential 2 Consideration of Cognitive Reserve 15 neural implementations of cognitive reserve as multiple ways of approaching a spatial task but neural reserve and neural compensation [4, 37, less fl exibility for a verbal task, whereas the 38] . The idea behind neural reserve is that there opposite pattern may exist in another individual. is natural interindividual variability in the brain If the crux of cognitive reserve is the ability to networks or cognitive processes that underlie the apply alternative approaches to accomplish performance of any task. This variability could tasks, then the benefi t of reserve may be linked be in the form of differing effi ciency or capacity directly to the fl exibility of the task (and corre- of these networks, or in greater fl exibility in the sponding skill) itself or to a person’s premorbid networks that can be invoked to perform a task. cognitive style. While healthy individuals may invoke these net- One fi nal question is whether or not deteriora- works when coping with increased task demands, tion of speci fi c cognitive functions can directly the networks could also help an individual cope affect cognitive reserve. For example, if cogni- with brain pathology. An individual whose net- tive reserve is closely aligned or even overlaps works are more effi cient, have greater capacity, with executive abilities [ 39 ] , is it the case that or are more fl exible might be more capable of cognitive reserve is less able (or unable) to stave coping with the challenges imposed by brain off executive de fi cits as opposed to declines in pathology. In contrast, neural compensation other domains such as memory or language? refers to the process by which individuals suffer- That is, is cognitive reserve itself vulnerable to a ing from brain pathology use brain structures or particular presentation of disease? Or, is cogni- networks (and thus cognitive strategies) not tive reserve a construct that is “immune” to the normally used by individuals with intact brains in regional distribution of pathology, independent order to compensate for brain damage. The term of the cognitive abilities that may be affected, compensation is reserved for a situation where it functioning universally under a wide variety of can be demonstrated that the more impaired lesions? While the answer to this question is not group is using a different network than the unim- entirely clear, recent studies examining the paired group. effects of reserve on information processing It is not yet clear whether or when each of ef fi ciency in individuals with multiple sclerosis these forms of reserve come into play. The answer may shed light on the issue [40Ð 43] . For example, to this question has several implications, one of Sumowksi and colleagues showed that the which pertains to the applicability of cognitive negative effect of brain atrophy on rapid infor- reserve under various conditions. Specifi cally, if mation processing was attenuated in individuals the benefi ts of cognitive reserve are attributable with higher levels of reserve [ 41 ] , suggesting to the fl exible application of alternative strategies that reserve confers benefi ts to cognitive func- for completing a task (compensation), speci fi c tions whose nature is quite similar to some con- aspects of brain function may receive less assis- ceptualizations of reserve. That is, the information tance from cognitive reserve than others. It may processing measure was comprised of the be that a cognitive skill such as verbal recall can Symbol Digit Modalities Test [ 44 ] and the Paced be accomplished in a number of ways that dif- Auditory Serial Addition Test [45 ] , tasks which ferentially employ serial rehearsal, semantic require mental fl exibility and fl uidity. Similarly, processing, or working memory. In contrast, there although speculative, one perspective of cogni- may be fewer cognitive routes to reproduce a tive reserve is that it represents the mental complex fi gure or detect a subtle visual detail fl exibility to develop alternative strategies in the amid a complex scene. In this scenario, a com- face of pathology, and to fl uidly apply such strat- pensatory reserve mechanism might be less egies to the task at hand. The reported benefi ts of applicable to spatial skills than to verbal memory. reserve on information processing and ef fi ciency However, it is also possible that critical issue is in the above studies are interesting and raise not task specifi c, but rather, person specifi c. That many questions for future work. For the time is, based on life experience, one person may have being, such studies may offer preliminary evidence 16 S. Cosentino and Y. Stern either that (1) reserve is immune to the distribu- of this approach is that these variables are relation of pathology or (2) reserve is fundamen- tively easy to acquire and quantify, and at face tally different than the cognitive skills assessed value, are generally plausible proxies for reserve. in these studies. A disadvantage is that these variables may be singular representations of a multidimensional mechanism such that characterization of educa- Estimating Cognitive Reserve tion in isolation, for example, might account for a relatively small proportion of the variance in A practical question for the clinician is how to overall cognitive reserve. Moreover, these vari- account for cognitive reserve in the diagnostic ables are rather agnostic with regard to the source process. In this section, we review the advantages and nature of cognitive reserve and may confound and disadvantages of several approaches includ- multiple other factors with “true” reserve (e.g., ing the following: (1) measurement of individual education may impart greater knowledge and characteristics (demographic and lifestyle), (2) access to health care which in turn may promote consideration of cumulative life experiences, (3) health-related behaviors and enhance cognitive estimation of intellectual functioning, (4) imple- functioning). As such, use of variables such as mentation of statistical approaches (use of latent those listed above, although convenient, should or residual variables), and (5) derivation of brain not be the sole indicators of CR. network patterns. Prior to discussing these approaches, it is also important to consider that although epidemiological work has led to the Cumulative Life Experiences conceptualization of reserve as a refl ection of important lifetime experiences, the cognitive A second approach for characterizing cognitive advantage which manifests as reserve might also reserve is one in which multiple or cumulative have played an important role early in life to life experiences are synthesized to develop a afford individuals the desire and ability to pur- more comprehensive estimation of an individual’s sue certain life experiences such as graduate reserve. The purported benefi t of this approach is school, for example. Thus, the effects of lifetime that it synthesizes numerous experiences, all of experiences are not necessarily separate from which have been shown through epidemio- early life factors. Although certain work has sug- logical work to confer protection against the gested that reserve is a cumulative process built development of dementia. The consideration of on both early life and late life experiences [46 ] , comprehensive life experiences offers the the causal pathway of cognitive reserve has not opportunity to capture a wide array of factors that been fully delineated. As the reader considers the may uniquely contribute to reserve, if indeed clinical implications of cognitive reserve and the reserve is created through a cumulative process. various methods for measuring reserve, it is Valenzuela and Sachdev [ 47 ] developed the important to be aware of the larger questions Lifetime of Experiences Questionnaire (LEQ) as surrounding its origins and characteristics. a means of capturing and quantifying various social, academic, occupational, and leisure activities spanning young to late adulthood. The ques- Individual Characteristics tionnaire showed good reliability and validity and was useful in predicting which individuals One of the most commonly used methods of would demonstrate cognitive decline over an characterizing reserve involves quantifying indi- 18-month period. vidual characteristics that have been associated While this appears to be a powerful method of with reduced risk of dementia including educa- capturing a myriad of experiences relevant to the tion, occupation, intellectual functioning, leisure construct of cognitive reserve, there are several activity, and social engagement. The advantage issues to consider. It is possible that the summation 2 Consideration of Cognitive Reserve 17 of experiences within this questionnaire may not tion or occupation, an internal and broadly stable be more predictive than any individual variable, capability such as IQ is presumably more closely and compiling these experiences may even obscure associated with the cognitive and neural repre- the effect of the most relevant variable. For exam- sentation of reserve. Unfortunately, a correspond- ple, Hall and colleagues found that the effect of ing disadvantage is that IQ scores do change in education on cognitive decline prior to dementia the course of disease and therefore can be con- diagnosis was negligible after accounting for cog- taminated by the disease process itself (unlike nitively stimulating leisure activities later in life education or occupation). Moreover, while read- [48 ] , suggesting one of two possible scenarios ing scores are fairly stable in the very early stages raised by the authors. First, it could be that the of degenerative illnesses, they are certainly not effects of education were mediated by mental valid estimates of premorbid IQ in a language activities late in life or second, that education predominant illness, nor are they valid estimates in fl uenced reserve directly with no additional in non-native English speakers. benefi t conferred by later life mental stimulation. Despite the differences in applying IQ versus Researchers must carefully consider these issues; an exposure variable such as education, there is however, a lifetime approach to characterizing statistical evidence that both share common statis- reserve for clinical purposes is certainly useful in tical variance that is distinct from cognitive func- that it comprehensively quantifi es important expe- tions more broadly [39 ] . The presence of both riences that may delay cognitive decline in the face convergent and discriminant validity in this con- of advancing pathology. text provides support for both of these variables as independent proxies for reserve, as well as evidence for the construct validity of reserve. This is Intellectual Function an important fi nding because the coherence of cognitive reserve as a construct remains under A third and very different means of characterizing question, leading several groups to argue that reserve is the assessment of intellectual function- latent variables derived through structural equa- ing, typically via a single-word reading test, such tion modeling may be the most appropriate way to as the Wechsler Test of Adult Reading [49 ] or the capture the essence of reserve [57, 58 ] . Although North American Adult Reading Test [ 50 ] , or a the details of these models are beyond the scope subtest of the Wechsler Adult Intelligence Scales of this chapter, the idea is that through statistical such as Vocabulary or Information [51 ] . Word data reduction, we can boil down the overgeneral- reading measures evaluate an individual’s ability ized concept of reserve into its core elements and to pronounce a series of phonologically regular identify those variables that are central to its con- and irregular words ranging in diffi culty, and are struct versus those that may be extraneous. A nec- based on the idea that correct pronunciation of the essary drawback, however, is that representation more diffi cult items requires previous exposure to of cognitive reserve through shared variance may such words. Like vocabulary and fund of infor- not re fl ect aspects of reserve potentially captured mation, this ability is generally spared early in the selectively by each unique variable. course of dementia, re fl ecting its reliance on long- term, crystallized knowledge versus the more fl uid abilities affected early in disease [52Ð 56 ] . Statistical Approaches The characterization of IQ is believed to offer a thumbnail sketch of an individual’s lifetime A statistical approach to identifying reserve has intellectual achievement, highly related to, though recently been proposed by Reed and colleagues not necessarily synonymous with, the concept of [ 59] by decomposing the variance of a specifi c cognitive reserve. An advantage of using IQ to cognitive skill such as episodic memory. characterize cognitive reserve is that in contrast Speci fi cally, the authors partitioned the variance to an external exposure variable such as educa- explained by demographic variables (education, 18 S. Cosentino and Y. Stern sex, and ethnicity), structural brain imaging functional imaging techniques that capture the variables, and a third residual component. By neural signature of cognitive reserve. For exam- defi nition, this residual component approxi- ple, Stern and colleagues examined whether or mates the concept of cognitive reserve as it rep- not a common neural network, whose expression resents the unexplained variance in cognitive varied as a function of cognitive reserve, could be performance after accounting for brain struc- detected across verbal and spatial delayed match- ture, and in this case, demographics. Interestingly, to-sample tasks [ 60 ] . Indeed, in the group of the authors included education as part of the young adults, such a network was identifi ed, and demographics variable to isolate a component expression of this network was entirely indepen- that would be uncontaminated by the indirect dent of task performance. The invocation of this effects of education on brain integrity (e.g., network on divergent tasks was uniquely related access to health care and knowledge of health- to cognitive reserve, as assessed with a compos- promoting behaviors). Results showed that ite of vocabulary and word reading, suggesting residual scores correlated with another measure that the network may represent a generalized of reserve (word reading), modifi ed rates of con- neural instantiation of reserve. version from mild cognitive impairment to The utility of a brain network for capturing dementia over time, and modifi ed rates of cognitive reserve is multifold. First, to the extent decline in executive function. Finally, baseline that reserve truly has a neural signature, the brain status had less of an effect on cognitive identifi cation of a brain network that “behaves” decline over time in individuals with high resid- like cognitive reserve (e.g., correlates with tradi- ual scores than low residual scores. tional reserve variables, persists across divergent In addition to providing an operational mea- task demands, and interacts with task performance sure of reserve that is quantitative, continuous, in the expected way) would be a more direct way and specifi c to the individual, the residual to measure the construct. Second, a brain net- approach to characterizing reserve allows the work would be a nonbiased characterization of estimate of cognitive reserve to change over time. reserve that could be used universally in a This fl uid characteristic may or may not be manner that tests such as vocabulary or single- appealing to individual researchers and clini- word reading cannot, due to their in fl uences from cians, depending on the particular question or culture and language. Third, a brain network is task at hand. The authors also note that a poten- malleable in a way that fi xed life experiences are tial problem with this approach is that, depending not, and thus lends itself to examination in the on the speci fi c brain and cognitive variables used context of a longitudinal study. For example, to defi ne reserve, different measures of reserve interventional studies aimed at increasing reserve will be applicable to a person at any given time. could use a brain network to measure reserve Practically speaking, a primary drawback to both pre- and post-intervention, and unlike using residual scores is that it is currently not fea- cognitive testing, this network would be resis- sible for the clinician to apply such scores on an tant to practice effects. individual basis. This may change in the future with greater access to imaging technologies, and availability of normative or group data with Application of Cognitive Reserve which to derive an individual’s residual score. in Clinical Practice

While the concept of cognitive reserve is on the Brain Network Patterns one hand intuitive, it is also easily misunderstood and conducive to misapplication in part due to the A future goal for representing reserve is through thorny theoretical and methodological issues dis- an identifi able brain network or series of net- cussed above. However, there is nothing magical works. Such networks might be derived using about the concept of reserve, and most clinicians 2 Consideration of Cognitive Reserve 19 generally consider the role of reserve in their early stages of AD pathology. That is, those with assessment and case conceptualization (even if higher IQ (i.e., reserve) had greater pathology not explicitly). In this section, we provide con- despite similar cognitive performance, and these crete suggestions for the consideration and appli- individuals showed greater cognitive decline over cation of cognitive reserve in clinical practice. the following 3 years than the individuals whose First, when assessing cognition as part of a IQ-adjusted memory scores were intact [65 ] . diagnostic evaluation, it is important to take into In theory, there would still be a period of account the most appropriate and valid indicator time during which even the most sensitive mea- of cognitive reserve for a given patient. In the sures would fail to detect change in those with event that an individual’s level of education is not high reserve given the apparent “lag” between believed to be a good representation of his or her pathological changes and their cognitive seque- optimal cognitive functioning, assessment of IQ lae. Therefore, from a clinical standpoint, or consideration of occupation may provide a neuropsychological testing will be less sensitive more accurate estimate. Alternatively, in a non- to the presence of early pathology in those with native English speaker, education may be a bet- high reserve even when we consider current ter representation than single-word reading to test scores in the context of a person’s optimal estimate IQ. Although, it should be noted that level of functioning (e.g., IQ, education ). As the availability of tests in other languages is such, the only action to be taken by clinicians increasing, such as Spanish [ 61 ] , French [ 62 ] , is to be aware of this conundrum and to appre- Japanese [63 ] , and Swedish [ 64 ] . Application of ciate that intact cognition in individuals with a non-English assessment tool would be appro- high levels of reserve does not preclude the priate only in circumstances when the remainder presence of disease. of the neuropsychological battery can also be The standard and generally useful approach validly administered in the same language, as taken by neuropsychologists is to formally direct comparisons of IQ and neuropsychological adjust cognitive scores for education, a proce- scores would be otherwise impossible. dure which, in theory, allows for the interpreta- Integration of the most appropriate and valid tion of current cognitive performance in the measure of cognitive reserve into the diagnostic for- context of an individual’s expected performance. mulation is critical. Individuals with high reserve, For example, we know that there are baseline by defi nition, will not demonstrate clinical symp- differences in cognitive performance such that toms as early as individuals with low levels of in the absence of pathology, a 70-year-old with reserve. On the one hand, this issue could partially 8 years of education might recall fewer words be a problem with instrumentation, such that (1) over the course of a list learning test than a more challenging tests with higher ceilings may 70-year-old with 19 years of education. The better detect changes in individuals with very high corollary of this phenomenon is that the patient levels of functioning, (2) tests that are more patho- with 19 years of education would have had to logically speci fi c (e.g., associative learning tasks for sustain a greater degree of neuropathology to the hippocampus) may have greater sensitivity in reach a certain score than the individual with high reserve individuals, or (3) better normative 6 years of education, all other things being data may allow for better detection of impairment in equal. However, this observation does not, in individuals with high levels of intellectual function- and of itself, refl ect cognitive reserve. Rather, ing. Indeed, quantitative consideration of IQ scores reserve accounts for the ability of the individual appears to improve the sensitivity of cognitive test- with 19 years of education to maintain baseline ing for detecting pathology. Rentz and colleagues cognitive functioning for a longer period of time [ 65 ] found that when memory scores in a group of than the individual with 6 years of education in cognitively “normal” individuals were adjusted the face of advancing pathology. based on IQ, the adjusted memory scores correlated Information regarding brain integrity should be with cerebral perfusion in areas vulnerable to the integrated with cognitive data for diagnostic pur- 20 S. Cosentino and Y. Stern poses, whenever possible. Of course, this process cognitive reserve delays the manifestation of cog- is done regularly in most clinical settings and adds nitive de fi cits, symptoms progress fairly rapidly important information and greater clarity to the once evident (see Fig. 2.1 ). In fact, decline is more overall clinical picture. In this context, however, rapid in individuals with high reserve than those the focus is on the relevance of neuroimaging as a with low reserve, even when accounting for a mul- means to understand the infl uence of cognitive titude of other factors that may contribute to dis- reserve on the clinical presentation. Neuroimaging ease course [ 73Ð 75 ] . This counterintuitive tools have the potential, particularly in individuals acceleration in rate of change is believed to re fl ect with high reserve who maintain cognitive func- the increasingly high pathological burden that the tioning for an extended period of time, to detect brain can no longer tolerate. Certainly, this has pathological changes when impairment on neu- practical implications for the patient, family, and ropsychological testing is absent or subtle. For health-care providers. It may also have direct rel- example, at a given level of clinical severity, AD evance for the effectiveness of treatment. patients with higher education have a more severe Cognitive reserve may infl uence an individu- pattern of AD-related changes on PET scan than al’s response to treatment with currently avail- those with lower education [66, 67 ] . able medications as well as future drug therapies. More recently, the sensitivity of a variety of imag- The treatment of degenerative diseases such as ing tools for detecting pathological changes prior to Alzheimer’s disease is certain to be most effec- cognitive change has been demonstrated on struc- tive when done preventatively, when the burden tural MRI [ 68 ] and functional MRI (fMRI) [ 69 ] , as of pathology in the brain is very low or absent well as through examination of activity level in the altogether. Thus, in order to develop reasonable default network on resting fMRI [70 ] . Moving for- expectations about a medication’s effectiveness, ward, in vivo amyloid imaging, although not cur- it will be important to have knowledge of three rently used in clinical practice, will certainly play an variables: cognitive performance, cognitive reserve, important role in identifying neuropathological and pathological burden. As we have reinforced changes in asymptomatic individuals as the fi eld throughout this chapter, it is the combination of moves toward earlier identi fi cation of disease. While these three variables that enables an accurate these various technologies enable the consideration understanding of disease severity. From a clinical of cognitive reserve as a factor infl uencing the clini- standpoint, treatment in an individual with mildly cal presentation and diagnosis of a patient, a current impaired cognition and high cognitive reserve challenge to integrating imaging information is may be more or less effective depending on the applying results from group studies to individual status of the third variable, pathological burden. patients. Ideally, research studies might generate a With little to no evidence of pathology, an indi- cutoff value so that performance scores below this vidual with these characteristics would be an cutoff would raise concern for the presence of patho- ideal candidate for therapy. In contrast, in the logical changes. Such a value would be selected context of signifi cant pathology, disease-delaying based on its utility in distinguishing between cogni- agents may be entirely ineffective, and this pos- tively normal individuals who go on to develop cog- sibility should be anticipated by the clinician. nitive impairment and other clinical endpoints versus A fi nal insight for clinicians is that while a wide those who remain cognitively healthy. This type of range of evidence exists from epidemiological value has been identifi ed for the purposes of distin- studies linking certain life experiences and indi- guishing healthy elders from those diagnosed with vidual characteristics to lower rates of dementia, AD [71, 72] , and future work will aim to make this this evidence is not suf fi cient to determine distinction at earlier time points. de fi nitively whether or not such experiences Another recommendation for applying the con- directly prevent or delay dementia. As mentioned cept of cognitive reserve to clinical practice is to earlier, there may be a separate unidenti fi ed vari- consider it as a factor that will infl uence rate of able accounting for the observed relationship cognitive decline following diagnosis. Although between specifi c experiences (e.g., completing 2 Consideration of Cognitive Reserve 21 crossword puzzles) and dementia risk. As such, References intervention studies are needed to fi rmly establish causal links between life experiences, individual 1. Katzman R, Aronson M, Fuld P, Kawas C, Brown T, characteristics, and cognitive reserve, and such Morgenstern H, et al. Development of dementing studies are underway. Therefore, while recom- illnesses in an 80-year-old volunteer cohort. Ann mending that patients engage in certain activities Neurol. 1989;25:317Ð24. such as mental enrichment and physical fi tness is 2. Ince PG. Pathological correlates of late-onset dementia in a multicenter community-based population in likely not to be harmful and may in fact have England and Wales. Lancet. 2001;357(9251):169Ð75. numerous positive effects, clinicians should be 3. Stern Y. What is cognitive reserve? theory and research careful not to present these activities as established application of the reserve concept. J Int Neuropsychol treatments or fully proven preventative strategies Soc. 2002;8:448Ð60. 4. Stern Y. Cognitive reserve. Neuropsychologia. 2009; against dementia. 47:2015Ð28. 5. Katzman R. Education and the prevalence of dementia and Alzheimer’s disease. Neurology. 1993;43:13Ð20. Clinical Pearls 6. Qiu C, Backman L, Winblad B, Aguero-Torres H, Fratiglioni L. The infl uence of education on clinically diagnosed dementia incidence and mortality data ¥ When formulating clinical impressions, apply from the Kungsholmen Project. Arch Neurol. the most appropriate and valid indicator of cog- 2001;58(12):2034Ð9. nitive reserve for each individual patient. This 7. Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D, Mayeux R. Infl uence of education and occupation may be an individual characteristic such as on the incidence of Alzheimer’s disease. J Am Med level of education; a representation of cumula- Assoc. 1994;271:1004Ð10. tive life experiences spanning social, academic, 8. Akbaraly TN, Portet F, Fustinoni S, Dartigues JF, occupational, and leisure activities; or a mea- Artero S, Rouaud O, et al. Leisure activities and the risk of dementia in the elderly: results from the Three- sure of intellectual functioning. Moving for- City Study. Neurology. 2009;73(11):854Ð61. ward, statistically and neuroanatomically 9. Scarmeas N, Levy G, Tang MX, Manly J, Stern Y. derived measures of cognitive reserve may also Infl uence of leisure activity on the incidence of become valuable for clinical purposes. Alzheimer’s disease. Neurology. 2001;57(12):2236Ð42. 10. Schmand B, Smit JH, Geerlings MI, Lindeboom J. ¥ Integrate neuroimaging tools to complement The effects of intelligence and education on the devel- cognitive data for diagnostic purposes. opment of dementia. A test of the brain reserve ¥ Consider cognitive reserve as a factor that hypothesis. Psychol Med. 1997;27(6):1337Ð44. may affect rate of decline. The apparent yet 11. Valenzuela MJ, Sachdev P. Brain reserve and dementia: a systematic review. Psychol Med. 2005;25:1Ð14. counterintuitive acceleration of decline asso- 12. Albert MS, Jones K, Savage CR, Berkman L, Seeman ciated cognitive reserve may re fl ect a state of T, Blazer D, et al. Predictors of cognitive change in increasingly high pathological burden that the older persons: MacArthur studies of successful aging. brain can no longer tolerate. Psychol Aging. 1995;10:578Ð89. 13. Butler SM, Ashford JW, Snowdon DA. Age, educa- ¥ Appreciate that cognitive reserve may be a tion, and changes in the Mini-Mental State Exam factor that in fl uences response to treatment. scores of older women: fi ndings from the Nun Study. ¥ Be aware that epidemiological studies linking J Am Geriatr Soc. 1996;44:675Ð81. life experiences to reduced dementia risk are 14. Chodosh J, Reuben DB, Albert MS, Seeman TE. Predicting cognitive impairment in high-functioning observational, and intervention studies are community-dwelling older persons: MacArthur needed to determine defi nitively if specifi c Studies of Successful Aging. J Am Geriatr Soc. experiences and activities enhance reserve and 2002;50:1051Ð60. lower dementia risk. 15. Christensen H, Korten AE, Jorm AF, Henderson AS, Jacomb PA, Rodgers B, et al. Education and decline in cognitive performance: compensatory but not protec- Acknowledgments This project was supported by tive. Int J Geriatr Psychiatry. 1997;12:323Ð30. Dr. Cosentino’s Beeson Career Development Award in 16. Colsher PL, Wallace RB. Longitudinal application of Aging (1K23 AG032899-01) and Dr. Stern’s project, cognitive function measures in a defi ned population “Imaging of Cognition and Memory” (R01 AG26158). of community-dwelling elders. Ann Epidemiol. 1991;1(3):215Ð30. 22 S. Cosentino and Y. Stern

17. Farmer ME, Kittner SJ, Rae DS, Bartko JJ, Regier 31. Willerman L, Schultz R, Rutledge JN, Bigler ED. In DA. Education and change in cognitive function: the vivo brain size and intelligence. Intelligence. epidemiologic catchment area study. Ann Epidemiol. 1991;15:223Ð8. 1995;5:1Ð7. 32. Brown J, Cooper-Kuhn CM, Kemperman G, van 18. Lyketsos CG, Chen L-S, Anthony JC. Cognitive Praag H, Winkler J, Gage FH. Enriched environment decline in adulthood: an 11.5-year follow-up of the and physical activity stimulate hippocampal but not Baltimore Epidemiologic Catchment Area Study. Am olfactory bulb neurogenesis. Eur J Neurosci. J Psychiatr. 1999;156(1):58Ð65. 2003;17:2042Ð6. 19. Snowdon DA, Ostwald SK, Kane RL. Education, 33. van Praag H, Shubert T, Zhao C, Gage FH. Exercise survival and independence in elderly Catholic sis- enhances learning and hippocampal neurogenesis in ters, 1936Ð1988. Am J Epidemiol. aged mice. J Neurosci. 2005;25:8680Ð5. 1989;130:999Ð1012. 34. Lazarov O, Robinson J, Tang YP, Hairston IS, Korade- 20. Stern Y, Alexander GE, Prohovnik I, Mayeux R. Mirnics Z, Lee VM, et al. Environmental enrichment Inverse relationship between education and parieto- reduces Abeta levels and amyloid deposition in temporal perfusion de fi cit in Alzheimer’s disease. transgenic mice. Cell. 2005;120(5):701Ð13. Ann Neurol. 1992;32:371Ð5. 35. Manly JJ, Touradji P, Tang MX, Stern Y. Literacy and 21. Alexander GE, Furey ML, Grady CL, Pietrini P, Brady memory decline among ethnically diverse elders. DR, Mentis MJ, et al. Association of premorbid intel- J Clin Exp Neuropsychol. 2003;25(5):680Ð90. lectual function with cerebral metabolism in 36. Boyle PA, Wilson RS, Schneider JA, Bienias JL, Alzheimer’s disease: implications for the cognitive Bennett DA. Processing resources reduce the effect of reserve hypothesis. Am J Psychiatry. 1997; Alzheimer pathology on other cognitive systems. 154(2):165Ð72. Neurology. 2008;70(17):1534Ð42. 22. Stern Y, Alexander GE, Prohovnik I, Stricks L, Link 37. Stern Y. Cognitive reserve and Alzheimer disease. B, Lennon MC, et al. Relationship between lifetime Alzheimer Dis Assoc Disord. 2006;20(3 Suppl 2): occupation and parietal fl ow: implications for a S69Ð74. reserve against Alzheimer’s disease pathology. 38. Stern Y, Habeck C, Moeller J, Scarmeas N, Anderson Neurology. 1995;45:55Ð60. KE, Hilton HJ, et al. Brain networks associated with 23. Scarmeas N, Zarahn E, Anderson KE, Habeck CG, cognitive reserve in healthy young and old adults. Hilton J, Flynn J, et al. Association of life activities Cereb Cortex. 2005;15(4):394Ð402. with cerebral blood fl ow in Alzheimer disease: impli- 39. Siedlecki KL, Stern Y, Reuben A, Sacco RL, Elkind cations for the cognitive reserve hypothesis. Arch MS, Wright CB. Construct validity of cog- Neurol. 2003;60:359Ð65. nitive reserve in a multiethnic cohort: the Northern 24. Brickman AM, Siedlecki KL, Muraskin J, Manly JJ, Manhattan Study. J Int Neuropsychol Soc. Luchsinger JA, Yeung LK, et al. White matter hyper- 2009;15(4):558Ð69. intensities and cognition: testing the reserve hypothe- 40. Benedict RH, Morrow SA, Weinstock Guttman B, sis. Neurobiol Aging. 2011;32(9):1588Ð98. Cookfair D, Schretlen DJ. Cognitive reserve moder- 25. Rentz DM, Locascio JJ, Becker JA, Moran EK, Eng E, ates decline in information processing speed in mul- Buckner RL, et al. Cognition, reserve, and amyloid depo- tiple sclerosis patients. J Int Neuropsychol Soc. sition in normal aging. Ann Neurol. 2010;67(3):353Ð64. 2010;16(5):829Ð35. 26. Bennett DA, Wilson RS, Schneider JA, Evans DA, 41. Sumowski JF, Chiaravalloti N, Wylie G, Deluca J. Mendes De Leon CF, Arnold SE, et al. Education Cognitive reserve moderates the negative effect of modi fi es the relation of AD pathology to level of cog- brain atrophy on cognitive ef fi ciency in multiple nitive function in older persons. Neurology. sclerosis. J Int Neuropsychol Soc. 2009;15(4): 2003;60(12):1909Ð15. 606Ð12. 27. Roe CM, Xiong C, Miller JP, Morris JC. Education 42. Sumowski JF, Wylie GR, Deluca J, Chiaravalloti N. and Alzheimer disease without dementia: support for Intellectual enrichment is linked to cerebral effi ciency the cognitive reserve hypothesis. Neurology. in multiple sclerosis: functional magnetic resonance 2007;68(3):223Ð8. imaging evidence for cognitive reserve. Brain. 28. Valenzuela MJ. Brain reserve and the prevention of 2010;133(Pt 2):362Ð74. dementia. Curr Opin Psychiatry. 2008;21(3):296Ð302. 43. Sumowski JF, Wylie GR, Gonnella A, Chiaravalloti 29. Piras F, Cherubini A, Caltagirone C, Spalletta G. N, Deluca J. Premorbid cognitive leisure indepen- Education mediates microstructural changes in dently contributes to cognitive reserve in multiple bilateral hippocampus. Hum Brain Mapp. 2011; sclerosis. Neurology. 2010;75(16):1428Ð31. 32(2):282Ð9. 44. Smith A. Symbol digit modalities test manual. Los 30. Kesler SR, Adams HF, Blasey CM, Bigler ED. Angeles, CA: Western Psychological Services; 1982. Premorbid intellectual functioning, education, and 45. Cutter GR, Baier ML, Rudick RA, Cookfair DL, brain size in traumatic brain injury: an investigation of Fischer JS, Petkau J, et al. Development of a multiple the cognitive reserve hypothesis. Appl Neuropsychol. sclerosis functional composite as a clinical trial out- 2003;10:153Ð62. come measure. Brain. 1999;122(Pt 5):871Ð82. 2 Consideration of Cognitive Reserve 23

46. Richards M, Sacker A. Lifetime antecedents of cogni- Alzheimer’s disease using Japanese ideographic script tive reserve. J Clin Exp Neuropsychol. 2003;25(5): (Kanji) compound words: Japanese version of 614Ð24. National Adult Reading Test. Psychiatry Clin 47. Valenzuela MJ, Sachdev P. Assessment of complex Neurosci. 2006;60(3):332Ð9. mental activity across the lifespan: Development of 64. Rolstad S, Nordlund A, Gustavsson MH, Eckerstrom the lifetime of experiences questionnaire (LEQ). C, Klang O, Hansen S, et al. The Swedish National Psychol Med. 2007;37(7):1015--25. Adult Reading Test (NART-SWE): a test of premor- 48. Hall CB, Lipton RB, Sliwinski M, Katz MJ, Derby bid IQ. Scand J Psychol. 2008;49(6):577Ð82. CA, Verghese J. Cognitive activities delay onset of 65. Rentz DM, Huh TJ, Sardinha LM, Moran EK, memory decline in persons who develop dementia. Becker JA, Daffner KR, et al. Intelligence quotient- Neurology. 2009;73(5):356Ð61. adjusted memory impairment is associated with 49. Holdnack JA. Wechsler test of adult reading (WTAR) abnormal single photon emission computed tomog- manual. San Antonio, TX: The Psychological raphy perfusion. J Int Neuropsychol Soc. Corporation; 2001. 2007;13(5):821Ð31. 50. Nelson HE. Nelson adult reading test manual. London: 66. Garibotto V, Borroni B, Kalbe E, Herholz K, Salmon The National Hospital for Nervous Disease; 1982. E, Holtoff V, et al. Education and occupation as prox- 51. Wechsler D. WAIS-IV administration and scoring ies for reserve in aMCI converters and AD: FDG-PET manual. San Antonio, TX: Pearson; 2008. evidence. Neurology. 2008;71(17):1342Ð9. 52. Crawford JR, Parker DM, Stewart LE, Besson JAO, 67. Kemppainen NM, Aalto S, Karrasch M, Nagren K, De Lacey G. Prediction of WAIS IQ with the national Savisto N, Oikonen V, et al. Cognitive reserve hypoth- adult reading test: cross-validation and extension. Br esis: Pittsburgh Compound B and ﬂ uorodeoxyglucose J Psychol. 1989;27:181Ð2. positron emission tomography in relation to educa- 53. Hart S, Smith CM, Swash M. Assessing intellectual tion in mild Alzheimer’s disease. Ann Neurol. deterioration. Br J Clin Psychol. 1986;25:119Ð24. 2008;63(1):112Ð8. 54. Nelson HE, O’Connell A. Dementia: the estimation of 68. Smith CD, Chebrolu H, Wekstein DR, Schmitt FA, premorbid intelligence levels using the New Adult Jicha GA, Cooper G, et al. Brain structural alterations Reading Test. Cortex. 1978;14(2):234Ð44. before mild cognitive impairment. Neurology. 55. O’Carroll RE, Gilleard CJ. Estimation of premorbid 2007;68(16):1268Ð73. intelligence in dementia. Br J Clin Psychol. 1986; 69. Smith CD, Andersen AH, Kryscio RJ, Schmitt FA, 25:157Ð8. Kindy MS, Blonder LX, et al. Altered brain 56. Sharpe K, O’Carroll RE. Estimating premorbid activation in cognitively intact individuals at high intellectual level in dementia using the National risk for Alzheimer’s disease. Neurology. Adult Reading Test: a Canadian study. Br J Clin 1999;53(7):1391Ð6. Psychol. 1991;30:381Ð4. 70. Sperling RA, Dickerson BC, Pihlajamaki M, Vannini 57. Jones RN, Manly J, Glymour MM, Rentz DM, P, LaViolette PS, Vitolo OV, et al. Functional Jefferson AL, Stern Y. Conceptual and measurement alterations in memory networks in early Alzheimer’s challenges in research on cognitive reserve. J Int disease. Neuromolecular Med. 2010;12(1):27Ð43. Neuropsychol Soc. 2011;17:1Ð9. 71. Asllani I, Habeck C, Scarmeas N, Borogovac A, 58. Satz P, Cole MA, Hardy DJ, Rassovsky Y. Brain and Brown TR, Stern Y. Multivariate and univariate analy- cognitive reserve: mediator(s) and construct validity, a sis of continuous arterial spin labeling perfusion MRI critique. J Clin Exp Neuropsychol. 2011;33(1):121Ð30. in Alzheimer’s disease. J Cereb Blood Flow Metab. 59. Reed BR, Mungas D, Farias ST, Harvey D, Beckett L, 2008;28(4):725Ð36. Widamen K, et al. Measuring cognitive reserve based on 72. Friese U, Meindl T, Herpertz SC, Reiser MF, Hampel the decomposition of episodic memory variance. Brain. H, Teipel SJ. Diagnostic utility of novel MRI-based 2010;133(Pt 8):2196--209. biomarkers for Alzheimer’s disease: diffusion tensor 60. Stern Y, Zarahn E, Habeck C, Holtzer R, Rakitin BC, imaging and deformation-based morphometry. Kumar A, et al. A common neural network for cogni- J Alzheimers Dis. 2010;20(2):477Ð90. tive reserve in verbal and object working memory in 73. Hall CB, Derby C, LeValley A, Katz MJ, Verghese J, young but not old. Cereb Cortex. 2008;18(4):959Ð67. Lipton RB. Education delays accelerated decline on a 61. Del Ser T, Gonzalez-Montalvo JI, Martinez-Espinosa memory test in persons who develop dementia. S, Delgado-Villapalos C, Bermejo F. Estimation of Neurology. 2007;69(17):1657Ð64. premorbid intelligence in Spanish people with the 74. Scarmeas N, Albert SM, Manly JJ, Stern Y. Education Word Accentuation Test and its application to the diag- and rates of cognitive decline in incident Alzheimer’s nosis of dementia. Brain Cogn. 1997;33(3):343Ð56. disease. J Neurol Neurosurg Psychiatry. 62. Mackinnon A, Mulligan R. The estimation of premor- 2006;77(3):308Ð16. bid intelligence levels in French speakers. Encéphale. 75. Stern Y, Albert S, Tang MX, Tsai WY. Rate of 2005;31(1 Pt 1):31Ð43. memory decline in AD is related to education and 63. Matsuoka K, Uno M, Kasai K, Koyama K, Kim Y. occupation: cognitive reserve? Neurology. 1999; Estimation of premorbid IQ in individuals with 53:1942Ð57. Considerations for the Neuropsychological Evaluation 3 of Older Ethnic Minority Populations

Monica Rivera Mindt , Alyssa Arentoft , Kelly Coulehan , and Desiree Byrd

Abstract The US population is rapidly becoming both older and more culturally diverse [1 ] . These changes in the demographic proﬁ le of the US highlight the need for clinical neuropsychologists to be equipped to competently evaluate the growing population of older individuals from culturally diverse backgrounds. However, there is a relative dearth of empirically based, practical resources speciﬁ cally targeted toward serving such individuals. The aim of this chapter is to identify some of the most salient challenges in the evaluation of culturally diverse ethnic minority older adults and provide some guidelines to help face these challenges. We will examine sociocultural issues germane to older ethnic minority patients referred for neuropsychological evaluation and discuss relevant assessment considerations. Although the focus of this chapter is on ethnic minority older adults, this discussion may also be germane to other nontraditional, older populations including those from rural and low socioeconomic backgrounds.

Keywords Racial/ethnic minorities ¥ Dementia ¥ Neuropsychological evaluation ¥ Assessment ¥ Diversity ¥ Cultural competence ¥ Neurocognitive impairment

M. R. Mindt , Ph.D. () D. Byrd , Ph.D. Department of Psychology , Fordham University , Departments of Pathology and Psychiatry , The Mount 113 West 60th Street, LL 808F , New York , Sinai School of Medicine , One Gustave Levy Place NY 10023 , USA MHBB 1134 , New York , NY 10029 , USA e-mail: [email protected] Departments of Pathology and Psychiatry , The Mount Sinai School of Medicine , One Gustave Levy Place MHBB 1134 , New York , NY 10029 , USA e-mail: [email protected] A. Arentoft , M.A. ¥ K. Coulehan , M.A. Department of Psychology , Fordham University , 113 West 60th Street, LL 808F, New York, NY 10023 , USA e-mail: [email protected]; [email protected]

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 25 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_3, © Springer Science+Business Media, LLC 2013 26 M.R. Mindt et al.

The US population is rapidly becoming both older impacted by higher rates of poverty and limited and more culturally diverse [ 1 ] . Currently, there access to, or use of, healthcare services, which con- are over 38 million people in the USA over 65 tribute to greater vulnerability for particular medi- years old, comprising over 10% of the US popula- cal disorders and worse disease burden [17Ð 19] . Of tion [2 ] . In 2030, there will be approximately 72 particular interest to neuropsychologists, several million individuals over 65 years, comprising ethnic minority groups (particularly African about 20% of the US population [3 ] . Among older Americans, Hispanics/Latinos, and American adults, ethnic minority populations, particularly Indians/Alaska Natives) are disproportionately Latinos and African Americans, are growing much affected by medical conditions (e.g., hypertension, faster than the non-Hispanic white population [ 4 ] . HIV/AIDS, Hepatitis, diabetes, etc.) that may In 2050, ethnic minority individuals will represent increase their need for neuropsychological services approximately 42% of the older adult (65 and compared with the general population [20 ] . older) population in the USA. These changes in the demographic profi le of the US highlight the need for clinical neuropsychologists to be equipped to competently evaluate the growing population of Culture and Cognitive Aging older individuals from culturally diverse backgrounds. However, there is a relative dearth of Dementia empirically based, practical resources specifi cally Evidence suggests that rates of diagnosed dementia targeted toward serving such individuals. differ between ethnic minority and non-Hispanic white older adults, with the former receiving higher rates of dementia diagnoses. Prevalence estimates Sociocultural Framework suggest that African American, Latinos, and Asian American elders have higher rates of vascular Working from a biopsychosociocultural theoretical dementia compared to non-Hispanic white elders framework [ 5 ] , the sociocultural level of analysis [21Ð 24 ] , and African American and Latino elders includes consideration of how social, socioeco- have higher rates of Alzheimer’s disease compared nomic, institutional, and cultural (i.e., the shared to non-Hispanic whites [ 25 ] . Evidence also suggests attitudes, values, goals, and practices that character- that Latinos have an earlier onset of Alzheimer’s ize a group from one generation to the next) [6Ð 8 ] symptoms compared to their non-Hispanic white factors modulate an individual’s or a group’s behav- counterparts [26 ] . In contrast, some research has iors. Sociocultural issues are critical for understand- shown that African Americans have lower rates of ing neuropsychological test performance and Parkinsonian dementia and Latinos have lower rates neurobehavioral functioning [9Ð 14] . In particular, it of Alzheimer’s disease compared to non-Hispanic is important to consider sociocultural issues as they whites [21, 27] . Preliminary research suggests that relate to health disparities, cognitive aging, and neu- rates of dementias (i.e., Alzheimer’s and vascular rologic disease among ethnic minority older adults. dementia) among Asian Americans are similar to non-Hispanic whites [28, 29 ] , although this has not been thoroughly investigated, particularly with rep- Health Disparities resentative samples of Asian American populations (e.g., Chinese, Japanese, Vietnamese, Hmong, A health disparity refers to a signi fi cant discrepancy Korean, Native Hawaiian). Although the current lit- in the overall disease incidence, prevalence, mor- erature is somewhat equivocal, there is a growing bidity, mortality, or survival rates in a specifi c popu- body of evidence that suggests that African American lation as compared to the general population. This is and Latino populations are at greater risk for both mutable and disproportionately affects vulnerable vascular and Alzheimer’s-related dementias than populations [ 15, 16] . In the USA, many ethnic non-Hispanic whites, with Asian Americans also at minority populations are disproportionately greater risk for vascular dementia. 3 Considerations for the Neuropsychological Evaluation of Older Ethnic Minority Populations 27

The mechanisms that contribute to the differing support for the cultural equivalence and construct rates of dementia between ethnic groups remain validity of several measures with ethnic minority poorly understood. Ethnic minority individuals are populations [13, 68, 69] . Thus, it is important for at greater risk of developing cardiovascular dis- clinical neuropsychologists to be aware of these ease, particularly individuals of low socioeco- research ﬁ ndings to more accurately diagnose and nomic status (SES) [ 30, 31 ] . Ethnic minority serve ethnic minority patients. individuals also have higher rates of hypertension, In addition, disproportionate rates of disease diabetes, heart disease [32 ] , cancer, obesity, and and disease burden (health disparities), poten- HIV/AIDS [33 ] . Many of these conditions are risk tially increased risk for dementia due to related factors for illnesses with neuropsychological health disparities, and risk for misdiagnosis due, sequelae, such as dementia. For instance, evidence at least in part, to poor construct validity and lim- indicates that the presence of vascular risk factors ited appropriate normative data together set the (e.g., diabetes and hypertension) among persons stage for a unique set of assessment challenges diagnosed with Alzheimer’s dementia is associ- for working with ethnic minority older adults. In ated with worse neuropsychological test perfor- the following section, these challenges, and sug- mance at the time of diagnosis compared to those gestions for addressing them, are considered at without such risk factors [ 34 ] . However, higher each point in the evaluation process. rates of diagnosed dementia among these ethnic groups may also be signiﬁ cantly affected by the lower diagnostic accuracy of many of the neurop- Considerations for Neuropsychological sychological measures utilized to diagnose ethni- Evaluation with Ethnic Minority cally diverse individuals [35, 36 ] . Older Adults

Ethical Issues and Competence Risk for Misdiagnosis The American Psychological Association’s Multicultural research has demonstrated that neu- (APA) Ethical Principles of Psychologists and ropsychological performance among neurologi- Code of Conduct [ 70 ] provides some guidance on cally healthy younger and older adults signi fi cantly the ethical standards necessary to conduct a differs between ethnic minority and non-Hispanic culturally competent neuropsychological evalua- white groups, even after statistically adjusting for tion. For example, Ethical Standard 2.01 [ 71 ] other demographic factors (e.g., age, education, explains that “cultural expertise or competence at and gender) [37Ð 44 ] . Further, the poor speci fi city the individual level is essential for the clinician of many neuropsychological tests often results in who is working with cross-cultural populations.” misdiagnosis of neurocognitive disorders among But how does a clinician actually ascertain African Americans and Latinos [ 38 , 45Ð 56 ] . whether or not s/he is competent to evaluate Although utilizing normative data that correct for an ethnic minority older adult? race/ethnicity (in addition to age, education, and Rivera Mindt et al. [ 13 ] proposed a cultural gender) substantially reduce the risk for misdiag- competence in neuropsychology (CCN) model nosis [39 ] , such norms do not address the source of [ 71Ð 74] that assists neuropsychologists in examin- these performance differences. ing their cultural competence by evaluating their Emerging literature points to the signifi cant own cultural awareness and knowledge of the impact of numerous sociocultural factors on test ethnically diverse populations they would like to performance among ethnic minority individuals, serve. If a neuropsychologist determines that they including quality of education [57Ð 59] , accultura- s/he does not currently have the requisite compe- tion [ 37, 60Ð 62] , language (including bilingual- tence to evaluate a particular ethnic minority ism) [ 59, 63Ð 66] , and stereotype threat [ 67 ] . There patient, s/he may be able to cultivate that compe- is also potential test bias related to the lack of tence through the acquisition of speci fi c, culturally 28 M.R. Mindt et al. appropriate assessment, intervention, and commu- through use of a well-trained interpreter (which is nication skills necessary to effectively work with less than ideal, but sometimes necessary) or in individuals from speci fi c ethnic minority groups consultation with a neuropsychologist who does [13 ] . For instance, supplemental training can be have the necessary cultural competence to ethi- acquired through continuing education courses or cally provide supervision. More thorough discus- workshops focused on working with culturally sion of ethical obligations and competency issues diverse populations (such as those offered through related to neuropsychological evaluation with APA Division 40, the National Academy of Neuro- ethnic minority individuals is provided elsewhere psychology, the American Academy of Clinical and the interested reader is encouraged to review Neuropsychology, or the Hispanic Neuropsycho- the available literature [13, 70, 71, 78Ð 81 ] . logical Society) [ 75 ] , readings, and consultation [13 ] . In addition, neuropsychologists are also responsible for carefully considering the cultural The Physical Space competence of their psychometrists or graduate students, if used in the assessment process. Once the decision has been made to evaluate an In terms of day-to-day practice, prior to the ethnic minority older patient, neuropsychologists evaluation of an ethnic minority older patient, are encouraged to consider each aspect of the some relevant demographic information about evaluation through a “sociocultural lens.” For the patient should fi rst be collected (i.e., patient’s instance, what is the potential impact of a neu- age, years of education, race/ethnicity, birthplace, ropsychologist’s physical space (i.e., the of fi ce or and language use and history) preliminarily to hospital environment) on their ethnic minority determine if one is competent to evaluate the older patients? Expanding on Rivera Mindt et al.’s older client. The issue of linguistic competence is [13 ] original recommendations, neuropsycholo- particularly important for planning the evalua- gists are encouraged to consider the following: tion. Although detailed discussion of linguistic 1 . First impressions. Does your practice (or facil- competence is beyond the scope of the current ity) contain images of diverse people (i.e., age, chapter, useful guidance on determining one’s gender, race/ethnicity, etc.) via brochures, own linguistic competence to examine non- websites, or fl yers, anti-discrimination state- English or bilingual patients is available else- ments, diversity intentions, or related services? where [5, 76Ð 78 ] . To further inform this decision, Is your practice accessible and convenient for the neuropsychologist may also consider explicitly patients with physical or transport limitations asking about a patient’s linguistic preference. (i.e., parking and close to public transport)? In cases in which a neuropsychologist is unsure 2 . Waiting area. Is your waiting area a welcom- of her or his cultural competence to examine a ing place for ethnic or linguistic minorities particular ethnic minority patient, consultation (i.e., written signs, symbols, magazines, art, with colleagues who are familiar with multi- decorations, greetings, staff)? cultural neuropsychology is recommended. Extensive resources for such consultation are available elsewhere [ 13 ] . If a neuropsychologist Clinical Interview and History determines that he or she does not have the requisite competence (either due to language or other The clinical interview and history taking portion concerns), it is recommended that the patient be of a neuropsychological evaluation is critical for referred to a more appropriate clinician. If such a the purposes of establishing rapport, ensuring referral is not feasible (due to geographic location accurate diagnosis, and developing appropriate or other barriers), then the neuropsychologist follow-up recommendations. However, sociocul- should consider how best to evaluate the patient, tural issues can signi fi cantly impact this process. 3 Considerations for the Neuropsychological Evaluation of Older Ethnic Minority Populations 29

Pre-interview sociocultural norms that may pertain to their Working from the CCN model, it is recommended patient in order to interact appropriately and that neuropsychologists have some empirically ensure that the patient is comfortable with the based knowledge of the culture of origin of their testing process. If a cultural accommodation older ethnic minority patients prior to beginning requires any deviation from standardized testing the clinical interview, if possible. The literature procedure, it should be noted in the report. in multicultural counseling and community psychology may be particularly useful in this regard Interviewing Considerations and may help identify any culturally accepted In terms of the “nuts and bolts” of interview and social norms that may come into play during the history taking, neuropsychologists are encour- interview or latter portions of the evaluation. aged to consider whether the content of their interview is culturally appropriate for the various Establishing and Maintaining Rapport ethnic minority patients they encounter [ 85, 86 ] . Prior to test administration, suffi cient time should During the interview, information is typically be dedicated to rapport building. Research indi- gathered that relates to the referral question, cates that level of formality, authority, eye concurrent symptoms and complaints, and the tact, and personal space can all have an impact on patient’s developmental, medical, psychiatric, establishing and maintaining rapport among per- and psychosocial history. In collecting this infor- sons of different ethnic groups [ 75, 82, 83 ] . These mation, neuropsychologists are again encouraged issues, along with cultural attitudes about the age to approach this task through a “sociocultural and gender of the neuropsychologist or psy- lens,” and explicitly consider how sociocultural chometrist, may be especially salient points for issues might impact an individual at each level consideration among older ethnic minority patients of analysis. who may be less acculturated to majority culture In terms of current symptoms and complaints, (i.e., mainstream US culture). For instance, in terms knowledge of culturally based idioms of distress of verbal and nonverbal communication, consider is particularly important as symptom reporting how to initially approach the patient. The commu- can vary greatly across individuals of different nication of respect may be particularly important ethnic backgrounds and acculturation levels. For with older patients. For instance, it may be best to example, some literature suggests that Asian and have the patient introduce herself/himself to deter- Latino individuals are more likely to report mine whether or not they wish to be called by their somatic rather than depressive symptoms [87, 88 ] . fi rst or last name. Do not assume that the patient From a development perspective, assess whether is comfortable with the use of their fi rst name the person grew up with stable housing and ade- unless s/he specifi es, as this may be interpreted as quate nutrition. From a medical perspective, might disrespectful or overly familiar [ 75 ] . there be any comorbid medical conditions that It is also important to be aware of and sensi- disproportionately impact a certain ethnic popula- tive to specifi c cultural or religious guidelines tion? In terms of past psychiatric history, it may that may affect the interaction with a particular be useful to know about the different base rates older ethnic minority patient. For example, it may of psychiatric disorders, as well as disparities be inappropriate for some women to attend their in access and utilization of psychological appointment without a male family member being and psychiatric services, across different ethnic present. Some Orthodox Jewish individuals do minority populations. These issues could signi- not shake hands with members of the opposite sex fi cantly inform both current diagnosis and follow- [84 ] . Some individuals from American Indian, up treatment recommendations. Native Alaskan, or Asian/Asian American back- With regard to psychosocial history, issues grounds, particularly older individuals, may view related to quality of education (QoE) are particu- direct eye contact as a sign of disrespect [85 ] . larly important with ethnic minority elders. Therefore, neuropsychologists should be aware of Caution should be exercised with older patients 30 M.R. Mindt et al. educated in other countries (particularly non- Further explanation of these categories may Western or less-industrialized countries, as this be needed, but at least this provides a common may affect familiarity with Western construct- nomenclature. laden measures), as well as disadvantaged areas in 2 . Country of origin and region. Western or non- the USA. In both of these cases, using years of Western? Was the region rural, urban, or subur- education to determine expected performance ban? Safety and access to resources in the level may overestimate the individual’s expected community? Issues related to acculturation are performance on Westernized neuropsychological also important and discussed later in this chapter. tests. Therefore performance on the Wide Range 3 . Current US region of origin/neighborhood . Achievement Test (WRAT) reading subtest or the Rural, urban, or suburban? Safety and access Wechsler Test of Adult Reading (WTAR) should to resources in the community? be examined. Both estimate reading level, and are 4 . Immigration history (if applicable) . This often used as proxies for quality of education [57 ] . would include years in the USA and years When total years and quality of education vary educated in the USA, as well as any relevant signi fi cantly, this should be noted as a limitation sociopolitical issues related to immigration. and considered when examining performance on 5 . Linguistic background. For linguistic minori- neuropsychological tests that are normatively cor- ties, questions about language of origin, how rected for education. In such instances, it will be often a patient uses English versus the lan- important to ensure that the reading materials used guage of origin (and in which contexts), their during testing are written at an appropriate educa- ease with the respective languages, and prefer- tional level so that the patient can reasonably be ence for testing are all potentially useful areas expected to understand them. Further, when large of inquiry. Comprehensive discussion about discrepancies between education and reading this issue is beyond the scope of this chapter. level (i.e., QoE) exist, utilizing Dotson et al ’s. For more information, readers are referred [89 ] battery and literacy-based norms may be a elsewhere [5, 76, 81, 90 ] . useful option for patients who are up to age 64, 6 . Quality of education . Tests of reading level African American, and of predominantly low SES (such as WTAR and WRAT-4) are helpful to background. Moreover, gathering information disentangle quality of education issues. regarding SES is important considering that there Further, questions regarding patient’s type is some evidence indicating SES affects neuropsy- of school and classroom experience, as well chological performance, although this has not been as geographic region are helpful in this thoroughly investigated [ 11, 14 ] . regard. Finally, it is strongly recommended that infor- 7 . Social support. This may include questions mation related to sociocultural history is col- about both biological and nonbiological fam- lected when working with ethnic minority elders. ily, church-related and spiritual resources, While the following is not an exhaustive list, and other potential, nontraditional resources below are some suggestions to consider when (e.g., community organizations). taking the sociocultural history. For an excep- 8 . Current and childhood SES and nutrition . This tional review of sociocultural considerations for may include questions about having enough to working with Latino patients, see Llorente [81 ] . eat and fi nancial resources at present and during 1 . Race and ethnicity . It is important to ask childhood. patients to self-identify their race and ethnic- 9 . Access and utilization of health and mental- ity, rather than solely relying on physical health services. Beyond health insurance, this appearance. Sometimes, these questions may may include questions about healthcare access be challenging for patients. Listing out racial/ and perceived quality, attitudes about traditional ethnic categories provided through the US and nontraditional health and mental-health Census can serve as a useful starting point. services and providers, and health literacy. 3 Considerations for the Neuropsychological Evaluation of Older Ethnic Minority Populations 31

Informants to avoid using jargon, and to explain aspects of the testing that may be unfamiliar or are particularly When obtaining collateral information on older important for the patient to understand. In addi- patients, it is important to gather reports from a tion, as noted earlier, if there is any deviation from reliable source (e.g., a cognitively intact caregiver, standardized testing procedure, it should be noted child, or spouse), as older adults may not be reli- in the report and considered in the fi nal interpre- able historians if they are experiencing memory tation of the data. or executive dysfunction. Among patients with mild cognitive impairment (MCI), some research shows that African American informants may be Neuropsychological Test and more likely to under-report the patient’s symp- Normative Data Selection toms or functioning, while non-Hispanic white informants may be more likely to over-report [91 ] . According to APA Ethical Standard 9.02b [ 70 ] , However, anecdotally, one investigator reported “psychologists use assessment instruments whose that in his clinical experience with Mexican validity and reliability have been established American patients with dementia, many of his for use with members of the population tested.” patients’ children were hesitant to report their Therefore, neuropsychologists have an ethical parent’s cognitive or functional decline, despite responsibility to use appropriate and non-biased having observed such declines [92 ] . He noted that assessment instruments whenever they are avail- the children were only willing to report these able. However, relatively few neuropsychological observations after lengthy interview when rapport tests have been specifi cally standardized and val- had been well established, and many apologized to idated with culturally diverse samples. Therefore, their parent prior to reporting their observations. it is often unclear how performance may vary This example demonstrates the powerful potential with cultural background and whether or not the impact of culture on the interview process, and intended construct is appropriately assessed [ 68 ] . clinicians should consider that reporting defi cits Whenever possible, neuropsychologists should may be uncomfortable or culturally inappropriate use tests that have been normed and validated with for many informants and patients [ 93] . Therefore, individuals from the same cultural background as rapport building and culturally sensitive but thor- the patient being evaluated. ough interviewing is imperative. Screening Instruments In terms of screening instruments, there are some Testing Considerations cross-cultural assessments for dementia available, including the Rowland Universal Dementia Socioculturally, many ethnic minority elders may Assessment Scale (RUDAS) [ 97 ] . Moreover, in be less familiar with assessment procedures than screening general cognitive abilities, Wolfe [98 ] elders from majority culture [94, 95 ] . They may suggested that the Cognitive Abilities Screening also have misperceptions about or be wary of the Instrument (CASI) [99 ] be used in place of the assessment process, so it is important that the Mini-Mental Status Exam (MMSE), since it has neuropsychologist clarify the purpose of the eval- been culturally validated in Japan, China, and uation and make sure that instructions are under- the USA, or the Cross-Cultural Cognitive stood. For example, it may be useful to explain test Examination (CCCE) [100 ] , which was devel- format or when speeded performance is being oped in Guam and may be particularly useful for assessed, as these constructs may be unfamiliar individuals with low literacy. Additional brief or carry different valence to certain ethnic minor- screening instruments, which have been used for ity older patients [ 95, 96] . Thus, it is critical to detecting possible dementia among ethnically clearly explain the purpose of the neuropsycho- diverse older adults, include both a measure logical evaluation to the individual—making sure for patients (i.e., the Taussig Cross-Cultural 32 M.R. Mindt et al.

Memory Test), [ 101] and informants (i.e., the they have not been validated with culturally Informant Questionnaire on Cognitive Decline in diverse samples. For example, research has the Elderly, also known as IQCODE) [102 ] . shown that healthy Spanish-speaking elders performed signi fi cantly worse on several visuospa- English Language Tests and Normative Data tial and visuoconstructional tasks compared to A key aspect of determining which neuropsycho- their non-Hispanic white peers [ 40 ] . Therefore, logical tests to administer often lies in the availability the use of well-validated, empirically supported, and appropriateness of the relevant normative and linguistically appropriate neuropsychological data. Demographically corrected normative data tests or batteries for linguistic minority individuals that can be used with English-speaking ethnic is essential. minority elders are available for some neuropsy- Although this overview is certainly not exhaus- chological batteries and tests. Heaton et al. [ 103 ] tive, herein we provide resources that we believe provide excellent normative data (corrected for would be useful for those working with older eth- age, education, gender, and race/ethnicity) on the nic minority individuals. In the case of Spanish- expanded Halstead-Reitan battery for non-Hispanic speaking older adults, there are a number of white and African American adults up to age 85. available batteries that may be appropriate for this The WAIS-IV and WMS-IV provide normative population, including La Batería Neuropsicológica data (corrected for age, education, gender, and en Español [ 76 ] , the NEUROPSI [ 106 ] , the race/ethnicity) for non-Hispanic white, African Batería-III Woodcock-Muñoz [107 ] , Woodcock- American, and Latino adults up to age 90 [104 ] . Muñoz Language Survey-Revised [ 108 ] , the As mentioned earlier, Dotson et al. [ 89 ] provide Neuropsychological Screening Battery for literacy-based normative data (corrected for age, Latinos (NeSBHIS) [ 109 ] , and the Spanish and gender, and WRAT-3 Reading Total Score) for English Neuropsychological Assessment Scales African American adults up to age 64, for the (SENAS) [110 ] . following tests: California Verbal Learning Test, In addition, the Canadian Study of Health and Benton Visual Retention Test (5th ed.), COWAT Aging (CSHA) neuropsychological test battery Animal Fluency, Card Rotation Test, Brief Test provides English and French versions of their of Attention, Digit Span, Trail Making Test, and tests, along with normative data [111 ] . What is Identical Pictures. A particular weakness in the notable about both the SENAS and the CSHA literature is the paucity of normative data available batteries is that they utilized statistical modeling for English-speaking Asian-American/Paci fi c methods to test the cultural equivalence (i.e., Islander and Latino elders. One notable exception invariant structures) of their respective batteries is Kempler et al.’s [ 105 ] normative data (corrected in their dual respective languages. Both Mungas for age, education, and race/ethnicity) for verbal et al. [ 110 ] and Tuokko et al. [ 111 ] provide fl uency measures, which provide norms for empirical support for the cross-linguistic con- non-Hispanic white, African American, Latino, struct validity of their respective neuropsycho- and Asian American adults up to age 99. logical batteries utilizing state-of-the-art statistical modeling. (e.g., item response theory Non-English Language Tests (IRT) techniques to reduce test bias and covari- and Normative Data ance structure analysis [112 ] in the case of the For linguistic minorities, it is important to note SENAS battery and a relatively straightforward that use of nonverbal measures does not mitigate multi-group con fi rmatory factor analysis (CFA) the impact of linguistic and cultural differences framework in the case of the CSHA battery.) on neuropsychological measures. These tests These approaches represent promising method- contain verbal instructions and may still involve ologies for examining the construct validity (via verbally mediated approaches. Even when this is measurement invariance) of other neuropsycho- not the case, nonverbal measures are still cultur- logical instruments across a variety of ethnic and ally laden and interpretation may be limited if linguistic groups [69, 110, 111, 113 ] . 3 Considerations for the Neuropsychological Evaluation of Older Ethnic Minority Populations 33

For Mandarin-speaking older adults, Hsieh should determine their birthplace and the and Tori [ 114 ] provide normative data on cross- birthplace of the parents. This will help guide the cultural neuropsychological tests across the life selection of appropriate tests, norms, and inter- span (up to age 81). For Korean-speaking older preters (if needed). For example, in the case of adults, there is a Korean version of the California Spanish language tests, the neuropsychologist Verbal Learning Test (K-CVLT) [ 115 ] available, should consider the country where the test was which provides norms correcting for ages 20Ð79. developed, particularly in regard to language and While the resources available for examining dialect—a test developed in Puerto Rico may ethnic minority elders have signi fi cantly improved contain colloquialisms unfamiliar to a patient over the course of the past 20 years, several from Mexico [ 118 ] . Further discussion of the important limitations merit discussion. First, only issue can be found elsewhere [13, 59, 81, 109 ] . two neuropsychological batteries (of which we For Latino patients, formal assessments of are aware) provide rigorous empirical support for level of acculturation are available and should their cultural equivalence and construct validity be completed. As described in a recent posi- (the SENAS and the CHSA). Providing such sup- tion paper from the National Academy of port is important not only in the case of tests or Neuropsychology [78 ] , the following measures batteries utilized in different languages but also can be used to assess acculturation: Acculturation for tests and batteries utilized across different Rating Scale for Mexican Americans-II [119 ] , ethnic groups [ 68 ] . The absence of this research the Bidimensional Acculturation Scale for remains a signifi cant weakness in the discipline. Hispanics [120 ] , and Short Acculturation Scale Second, no comprehensive batteries or norms for Hispanics [121 ] . The abbreviated multidi- exist for adequately characterized English- mensional acculturation scale (AMAS) is also a speaking Latinos; Spanish-speakers who are not well-validated tool, which assesses both Latino from Spain, Mexico, or of Mexican-American and US American identity and acculturation origin; Asian Americans (including Native [122 ] . Unlike other acculturation instruments, Hawaiians, Pacifi c Islanders, and South Asians); which largely used Mexican-American or Puerto American Indians or Alaska Natives; persons Rican standardization samples, the AMAS uti- from Middle-Eastern backgrounds; and bilin- lized a heterogeneous Latino sample that included guals. For a more comprehensive discussion of individuals of Central and South American, these issues, see Rivera Mindt et al. [ 13 ] . Third Caribbean, and Mexican origins. For other ethnic and perhaps most importantly, use of race/ethnic- groups, where standardized measures of accul- ity-based norms do not explain performance dif- turation are not available, language use (English ferences between groups and may inadvertently versus language of origin) and years in the USA leave unexplained racial/ethnic differences in have been shown to serve as proxies of accultura- neuropsychological test performance open to tion [61, 123, 124 ] . harmful misinterpretation [13, 116, 117 ] . The practical application of acculturation information to the interpretation of neuropsychological test data is limited by the lack of formalized algo- Sociocultural Testing Issues rithms or normative data that incorporate acculturation level. However, research indicates that Culture and Acculturation lower levels of acculturation to majority culture As noted above, neuropsychologists should are associated with worse neuropsychological test inquire about patient-speci fi c cultural background performance, particularly in the areas of abstrac- (e.g., is the patient/patient’s family from the tion/executive functioning, attention, working Dominican Republic, Puerto Rico, Cuba, etc.). memory, language, visuoconstruction, learning, They should also ascertain the individual’s degree and memory [ 37, 60Ð 62, 92, 125Ð 127 ] . Therefore, of acculturation to majority US culture. For neuropsychologists should consider the potential instance, when assessing a Latino patient, one contribution of acculturation level when impaired 34 M.R. Mindt et al. scores are present in these areas among ethnic and verbal fl uency (particularly semantic) [ 130, minority older patients with low acculturation levels. 131] . In contrast, there are subtle bilingual advantages on measures of attention/executive func- Bilingual Older Adults tioning, particularly cognitive control, and these When evaluating a bilingual older patient, test advantages may confer some neuroprotection in selection also involves several specifi c consider- the face of normal cognitive aging and Alzheimer’s ations. Factors that should be considered include disease [64, 132 ] . These disadvantages and (1) which language is the individual’s fi rst or advantages should be considered when interpret- native language, or did they learn both languages ing test data of bilingual older adults, and should simultaneously? If they did not, at what age was be explicitly discussed in reports. For a thorough the second language acquired? (2) Which lan- review of the neuropsychological implications of guage is currently their primary language? What bilingualism, see Rivera Mindt et al. [5 ] . is their degree of bilingualism (e.g., balanced bilingual, English-dominant bilingual, Spanish- Qualitative Information dominant bilingual, etc.)? It may also be impor- For some ethnic minority patients for whom a tant to consider how many years of formal standard evaluation may not be appropriate education the individual completed in their pri- because of language or other cultural limitations, mary language. Rivera Mindt et al. [ 5 ] should be a process approach may be useful [ 133, 134 ] in consulted for further discussion of these issues. estimating level of neuropsychological abilities. Brie fl y, individuals should be tested in their most This provides qualitative information by examin- competent (e.g., strongest or primary) language ing the types of errors the patient makes, their whenever possible and appropriate. Ideally, lan- approach to the tests, and their response to testing guage competency should be determined on the limits. For example, one may allow a patient to basis of both objective language measurement and continue past the standard time limit on a test, subjective report, although it is also important to such as Block Design. Although points would not note that older individuals are more likely to be awarded for a response given after the speci fi ed underestimate their language fl uency [5, 66 ] . Some amount of time, this would allow the examiner to objective measures for assessing SpanishÐEnglish assess whether or not the patient’s diffi culty is due language dominance include the Woodcock- to time constraints. Muñoz Language Survey-Revised and examination of the difference in performance between the English and Spanish versions of verbal fl uency or Post-evaluation Considerations naming measures [ 5 ] . Care should be taken to select tests that have been standardized and normed Upon completion of the neuropsychological eval- with the population and language of interest, uation, which has been conducted in a culturally whenever possible. competent manner, using the best available tests, Awareness of the bilingualism literature can the results must be examined and interpreted. further aid in interpreting the neuropsychological There are several factors that must be considered, test performance of bilingual ethnic minority including which norms to apply to tests and cave- elders, especially given the lack of normative ats that limit test interpretation. data for this population. Research has generally Neuropsychologists should consider their use shown a robust bilingual disadvantage in terms of race/ethnicity-based norms depending on the of performance on verbal measures when com- situation and the referral question. For example, pared with monolinguals (who can be viewed as Brickman et al. [ 80] point out, “comparing test as hyperpro fi cient in their language) [ 66 ] . scores from a highly educated African American Speci fi cally, bilinguals may perform worse in man from New York City to an African American expressive vocabulary [128 ] , receptive vocabu- normative data set collected in the rural South lary (including response latency times) [ 129 ] , might not be appropriate.” Additionally, one 3 Considerations for the Neuropsychological Evaluation of Older Ethnic Minority Populations 35 should consider whether the goal of the referral and develop more relevant, culturally tailored question is to determine how well the individual recommendations for their ethnic minority older is likely to be functioning in their environment, patients. or whether the goal is to determine whether Finally, in terms of providing feedback, atten- decline is suspected relative to peers. In the fi rst tion to the same sociocultural norms and commu- instance, raceÐethnicity-based norms would nication issues (clear, jargon-free language) also likely be inappropriate, while in the second apply to this “fi nal” aspect of the neuro- instance, they may be more appropriate [ 135 ] . psychological evaluation (see section “Establi- Next, neuropsychologists must incorporate shing and Maintaining Rapport”). The critical and synthesize the sociocultural information goals of the feedback session are (1) that the collected during the clinical interview, history, patient, or her/his family member, or caregiver and throughout the evaluation into the test understand the pertinent test fi ndings and follow- interpretation and case conceptualization. This up recommendations; (2) that the neuropsycholo- can be accomplished utilizing an empirically gist confi rms that these recommendations are based, hypothesis testing approach grounded in appropriate and feasible for the patient; and (3) the quantitative and qualitative data gathered that the neuropsychologist maintains a stance of during the evaluation. How does this converging respect, fl exibility, creativity, and advocacy to evidence point to a particular conclusion and modify the recommendations if needed and to help how does this fi t (or does not) with the existing advocate on behalf of the patient, if necessary, to empirical literature? Equally important, it is ensure appropriate follow-up. For a more thorough recommended that neuropsychologists explic- discussion regarding the provision of feedback, itly discuss in the report how the sociocultural the reader is referred elsewhere [137, 138 ] . data from the evaluation and the empirical literature factored into the test interpretation, case conceptualization, diagnosis, and recom- Final Thoughts mendations. Careful consideration should also be taken to Given the paucity of empirically based and practi- avoid over-interpreting low performance that cal resources that are specifi cally targeted toward may be attributed, at least in part, to sociocultural serving ethnic minority older adults in neuropsy- factors. For example, if a test has been shown to chology, this chapter reviewed sociocultural issues have cultural biases, but is administered because germane to this population and discussed consid- a more appropriate alternative does not exist, the erations for the culturally competent evaluation neuropsychologist should be sure to include this of older ethnic minority adults. Overall, a number information in the report and to limit any conclu- of factors must be considered to provide a com- sions drawn from these scores. For bilingual petent neuropsychological evaluation with ethnic patients, Ardila et al. [ 136 ] recommend explicitly minority individuals, and neuropsychologists are noting in the report the language the patient was reminded to maintain a “sociocultural lens” tested in, formal documentation of the patient’s throughout each step of the evaluation. degree of bilingualism, and whether or not an Speci fi cally, neuropsychologists must fi rst interpreter was used. In terms of differential diag- consider whether or not they have the appropriate nosis and the recommendations for ethnic minor- training and experience to conduct a competent ity older adults, it is also especially important to evaluation with a given ethnic minority elder. consider the possible infl uence of other factors Neuropsychologists should consider the infl uence (i.e., comorbid medical or psychiatric conditions, that cultural factors may play in patient self- SES, access to care, etc.). In bringing together all report, informant report, and expression of symp- of the information, including the sociocultural toms. The neuropsychologist should be culturally information, it is hoped that neuropsychologists sensitive during the evaluation, including in the will be better able to improve diagnostic accuracy selection of appropriate tests and norms, and in 36 M.R. Mindt et al. the manner in which they interact with the patient ¥ Consider psychometric characteristics to and her/his family members or caregivers from determine how “low” scores should be inter- the clinical interview until the feedback session. preted to avoid misdiagnosis and mismanage- While the focus of this chapter has been ethnic ment of neurocognitive disorders. minority older adults, much of this information ¥ Suggest longitudinal assessments to better may also be relevant for nontraditional, older disentangle the impact of sociocultural factors populations including those from rural or low versus neurodegenerative processes. socioeconomic backgrounds. ¥ Explicitly state the normative data sets used within the report, if different from the manual, and discuss any limitations to the interpret- Clinical Pearls ability of the data based on these norms. ¥ Be careful not to erroneously attribute prob- ¥ Remember to maintain a “sociocultural lens” lems to cultural or linguistic issues. and to be mindful of potential sociocultural ¥ Consider the whole person, including their norms throughout the evaluation, from the sociocultural context, in the development and clinical interview to the feedback session. communication of recommendations. ¥ In working with informants of ethnic minority ¥ Become actively involved in advancing your elders, be cognizant that there may be hesitance own cultural competence, as well as that of our to report the cognitive or functional decline of a fi eld (see Rivera Mindt et al. [13 ] for resources). loved one, despite having observed such declines. Such reticence may be reduced through taking Acknowledgements The authors wish to thank Ms. the time to establish solid rapport. Franchesca Arias, MA for her assistance with this manu- ¥ Utilize the best available neuropsychologi- script. Supported by grant K23MH079718 (to MRM) from the National Institutes of Health. cal instruments and norms and acknowledge the potential limitations in the interpretation section of your neuropsychological report. References ¥ Consult literature regularly for recent developments in measures and norms. 1. Heron MP, Hoyert DL, Xu J, Scott C, Tejada-Vera B. ¥ Carefully evaluate the psychometric appropri- Deaths: preliminary data for 2006. Natl Vital Stat ateness of tests under consideration, particu- Rep. 2008;56(16):1Ð50. larly if the patient is bilingual. 2. US Census Bureau News. (2010, May 20). Aging population: aging boomers will increase dependency ¥ Consider the purpose of the evaluation (diag- ratio, census bureau projects. Retrieved from http:// nostic or descriptive) and whether race/ethnic- www.census.gov/newsroom/releases/archives/aging_ ity corrected norms are indicated. population/cb10-72.html . ¥ Gather as much sociocultural information as 3. US Census Bureau News. (2008, Aug. 14). Press releases: an older and more diverse nation by mid- possible (i.e., acculturation, quality of educa- century. http://www.census.gov/Press . http://www. tion, linguistic background, etc.) to best con- census.gov/newsroom/releases/archives/population/ textualize the neuropsychological fi ndings. cb08-123.html. ¥ For non-English speaking elders or those from 4. Robnett RH, Chop WC. Gerontology for the health care professional. Sudbury: Jones & Bartlett; 2010. ethnic groups for which the neuropsychologist 5. Rivera Mindt M, Arentoft A, Kubo Germano K, does not feel competent to examine, refer to D’Aquila E, Scheiner D, Pizzirusso M, Sandoval TC, a neuropsychologist who has expertise with Gollan T. Neuropsychological, cognitive, and theo- the population or consult with such a neuropsy- retical considerations for the evaluation of bilingual individuals. Neuropsychol Rev. 2008;18(3):255Ð68. chologist when referring out is not feasible. 6. Bentacourt H, Lopez ER. The study of culture, eth- ¥ Use an interpreter when outside referral is not nicity, and race in American psychology. Am Psychol. feasible. Only use professional interpreters 1993;48:629Ð37. (not children of patients, hospital staff, or 7. Okazaki S, Sue S. Methodological issues in assessment research with ethnic minorities. Psychol other nonprofessionals) [5 ] . Assess. 1995;7(3):367Ð75. 3 Considerations for the Neuropsychological Evaluation of Older Ethnic Minority Populations 37

8. Phinney JS. When we talk about American ethnic of health care services. Psychiatr Serv. 2003;54(1): groups, what do we mean? Am Psychol. 1996;51: 92Ð6. 918Ð27. 24. Kuller LH, Lopez OL, Jagust WJ, Becker JT, 9. Ardila A. Cultural values underlying psychometric DeKosky ST, Lyketsos C, Kawas C, Breitner JC, cognitive testing. Neuropsychol Rev. 2005;15(4): Fitzpatrick A, Dulberg C. Determinants of vascular 185Ð95. doi:10.1007/s11065-005-9180-y . dementia in the Cardiovascular Health Cognition 10. Byrd D, Miller S, Reilly J, Weber S, Wall ST, Heaton Study. Neurology. 2005;64(9):1548Ð52. R. Early environmental factors, ethnicity, and adult 25. Livney MG, Clark CM, Karlawish JH, Cartmell S, cognitive test performance. Clin Neuropsychol. Negrón M, Nuñez J, Xie SX, Entenza-Cabrera F, 2006;20:243Ð60. Vega IE, Arnold SE. Ethnoracial differences in the 11. Dotson VM, Kitner-Triolo M, Evans MK, Zonderman clinical characteristics of alzheimer’s disease at initial AB. Effects of race and socioeconomic status on presentation at an urban alzheimer’s disease center. the relative infl uence of education and literacy on Am J Geriatr Psychiatry. 2011;19(5):430Ð9. cognitive functioning. J Int Neuropsychol Soc. 26. Clark CM, DeCarli C, Mungas D, Chui HI, Higdon 2009;15:580Ð9. R, Nuñez J, Fernandez H, Negrón M, Manly J, Ferris 12. Manly JJ. Critical issues in cultural neuropsychol- S, Perez A, Torres M, Ewbank D, Glosser G, van ogy: profi t from diversity. Neuropsychol Rev. Belle G. Arch Neurol. 2005;62(5):774Ð8. 2008;18:179Ð83. 27. Froehlich TE, Bogardus ST, Inouye SK. Dementia 13. Rivera Mindt M, Byrd D, Saez P, Manly J. Increasing and race: are there differences between African culturally competent neuropsychological services Americans and Caucasians? J Am Geriatr Soc. 2001; for ethnic minority populations: a call to action. Clin 49:477Ð84. Neuropsychol. 2010;24:429Ð53. 28. Flaskerud JH. Dementia, ethnicity, and culture. 14. Schwartz BS, Glass TA, Bolla KI, Stewart WF, Glass Issues Ment Health Nurs. 2009;30(8):522Ð3. G, Rasmussen M, Bressler J, Shi W, Bandeen-Roche 29. Chiu HEK, Zhang M. Dementia Research in China. K. Disparities in cognitive functioning by race/eth- Int J Geriatr Psychiatry. 2000;15:947Ð53. nicity in the Baltimore Memory Study. Environ 30. National Institutes of Health. (2010, Oct.). Fact Sheet— Health Perspect. 2004;112(3):314Ð20. Health Disparities. http://report.nih.gov/NIHfactsheets/ 15. Minority Health and Health Disparities Research ViewFactSheet.aspx?csid=124 . and Education Act of 2000. Public Law 106-525, S. 31. Dodani S. Excess coronary artery disease risk in 1880 , 2000. p. 2498. South Asian immigrants: can dysfunctional high- 16. Richardson LD, Babcock Irvin C, Tamayo-Sarver density lipoprotein explain increased risk? J Vasc JH. Racial and ethnic disparities in the clinical Health Risk Manag. 2008;4:953Ð61. practice of emergency medicine. Acad Emerg 32. Gallant MP, Spitze G, Groove JG. Chronic illness Med. 2003;10:1184Ð8. doi:10.1197/S1069- delf-care and the family lives of older adults: a syn- 6563(03)00487-1 . thetic review across four ethnic groups. J Cross Cult 17. Cargill VA, Stone VE. HIV/AIDS: a minority health Gerontol. 2010;25(1):21Ð43. issue. Med Clin N Am. 2005;89:895Ð912. 33. Of fi ce of Minority Health, US Department of Health 18. Fiscella K, Franks P, Gold MR, Clancy CM. and Human Services. (2007, Dec. 7). Minority health Inequality in quality: addressing socioeconomic, disparities at a glance. http://minorityhealth.hhs.gov/ racial, and ethnic disparities in health care. J Am templates/content.aspx?ID=2139 . Med Assoc. 2000;283:2579Ð84. 34. Reitz C, Patel B, Tang M, Manly J, Mayeux R, 19. US Census Bureau. Press release CB07-FF, Facts for Luchsinger JA. J Neurol Sci. 2007;257(1Ð2):194Ð201. features: (2007, July 16). Hispanic Heritage Month: 35. Rilling LM, Lucas JA, Ivnik RJ, Smith GE, Willis Sep 15ÐOct 15. www.census.gov/newsroom/releases/ FB, Ferman TJ, Petersen RC, Graff-Radford NR. pdf/cb07-ff14.pdf . Mayo’s older African American normative studies: 20. Centers for Disease Control. (2007, June 6). About norms for the mattis dementia rating scale. Clin minority health. http://www.cdc.gov/omhd/AMH/ Neuropsychol. 2005;19(2):229Ð42. AMH.htm . 36. Evans JD, Miller SW, Byrd DA, Heaton RK. Cross- 21. Fitten LJ, Ortiz F, Ponton M. Frequency of cultural applications of the Halstead-Reitan batter- Alzheimer’s disease and other dementias in a com- ies. In: Fletcher-Janzen E, Strickland TL, Reynolds munity outreach sample of Hispanics. J Am Geriatr CR, editors. Handbook of cross-cultural neuropsy- Soc. 2001;10:1301Ð8. chology. New York: Springer; 2000. p. 287Ð303. 22. von Strauss E, Fratiglioni L, Viitanen M, Forsell Y, 37. Arnold BR, Montgomery GT, Castaneda I, Longoria Winblad B. Morbidity and comorbidity in relation to R. Acculturation and performance of Hispanics on functional status: a community-based study of the selected Halstead-Reitan neuropsychological tests. oldest old (90+ years). J Am Geriatr Soc. 2000; Assessment. 1994;1:239Ð48. 48(11):1462Ð9. 38. Gladsjo JA, Evans JD, Schuman CC, Peavy GM, 23. Husaini BA, Sherkat DE, Moonis M, Levine R, Miller SW, Heaton RK. Norms for letter and cate- Holzer C, Cain VA. Racial differences in the diagno- gory fl uency: demographic corrections for age, edu- sis of dementia and in its effects on the use and costs cation, and ethnicity. Assessment. 1999;6:147Ð78. 38 M.R. Mindt et al.

39. Heaton RK, Taylor M, Manly J. Demographic effects 51. Bohnstedt M, Fox PJ, Kohatsu ND. Correlates of and demographically corrected norms with the mini-mental status examination scores among elderly WAIS-III and WMS-III. In: Tulsky DS, Saklofske demented patients: the infl uence of race-ethnicity. DH, Chelune GJ, Heaton RK, Ivnik RJ, Bornstein R, J Clin Epidemiol. 1994;47:1381Ð7. Prifi tera A, Ledbetter M, editors. Clinical interpreta- 52. Gurland BJ, Wilder DE, Cross P, Teresi J, Barrett tion of the WAIS-III and WMS-III. San Diego: VW. Screening scales for dementia: toward recon- Academic; 2003. p. 181Ð210. ciliation of confl icting cross-cultural fi ndings. Int J 40. Jacobs DM, Sano M, Albert S, Scho fi eld P, Dooneief Geriatr Psychiatry. 1992;7:105Ð13. G, Stern Y. Cross-cultural neuropsychological 53. Mungas D, Marshall SC, Weldon M, Haan M, Reed assessment: a comparison of randomly selected, BR. Age and education correction of mini-mental demographically matched cohorts of English- and state examination for English and Spanish-speaking Spanish-speaking older adults. J Clin Exp elderly. Neurology. 1996;46:700Ð6. Neuropsychol. 1997;19:331Ð9. 54. Patton D, Duff K, Schoenberg M, Mold J, Scott J, 41. Longobardi P, Cummings J, Anderson-Hanley C. Adams R. Performance of cognitively normal African Multicultural perspectives on the neuropsychological Americans on the RBANS in community dwelling and neuropsychiatric assessment and treatment of the older adults. Clin Neuropsychol. 2003;17:515Ð30. elderly. In: Fletcher-Janzen E, Strickland TL, Reynolds 55. Welsh KA, Fillenbaum G, Wilkinson W, Heyman A, CR, editors. Handbook of cross-cultural neuropsy- Mohs RC, Stern Y, Harrell L, Edland SD, Beekly D. chology. New York: Springer; 2000. p. 123Ð42. Neuropsychological test performance in African- 42. Lowenstein DA, Duara R, Arguelles T, Arguelles S. American and white patients with Alzheimer’s dis- Use of the fuld object-memory evaluation in the ease. Neurology. 1995;45:2207Ð11. detection of mild dementia among Spanish- and 56. Whit fi eld KE, Weidner G, Clark R, Anderson NB. English-speaking groups. Am J Geriatr Psychiatry. Sociodemographic diversity and behavioral medi- 1995;3:300Ð7. cine. J Consult Clin Psychol. 2002;70(3):463Ð81. 43. Manly JJ, Jacobs DM, Sano M, Bell K, Merchant CA, 57. Manly JJ, Jacobs DM, Touradji P, Small SA, Stern Y. Small SA, Stern Y. Neurocognitive test performance Reading level attenuates differences in neuropsycho- among non-demented elderly African Americans and logical test performance between African American and Whites. Neurology. 1998;50:1238Ð45. white elders. J Int Neuropsychol Soc. 2002;8:341Ð8. 44. Stricks L, Pittman J, Jacobs D, Sano M, Stern Y. 58. Manly JJ, Touradji P, Tang MX, Stern Y. Literacy Normative data for a brief neuropsychological bat- and memory decline among ethnically diverse elders. tery administered to English- and Spanish-speaking J Clin Exp Neuropsychol. 2003;25:680Ð90. community-dwelling elders. J Int Neuropsychol Soc. 59. Rivera Mindt M, Byrd D, Ryan E, Robbins R, 1998;4:311Ð8. Monzones J, Arentoft A, Kubo Germano K, 45. Adams RL, Boake C, Crain C. Bias in a neuropsy- Henninger D, Morgello S, for the Manhattan HIV chological test classi fi cation related to education, Brain Bank. Characterization and sociocultural pre- age, and ethnicity. J Consult Clin Psychol. dictors of neuropsychological test performance in 1982;50:143Ð5. doi:10.1037/0022-006X.50.1.143 . HIV+ Hispanic individuals. Cultur Divers Ethnic 46. Diehr MC, Cherner M, Wolfson TJ, Miller SW, Minor Psychol. 2008;14(4):315Ð25. Grant I, Heaton RK. The 50 and 100-item short 60. Manly JJ, Jacobs DM, Sano M, Bell K, Merchant forms of the Paced Auditory Serial Addition Task CA, Small SA, Stern Y. African American acculturation (PASAT): demographically corrected norms and and neuropsychological test performance among comparisons with the full PASAT in normal and nondemented community elders. J Int Neuropsychol clinical samples. J Clin Exp Neuropsychol. 2003; Soc. 1998;4:77. 25:571Ð85. 61. Harris JG, Tulsky DS, Schultheis MT. Assessment 47. Taylor MJ, Heaton RK. Sensitivity and speci fi city of of the non-native English speaker: assimilating his- WAIS-III/WMS-III demographically corrected fac- tory and research fi ndings to guide clinical practice. tor scores in neuropsychological assessment. J Int In: Tulsky DS, Saklofske DH, Chelune GJ, Heaton Neuropsychol Soc. 2001;7:867Ð74. RK, Ivnik RJ, Bornstein R, Pri fi tera A, Ledbetter M, 48. Klusman LE, Moulton JM, Hornbostel LK, Picano editors. Clinical interpretation of the WAIS-III and JJ, Beattie MT. Neuropsychological abnormalities in WMS-III. San Diego: Academic; 2003. p. 343Ð87. asymptomatic HIV seropositive military personnel. 62. Kennepohl K, Douglas S, Nabors N, Hanks R. J Neuropsychiatry Clin Neurosci. 1992;3:422Ð8. African American acculturation and neuropsycho- 49. Manly JJ, Jacobs DM, Sano M, Bell K, Merchant logical test performance following traumatic brain CA, Small SA, et al. Cross-cultural comparison of injury. J Int Neuropsychol Soc. 2004;10:566Ð77. neuropsychological test performance and diagnosis 63. Bialystok E, Craik FIM. Bilingualism and naming: of dementia. Neurology. 1998;50:91. implications for cognitive assessment. J Int 50. Norman MA, Evans JD, Miller WS, Heaton RK. Neuropsychol Soc. 2007;13:209Ð11. Demographically corrected norms for the california 64. Bialystok E, Craik FIM, Freedman M. Bilingualism verbal learning test. J Clin Exp Neuropsychol. as a protection against the onset of symptoms of 2000;22:80Ð94. dementia. Neuropsychologia. 2007;45:459Ð64. 3 Considerations for the Neuropsychological Evaluation of Older Ethnic Minority Populations 39

65. Bialystok E, Craik FIM, Ruocco AC. Dual-modality and culturally diverse populations. Am Psychol. monitoring in a classi fi cation task: the effects of 1993;48:45Ð8. bilingualism and ageing. Q J Exp Psychol. 2006;26: 80. Brickman AM, Cabo R, Manly JJ. Ethical issues in 1968Ð83. cross-cultural neuropsychology. Appl Neuropsychol. 66. Gollan T, Montoya R, Cera C, Sandoval T. More use 2006;13(2):91Ð100. almost always means a smaller frequency effect: 81. Llorente AM. Principles of neuropsychological aging, bilingualism, and the weaker links hypothesis. assessment with Hispanics: theoretical foundations J Mem Lang. 2008;58:787Ð814. and clinical practice. New York: Springer; 2007. 67. Steele CM, Aronson J. Stereotype threat and the 82. Shiraev E, Levy DA. Cross-cultural psychology: intellectual test performance of African Americans. critical thinking and contemporary applications. 4th J Pers Soc Psychol. 1995;69:797Ð811. ed. Boston: Allyn & Bacon; 2010. 68. Helms JE. Why is there no study of cultural equiva- 83. Sue DW, Sue D. Counseling the culturally different: lence in standardized cognitive ability testing? Am theory and practice. New York: Wiley; 1990. Psychol. 1992;47:1083Ð101. 84. Schnall E. Multicultural counseling and the Orthodox 69. Teresi JA, Holmes D, Ramírez M. Performance of Jew. J Counsel Dev. 2006;84:276Ð82. cognitive tests among different racial/ethnic and 85. Jackson Y. Encyclopedia of multicultural psychol- education groups: fi ndings of differential item func- ogy. Thousand Oaks: Sage; 2006. tioning and possible item bias. J Ment Health Aging. 86. Weiss M. Explanatory model interview catalogue 2001;7(1):79Ð89. (EMIC): framework for comparative study of illness. 70. American Psychological Association. Ethical prin- Transcult Psychiatry. 1997;34:235Ð63. ciples of psychologists and code of conduct. Am 87. Lewis-Fernandez R, Das AK, Alfonso C, Weissman Psychol. 2002;57:1060Ð73. MM, Olfson M. Depression in US Hispanics: diag- 71. American Psychological Association. Guidelines for nostic and management considerations in family multicultural education, training, research, practice, practice. J Am Board Fam Pract. 2005;18:282Ð96. and organizational change for psychologists. Am 88. Gotlib IH, Hammen CL. Handbook of depression. Psychol. 2003;58:377Ð402. New York: Guilford; 2002. 72. Sue DW. Multidimensional facets of cultural compe- 89. Dotson VM, Kitner-Triolo M, Evans MK, Zonderman tence. Counsel Psychol. 2001;29:790Ð821. AB. Literacy-based normative data for low socio- 73. Sue DW, Arredondo P, McDavis RJ. Multicultural economic status African American. Clin competencies/standards: a pressing need. J Counsel Neuropsychol. 2008;22:989Ð1017. Dev. l992;70:477Ð86. 90. Pontón M. Research and assessment issues with 74. Sue DW, Carter RT, Casas JM, Fouad NA, Ivey AE, Hispanic populations. In: Pontón M, León-Carrión J, Jensen M, LaFromboise T, Manese JE, Ponterotto editors. Neuropsychology and the Hispanic patient: a JG, Vasquez-Nuttall E. Multicultural counseling clinical handbook. Mahwah: Erlbaum; 2001. p. 39Ð58. competencies: individual and organizational devel- 91. Potter GG, Plassman BL, Burke JR, Kabeto MU, opment. Thousand Oaks: Sage; 1998. Langa KM, Llewellyn DJ, Rogers MA, Steffens DC. 75. Wong TM, Strickland TL, Fletcher-Janzen E, Ardila Cognitive performance and informant reports in the A, Reynolds CR. Theoretical and practical issues in diagnosis of cognitive impairment and dementia in the neuropsychological assessment and treatment of African Americans and whites. Alzheimers Dement. culturally dissimilar patients. In: Fletcher-Janzen E, 2009;5(6):445Ð53. Strickland TL, Reynolds CR, editors. The handbook 92. O’Bryant S. Exploring the relationship between of cross cultural neuropsychology. New York: culture and cognition. J Clin Exp Neuropsychol. Kluwer-Plenum; 2000. p. 3Ð18. 2008;30(8):967Ð70. 76. Artiola i Fortuny L, Mullaney HA. Assessing patients 93. Millet PE, Sullivan BF, Schwebel AI, Myers LJ. whose language you do not know: can the absurd be Black Americans’ and White Americans’ views of ethical? Clin Neuropsychol. 1998;12:113Ð26. the etiology and treatment of mental health prob- 77. Artiola i Fortuny L, Garolera M, Hermosillo Romo lems. Community Ment Health J. 1996;32:235Ð42. D, Feldman E, Fernandez Barillas H, Keefe R, 94. Poreh A. Neuropsychological and psychological et al. Research with Spanish-speaking populations issues associated with cross-cultural and minority in the United States: lost in translation a commen- assessment. In: Ferraro RF, editor. Minority and cross- tary and a plea. J Clin Exp Neuropsychol. 2005; cultural aspects of neuropsychological assessment. 27:555Ð64. Studies on neuropsychology, development, and cog- 78. Judd T, Capetillo D, Carrión-Baralt J, Mármol LM, nition. Bristol: Swets & Zeitlinger; 2002. p. 329Ð43. San Miguel-Montes L, Navarrete MG, Silver CH. 95. Echemendia RJ, Julian L. Neuropsychological Professional considerations for improving the neu- assessment of Latino children. In: Ferraro FR, editor. ropsychological evaluation of hispanics: A National Minority and cross-cultural aspects of neuropsycho- Academy of Neuropsychology education paper. Arch logical assessment. Lisse: Swets & Zeitlinger; 2002. Clin Neuropsychol. 2009;24(2):127Ð35. p. 182Ð203. 79. American Psychological Association. Guidelines for 96. Perez-Arce P. The in fl uence of culture on cognition. providers of psychological services to ethnic, linguistic, Arch Clin Neuropsychol. 1999;14(7):581Ð92. 40 M.R. Mindt et al.

97. Storey JE, Rowand JTJ, Conforti DA, Dickson HG. 110. Mungas D, Reed BR, Haan MN, Gonzalez H. The rowland universal dementia assessment scale Spanish and English neuropsychological assessment (RUDAS): a multicultural cognitive assessment scales: relationship to demographics, language, cog- scale. Int Psychogeriatr. 2004;16:13Ð31. nition, and independent functioning. Neuropsy- 98. Wolfe N. Cross-cultural neuropsychology of aging chology. 2005;19:466Ð75. and dementia: an update. In: Ferraro FR, editor. 111. Tuokko H, Chou P, Bowden S, Simard M, Ska B, Minority and cross-cultural aspects of neuropsycho- Crossley M. Partial measurement equivalence of logical assessment. Bristol: Swets & Zeitlinger; French and English versions of the canadian study of 2002. p. 285Ð97. health and aging neuropsychology battery. J Int 99. Teng LE, Hasegawa K, Homma A, Imai Y, Larson E, Neuropsychol Soc. 2009;15:416Ð25. Graves A, Sugimoto K, Yamaguchi T, Sasaki H, 112. Mungas D, Reed BR, Crane PK, Haan MN, González Chiu D, White LR. The cognitive abilities screening H. Spanish and English neuropsychological assess- instrument (CASI): a practical test for cross-cultural ment scales (SENAS): further development and psy- epidemiological studies of dementia. Int chometric characteristics. Psychol Assess. 2004;16: J Psychogeriatr. 1994;6:45Ð58. 347Ð59. 100. Glosser G, Wolfe N, Albert ML, Lavine L, Steele JC, 113. Bowden SC, Cook MJ, Bardenhagen FJ, Shores EA, Calne DB, Schoenberg BS. Cross-cultural cognitive Carstairs JR. Measurement invariance of core cogni- examination: validation of a dementia screening tive abilities in heterogeneous neurological and instrument for neuroepidemiological research. J Am community samples. Intelligence. 2004;33:363Ð89. Geriatr Soc. 1993;41(9):931Ð9. 114. Hsieh J, Tori C. Normative data on cross-cultural 101. Taussig IM, Dick M, Teng E, Kempler D. The taus- neuropsychological tests obtained from Mandarin- sig cross-cultural memory test. Los Angeles: speaking adults across the life span. Arch Clin Available from Andrus Gerontology Center, Neuropsychol. 2007;22:283Ð307. University of Southern California; 1993. 115. Kang YW, Kim JK. Korean-California verbal learn- 102. Fuh J, Teng E, Lin K, Larson E, Wang S, Liu C, ing test (K-CVLT):a normative study. Kor J Clin Chou P, Kuo BI, Liu H. The informant questionnaire Psychol. 1997;16:379Ð96. on cognitive decline in the elderly (IQCODE) as a 116. Manly JJ, Schupf N, Tang MX, Stern Y. Cognitive screening tool for dementia for a predominantly illit- decline and literacy among ethnically diverse elders. erate Chinese population. Neurology. 1995; J Geriatr Psychiatry Neurol. 2005;18(4):213Ð7. 45(1):92Ð6. 117. Nell V. Cross-cultural neuropsychological assess- 103. Heaton RK, Miller SW, Taylor MJ, Grant I. Revised ment: theory and practice. Mahwah: Erlbaum; comprehensive norms for an expanded Halstead- 2000. Reitan Battery: demographically adjusted neuropsy- 118. Taussig M, Pontón MO. Issues in neuropsycho- chological norms for African American and logical assessment of hispanic older adults: cul- Caucasian adults. Odessa: Psychological Assessment tural and linguistic factors. In: Yeo G, Resources, Inc.; 2004. Gallagher-Thompson D, editors. Ethnicity and the 104. Weiss LG, Saklofske DH, Coalson D, Raiford SE. dementias. San Francisco: Taylor & Francis; 1996. WAIS-IV clinical use and interpretation scientist- p. 47Ð58. practitioner perspectives. London: Academic; 119. Cuellar I, Arnold B, Maldonado R. Acculturation 2010. rating scale for Mexican Americans-II: a revision of 105. Kempler D, Teng EL, Dick M, Taussig IM, Davis DS. the original ARSMA scale. Hispanic J Behav Sci. The effects of age, education, and ethnicity on verbal 1995;17:275Ð304. ﬂ uency. J Int Neuropsychol Soc. 1998;4:531Ð8. 120. Marin G, Gamba RJ. A new measurement of accul- 106. Ostrosky-Solís F, Gomez-Perez M, Matute E, turation for Hispanics: the bidimensional accultura- Rosselli M, Ardila A, Pineda D. Neuropsi attention tion scale for hispanics (BAS). Hispanic J Behav Sci. and memory: a neuropsychological test battery in 1996;18:297Ð316. Spanish with norms by age and education level. Appl 121. Marin G, Sabogal F, Marin BV, Otero-Sabogal R, Neuropsychol. 2007;14:156Ð70. Perez-Stable EJ. Development of a short accultura- 107. Muñoz-Sandoval AF, Woodcock RW, McGrew KS, tion scale for Hispanics. Hispanic J Behav Sci. Mather N. Batería III Woodcock-Muñoz. Itasca: 1987;9:183Ð205. Riverside Publishing; 2005. 122. Zea MC, Asner-Self KK, Birman D, Buki LP. The 108. Woodcock RW, Munoz-Sandoval AF, Ruef ML, abbreviated multidimensional acculturation scale: Alvarado CG. Woodcock-munoz language survey- empirical validation with two Latino/Latina samples. revised. Itasca: Riverside Publishing; 2005. Cultur Divers Ethnic Minor Psychol. 2003;9(2): 109. Pontón MO, Satz P, Herrera L, Ortiz F, Urrutia CP, 107Ð26. Young R, D’Elia LF, Furst CJ, Namerow N. 123. Berry J. Conceptual approaches to acculturation. Normative data strati ﬁ ed by age and education for In: Chun KM, Organista PB, Marin G, editors. the neuropsychological screening battery for latinos Acculturation: advances in theory, measurement, (NeSBHIS): initial report. J Int Neuropsychol Soc. and applied research. Washington: American 1996;2:96Ð104. Psychological Association; 2003. p. 83Ð93. 3 Considerations for the Neuropsychological Evaluation of Older Ethnic Minority Populations 41

124. Choi J, Madhavappallil T. Predictive factors of 132. Bialystok E, Klein R, Craik FIM, Viswanathan M. acculturation attitudes and social support among Bilingualism, aging, and cognitive control: evidence Asian immigrants in the USA. Int J Soc Welfare. from the simon task. Psychol Aging. 2004;19:290Ð303. 2009;18:76Ð84. 133. Milberg WP, Hebben N, Kaplan E. The boston 125. Boone K, Victor T, Wen J, Razani J, Ponton M. The process approach to neuropsychological assess- association between neuropsychological scores and ment. In: Grant I, Adams K, editors. Neuro- ethnicity, language, and acculturation variables in a psychological assessment of neuropsychiatric large patient population. Arch Clin Neuropsychol. disorders. 2nd ed. New York: Oxford University 2007;22(3):355Ð65. Press; 1996. p. 58Ð80. 126. Razani J, Burciaga J, Madore M, Wong J. Effects of 134. White R, Rose F. The boston process approach: a acculturation on tests of attention and information brief history and current practice. In: Goldstein G, processing in an ethnically diverse group. Arch Clin Incagnoli TM, editors. Contemporary approaches to Neuropsychol. 2007;22:333Ð41. neuropsychological assessment: critical issues in 127. Coffey DM, Marmol L, Schock L, Adams W. The neuropsychology. New York: Plenum; 1997. p. effects of acculturation on the wisconsin card sorting 171Ð211. test by Mexican Americans. Arch Clin Neuropsychol. 135. Manly JJ, Echemendia R. Race-speci fi c norms: 2005;20(6):795Ð803. using the model of hypertension to understand issues 128. Nicoladis E, Giovanni S. The role of a child’s pro- of race, culture, and education in neuropsychology. ductive vocabulary in the language choice of a bilin- Arch Clin Neuropsychol. 2007;22(3):319Ð25. gual family. First Lang. 2000;20:3Ð28. 136. Ardila A, Rodriguez-Menendez G, Rosselli M. 129. Martin-Rhee M, Bialystok E. The development of Current issues in neuropsychological assessment two types of inhibitory control in monolingual with Hispanics/Latinos. In: Ferraro FR, editor. and bilingual children. Biling Lang Cognit. 2008; Minority and cross-cultural aspects of neuropsycho- 11(1):81Ð93. logical assessment. Lisse: Swets & Zeitlinger; 2002. 130. Gollan TH, Montoya RI, Werner G. Semantic and p. 161Ð79. letter fl uency in SpanishÐEnglish bilinguals. 137. Gass C, Brown M. Neuropsychological test feed- Neuropsychology. 2002;16:562Ð76. back to patients with brain dysfunction. Psychol 131. Rosselli M, Ardila A, Araujo K, Weekes VA, Assess. 1992;4(3):272Ð7. Caracciolo V, Padilla M, Ostrosky-Solis F. Verbal 138. Post and Armstrong (in preparation). Feedback that fl uency and repetition skills in healthy older sticks: the art of effectively communicating neurop- SpanishÐEnglish bilinguals. Appl Neuropsychol. sychological assessment results. New York, NY: 2000;7:17Ð24. Oxford University. The Assessment of Change: Serial Assessments in Dementia 4 Evaluations

Gordon J. Chelune and Kevin Duff

Abstract The focus of the clinical neuropsychologist in everyday practice is on neurocognitive change. Because the diagnosis of dementia as well as mild cognitive impairment requires evidence of cognitive decline over time, the assessment of meaningful neurocognitive change is especially relevant in the evaluation of older adults. We brie ﬂ y discuss the clinical use of norm- referenced tests used in traditional single-point assessments and then focus on the use of serial assessments to objectively monitor and assess cognitive changes over time, discussing the unique advantages and challenges of serial assessments. An overview and distillation of reliable change methods are presented and applied to a case example, demonstrating how these methods can be used as effective tools to inform the clinical evaluation of the individual patient. In the end, we hope to leave the reader with an appreciation that change is a unique variable with its own inherent statistical properties and clinical meaning.

Keywords Predicting reliable change • Practice effects • Dementia and cognitive decline • Serial assessment

The Assessment of Change: Serial Assessments in Dementia Evaluations

G. J. Chelune , Ph.D., ABPP(CN) • K. Duff, Ph.D., ABPP(CN) () As a multidisciplinary area of scientiﬁ c inquiry, Department of Neurology , Center for Alzheimer’s Care, neuropsychology is often deﬁ ned as the study of Imaging and Research, University of Utah School brain–behavior relationships. However, as an area of Medicine , 650 Komas Drive, Ste. 106a , of psychological practice, clinical neuropsychology Salt Lake City , UT 84108 , USA e-mail: [email protected]; has been described as the application of neu- [email protected] ropsychological principles of brain–behavior

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 43 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_4, © Springer Science+Business Media, LLC 2013 44 G.J. Chelune and K. Duff relationships to the assessment, diagnosis, and tests, contrasting two underlying approaches to rehabilitation of changes in human behavior that interpreting these norms in traditional single-point arise across the lifespan from known or suspected assessments. With this as a backdrop, we will then illnesses or injuries affecting the brain [ 1 ] . To this turn our attention to the use of serial assessments de fi nition, we can also add the assessment of cog- to objectively monitor and assess cognitive changes nitive changes associated with medical interven- over time, discussing the unique advantages and tions (e.g., open heart surgery, epilepsy surgery) challenges of serial assessments. An overview and and treatments (e.g., deep brain stimulation, phar- distillation of reliable change methods will be macologic treatments). Whether the focus is on presented and applied to a case example, demon- changes in cognition induced by abnormal medi- strating how these methods can be used as effec- cal conditions or those in response to treatments tive tools to inform the clinical evaluation of the and interventions, the focus of the clinical neurop- individual patient. In the end, we hope to leave sychologist in everyday practice is on change . the reader with an appreciation that change is a The assessment of meaningful neurocognitive unique variable with its own inherent statistical change is particularly relevant for the evaluation properties and clinical meaning. of older adults suspected of having underlying neurodegenerative disorders. Because the diagnosis of dementia as well as mild cognitive impair- Norms and How We Use Them ment (MCI) requires evidence of cognitive decline in Single-Point Assessments over time [2 ] , it is critical to distinguish between age-related decrements in cognition (e.g., memory, In clinical practice, when we see a patient for the processing speed, executive functions) believed fi rst time, we use norm-referenced tests so that we to be part of “normal” aging [ 3– 5] and those can compare the performances of the individual early clinical changes that are pathological and patient to an external reference group. The norms disease-related (e.g., neurodegenerative disorders, simply describe the distribution of scores on a cerebrovascular disease, stroke, diabetes, etc.). given test obtained by a reference group, which Traditional single-point evaluations are limited in can be a sample from the general population, a this context as they only capture a picture of the well-screened group of healthy community-living patient’s current abilities at a single point in time. individuals (i.e., robust norms), or a patient group Unless the patient’s performances deviate mark- with a speci fi c condition of interest. To infer mean- edly from an inferred premorbid baseline, it is ing from our patient’s scores, we can take two very diffi cult for the practitioner to know whether these distinct approaches to answer different clinical point estimates of a patient’s abilities are meaning- questions [6 ] . The fi rst approach is descriptive , that fully different from expectation [6 ] . To overcome is, where does my patient’s score fall with respect the limitations of single-point assessments, clini- to the reference population along a standardized cians increasingly are turning to serial assessments metric (e.g., standard scores, z -scores, percentile to determine whether patients’ observed trajecto- ranks)? We often apply descriptive labels such as ries of change over time signifi cantly deviate from “above average” or “below average” for ranges of those seen in normal aging [7, 8 ] . Unlike single- scores in relation to the mean of the sample, and point assessments where the clinician must infer a using standardized measures of the distribution premorbid baseline, the patient’s initial scores of scores, we can assign percentile ranks that tell serve as their observed baseline. Armed with an us how common or uncommon the speci fi c score appropriate conceptual framework and some sim- is within the reference population. ple tools, serial assessments provide the informed While the descriptive approach is useful in practitioner a powerful means for assessing diag- identifying where our patient’s scores fall within a nostically meaningful change. reference population, it does not address whether In this chapter, we will briefl y discuss the clini- our patient’s scores are impaired or not. To do cal use of norm-referenced neuropsychological this, we must take a diagnostic approach where 4 The Assessment of Change: Serial Assessments in Dementia Evaluations 45 we ask the question “does my patient’s score absence of an intervening illness or injury. deviate from premorbid expectations (i.e., where However, after carefully reading the chapter on I expect the score to have been in the absence of validity in the test manual for MegaMemory, an intervening illness or injury), and if so, by how Dr. Bob fi nds that the publisher conducted a case- much?” The reference standard is now the indi- controlled study using MegaMemory that com- vidual’s premorbid status, not the mean of the pared equal numbers of patients with amnesic reference population. In the absence of having MCI and normal controls, a prevalence rate simi- baseline information, the clinician must infer this lar to what Dr. Bob sees in his clinic. The manual and often relies on demographic information [9 ] reports that individual deviations of one standard and performance on crystallized ability measures deviation or more from estimated premorbid such as oral reading derived from normative levels occurred in 64% of cases with amnesic reference groups (e.g., the Test of Premorbid MCI compared to only 16% of controls. Performing Functioning [10 ] ). Deviations from this individual a Bayesian analysis of the base rates between the comparison standard can also be placed on a two groups [ 11 ] yielded an odds ratio of 9.3 and standardized metric (e.g., T-scores, z -scores), and a likelihood ratio of 4.0. Based on this empirical percentile ranks assigned to the deviations if we evidence, Dr. Bob now feels he can interpret a know the characteristics of the distribution of the deviation score of one standard deviation or more deviation scores between the premorbid estimate on MegaMemory as not only relatively uncom- and observed performance on a given test. Note mon among healthy older adults but also as being that the focus is on the distribution of the deviation “impaired” since deviations of this magnitude are scores, not the distribution of either the premorbid four times more likely to occur in patients with estimates or the observed scores on a given test. amnesic MCI than in healthy controls, and among While the diagnostic approach allows us to patients with amnesic MCI, deviations of this quantify whether an individual’s current perfor- magnitude are nine times more likely to occur mance deviates from estimates of his or her than deviations of lesser magnitude. demographically predicted premorbid ability level, we are still constrained to describing the deviation in terms of base rates—how common Using Serial Assessments or uncommon the deviation is for our patient rel- to Identify Meaningful Change ative to premorbid expectations. To be diagnostically useful, the clinician must further establish Although neuropsychological tests are gener- validity evidence, through a review of the test ally designed to assess the current state or capac- manual, his or her personal case records, or per- ity of an individual, repeated assessments are haps through an evidence-based review of the increasingly common in neuropsychological literature [11 ] , that discrepancies of a certain practice and outcomes research [ 12, 13 ] . This magnitude are statistically more frequent in pop- has become especially true in geriatric settings ulations that have a speci fi c condition of interest, where the determination of meaningful changes such as amnesic MCI, than would be expected at in cognition over time is essential for both the this level of discrepancy in a normal population. diagnosis of dementia and for planning thera- To illustrate the points above, let us consider peutic provisions and long-term care for patients the example of super clinician, Dr. Bob, who and caregivers [ 6, 14 ] . Serial observations and works in a memory disorders clinic and uses the longitudinal comparisons are classic tools in test MegaMemory to evaluate memory com- science, and their use in clinical practice requires plaints. Knowing that a patient’s memory score clinicians to understand test–retest change on MegaMemory is one standard deviation below scores as unique cognitive variables with their the estimated premorbid level informs Dr. Bob own statistical and clinical properties that are that the base rate of deviations of this magnitude different from the test measures from which occurs in only 16% of cases where there is an they were derived [ 15 ] . 46 G.J. Chelune and K. Duff

Like single-point diagnostic assessments dis- Error. In addition to systematic biases, tests cussed above, serial assessments share (a) a focus themselves are imperfect tools and can introduce on change between two points in time (albeit one an element of random error. For our purposes observed and the other inferred); (b) estimates of here, we will only consider two sources of error change based on individual comparison standards affecting serial assessment, both of which are rather than population standards; (c) a focus on the inversely related to the test’s reliability. The fi rst psychometric properties of the discrepancy or is measurement error or the fi delity of the test, change scores rather than on the test scores them- and it refers to the theoretical distribution of selves (i.e., the properties of the distribution of random variations in observed test scores around change scores); (d) use of base-rate information to an individual’s true score, which is characterized determine whether a change or discrepancy score by the standard error of measurement (SEM ). is common or uncommon; and (e) impairment Because the SEM is inversely related to a test’s inferred on the basis of validity studies that dem- reliability, tests with low reliability (<0.70) have onstrate that large and relatively rare change scores large SEM s surrounding a person’s true score at are statistically more common in patient groups both baseline and on retest, and large test–retest with a known condition of interest than would be differences can occur simply as random expected among the reference population. fl uctuations in measurement. Conversely, small Although serial assessments share much in test–retest changes can be reliable and clinically common with single-point assessments, they also meaningful for tests with high reliability (>0.90). pose unique interpretative challenges because Test–retest reliabilities of 0.70 or greater are two or more sets of scores are involved. Under often considered to be the minimum acceptable ideal test–retest conditions, a patient’s retest per- standard for psychological tests in outcome stud- formance should be the same as that observed at ies [20 ] , and practitioners should be wary when baseline, and any change or deviation from base- interpreting cognitive change scores on tests that line would be clinically relevant. However, in the have lower reliabilities. absence of perfect test stability and reliability, The second source of error affecting change the clinician must deal with the residuals of these scores is regression to the mean, which refers to statistical properties, namely bias and error. the susceptibility of retest scores to regress toward the mean of the scores at baseline. The more a Bias . Bias represents a systematic change in per- score deviates from the population mean at base- formance. The most important source of system- line, the more likely it will regress back toward atic bias in clinical practice is the variable of the mean on retest. How much a score regresses interest, that is, the effect of disease progression depends on the reliability of the test. Again, over time, the impact of a surgical or pharmaco- scores on tests with high reliability show less logical intervention, or the effect of rehabilita- susceptibility to regression to the mean than those tion. However, second only to the variable of on tests with lower reliability. The bottom line for interest, the most common source of bias in serial clinicians when planning to perform serial assess- cognitive assessment is a positive practice effect ments and faced with two tests purported to assess in which performance is enhanced by previous the same cognitive construct—choose the one test exposure, although negative biases can also with the better reliability! occur such as those seen in aging [ 16 ] . Other forms of systematic bias on retest performance Alternate forms . Alternate forms are often touted as are education, gender, baseline level of perfor- an effective means for avoiding or minimizing mance, and retest interval [ 17– 19 ] . Where large, practice effects due to test familiarity. Carefully positive practice effects are expected, the absence constructed alternative forms may attenuate the of change may actually re fl ect a decrement in effects of content-speci fi c practice for some mea- performance. To make accurate diagnoses, the sures [21 ] . However, research demonstrates that clinician must separate the effects of the variable alternate forms used in serial assessments still show of interest from other sources of bias. signi fi cant practice effects [22 ] . While alternate 4 The Assessment of Change: Serial Assessments in Dementia Evaluations 47 forms may dampen practice effects due to content prede fi ned probability level (e.g., p < 0.05). familiarity, they do not control for procedural learn- However, the base rates of such differences at the ing and other factors that contribute to the overall level of the individual may actually occur with practice effect. More importantly, rote use of alter- some regularity even when no real behavioral nate forms in serial assessment ignores other fac- difference. For this reason, Matarazzo and tors that impact interpretation of test–retest change Herman have urged clinicians to routinely con- scores, namely reliability and error [15 ] . sider base-rate data in their clinical interpretation of test–retest evaluations [25 ] .

Reliable Change in Serial Assessments with Older Adults Reliable Change: The Basic Model

It should be clear that the interpretation of test– Reliable change methods all fundamentally strive retest change scores is not a straightforward to evaluate the base rates of difference scores in a matter, and making accurate diagnostic judgments population and to determine whether the differ- about whether an older adult has shown signifi cant ence between scores for an individual is statisti- deterioration (or improvement) in cognitive sta- cally rare and cannot be accounted for by various tus over a retest interval requires us to consider sources of bias (e.g., practice) or error (e.g., mea- the role of bias and error in our measurements. surement error and regression to the mean). Like Bias and error are problems only to the degree a ruler or yardstick that measures change from that they are unknowns and not taken into account point A to point B along a standard metric (inches/ when interpreting change scores. In this section, yards), the basic form for any reliable change we will discuss reliable change methods , a fam- method is a ratio: reliable change (RC) = (change ily of related statistical procedures that attempt to score)/( standard error), where the standard error take into account the impact of differential prac- describes the dispersion of change scores that tice effects and other systematic biases, measure- would be expected if no actual change had ment error, and regression to the mean on the occurred [26 ] . This is simply the distribution of interpretation of change scores. We do not intend test–retest scores one would see in a reference to do a comprehensive or in-depth review of these population. RC is typically expressed as a stan- procedures, and the interested reader is directed dardized z -score under the unit curve that has a to other sources for more complete coverage mean of 0 and a standard deviation of 1.0. The [13, 15, 18, 19, 23, 24] . Rather, we wish to distill base rate of a given RC value being equal to the the essential features of reliable change methods percentile associated with the z -score, for exam- and demonstrate how these tools can be used ple, a z -score or RC of −1.64, falls at the bottom diagnostically to evaluate meaningful cognitive fi fth percentile. The various reliable change meth- change in older adults. ods reported in the literature primarily vary along two dimensions: whether the change score in the numerator is a simple-difference or a predicted- Reliable Change: A Statistical Approach difference score and whether the standard error in to Meaningful Change the denominator represents a measure of dispersion (observed or estimated) around the mean of To understand the concept of reliable change, we difference scores or around a regression line. need to distinguish between what is statistically signifi cant at a group level and what is clinically Simple versus predicted-difference change scores . meaningful at the individual level. Repeated mea- For the change score component of the RC ratio, sures tests of statistical signifi cance tell us when we do follow-up evaluations on a patient, whether the mean difference between two groups we generally look at the retest scores and com- of a given magnitude is a reliable difference that pare them with the baseline score (retest − base- would not be expected to occur by chance at some line) to see if the difference is positive or negative. 48 G.J. Chelune and K. Duff

This is the simple-difference approach. When no bias as predictors, such as age, education, gender, difference is expected over the retest interval and retest interval. In the example above of the (perfect stability), the simple-difference change 68-year-old male patient suspected of dementia, a score re fl ects the patient’s individual deviation regression-based equation using baseline WMS-III from a population mean difference score of 0 or Immediate Memory Index scores and age was no expected change. However, as we have noted computed for the WMS-III test–retest standard- earlier, there are many sources of bias affecting ization sample [ 15 ] . Given a baseline score of 97 retest scores, with practice often exerting a strong for a 68-year-old normal individual, the predicted positive bias. As a result, the actual population retest score would be 108.8. Our patient’s predicted mean of the test–retest change scores is positive change score deviation is −8.8 points (observed and has led to the development of a practice- retest score of 100 minus the predicted test score of adjusted simple-difference approach [ 27 ] . For 108.8). The reader will note that the −8.8-point pre- example, the mean retest performance on the dicted change score discrepancy is smaller than the Wechsler Memory Scale-III (WMS-III) −10.4-point simple-difference change score . The Immediate Memory Index is 13.4 points higher reason for this is that the regression-based predicted than at baseline when readministered several change score modeled not only practice effects (a weeks later [28 ] . If our 68-year-old male patient positive bias) but also age (a negative bias), which that we are following for suspected dementia has dampened the expected practice effect, resulting a baseline score of 97 and a retest score of 100, in a smaller (although perhaps more accurate) has he actually shown an improvement of 3 points expected retest score. when the average retest change score is 13.4 or a decrement of −10.4 points (13.4 − 3 = −10.4) from Measures of dispersion for the simple-difference expected change? To adjust for expected practice method. Once the individual’s change score dis- effects, Chelune and colleagues have suggested crepancy has been computed, we have a measure centering the change score component of the RC of change but do not know whether the change is deviations around the mean of the expected prac- large or small without having a standard metric to tice effect and calculating the change score dis- evaluate the dispersion of change scores that crepancy from this mean [27 ] . would occur in the absence of real change (i.e., The second approach to calculating the change changes simply due to error). This is refl ected in score component of the RC ratio is the predicted- the denominator of the RC ratio, and the choice difference method. This is a regression-based of the measure of dispersion has been the subject approach that uses a patient’s baseline performance of much debate and re fi nement in the reliable to predict what his/or her retest score is expected to change literature [13, 15, 19, 23, 24, 30 ] . The be at retest, with the regression equation being one simplest version of the standard error component derived from an appropriate reference sample. The of the RC ratio is simply the standard deviation discrepancy between the patient’s actual observed of the observed change score discrepancies. In retest score and the predicted retest score (Y − Y ¢ ) our dementia case example with the WMS-III, constitutes the change score discrepancy. Entering the mean test–retest change score obtained from the baseline score as a predictor of the retest score the WAIS-III/WMS-III Technical Manual is 13.4 into the regression equation allows practice effects [28 ] . However, like many test manuals and nor- to be modeled as a function of baseline perfor- mative studies that report the means and standard mance (rather than as a constant) while also deviations of the test and retest scores, the stan- accounting for regression to the mean [29 ] , two dard deviation of difference (change) scores was aspects not accounted for by the simple-difference not reported. With permission from the test pub- approach. As in any regression approach, the equa- lisher, Chelune calculated the actual standard tion can be univariate, using only the baseline score deviation of change scores for the WMS-III as the sole predictor, or multivariate, using addi- Immediate Memory Index from the retest sample tional information from other potential sources of and found it to be 10.2 [15 ] . With this measure of 4 The Assessment of Change: Serial Assessments in Dementia Evaluations 49 dispersion, we can calculate the RC magnitude of the standardized beta coeffi cient [ 15 ] . In our our patient’s change score by dividing the observed WMS-III example, the standard error of predic- practice-adjusted simple-difference score (−10.4) tion for the Immediate Memory Index is 10.1, by the standard deviation of differences (10.2) very close to the observed standard deviation of and obtain an RC z -score of −1.02. A z -score of actual change scores, namely 10.2. this magnitude would be expected to occur in only about 15% of cases when no real change has Standardized regression-based (SRB ) approach . occurred. Is this suffi ciently rare to classify our As noted in our discussion of the simple versus patient’s change score as meaningful? Most stud- predicted methods of calculating the change ies of reliable change invoke a 90% RC confi dence score discrepancy in the RC ratio, the predicted- interval ( z -score ± 1.64), in which only 5% of difference method generates predicted retest cases would be above or below this level of scores (Y ¢ ) for individuals based on their speci fi c change. For our patient’s change score to reach baseline performances (X ) using linear regression this level of decline, he would have needed a and then subtracts this from their observed retest retest score between 93 and 94. It is worth empha- scores (Y ) to obtain their personal change score sizing that a seemingly minor decrement in per- discrepancy (Y − Y ¢ ). Additional sources of poten- formance (e.g., 3–4 standard score points in this tial bias (e.g., age, education, gender) can be case), a change that many clinicians might call added to the regression equation in a multivariate “within the range of the test’s variability,” actu- manner [29 ] . As noted earlier, this approach ally re fl ects a reliable change when corrected for allows practice effects to be modeled as a func- expected practice effects and measurement error. tion of individual baseline performance as well as In the absence of having the actual standard accounting for regression to the mean. This might deviation of difference scores, it is possible to be particularly important as these two variables estimate it in one of several ways. Jacobsen and interact (e.g., the practice effects may be attenu- Truax initially introduced the Reliable Change ated by regression to the mean for someone with Index (RCI) as a means for calculating RC with a high baseline score, whereas practice effects only knowledge of the simple-difference change are enhanced by regression to the mean for an score and the standard error of the difference individual with a low initial baseline score). However, unlike the simple-difference approach scores (S diff ), a measure of dispersion derived from SEM for the test at baseline [ 31 ] . Chelune where the standard error term in the denominator and colleagues later adapted the RCI by adjusting of the RC ratio re fl ects the dispersion of change for the mean practice effect [ 27 ] . In a further scores around the mean of the change scores , refi nement, Iverson suggested a modifi ed RCI the predicted-difference approach typically uses that used the SEM at both baseline and at retest to the standard error of the estimate ( SEE) for the regression equation in the denominator of the calculate the S diff [32 ] . Comparison of the two RC ratio to refl ect the dispersion of scores around versions of the S diff suggests that Iverson’s method produces a closer estimate of the actual disper- the regression line. In our case example with the sion of change scores than that of Jacobsen and WMS-III Immediate Memory Index [ 15 ] , the Truax. In the case of our WMS-III Immediate regression equation for predicting retest scores Memory example, the Iverson method produces a was given as:

Sdiff of 9.9 compared to 8.8 for the Jacobson and Truax method, where the actual standard devia- Y’ = (Baseline score * 1.00) + (Age * -0.097) tion of differences was 10.2. A fi nal common + 18.45, with an SEE of 10.24 estimate of the observed dispersion of change scores is the standard error of prediction , which The fi rst part of this equation gives us an indi- represents the standard error of a retest score vidual’s predicted retest score that can be used to predicted from a baseline score in a regression calculate the change-score discrepancy compo- equation where the test-reliability coef fi cient is nent of the RC ratio, whereas the SEE gives us 50 G.J. Chelune and K. Duff the standard error term for the denominator. Table 4.1 Output from Crawford and Garthwaite’s [ 35 ] The reader will note that the SEE for the regression calculator to build regression equations from sample summary data for a hypothetical patient with test–retest line is the same as the observed standard devia- scores of 97 and 100 on the Wechsler Memory Scale-III tion of the simple-difference change scores . Immediate Memory Index While several authors have noted that the vari- Inputs ous RC methods produce relatively similar results Mean for predictor variable (X ) in sample used to build [ 19, 26 ] , the SRB RC-approach has generally the equation = 100.2 become the preferred method for individual pre- Standard deviation for predictor variable (X ) in diction, provided that the clinician has access to sample = 15.9 prediction equations derived from reference sam- Mean for the criterion variable (Y ) in sample = 113.7 ples appropriate to their patients. While there is a Standard deviation for the criterion variable (Y ) in sample = 19.2 growing body of such SRB equations for a vari- Correlation between predictor and criterion ety of tests commonly used with older adults [8, variable = 0.85 9, 14, 17, 33, 34 ] , and some tests such as the Sample size = 297 fourth edition of the Wechsler Adult Intelligence Individual’s score on the predictor (X ) variable = 97 and Memory Scales are incorporating RC algo- Individual’s obtained score on Y = 100 rithms into their scoring software [ 10 ] , there is Outputs still a paucity of published longitudinal SRB Regression equation built from the summary data: data. Fortunately, as will be seen in the next sec- Y = 10.8532 + (1.0264 * X ) tion, John Crawford and Paul Garthwaite have Standard error of estimate for regression equation = 10.1314 developed a simple but powerful tool for building Analysis of the individual case regression equations from summary data that can Individual’s predicted score from regression be applied to the individual case [35 ] . equation = 110.4155 Discrepancy (obtained minus predicted) between Regression models of reliable change derived individual’s obtained and predicted scores = −10.4155 from summary data. As noted by Crawford and Standardized discrepancy between individual’s obtained Garthwaite [35 ] , not all neuropsychologists are and predicted scores = −1.0262 aware that it is possible to construct regression Signi fi cance test (t ) on the standardized discrepancy between individual’s obtained and predicted scores: equations for predicting an individual’s retest One-tailed probability = 0.1528 performance from their baseline performance Estimated percentage of population obtaining a simply using sample summary data, for which discrepancy more extreme than individual = 15.280799% there is a potential wealth of clinically useful information available in test manuals and the published literature. To build univariate regres- http://www.abdn.ac.uk/~psy086/dept/regbuild. sion equations from summary data alone, one htm. only needs the means and standard deviations for To use this calculator, one only need input the test and retest scores, the size of the sample, and sample summary data and the patient-specifi c the test–retest reliability coeffi cient (or alter- test–retest scores. Using the summary data from nately the t-value from a pair-samples t test). In Chelune [ 15 ] , Table 4.1 illustrates the output gen- their 2007 paper, Crawford and Garthwaite delin- erated for our hypothetical 68-year-old patient eate the statistical steps necessary to build such whose baseline Immediate Memory Index was regression equations, as well as the further steps 97 at baseline and 100 on retest. The output is needed to compute the associated statistics for remarkably similar to that presented in previous drawing inferences concerning the individual sections for our patient example using various case. Recognizing that the computations involved RC methods. Generally, the various approaches are tedious and prone to error, Crawford and would predict our patient to have a retest score Garthwaite also developed a compiled calculator of 109−110 given his baseline score of 97. His that is available for download at no cost from the observed retest score of 100 is 9–10 points below following web address: expectations (RC z -score deviation of about −1.0), 4 The Assessment of Change: Serial Assessments in Dementia Evaluations 51 which would likely occur in only about 15% of a Other investigators have focused on developing sample for which there were no signi fi cant inter- regression models that compare an individual’s vening events affecting cognition. slope of performance across multiple time points Although the Crawford and Garthwaite’s to that of a control sample [39, 40 ] . Still others regression calculator presented here is univariate are using variations of longitudinal linear mixed [35 ] , it has recently been expanded to handle models to estimate age-adjusted mean slopes and multiple predictors, and this executable calcu- confi dence intervals of change to identify indi- lator is also available for download online at: viduals whose performances begin to deviate http://www.abdn.ac.uk/~psy086/dept/RegBuild_ from expectation [ 7, 41 ] . Growth mixture model- MR.htm [36 ] . ing has also been applied to longitudinal data sets to identify subgroups of individuals who show Advanced concepts and models of reliable change . different cognitive trajectories over time [42– 45 ] . The various RC methods we have described so far Clearly, we are on the verge of seeing a new gen- only consider measuring change as a discrete event eration of RC methods to assess reliable change across two points in time. However, there are many in patients’ performances over time. clinical situations where individuals are assessed serially across multiple time points, and change may be better described in terms of trajectories of A Case Example: Application change and intra-individual rates of cognitive of Reliable Change Methods decline. Early attempts to assess reliable change in Clinical Practice across multiple time points either averaged reliability coeffi cients and measures of dispersion The accumulation of pathophysiological changes between the various time points to arrive at com- characteristic of Alzheimer’s disease (AD) is posite indices of RC [ 37 ] or computed separate believed to develop years, if not decades, before RC indices between each pair of time points [ 34 ] . the clinical expression of frank memory loss and Recently, more innovative approaches have been general cognitive decline [46 ] . To maximize the employed to model change as a trajectory or slope effi cacy of emerging disease-modifying thera- across multiple time points. pies and to support continued functional inde- It is beyond the scope of this chapter to do pendence, early detection of Alzheimer’s disease more than alert the reader to some of these inno- (AD) and other neurodegenerative disorders is vative approaches and to provide exemplars. paramount [42, 47 ] . Descriptive clinical states Some investigators are using regression models such as cognitive impairment but not dementia that attempt to predict an individual’s perfor- (CIND) and MCI have been introduced to mance at time point2 + n by entering into regression describe abnormal cognitive states that place formula not only baseline performance but the individuals at increased risk for progressing to practice effects between previous time points. AD [ 48 ] . However, these clinical states describe For example, Duff and associates [ 8 ] developed individuals who are already symptomatic. One multivariate SRB equations for several neuropsy- does not wake up one day with dementia or MCI. chological tests widely used with older adults Rather, cognitive decline, like neurodegenerative that used baseline performance, demographic disease, is a dynamic process that evolves over variables, and short-term practice effects (base- time. Hence, serial neuropsychological evalua- line to 1 week) in predicting retest scores 1 year tions have come to play an important role in later. Attix and colleagues [38 ] developed SRB documenting cognitive decline in geriatric normative neuropsychological trajectories for a settings. variety of test measures administered fi ve times Let us consider a case example of a 63-year- at 6-month intervals by entering in successive old, right-handed man with a Ph.D. Our patient is performances at each time point as predictors of a successful professor of sociology at a major subsequent performance at the next time point. university and a married father of three children. 52 G.J. Chelune and K. Duff

His past medical history is signi fi cant for depres- In the right-hand columns of Table 4.2 , we present sion and some cardiac issues, both currently well the patient’s predicted retest scores given his controlled. He has been stable on his medications baseline performances, the observed–predicted for many years, and they are not thought be an discrepancy (Y − Y ¢ ), and the associated z -scores issue with respect to cognition. Our patient has and population percentiles associated with the noticed insidious and progressive memory predicted-difference discrepancies. From these dif fi culties for about 2 years and presents to our data, we can see that the patient’s memory has Cognitive Disorders Clinic for evaluation. His continued to signifi cantly deteriorate. We also neurologist obtains a Mini Mental State Exam note that his global mental status on the Mattis score of 30/30 but on further bedside testing notes Dementia Rating Scale [ 51 ] and on the WAIS-III some subtle memory diffi culties. The neurologist Verbal Comprehension Index [ 28 ] show signs of decides to refer the patient to us for comprehen- notable deterioration. At this point, we can sive neuropsychological evaluation. We perform confi dently say that the patient’s current test our evaluation and fi nd that the patient has a rela- results re fl ect some further deterioration in his tively circumscribed pattern of memory defi cit capacity to learn and remember new information within the context of otherwise normal fi ndings as well as some increased dif fi culties with verbal (see Baseline Scores in Table 4.2 ). Our impres- intellectual abilities. While he is still likely to sion is that this patient has amnesic MCI. We meet the criteria for MCI rather than dementia, know from the research literature that patients his increased diffi culties with verbal skills are with MCI have an increased risk of showing fur- worrisome for a neurodegenerative disorder such ther decline and developing a frank dementia. as Alzheimer’s disease. However, we also know that some of these individuals revert back to “normal” when seen in follow-up [49, 50 ] . We share these observations Future Directions: Change with our referring neurologist and recommend as a Neurocognitive Biomarker that the patient be referred for a follow-up evaluation in 1 year to assess whether there has been As noted earlier, practice effects are defi ned as any evidence of signi fi cant interval change in his improvements in test scores due to repeated expo- neurocognitive status. Seeing the wisdom in our sure to the testing materials. Traditionally, prac- recommendations, the neurologist agrees and tice effects have been viewed as error variance orders repeat testing in a year. that need to be controlled, managed, or otherwise The patient returns 12 months later, and we accounted for in our interpretation of change. repeat his evaluation. As we can see from the However, practice effects, like cognitive change test–retest data summarized in Table 4.2, some in general, seems to be a unique variable that can of our patient’s scores have gotten worse and potentially provide clinically useful information some have gotten better. To understand which of about diagnosis, prognosis, and treatment recom- these changes are reliable and meaningful given mendations for our patients. Over the past several the different psychometric properties of the tests years, we have been prospectively examining in our battery and to place them on a common practice effects as a neurocognitive biomarker in metric, we turned to RC methods. For our pur- the development of dementia in older adults. poses here, we computed reliable change infor- In an initial study examining practice effects mation using the predicted-difference method. in community-dwelling seniors with MCI, we Using the test–retest data presented in the manu- observed two subgroups: those that benefi ted als for the tests or from longitudinal research from practice across 1 week and those that did not studies with samples of healthy older adults, we [ 52 ] . Those that showed signi fi cant gains after entered the sample summary data into Crawford repeat testing could no longer be classi fi ed as MCI, and Garthwaite’s regression calculator [35 ] along as they now appeared intact. These MCI partici- with our patient’s baseline and retest scores. pants might refl ect “accidental” MCI [ 49, 50 ] . Table 4.2 Clinical case example of test–retest scores and reliable change (RC) information based on data in bold using Crawford and Garthwaite’s [35 ] approach to derive RC regression equation from sample summary data Test Baseline scores Follow-up scores Reliable change (RC) information Predicted Standard Standard retest Discrepancy RC Population Raw score T -score Raw score T -score score (Y − Y ¢ ) z -score percentile Global mental status Mini mental state 29 28 28.57 −0.58 −0.33 37 exam a Mattis Dementia 140 11 133 8 135.5 −6.36 −1.48 7 Rating Scale: Totalb Wechsler tests Test of premorbid 125 118 124.25 −6.25 −1.13 13 functioning c WAIS-III Adult Intelligence Scale d General ability index 82 126 58 77 119 43 Verbal comprehension 46 131 61 40 118 49 130.43 −12.43 −3.07 <1 Perceptual organization 36 111 47 37 114 50 115.11 −1.11 −0.19 43 Processing speed 19 96 41 20 99 43 100.14 −1.14 −0.17 43 Memory measures WMS-III memorye Logical 30 8 35 20 4 21 9.88 −5.88 −3.14 <1 memory-immediate Logical 14 8 37 4 3 18 10.61 −7.61 −3.87 <1 memory-delayed Digit spand 20 13 53 21 13 53 13.26 −0.26 −0.20 42 Hopkins Verbal Learning Testf Total trials 1–3 22 37 17 28 23.36 −6.36 −1.35 9 Delay 0 <20 0 <20 2.61 −2.61 −0.95 17 Brief Visuospatial Memory Testf Trials 1–3 12 31 2 <20 13.46 −11.46 −2.21 <1 Delay 0 <20 0 <20 2.25 −2.25 −1.01 16 Language Boston Naming Testg 58 13 58 13 57.72 0.28 0.12 55 Controlled Oral Word 46 13 49 13 45.32 3.68 0.41 66 Associationf Visuospatial functions Judgment of line 30 16 28 14 23.48 4.52 0.83 79 orientationh KBNA complex fi gure 54 12 55 14 10.98 3.02 1.21 88 and clock drawing totali Executive functions Trail-making A timef 38 8 33 10 39.39 −6.93 0.44 67 Trail-making B timef 63 11 97 8 70.89 26.12 −0.51 30 KBNA practical 29 13 29 13 11.53 1.47 0.58 70 problem and conceptual shifting totali Notes: Sources of normative data used in developing RC prediction equations a [34 ] b [51 ] c [10 ] d [28 ] ; Table 3.8 e [28 ] ; Table 3.11 f [8 ] g [57 ] h [58 ] i [59 ] 54 G.J. Chelune and K. Duff

Fig. 4.1 Cognitive change across 1 year in patients with cognitive impairment who showed minimal practice effects differential practice effects. Note MCI + PE = individuals across 1 week; y-axis = age-corrected standard score with mild cognitive impairment who showed large practice (M = 100, SD = 15) on total scale score of the Repeatable effects across 1 week; MCI − PE = individuals with mild Battery for the Assessment of Neuropsychological Status

Conversely, the MCI participants that did not effects predicted response to a memory training benefi t from practice retained their original diag- course: those that showed practice effects dis- nostic classifi cation, and these participants more played larger gains related to the cognitive inter- likely demonstrate the concept of MCI. In this vention than those that did not show robust way, short-term practice effects provide diagnostic practice effects [ 56 ] . Although these fi ndings information that was not available with baseline need to be replicated, practice effects appear to data. Others also have found practice effects to be contribute to a clinician’s decision about diagno- diagnostically useful in MCI [53 ] . sis, prognosis, and treatment response, especially Prognostically, the presence of practice in older adults with memory dif fi culties. effects suggests a better outcome, whereas the absence of practice effects suggests a poorer outcome. In two independent samples of indi- Conclusions viduals with MCI, we have observed that practice effects predict future cognition, above and The assessment of cognitive change lies at the very beyond baseline cognition [ 8, 54 ] . As seen in heart of clinical neuropsychology. Understanding the Fig. 4.1 , when we followed our two MCI change and how we assess it with our various test subgroups across 1 year, those that benefi tted measures is complex and challenging, yet given an from practice across 1 week tended to remain appropriate conceptual framework and some sim- cognitively stable across 1 year and those that ple statistical tools, it is something that neuropsy- did not show the expected practice effects across chologists can do uniquely well. Test–retest 1 week tended to decline across 1 year [ 55 ] . practice effects are not simply statistical artifacts Lastly, we have examined the utility of prac- and something to be suppressed but rather some- tice effects in predicting treatment response. In a thing to be understood. Especially among older small sample of community-dwelling and cogni- adults, the capacity to learn and benefi t from expo- tively intact older adults, within-session practice sures to new experiences to potentially guide 4 The Assessment of Change: Serial Assessments in Dementia Evaluations 55 future behavior has adaptive value and may be a using sample summary data, for which there is biological marker of neural integrity that has diag- a potential wealth of clinically useful informa- nostic signi fi cance. tion available in test manuals and the published literature. • For computing regression equations using Clinical Pearls sample summary data for individual cases, see Crawford and Garthwaite’s univariate online • Test–retest change scores are unique variables calculator and enter your patient speci fi c with their own statistical and clinical proper- test–retest scores: http://www.abdn.ac.uk/~ ties that are different from the test measures psy086/dept/regbuild.htm. For multivariate from which they were derived. data, see the website at: http://www.abdn.ac. • Where large positive practice effects are uk/~psy086/dept/RegBuild_MR.htm . expected, the absence of change may actually • Although traditionally viewed as a source of re fl ect a decrement in performance. bias, practice effects may provide valuable • When planning to perform serial assessments information about a patient’s diagnosis, prog- and faced with two tests purported to assess nosis, and treatment response, especially for the same cognitive construct, choose the one older adults with memory dif fi culties. with the better reliability. • Use of alternate forms in serial assessment may attenuate, but not eliminate, practice References effects and do not address other factors that affect the interpretation of change scores, 1. Barth JT, Pliskin N, Axelrod B, et al. Introduction to the NAN 2001 defi nition of a clinical neuropsycholo- namely bias and error. gist. NAN Policy and Planning Committee. Arch Clin • Test–retest reliabilities of 0.70 or greater are Neuropsychol. 2003;18:551–5. often considered to be the minimum accept- 2. Winblad B, Palmer K, Kivipelto M, et al. Mild cogni- able standard for psychological tests in out- tive impairment—beyond controversies, towards a consensus: report of the International Working Group come studies, and practitioners should be wary on Mild Cognitive Impairment. J Intern Med. 2004; when interpreting cognitive change scores on 256:240–6. tests that have lower reliabilities. 3. Salthouse TA. Does the meaning of neurocognitive • The basic form for any reliable change method change change with age? Neuropsychology. 2010;24: 273–8. is a ratio: reliable change (RC) = (change 4. Howieson D, Holm LA, Kaye JA, Oken BS, Howieson score )/( standard error ), where the standard J. Neurologic function in the optimally healthy oldest error describes the dispersion of change old: neuropsychological evaluation. Neurology. scores that would be expected if no actual 1993;43:1882–6. 5. Cullum CM, Butters N, Troster AI, Salmon DP. change had occurred . Normal aging and forgetting rates on the Wechsler • The various reliable change methods reported Memory Scale—Revised. Arch Clin Neuropsychol. in the literature primarily vary along two 1990;5:23–30. dimensions: (a) whether the change score in 6. Busch RM, Chelune GJ, Suchy Y. Using norms in the neuropsychological assessment of the elderly. In: the numerator is a simple-difference or a pre- Attix DK, Welsh-Bohmer KA, editors. Geriatric neu- dicted-difference score and (b) whether the ropsychology: assessment and intervention. New standard error in the denominator represents a York: Guilford; 2006. p. 133–57. measure of dispersion (observed or estimated) 7. Howieson D, Carlson NE, Moore MM, et al. Trajectory of mild cognitive impairment onset. J Int Neuropsychol around the mean of difference scores or around Soc. 2008;14:192–8. a regression line. 8. Duff K, Beglinger LJ, Moser DJ, Paulsen JS, Schultz • Not all neuropsychologists are aware that it is SK, Arndt S. Predicting cognitive change in older possible to construct regression equations for adults: the relative contribution of practice effects. Arch Clin Neuropsychol. 2010;25:81–8. predicting an individual’s retest performance 9. Duff K. Predicting premorbid memory functioning in from his/her baseline performance by simply older adults. Appl Neuropsychol. 2010;17:278–82. 56 G.J. Chelune and K. Duff

10. Pearson. Advanced clinical solutions for WAIS-IV editors. Clinical neuropsychology: a practical guide and WMS-IV clinical and interpretative manual. San to assessment and management for clinicians. 2nd ed. Antonio, TX: Pearson; 2009. Chichester: Wiley; 2011. 11. Chelune GJ. Evidence-based research and practice in 25. Matarazzo JD, Herman DO. Base rate data for the clinical neuropsychology. Clin Neuropsychol. 2010; WAIS-R: test-retest stability and VIQ-PIQ differ- 24:454–67. ences. J Clin Neuropsychol. 1984;6:351–66. 12. Heilbronner RL, Sweet JJ, Attix DK, Krull KR, Henry 26. Hinton-Bayre AD. Methodology is more important GK, Hart RP. Of fi cial position of the American than statistics when determining reliable change. J Int Academy of Clinical Neuropsychology on serial neu- Neuropsychol Soc. 2005;11:788–9. ropsychological assessments: the utility and challenges 27. Chelune GJ, Naugle RI, Luders H, Sedlak J, Awad IA. of repeat test administrations in clinical and forensic Individual change after epilepsy surgery: practice contexts. Clin Neuropsychol. 2010;24:1267–78. effects and base-rate information. Neuropsychology. 13. Hinton-Bayre AD. Deriving reliable change statis- 1993;7:41–52. tics from test-retest normative data: comparison of 28. The Psychological Corporation. Updated WAIS-III models and mathematical expressions. Arch Clin WMS-III technical manual. San Antonio, TX: The Neuropsychol. 2010;25:244–56. Psychological Corporation; 1997. 14. Stein J, Luppa M, Brahler E, Konig HH, Riedel-Heller 29. McSweeny AJ, Naugle RI, Chelune GJ, Luders H. SG. The assessment of changes in cognitive function- “T-scores for change”: an illustration of a regression ing: reliable change indices for neuropsychological approach to depicting change in clinical neuropsy- instruments in the elderly—a systematic review. chology. Clin Neuropsychol. 1993;7:300–12. Dement Geriatr Cogn Disord. 2010;29:275–86. 30. Maassen GH. Principles of de fi ning reliable change 15. Chelune GJ. Assessing reliable neuropsychological indices. J Clin Exp Neuropsychol. 2000;22:622–32. change. In: Franklin R, editor. Prediction in forensic and 31. Jacobson NS, Truax P. Clinical signi fi cance: a statisti- neuropsychology: new approaches to psychometrically cal approach to defi ning meaningful change in psy- sound assessment. Mahwah, NJ: Erlbaum; 2003. chotherapy research. J Consult Clin Psychol. 1991; 16. Salthouse TA. In fl uence of age on practice effects in 59:12–9. longitudinal neurocognitive change. Neuropsychology. 32. Iverson GL. Interpreting change on the WAIS-III/ 2010;24:563–72. WMS-III in clinical samples. Arch Clin Neuropsychol. 17. Duff K, Schoenberg MR, Patton D, et al. Regression- 2001;16:183–91. based formulas for predicting change in RBANS 33. Knight RG, McMahon J, Skeaff CM, Green TJ. subtests with older adults. Arch Clin Neuropsychol. Reliable Change Index scores for persons over the age 2005;20:281–90. of 65 tested on alternate forms of the Rey AVLT. Arch 18. Lineweaver TT, Chelune GJ. Use of the WAIS-III and Clin Neuropsychol. 2007;22:513–8. WMS-III in the context of serial assessments: inter- 34. Tombaugh TN. Test-retest reliable coef fi cients and preting reliable and meaningful change. In: Tulsky 5-year change scores for the MMSE and 3MS. Arch DS, Saklofske DH, Chelune GJ, et al., editors. Clinical Clin Neuropsychol. 2005;20:485–503. interpretation of the WAIS-III and WMS-III. New 35. Crawford JR, Garthwaite PH. Using regression equa- York: Academic; 2003. p. 303–37. tions built from summery data in the neuropsycho- 19. Temkin NR, Heaton RK, Grant I, Dikmen SS. logical assessment of the individual case. Detecting signifi cant change in neuropsychological Neuropsychology. 2007;21:611–20. test performance: a comparison of four models. J Int 36. Crawford JR, Garthwaite PH, Denham AK, Chelune Neuropsychol Soc. 1999;5:357–69. GJ. Using regression equations built from summary 20. Slick DJ. Psychometrics in neuropsychological assess- data in the psychological assessment of the individual ment. In: Strauss E, Sherman EMS, Spreen O, editors. case: Extension to multiple regression. Psychol A compendium of neuropsychological tests. New Assessment. 2012; in press. York, NY: Oxford University Press; 2006. p. 1–43. 37. Ivnik RJ, Smith GE, Lucas JA, et al. Testing normal 21. Benedict RHB, Zgaljardic DJ. Practice effects during older people three or four times at 1- to 2-year inter- repeated administrations of memory tests with and vals: defi ning normal variance. Neuropsychology. without alternate forms. J Clin Exp Neuropsychol. 1999;13:121–7. 1998;20:339–52. 38. Attix DK, Story TJ, Chelune GJ, et al. The prediction 22. Beglinger LJ, Gaydos B, Tangphao-Daniels O, et al. of change: normative neuropsychological trajectories. Practice effects and the use of alternate forms in serial Clin Neuropsychol. 2009;23:21–38. neuropsychological testing. Arch Clin Neuropsychol. 39. Chelune GJ, Ivnik R, Smith G. Application of reliable 2005;20:517–29. change methods for identifying abnormal rates of 23. Collie A, Darby DG, Falleti MG, Silbert BS, Maruff cognitive decline in dementia. Alzheimers Dement. P. Determining the extent of cognitive change after 2006;2(S1):374. coronary surgery: a review of statistical procedures. 40. Crawford JR, Garthwaite PH. Statistical methods for Ann Thorac Surg. 2002;73:2005–11. single-case studies in neuropsychology: comparing 24. Crawford JR. Quantitative aspects of neuropsycho- the slope of a patient’s regression line with those of a logical assessment. In: Goldstein LH, McNeil JE, control sample. Cortex. 2004;40:533–48. 4 The Assessment of Change: Serial Assessments in Dementia Evaluations 57

41. Darby DG, Pietrzak RH, Fredrickson J, Woodward subjects: a prospective longitudinal study. Eur J M, Moore L, Fredrickson A, Sach J, Maruff P. Intra- Neurol. 2005;12:879–85. individual cognitive decline using a brief computer- 51. Pedraza O, Smith GE, Ivnik RJ, et al. Reliable change ized cognitive screening test. Alzheimers Dement. on the Dementia Rating Scale. J Int Neuropsychol 2012; 8(2):95–104. Soc. 2007;13:716–20. 42. Albert M, Blacker D, Moss MB, Tanzi R, McArdle JJ. 52. Duff K, Beglinger LJ, Van Der Heiden S, et al. Short- Longitudinal change in cognitive performance among term practice effects in amnestic mild cognitive individuals with mild cognitive impairment. impairment: implications for diagnosis and treatment. Neuropsychology. 2007;21:158–69. Int Psychogeriatr. 2008;20:986–99. 43. Stern Y, Liu X, Albert M, et al. Application of a 53. Darby D, Maruff P, Collie A, McStephen M. Mild cog- growth curve approach to modeling the progression of nitive impairment can be detected by multiple assess- Alzheimer’s disease. J Gerontol A Biol Sci Med Sci. ments in a single day. Neurology. 2002;59:1042–6. 1996;51:M179–84. 54. Duff K, Beglinger LJ, Schultz SK, et al. Practice 44. Small BJ, Backman L. Longitudinal trajectories of effects in the prediction of long-term cognitive out- cognitive change in preclinical Alzheimer’s disease: a come in three patient samples: a novel prognostic growth mixture modeling analysis. Cortex. 2007;43: index. Arch Clin Neuropsychol. 2007;22:15–24. 826–34. 55. Duff K, Lyketsos CG, Beglinger LJ, et al. Practice 45. Hayden KM, Reed BR, Manly JJ, et al. Cognitive effects predict cognitive outcome in amnestic mild decline in the elderly: an analysis of population cognitive impairment. Am J Geriatr Psychiatry. 2011; heterogeneity. Age Aging. 2011;40(6):684–9. 19(11):932–9. 46. Morris JC, Storandt M, Miller JP, et al. Mild cognitive 56. Duff K, Beglinger LJ, Moser DJ, Schultz SK, Paulsen impairment represents early-stage Alzheimer disease. JS. Practice effects and outcome of cognitive training: Arch Neurol. 2001;58:397–405. preliminary evidence from a memory training course. 47. Amieva H, Le Goff M, Millet X, et al. Prodromal Am J Geriatr Psychiatry. 2010;18:91. Alzheimer’s disease: successive emergence of the 57. Zec RF, Markwell SJ, Burkett NR, Larsen DL. A clinical symptoms. Ann Neurol. 2008;64:492–8. longitudinal study of confrontation naming in the 48. Petersen RC, Smith GE, Waring SC, Ivnik RJ, “normal” elderly. J Int Neuropsychol Soc. 2005; Kokmen E, Tangelos EG. Aging, memory, and mild 11:716–26. cognitive impairment. Int Psychogeriatr. 1997;9 Suppl 58. Montse A, Pere V, Carme J, Francesc V, Eduardo T. 1:65–9. Visuospatial deﬁ cits in Parkinson’s disease assessed 49. Brooks BL, Iverson GL, White T. Substantial risk by judgment of line orientation test: error analyses of “Accidental MCI” in healthy older adults: base and practice effects. J Clin Exp Neuropsychol. 2001; rates of low memory scores in neuropsychological 23:592–8. assessment. J Int Neuropsychol Soc. 2007;13: 59. Leach L, Kaplan E, Rewilak D, Richards B. Kaplan 490–500. KBNA baycrest neurocognitive assessment: manual. 50. de Rotrou J, Wenisch E, Chausson C, Dray F, San Antonio, TX: The Psychological Corporation; Faucounau V, Rigaud AS. Accidental MCI in healthy 2000. After the Diagnosis of Dementia: Considerations in Disease 5 Management

Steven Hoover and Mary Sano

Abstract Once diagnosed with Alzheimer’s disease or related disorders, patients and caregivers must integrate treatment and management plans. While there are no cures for these disorders, there are opportunities to optimize function and quality of life. There are pharmacological treatments available for dementia as well as for the behavioral and psychiatric symptoms that often accompany these diagnoses. Persistence can insure that drug treatments provide optimal bene fi t. Also nonpharmacological interventions including environmental modifi cations can be helpful, particularly for the behavioral problems. Supervision to insure adequate medical care, maximize independence and social interaction, and preserve patient dignity will require ongoing review of the patient’s changing condition. A comprehensive approach to management will also consider legal and fi nancial needs, support for the caregiver, and the possibility of research participation. Clinicians can introduce the possibility of research for the hope it offers to their patients and to the generations to come.

Keywords Dementia treatment • Disease management • Caregiving • Experimental therapeutics

S. Hoover , Ph.D. Introduction Department of Psychiatry , Mount Sinai School of Medicine , New York , NY , USA When an individual begins to notice a decline in M. Sano , Ph.D. () his/her memory and cognitive functioning, the Department of Psychiatry , Mount Sinai School of Medicine , New York , NY , USA instinctual reaction is often one of denial and fear. People often rationalize these changes as James J Peters Veterans Administration Medical Center , 130 W. Kingsbridge Rd, Code 150 Rm 1F01 , simply being a part of normal aging, feeling as if Bronx , NY 10468 , USA the concerns of friends and family are excessive e-mail: [email protected] and unnecessary. The additional stigma of being

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 59 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_5, © Springer Science+Business Media, LLC 2013 60 S. Hoover and M. Sano formally diagnosed with dementia creates a chal- to patients to participate in dementia research and lenge to coping strategies for both patients and clinical trials are described and the crucial role their families. For decades, both the general public these studies play in ensuring continued advance- as well as the medical community held the mis- ment in understanding both the disease and its conception that individuals with cognitive defi cits treatment. or dementia, even in the initial stages of the disease, lacked insight into their disease and were unable to grasp the implications and future reper- Treating Dementia cussions of their diagnoses. However, recent research provides increasing evidence that even Although there are approved treatments for the those with dementia, including Alzheimer’s dis- cognitive symptoms of dementia, the effective- ease, retain a level of awareness into their own ness is modest (see Table 5.1), with cholinest- health and prognosis [ 1] . In addition, the progres- erase inhibition being the most established sion of dementia can be quite variable [2 ] . approach to treatment. This approach blocks the Particularly during the early stages of the disease, action of the enzyme acetylcholinesterase (AChe), those with dementia are often acutely aware of an enzyme that breaks down the neurotransmitter not only the relative impact of the disease on their acetylcholine in the synapse. The inhibitors per- own functioning but also of the responses and mit the transmitter to sustain activation of the reactions of others to their diagnosis. This reac- postsynaptic neuron, allowing the synapse to tion is exacerbated by the misconceptions about remain active longer. This class of agents has the disorder promulgated by popular culture, been used for the treatment of Alzheimer’s dis- such as comparisons of those with dementia to ease since 1993, when tacrine was fi rst approved. the “walking dead” [3 ] . These factors create a Tacrine, the fi rst drug in this class, is not com- very vulnerable population with unique needs monly used today as it is short acting, requiring and special considerations. treatment four times a day and routine assess- When dealing with a patient who has been ment of liver enzymes. The second agent to be recently diagnosed with dementia, it is crucial to approved in this class, donepezil, has proven eas- acknowledge that this is a disease and there are ier to use with once-a-day dosing. Donepezil is approved treatments and recommendations for indicated for the treatment of Alzheimer’s dis- medical management. It is also important to ease and has been demonstrated to be effective in facilitate an understanding of what it means to be patients with mild, moderate, and severe disease. diagnosed with dementia, its course, and prognosis. Donepezil is approved for mild to moderate (5 or This chapter will describe some of the hurdles 10 mg) as well as severe disease (10 and 23 mg). that lie ahead for patients and families, and provide Other drugs in this class include galantamine, information to help manage these hurdles. It is which is available in a sustained release at a dose important not only to educate those coping with a of 16–24 mg per day, and in a generic form. diagnosis of dementia but also to instill perspec- Rivastigmine, another agent in the same class, is tive and ensure quality of life for both patients available both as an oral agent and as a transder- and their families. This chapter aims to discuss mal preparation and has been approved for the frequently encountered questions, special consid- treatment of mild to moderate dementia, includ- erations, and resources available to this popula- ing Parkinson’s dementia, at a dose of 6–12 mg tion. It also discusses the importance of identifying per day, given as twice-a-day dosing. The side and treating comorbid behavioral conditions and effect profi le of these agents includes nausea and nonpharmacological approaches to treatment of vomiting in 10–30% of the cases, which may be both the patient and their family/caregivers. The reduced with exposure. Although cholinesterase identi fi cation and use of community resources inhibitors have been studied in many types of and social services by patients and their families dementia, approval is limited to Alzheimer’s dis- will also be discussed. The opportunities available ease and Parkinson’s disease. There is anecdotal 5 After the Diagnosis of Dementia: Considerations in Disease Management 61

Table 5.1 Pharmacological treatments of dementia Drug Drug class Indication Target dose Most common side effects Tacrinea Reversible Mild to 40–160 mg/day Transaminase elevations requiring LFT acetylcholinesterase moderate (10–40 mg, four times monitoring inhibitor dementia daily) Nausea and/or vomiting, diarrhea, dyspepsia, and anorexia (dose dependent) 4 weeks titration Myalgia, anorexia, and ataxia Donepezil Reversible Mild to 5 and 10 mg daily Nausea, diarrhea, vomiting, insomnia, acetylcholinesterase moderate AD 1 week titration muscle cramp, fatigue, anorexia inhibitor Severe AD 10 mg Nausea, diarrhea, vomiting, anorexia 23 mg Galantamine Reversible Mild to 16–24 mg/day Nausea, vomiting, diarrhea, weight acetylcholinesterase moderate AD (8–12 mg twice daily) decrease, anorexia, dizziness, headache, inhibitor OR depression 16–24 ER daily 4–8 weeks titration Rivastigmine Reversible Mild to 6–12 mg/day (3–6 mg Nausea, vomiting, anorexia, diarrhea, acetylcholinesterase moderate AD twice daily) dyspepsia, dizziness, headache inhibitor Dementia of 2–6 week titrationb Parkinson’s disease Memantine NMDA antagonist Moderate to 20 mg (10 mg twice Dizziness, headache, constipation, severe AD daily) confusion 3 weeks titration AD Alzheimer’s disease, ER extended release formulation a Tacrine, the fi rst drug to be approved for the treatment of AD, is rarely used because of the burden of QID administration and the need for routine assessment for liver enzyme elevations b Available as liquid and patch evidence that cholinesterase inhibitors may be most trials demonstrating statistically signi fi cant ineffective or cause clinical worsening in frontal benefi ts on measures of cognition and of clinical temporal dementia [4 ] . Although not approved for global change in subjects with AD [6 ] . treatment of mild cognitive impairment (MCI), several trials have demonstrated the benefi t of cholinesterase inhibitors on cognitive, functional, Vitamins, Supplements, and Medical and global clinical outcomes. Foods Memantine is another agent approved for the treatment of moderate to severe AD. It is an orally Many vitamin and neutraceutical regimens have active NMDA receptor antagonist. The recom- been examined in studies to determine benefi t in mended starting dose is 5 mg once daily, and the subjects with AD. For example, a multicenter recommended target dose is 20 mg per day. randomized trial of vitamin E in moderately Despite several trials, to date there is no evidence severe AD subjects demonstrated an effect in that this drug has an effect in mild disease. There clinical outcomes, including delayed time until is evidence that the combination of memantine nursing home placement [ 7 ] . However, no bene fi t and donepezil is more effective than donepezil was identifi ed in studies in milder individuals alone in the moderate to severe dementia popula- with MCI in either cognition or clinical outcomes tion [5 ] , which has been the basis of usage of [8 ] . Lowering of homocysteine through regimens memantine in combination with cholinesterase of folate, vitamin B6 and B12, has also been inhibitors. While the benefi ts from this agent studied with no evidence of benefi t in patients have been labeled as minimal, it is robust with with mild to moderate AD [ 9 ] . Further, there was 62 S. Hoover and M. Sano some indication of increased depressive symp- both randomized and nonrandomized studies, tomatology in those receiving the vitamin regi- Hulme et al. [ 14 ] identi fi ed 33 studies of non- men [9 ] . Omega-3 fatty acids have also been pharmacological interventions, 10 of which proposed as treatments for cognitive loss and addressed cognitive symptoms (described in dementia. A trial of DHA demonstrated no benefi t Table 5.2 ). Of these, eight also examined func- in clinical or cognitive outcomes in AD, even tional and behavioral outcomes. The single most among those who had relatively low levels of common nonpharmacologic approach described omega-3 in their diet [ 10 ] . Effects in malnour- in the literature is cognitive stimulation/cogni- ished elderly populations have not been studied, tive training. While individual studies report but these are infrequently seen in US aging moderate effects on a number of different cogni- cohorts. tive domains, no single domain was consistently Medical foods, a relatively new category improved. There is great diversity in the type of regulated by the FDA as part of the Orphan training proposed in these studies, making it Drug Act in 1988, are defi ned as products dif fi cult to prescribe any single approach. intended for the specifi c dietary management Counseling was found to have no benefi cial of a disease or condition that has distinctive effect on cognition or any other symptom. Two nutritional requirements, established by medi- research groups studied transcutaneous electrical evaluation. In contrast to FDA-approved cal nerve stimulation (TENS) and found some drugs, no premarket review process exists for cognitive bene fi t of very brief duration but no medical foods. Instead, they are regulated after lasting bene fi t. they have become available to consumers. In general, the critical elements of nonphar- Axona, an example of a medical food that macological interventions are not well described, became available in 2009, claims to target the study designs are weakened by poor or absent nutritional needs of people with AD. control groups, and effects are poorly character- Specifi cally, it has been proposed that AD hin- ized. Most importantly, there is little information ders the brain’s ability to break down glucose, on how these interventions might be translated and Axona provides an alternative source of for broad use, including limited discussion on glucose that the brain can use for energy. Axona required training of individuals who deliver the has been shown to improve cognition in AD intervention, and no information on the cost or [ 11 ] , and a review of available data indicates required resources needed to disseminate the relative safety [12 ] . Another medical food, intervention in the community. Souvenaid, which is not currently marketed, is now in clinical trials. A single trial reported in 2010 describes small positive effects on mem- Importance of a Comprehensive ory testing but not on other traditional mea- Physical and Psychological Exam sures of cognition, function, and quality of life [ 13 ] . In general, there is little evidence of When a patient receives a diagnosis of dementia, benefi t to recommend medical foods for the it is crucial to continue to address the presence of treatment of AD; however, there appears to be comorbid medical and psychiatric disorders. The little identifi ed risk with their use. presence of comorbid disorders may exacerbate a patient’s symptoms and create additional burden that can challenge the patient’s quality of life. Nonpharmacological Interventions In addition, the presence of these symptoms can for Cognitive Symptoms have a signi fi cant in fl uence on family members as well. These comorbid disorders can also increase Nonpharmacological interventions have been the use of health-care resources and ultimately, proposed for the range of symptoms in AD and the outcomes of care [ 15, 16 ] . Many medical and other dementias. In a recent review that included psychiatric comorbidities can be treated with 5 After the Diagnosis of Dementia: Considerations in Disease Management 63 Less effective in more advance in more advance Less effective stages of dementia – did not persist of therapy Effect time over – and may be confron- exible fl In tational in its administration – reported improvements Many cant. fi were not statistically signi were cial effects fi bene Overall not sustained – ] ) 14 May work for improving memory, cognitive functioning, cognitive memory, for improving May work depression, neuropsychiatric symptoms, behavior, of daily living quality of life, learning, and activities and behavioral when used to improve May work mood, psychological symptoms (sleep, behavior, agitation) and cognition symptoms, including agitation, aggression, wandering, culties, fi social and emotional dif restlessness, irritability, nutritional intake and improving and psychological symptoms for behavioral Effective may exercise Moderate intensive and functional ability. the quality of sleep and improve reduce wandering depression, and ability, cognitive to improve May work apathy cognition, mood, and general to improve May work behavior mood, depression, behavior, disruptive May improve cognition, social/emotional aggression, apathy, and neuropsychiatric symptoms. wandering, behaviors, May reduce apathy in the latter stages of dementia ts (directly after fi May produce short-term bene recognition, and motivation treatment) in recall, face disturbance and behavioral affect May improve – Description on information processing rather than Focus knowledge rehearsal of factual cial light sources fi natural and arti support, drama, etc. Effectiveness patterns in people and dysfunctional behavior with dementia by orientating patients to time, place, and person objects, or sensory items Photographs, familiar are used to prompt recall tactile, and Consists of visual, auditory, to people in a stimulation offered olfactory Used specially designed room or environment. to increase the opportunity for communication quality of experience and improved The application of an electric current through electrodes attached to the skin Weaknesses someone is saying rather than the factual by acknowledg- content. The patient is validated ing the emotions being expressed Nonpharmacological treatments for the cognitive symptoms of dementia (Adapted from Ref. [ [ symptoms of dementia (Adapted from Ref. Nonpharmacological treatments for the cognitive Cognitive stimulation therapy/ Cognitive training cognitive Light therapy Music therapy and timing to exposure the patient’s Improving Physical activity Exposing patients to music Reality orientation such as dance, Promoting physical activity Reminiscence therapy Reality orientation aims to decrease confusion and psychological in reducing behavioral Effective discussion of past experiences. Involves Snoezelen/multisensory stimulation Transcutaneous electrical stimulation (TENS) nerve therapy Validation on the emotional content of what Focuses Table 5.2 64 S. Hoover and M. Sano either pharmacological or nonpharmacological patients and their families to understand which interventions. Identifi cation of these conditions is symptoms are likely to improve as a result of the fi rst step, and appropriate management and treatment and which are not. For example, anti- follow-up care are essential. depressants are unlikely to have a noticeable impact on a patient’s memory or level of cognitive functioning. However, treatment of depres- Depression sion can have an impact on a patient’s mood and their ability to function on a daily basis. Depression is common in the aging population The pharmacology of depression in the pres- and is highly associated with cognitive loss and ence of dementia has some special considerations. dementia. Prevalence estimates suggest that Tricyclic antidepressants are contraindicated in approximately 20–25% of those with AD also dementia patients due to their anticholinergic experience clinical depression, with some esti- activity, which can adversely affect cognition [21 ] . mates as high as 50% [17 ] . Depressive symptoms Selective serotonin reuptake inhibitors (SSRIs) are in dementia may be due to the perceived loss of often used in this population; however, these medi- independence and the patient’s awareness of their cations have been associated with an increased own cognitive decline, particularly in the early risk of falls and to a lesser degree with the syn- stages of the disorder [16 ] . Depression has also drome of inappropriate antidiuretic hormone been associated with increased aggression and secretion (SIADH) [22 ] . agitation in those with dementia [18 ] . Caregivers Both cognitive and behavioral therapies have report that a patient’s depression is the single most shown to produce improvement in depressive distressing symptom, and high rates of depression symptoms in a dementia population [23 ] . are also observed in caregivers themselves [19 ] . Cognitive strategies are more successful in the Depression and dementia have several over- earlier stages of the disorder when a patient’s cog- lapping symptoms, and the differential diagnosis nitive abilities are still conducive to this style of can be diffi cult. Special diagnostic criteria have therapy [23 ] . Cognitive therapy has been success- been proposed by the National Institutes of ful in challenging the patient’s negative thought Mental Health (NIMH) in order to differentiate patterns and reducing cognitive distortions [24 ] . depressive symptoms associated with the patient’s When depression is reactive, focusing on primary cognitive decline or dementia and those increasing pleasant events and interactions and due to a secondary diagnosis of depression [ 20 ] . minimizing aversive events that maintain the The guidelines indicate that when diagnosing depression can be helpful [25 ] and can reduce depression, symptoms that can better be disruptive behaviors [ 26 ] . Behavioral therapies explained by the patient’s primary dementia can be used at all stages of dementia severity to diagnosis should be excluded (e.g., increased focus attention on simple and familiar single-step apathy). For the diagnosis of depression in the tasks that will likely lead to success and avoid presence of dementia, it is recommended to rely demanding activities with a high probability of more on objective evaluation of symptoms (i.e., failure [27 ] . observed tearfulness or more easily discouraged, presence of irritability, or social isolation) rather than exclusively on self-report of depressive Anxiety symptoms. Depressive symptoms include changes in mood, decreased positive affect, changes in Anxiety may be common in the early stages of sleep or appetite, psychomotor changes, fatigue, cognitive loss when a patient’s insight into his/ feelings of guilt, worthlessness, or hopelessness, her cognitive decline is high. At any stage of increased discouragement or tearfulness, or pos- dementia, anxiety has been associated with an sible suicidal ideation, and treatment should increased irritability, aggression, and pathological focus on these specifi c symptoms. It is helpful for crying [28 ] , as well as repetitive or stereotypical 5 After the Diagnosis of Dementia: Considerations in Disease Management 65 behaviors such as pacing, chanting, or focused benzodiazepines (e.g., lorazepam) because they motor movements [29 ] . Anxiety can impair the are less likely to accumulate and lead to eventual patient’s ability to function, including refusal to toxicity [35 ] . allow necessary care. These symptoms continue to increase as an individual’s cognitive decline and confusion become more severe [25 ] . Anxiety Other Behavioral Disturbances is present in more than 20% of patients with cognitive decline or dementia [30 ] . Anxiety often Delusions and hallucinations also occur in manifests as irritability, fear, paranoia, aggression, dementia, tend to increase as a patient’s disease or depression [ 16 ] . Patients can have dif fi culty progresses, and have been correlated to increased with articulating their emotional and psychiatric agitation and aggression [ 36 ] . For some, these symptoms, particularly in the later stages of the delusions may be an attempt to organize informa- disorder. It is often preferable to treat a patient’s tion in the face of poor memory. For example, symptoms without medications because the most commonly reported delusions such as the belief commonly used pharmacological agents have that people are stealing things (occurring in well-established side effects. For example, benzo- 18–43% of dementia patients), that the patient is diazepines, which may be useful as antianxiety being abandoned (3–18% of dementia patients), agents in younger individuals, can exacerbate and that the patient’s spouse is being unfaithful cognitive de fi cits and be associated with increased (1–9% of dementia patients) [ 37] may be a result falls [31 ] , and both the typical and atypical antip- of forgetting the antecedent observations (e.g., sychotics can be associated with signifi cant risks losing things, not recalling the details of a planned in older adults, including increased mortality [ 32 ] . absence of a spouse). Delusional or paranoid Behavioral management focuses on simplifying beliefs are associated with changes in a patient’s the environment, providing a structured routine, daily routine or the presence of strangers [ 27 ] . reducing choices, and avoiding new learning. It is The onset of delusional beliefs may be an indica- also useful to minimize anticipation of either tion that the patient’s current level of activity is positive or negative events, keeping a patient too stressful. Proper treatment of anxiety can also focused on the present day [27 ] . Anxiety may assist in alleviating suspicion and the formation manifest as repetitive questioning to family of delusions. These environmental circumstances members or caregivers, despite efforts to continu- can often be avoided if a caregiver is made aware ally providing newer or better answers. For these of them. patients, the answer to the question is not as Hallucinations occur in 12% to 15% of patients important as maintaining contact with the care- with AD and can be auditory or visual [38 ] . giver. It is typically the patient’s need for reassur- However, in some cases, these experiences may ance and comforting that leads to additional actually represent an independently treatable dis- questioning [27 ] , thus providing a supportive and order. For example, the presence of both tactile calming environment can be effective. and visual hallucinations may actually indicate a Treatment with antidepressants (e.g., SSRI) reversible drug-induced delirium (described has been reported with some success [ 22 ] . below), and auditory hallucinations instructing Cholinesterase inhibitors have been shown to the patients to harm themselves may be a symp- reduce symptoms of anxiety in those with mini- tom of clinical depression [27 ] . Hallucinations mal symptoms [33 ] , but there is little evidence may also be a manifestation of a patient’s specifi c that they can successfully treat more severe anxi- wishes and fears, particularly the fear of abandon- ety. In general, treatment with benzodiazepines ment [ 27 ] . This fear is often improved by keeping should be avoided as they have been shown to caregivers visible and providing a controlled envi- increase the risk of falls and delirium [ 16, 34 ] . ronment, adequate distractions, and continued If benzodiazepines are employed, it is generally reassurance. Pharmacological treatment of these preferable to use nonoxidated, short-acting symptoms can be quite diffi cult. Studies have 66 S. Hoover and M. Sano shown modest improvement of hallucinations, Delirium delusions, and the accompanying agitation in dementia patients when being treated with antip- Delirium is a sudden change in mental status sychotic medications such as olanzapine and ris- characterized by severe confusion that is attrib- peridone [ 16, 39] . In addition, these medications uted to a discrete physical or mental illness that is have signi fi cant side effects including sedation usually temporary and reversible [ 45 ] . Within an and extrapyramidal symptoms. In one study, que- elderly population, the most common causes of tiapine was associated with worsening of cogni- delirium are electrolyte disturbance (often from tion and no improvement in psychiatric dehydration), infection, and postsurgical recov- symptomatology [ 16 ] . Both conventional and ery. The presence of a dementia diagnosis atypical antipsychotics have also been linked to increases a patient’s susceptibility to developing increased mortality and risk of cerebrovascular a delirium [ 46 ] , and this risk continues to increase events in elderly patients [40 ] . as the dementia becomes more severe [ 47 ] . Prevalence estimates of delirium within a dementia population range from 22% to 89% in com- Aggression munity and hospital studies [ 16 ] , increasing the risk of developing delirium roughly twofold over Aggression in patients with dementia is the most elderly individuals without dementia [ 48 ] . common reason that caregivers contact their cli- Benzodiazepines increase the duration of a delir- nicians requesting assistance [41 ] , and is a com- ium, and as a result should primarily be used mon reason for placement a residential facility when the delirium is related to withdrawal from [42 ] . Physically aggressive behaviors are esti- alcohol, a benzodiazepine, or another cross-toler- mated to be present in 25–50% of community- ant sedative hypnotic [ 34 ] . After a delirium is based dementia patients and even more frequently successfully treated, the underlying cognitive and within a nursing home setting [ 43 ] . Some patients emotional symptoms of primary MCI or demen- will experience increased agitation that is iso- tia will remain. lated to later in the day (sundowning), which is particularly common in moderate to severe dementia. This may be related to fatigue or the Considerations for Specifi c loss of visual cues in the environment. An early Non-Alzheimer Dementias awareness of these behavioral problems may help in planning for future care but must be weighed Vascular dementia is the most common dementia against anticipation anxiety in family members. after AD. Memory impairment may be secondary Treatment of aggressive behaviors requires while executive and attention defi cits are typi- identifying the underlying reason for the agita- cally more prominent, particularly early in the tion. Some behavioral interventions for aggres- disease course. Vascular dementia is associated sive behaviors have shown promise. When with increased depression and anxiety [ 49 ] and aggression occurs as a consequence of a patient’s disrupted sleep–wake cycles [ 50 ] . It is important anxiety or delusional beliefs, then the contribut- to consider that vascular dementia and AD may ing symptoms should be addressed as described co-occur, and the expectation would be a com- above. Reassuring patients and providing them bined symptom constellation. with a controlled environment can alleviate their Another relatively common neurodegenerative fears and suspicions. Marginal success has been disorder is Lewy body dementia (LBD), which is noted in studies involving physical exercise, estimated to affect 1.3 million people in the United distraction-based interventions, and increased States. It is characterized by cognitive impair- caregiver training [44 ] ; however, additional ment, parkinsonian motor symptoms, fl uctuating research is necessary in order to determine their mental status, and visual hallucinations [ 51 ] . broad ef fi cacy. Rapid eye movement (REM) sleep disorders [52 ] 5 After the Diagnosis of Dementia: Considerations in Disease Management 67 and an increased sensitivity to neuroleptics [ 53 ] Association ( www.alz.org ) has instituted programs have also been associated with LBD. to help bring these patients together and provide Frontotemporal dementia (FTD) represents both education and support. These groups allow 10–20% of all dementias and is characterized by patients to share their experiences and concerns, changes in behavior, personality, and language or learn more about the disease, reduce feelings of motor skills, but memory may be relatively intact. isolation, and assist with coping and long-term The most disturbing symptoms in FTD are inap- planning [ 58 ] . These groups are often fl exible in propriate and disinhibited behaviors in social and structure to accommodate an individual patient’s work settings, including impulsivity, compulsivity, availability, level of function, speci fi c concerns, and verbal outbursts. Patients may have dif fi culty and inclusion of caregivers. organizing activities, and self-care may be impaired Patients may be resistant to the idea of attend- resulting in increasing dependence. The average ing support groups due to reluctance to accept age of onset is 60, although earlier and later onset their diagnosis or fear of having their stereotypes have been observed. Treatments with cholinest- of the disease confi rmed; however, several studies erase inhibitors are not effective and may actually have explored the effi cacy of these early-stage have deleterious effects [54, 55 ] . support groups and have consistently shown them to be benefi cial. Patients enrolled in these programs report an increased sense of camaraderie, Utilizing Support Groups, Social affi rmation, improved confi dence, education, and Services, and Planning for the Future a decrease in their perceived helplessness and frustration [58– 61 ] . Caregivers also reported increased Patients and their families may bene fi t from edu- awareness and acceptance, and stated that they cation and psychosocial services to provide sup- helped to initiate diffi cult discussions about plan- port and assistance with coping as they confront ning for the future (e.g., future medical, legal, and a dementia diagnosis [ 56 ] . Services are most fi nancial planning) and improved caregiver educa- useful when tailored to consider the patient’s tion regarding available community resources speci fi c level of functioning, support structure, [ 58, 61 ] . Those with the greatest level of distress at and cultural background. Education and services enrollment demonstrate the most signi fi cant can also address legal issues and fi nancial plan- improvement in quality of life by attending these ning. Early attention to these issues can take groups [58 ] . advantage of a patient’s ability to participate in their own decision making and treatment planning [57 ] . While the availability of resources Support Groups for Caregivers and services may vary in different locations, the current chapter attempts to discuss the types of Caregiving by family and friends can prove both options available and where to begin looking for satisfying and challenging. For informal caregiv- appropriate groups and services. ers, challenges include a shift in a relationship confronted by the patient’s loss of independence and the caregiver’s new responsibility, which Patient Support Groups requires time and energy, and can take a psychological toll. This toll can result from the loss of An effective approach for providing support and companionship of the patient, the weight of the coping strategies for patients, particularly in the responsibility, and the uncertainty regarding the initial stages of the disease, is to connect with course of the illness. High rates of depression and others experiencing the same emotions. The increased medical problems are observed in care- group setting can provide evidence that one is givers [19 ] . Caregiver support groups provide an not alone and provide comfort in shared experi- opportunity to exchange information and bene fi t ences. In response to this need, the Alzheimer’s from the experience and knowledge of those in a 68 S. Hoover and M. Sano similar situation [ 62 ] . Within these groups, care- begins as early as possible so that continuity of givers are offered the opportunity to discuss their care can be achieved. stressors and problems, and receive emotional Online resources are also available for manag- support [63 ] . Support groups have been shown to ing care needs. For example, the Alzheimer’s provide a positive effect on a caregiver’s knowl- Association provides a CareFinder service at edge, increase a caregiver’s well being and reduce www.alz.org/carefi nder . While web-based resources the sense of burden [ 64 ] . Mittelman et al. [65 ] can be helpful and easy to access, it is important demonstrated that structured caregiver support to understand their sponsorship, purpose, and groups had direct effects on patients including mission. Those sponsored by patient advocacy delay in nursing home placement by nearly 1 year. groups such as Alzheimer’s Association or by National organizations such as the National governmental entities such as the National Association of Area Agencies on Aging ( www. Institute on Aging usually vet information n4a.org ) can provide information on resources for through credible sources and disclose fi nancial programs, training, and support. confl ict. While providing easy-to-use informa- Support groups are underutilized, and esti- tion, commercial sites are likely to have product mates of participation range from 5% to 14% of sales as a goal, and caution should be used. caregivers [62 ] . It is important to make caregivers During the initial stages of dementia, the need aware of the options that are available to help to modify the environment may be minimal and them cope with these stressors and to help them the patient may remain very active in the deci- understand that attending caregiver support sion-making process. If informal caregiving is groups is not an indication of “failure” by the available, insuring that the caregiver is supported caregiver. and stable may be all that is required. Supplemental services at this early stage may include identifying support groups, community day programs, or Social Services and Patient Care respite care. Additional support in the home may include help with housekeeping and companion Service needs in aging and dementia may include services. Assistance from a home health aide may care for patients as well as support for caregivers; also be useful if medical problems interfere with these needs will change over time and require independence. Home health aides can also provide reassessment during the course of the disease. assistance managing medications and appoint- At each stage of the disease, service goals include ments, and facilitate travel. As the dementia pro- maximizing independence in a safe environment gresses, patients will require more assistance for the patient and supporting the social, psycho- including additional medical help such as a visiting logical, and physical needs of the caregiver. A case nurse or other professional, constant supervision, manager can be useful in assisting with identify- or even hospice for comfort care at end stages of ing these services. Typically trained in social the disease. For the majority of patients, at home work, their tasks are to assess needs, including services such as visiting nurses and home health the needs of the caregiver, and establish care aides are suffi cient throughout the progression of planning and implementation. This may include the disease. In addition, insurance providers and an assessment of current resources and fi nancial Medicare typically supply coverage for respite constraints, evaluation of coexisting medical services designed to lighten the burden of the needs of the patient, and establishing the capacity caregiver such as homemaking, housekeeping, of the informal caregiving provided by family and companionship services. and friends. The assessment may identify a need For some, circumstances necessitate consider- for patients and family members to acknowledge ation of residential placement. Patients may not their limitations and accept help. Case manage- have family members who are available or in ment can be particularly helpful for families who adequate health to assist with patient care, or the oversee care from a distance and when the process patient’s cognitive decline or behavioral symptoms 5 After the Diagnosis of Dementia: Considerations in Disease Management 69 may require greater resources than are available future medical care and decisions, either by in a home setting. Residential facilities can advance care directives or a living will. These provide different levels of care in these circum- decisions can record a patient’s wishes regarding stances, and one should consider the level of care issues such as the use of arti fi cial life support, that is most appropriate for each individual feeding tube placement, and comfort measures. patient at each stage of their illness. Assisted liv- By providing families and caregivers with speci fi c ing facilities may provide a transition between instructions regarding what actions should be living independently and residing in a nursing taken in different health-care scenarios, the home. These facilities typically provide a combi- patient ensures that their wishes will be followed. nation of housing and meals, as well as support- In the absence of these advance directives, a ive and health-care services. Skilled nursing patient’s health-care proxy will make decisions facilities provide continued medical supervision regarding their care. When assigning a proxy, and have services designed speci fi cally to address patients also have the option of providing the per- advanced care issues such as patient nutrition and son with varying degrees of authority. A proxy medical care. can be granted total control of medical decisions or can be given authority over only certain ones. When a patient decides to grant a proxy with only Medical–Legal Considerations limited authority, consideration should be given to other types of scenarios in order to ensure that When cognitive loss and dementia are present, appropriate accommodations are made. making plans to assist in future care decisions is If a proxy has not been appointed or if a advisable. It is useful to review existing advanced proxy’s authority does not address the issue at care directives or health-care proxy, and if they hand, then health-care decisions are made by do not exist, it is advisable to put them in place. It either the patient’s family or the doctors involved is important to note that as long as a patient main- in their care. Using substituted judgment, doctors tains his/her ability to competently make deci- and family members try to make the decision that sions on his/her own behalf, these opinions will the patient would have made if they were able to take precedence over family or caregiver wishes, make decisions. Given the diffi culty of these even if a health-care proxy or power of attorney decisions, as well as the moral considerations has been appointed. Below we review important involved, it is generally preferable to rely on options and considerations for advance care advance care directives and appointed health-care initiatives. proxies whenever possible. A power of attorney assigns a person with the Health-Care Proxy, Advance Care ability to speak (and sign documents) on a Directives, and Legal Planning patient’s behalf with regard to legal and fi nancial One of the key decisions to be made is who will matters. However, the power of attorney does not be responsible for making health-care decisions provide an individual with the authority to over- if the patient loses the ability to make his/her own ride a patient’s wishes. Patients maintain the decisions. The diagnosis of dementia is not syn- power to also make their own legal decisions, as onymous with incompetence, but as the dementia long as they maintain the capacity to do so. In progresses, the likelihood of losing the ability to addition, unless a power of attorney is irrevoca- make decisions is high. It is therefore advisable ble, patients have the authority to change and for a patient to appoint a health-care proxy while withdraw the appointment as they see fi t (again, they are still able. By appointing a health-care assuming the patient is still deemed to have the proxy, patients are assigning a person (typically a capacity to make this decision). Powers of attor- family member) to act on their behalf with regard ney may also be “durable,” which allows this to medical and end-of-life decisions. A patient appointment to be maintained even after a patient may choose to document specifi c wishes regarding is no longer able to make decisions for himself/ 70 S. Hoover and M. Sano herself. The power of attorney will also make attorneys in a specifi c area can be obtained from decisions regarding a patient’s fi nances and assets. the local chapter of the Alzheimer’s Association ( www.alz.org). Free legal advice is also avail- Legal Capacity and Guardianship able in some areas. Available resources can be In order to appoint representatives (i.e., health- found at the local Eldercare Locator ( www. care proxy or power of attorney) or make legal eldercare.gov ) . decisions, a patient must maintain the capacity to do so. Legal capacity is generally de fi ned as an individual’s ability to understand and appreciate Dementia Research: Current State, the consequences of one’s actions and to make Future Trends, and Opportunities rational and informed decisions. The diagnosis of to Participate cognitive loss or dementia is not synonymous with lack of capacity, and judgments of capacity There are many stakeholders in the efforts to fi nd may actually differ for each type of decision. a treatment for AD, and themes of research When patients maintain capacity to participate in include both better diagnostics to provide early their own legal planning, the wishes of others are detection and distinctions among types of demen- subordinate. However, as a dementia progresses, tias as well as initiatives to understand the a patient can become increasingly impaired and underlying pathological mechanisms of the dis- confused, and may even demonstrate paranoia ease in order to identify new treatments. Neuritic directed toward those trying to assist them. plaques composed of amyloid and neuro fi brillary In order to determine an individual’s capacity tangles composed of the protein tau, the hallmark to sign legal documents during the initial stages pathology of the disease, have been the primary of a dementia, family members are often able to target for drug discovery with the hope that modi- simply speak to the patient to ensure that they fying the aggregation of these proteins into path- adequately understand and can rearticulate the ological structures will modify the course of the implications of the documents they are signing. disease. The breadth of research initiatives is In other cases in which uncertainty regarding a wide, and there are three broad areas that have patient’s capacity persists, additional assistance received signi fi cant attention and support from can often be obtained by speaking to a lawyer or the National Institute on Aging (NIA): diagnos- by referring the patient to a psychologist to assess tics, interventions, and genetics. his/her mental status and cognitive limitations. For cases in which a patient is deemed to lack capacity to make decisions on his/her own behalf, Research on Diagnostics the court may appoint a guardian (typically a family member) to speak for the patient. A court- Early detection of AD may provide the ability to appointed guardian (also referred to as a conser- intervene more effectively. To this end, many stud- vator) can be responsible for making fi nancial ies of the transition from health to cognitive and health-care decisions for the patient. impairment and dementia are under way. One of the most prominent fi ndings is that memory de fi cits Finding a Lawyer predict the progression to AD, and from this work While health-care proxy, advanced care direc- the criteria for recognition of MCI were devel- tives, responsibility and power of attorney can oped. Work continues, de fi ning other cognitive all be executed without an attorney, it may be and biological markers that predict the disease. A preferable to seek legal advice to avoid unde- large effort in this area is the Alzheimer Disease sired consequences of these actions. Elder law Neuroimaging Initiative (ADNI) [66 ] . This pub- focuses on estate planning and administration, lic–private partnership has been working to iden- disability, long-term care issues, and issues of tify biomarkers that predict disease in the mildly guardianship including fi duciary. Elder law symptomatic and nonsymptomatic individual. 5 After the Diagnosis of Dementia: Considerations in Disease Management 71

Specifi c biomarkers that are being studied are and many clinical trials have examined agents quantitative MRI, PET images, and cerebrospinal that would reduce amyloid in the brain. Areas fl uid (CSF) and blood biomarkers. The imaging that remain active today are gamma secretase techniques measure the size of speci fi c brain struc- inhibition and immunization (both active and tures (MRI) and the energy used by speci fi c brain passive). Blocking the gamma secretase enzyme areas (PET). Additional imaging studies use appears to reduce the accumulation of amyloid ligands that label proteins in the brain to identify into plaques. However, to date, this mechanism the presence of amyloid and tau. Other studies are has not proven effective in modifying clinical measuring amyloid and tau in the CSF to fi nd early outcomes in AD. Immunization therapeutics, evidence of AD-like changes. These studies have both active and passive, are also being developed. been enrolling research participants with and with- Animal data support the notion that antibodies out dementia to determine which biomarkers dif- against amyloid beta (Ab ) can lead to clearance ferentiate the groups and to track change over time. of cerebral Ab deposits, and human trials have Today, these studies continue with the hope of further demonstrated this clearance [ 69 ] . recruiting very mildly impaired individuals, who However, clinical improvement has not always may only demonstrate biomarker evidence of dis- accompanied the clearance, leading researchers to ease without accompanying impairment [ 67 ] . The believe that effectiveness requires administration hope is that fi nding a marker to detect those at risk at much earlier stages of the disease, such as the will help to target a population most likely to “prodromal” stage proposed in new diagnostic benefi t from early intervention. More information criteria. Another mechanism under study is neural is available about ADNI at their Web site ( www. regeneration, and the NIA along with Ceregene adni-info.org ). pharmaceuticals has sponsored one such trial of Studies have suggested that these biomarkers nerve growth factor, which is stereotaxically are as important as the clinical presentation of the implanted in the brain. Other regenerative agents patient, and recent guidelines for the diagnosis of are also in development. Drug development in Alzheimer’s disease have been reevaluated to Alzheimer’s disease is very active with more than focus on cognitive change, regardless of type, 96 studies actively recruiting, as reported on the and the presence of an amyloid biomarker. clinicaltrials.gov Web site. Additionally, research guidelines have been proposed which include the concept of “prodromal” Alzheimer’s disease, a research diagnosis that Genetics requires a positive biomarker with no evidence of clinical impairment [68 ] . Three genes associated with the development of rare early-onset forms of familial AD have been known for many years: mutations in the amyloid Research on Interventions precursor protein (APP) gene found on chromosome 21, the presenilin 1 gene on chromosome Current treatments for Alzheimer’s disease are 14, and the presenilin 2 gene on chromosome 1. referred to as “symptomatic” in that they produce The most common form of the disease, late-onset a benefi t on the cognitive, functional, and behav- (typically defi ned as over the age of 60) AD, is a ioral symptoms associated with the disease. complex disorder, and it is likely that many genes Today, experimental therapeutics focus on treat- may play a role in disease development. Until ments that modify the disease course. This may recently, however, only one gene variant, apoli- include slowing or stopping the disease progres- poprotein E-e 4 (APOE-e 4), has been con fi rmed sion or preventing the onset of the clinical symp- as a signifi cant risk factor gene for late-onset toms of the disease. Some approaches to therapy Alzheimer’s disease. In the past several years, focus on modifying biomarkers of the disease in however, researchers have confi rmed additional the hope that it will change its clinical course, gene variants of complement receptor 1 (CR1), 72 S. Hoover and M. Sano clusterin (CLU), and the phosphatidylinositol- procedures, treatments, and study designs are made binding clathrin assembly protein (PICALM) as quickly. This attention can add con fi dence to par- possible risk factors for late-onset Alzheimer’s. ticipating in studies that might expose an individual The newest genome-wide association scan to unnecessary or ineffective procedures. In the (GWAS) con fi rms that a fi fth gene variant, Myc case of positive results, participants get the earliest box-dependent-interacting protein 1 (BIN 1), exposure. In many studies, even those initially also affects the development of late-onset AD. assigned to the placebo group are given the oppor- Several other genetic variants were identi fi ed at tunity to receive the active intervention, even before EPHA 1, MS4A, CD2AP, and CD33; these genes the agent is fully available for marketing or before may implicate pathways involved in in fl ammation, a diagnostic is fully approved. movement of proteins within cells, and lipid The nature of participation in research in transport as being important in the disease pro- dementia and cognitive impairment often requires cess. These studies utilized DNA samples from participation of a study partner, usually a friend more than 56,000 study participants and are or family member. Because they play an impor- made possible through the Alzheimer’s Disease tant role, support for family and friends is often Genetics Consortium (ADGC), a collaborative provided in research. This can take the form of body established and funded by the NIA [70 ] . activities to maximize retention such as support Identi fi cation of new genes may provide major groups or informational material that is often pro- clues as to the cause of AD. Genetic variants may vided by study staff who are experts in the par- infl uence risk of disease, the age of onset of symp- ticular aspect of dementia care and management. toms, rate of progression, the amount of amyloid It can also occur informally through exposure to plaques or neurofi brillary tangles, concentrations others participating in research who offer peer of amyloid beta and tau in CSF, and responses support and shared experiences. to environmental factors such as medications. The most common and sustaining reason for In addition, genetic studies can also provide research participation is altruism. The ability to new insights critical for drug discovery. The make contributions that benefi t others with the identi fi cation of new genes associated with AD is a disease remains the highest motivator. This is an very important preliminary step toward identify- important factor in research recruitment. Long- ing biological pathways leading to disease. These standing characteristics of generosity in an indi- pathways help to identify new targets for therapeutic vidual are often unchanged in the presence of strategies to treat and prevent the disease. illness, and in the face of mortality, they may even be enhanced. Offering research participation is acknowledging the patient as an important Participation in Research contributor to knowledge of his/her disease and to the welfare of others. There are many reasons why an individual may be motivated to participate in research. First, many individuals appreciate the opportunity for addi- Critical Information About Research tional standardized follow-up. Often, experimental Participation instruments and techniques are used to assess novel aspects of disease or health, and tracking that per- While many practitioners acknowledge the formance can provide support and insight for benefi t of research participation for their patients, research participants. Research participation can it is not always clear how to go about identifying also provide early access to new techniques and and evaluating studies or preparing patients for treatments. While there is no guarantee of a posi- the rejection they may feel if not eligible for a tive outcome, the requirement for safety in research given study. Additionally, many commercial enti- demands close observation to ensure that untoward ties can solicit participation with little oversight. results are identifi ed early and modifi cations to However, there are several resources that are well 5 After the Diagnosis of Dementia: Considerations in Disease Management 73 established that can be helpful to patients, fami- Science Awards (CTSA) program. ResearchMatch lies, and friends. For example, because of both has a simple goal—to bring together two groups regulatory and publication guidance, most clini- of people who are looking for one another: (1) cal trials as well as many other clinical studies are people who are trying to fi nd research studies and posted on www.Clinicaltrials.gov . Clinicaltrials. (2) researchers who are looking for people to par- gov offers up-to-date information for locating ticipate in their studies. It is a secure registry that federally and privately supported research studies has been developed by major academic institu- that use human volunteers to answer specifi c tions across the country in order to develop a health questions. The Web site was developed by nationwide effort to enrich participation in the US National Institutes of Health (NIH), research. This effort is not disease specifi c and through its National Library of Medicine (NLM), offers opportunities to both patients and healthy and in collaboration with the Food and Drug individuals. Administration (FDA), as a result of the FDA Research participation may not be for all indi- Modernization Act (Public Law Number 105-1 viduals, and both the investigator and the partici- 15, 1997). The registry describes studies con- pant have opportunities to evaluate the speci fi c ducted in all 50 States and in 174 countries. match of the potential subject and the project. The website receives over 50 million page views From the investigator perspective, a study must per month and 65,000 visitors daily. This registry be designed to answer a specifi c question. has an easy-to-use search engine, and as of this Selection criteria therefore focus on identifying writing, is posting over 900 studies in AD with subjects who can help answer specifi c questions. more than 200 currently recruiting. The study Inclusion criteria might defi ne the severity of the postings describe basic entry criteria for given disease or the age of a participant or exposure to studies along with location and contact informa- other treatments. Other criteria may be used to tion. The website requires annual updating of ensure safety, requiring exclusion of some indi- information and posting of study results. Another viduals based on the presence of comorbid con- opportunity for those with AD is the Alzheimer’s ditions or concurrent medications that could Association TrialMatch,™ a clearing house increase risks if exposed to a new treatment or designed to help people with AD, caregivers, test. Some criteria may be based on ensuring that families, and clinicians locate clinical trials based the effectiveness can be measured. For example, on specifi c criteria such as diagnosis, stage of studies involving cognitive evaluation may disease, and location. More than 100 research exclude subjects with signi fi cant hearing or studies pertaining to AD and related dementias visual loss that might potentially interfere with are underway and recruiting volunteers through testing. this service, and Alzheimer’s Association From a participant’s point of view, it is critical TrialMatch lets you search these trials quickly to work with a trusted group. The research group and easily. It also narrows results to those trials may be identi fi ed by a physician or vetted through where there is a reasonable chance to be accepted one of the Web sites described in this chapter. for enrollment. Individuals may register by It is also important to evaluate how much partici- providing information about a potential participation is right for the participant. A study may pant, and with the registrant’s permission, an require frequent visits. Some procedures may be Alzheimer’s Association Contact Center special- particularly noxious. The participant needs to ist will provide unbiased trial result options and weigh these against the bene fi t of making a con- trial site contact information. Specialists will not tribution. An important aspect for participants to recommend any particular trial but will identify keep in mind is that participation is voluntary and trials that match speci fi c eligibility criteria. one can always change his/her mind if circum- Finally, the National Center for Research stances change. In the end, it is the faithful par- Resources, part of the NIH, sponsors Research- ticipation in clinical research that will identify Match through the Clinical and Translational the treatments of tomorrow. 74 S. Hoover and M. Sano

Table 5.3 Additional internet resources Clinical Pearls Information available Web site For information, resources, and www.alz.org • Pharmacological treatments available for support groups speci fi cally Alzheimer’s disease require careful titration to pertaining to Alzheimer’s disease fi nd the best dose; modest effects have been For recent news and events www.nia.nih.gov/ observed at all stages of the disease. speci fi cally pertaining to Alzheimers • Nonpharmacological interventions can be par- Alzheimer’s disease ticularly helpful for behavioral problems For information, resources, and www.lbda.org support groups speci fi cally associated with dementia. Environmental pertaining to Lewy body dementia modifi cations can improve safety and extend For information, resources, and www.theaftd.org functional independence. support groups speci fi cally • Behavioral and psychiatric symptoms are pertaining to frontotemporal common and should be treated using both dementia For a directory of local programs www.eldercare.gov pharmacological and nonpharmacological and resources means. For additional programs, www.n4a.org • Acute medical problems can potentially exac- training, and support erbate cognitive and behavioral symptoms; For information regarding legal www.caringinfo.org routine health maintenance should be an inte- and fi nancial advice grated part of dementia care. For a list of clinical trials www.clinicaltrials.gov currently enrolling • Identifying the etiology of the dementing disorder is critical for planning and management, as subtypes have differential presenting symptoms and rates of disease progression. Resources • Support groups and resources are available and can improve the quality of life of both The websites listed in Table 5.3 are excellent patients and their caregivers. resources for information, programs, support • Care needs in dementia will change with the groups, and other resources ( Table 5.3 ) . progression of the disease. Matching the level of care with the patient’s disease severity will Acknowledgments This work was supported in part by contribute to maximizing independence. Case the Alzheimer Disease Research Center at Mount Sinai management can be helpful in identifying and funded by the following NIA grant: AG 005138 accessing care needs. • The cognitive decline associated with dementia has both legal and fi nancial implications, References and patients and their families should explore of assigning health-care proxy, power of attor- 1. Burgener SC, Berger B. Measuring perceived stigma ney, and making advance care directives. in persons with progressive neurological disease: Alzheimer’s dementia and Parkinson’s disease. • There are many opportunities for those with Dementia. 2008;7:31–53. dementia and cognitive loss to participate in 2. Kraemer HC, Tinklenberg J, Yesavage JA. ‘How far’ clinical research and clinical trials. Clinicians vs ‘how fast’ in Alzheimer disease: the question revis- can introduce the possibility of research par- ited. Arch Neurol. 1994;51:275–9. 3. Behuniak SM. The living dead? The construction of ticipation for the hope it offers to their patients people with Alzheimer’s disease as zombies. Ageing and to the generations to come. Soc. 2011;31:70–92. 5 After the Diagnosis of Dementia: Considerations in Disease Management 75

4. Kaye ED, Petrovic-Poljak A, Verhoeff NPLG, in Alzheimer’s disease study-2. Am J Geriatr Freedman M. Frontotemporal dementia and pharmaco- Psychiatry. 2006;14:920–30. logic interventions. J Neuropsychiatry Clin Neurosci. 18. Lyketsos CG, Steele C, Galik E, Rosenblatt A, 2010;22:19–29. Steinberg M, Warren A, et al. Physical aggression in 5. Tariot PN, Farlow MR, Grossberg GT, Graham SM, dementia patients and its relationship to depression. McDonald S, Gergel I, Memantine Study Group. Am J Psychiatry. 1999;156:66–71. Memantine treatment in patients with moderate to severe 19. Teri L. Behavior and caregiver burden: behavioral Alzheimer disease already receiving donepezil: a ran- problems in patients with Alzheimer disease and its domized controlled trial. JAMA. 2004;291(3):317–24. association with caregiver distress. Alzheimer Dis 6. Riordan KC, Hoffman Snyder CR, Wellik KE, Caselli Assoc Disord. 1997;11:35–8. RJ, Wingerchuk DM, Demaerschalk BM. Effectiveness 20. Olin JT, Katz IS, Meyer BS, Schneider LS, Lebowitz of adding memantine to an Alzheimer dementia treat- BD. Provisional diagnostic criteria for depression of ment regimen which already includes stable donepezil Alzheimer’s disease: rationale and background. Am therapy: a critically appraised topic. Neurologist. J Geriatr Psychiatry. 2002;10:129–41. 2011;17:121–3. 21. Breitbart W, Marotta R, Platt MM, Weisman H, 7. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer Derevenco M, Grau C, et al. A double-blind trial of K, Grundman M, et al. A controlled trial of selegiline, haloperidol, chlorpromazine, and lorazepam in the alpha-tocopherol, or both as treatment for Alzheimer’s treatment of delirium in hospitalized AIDS patients. disease. The Alzheimer’s Disease Cooperative Study. Am J Psychiatry. 1996;153:234–7. N Engl J Med. 1997;336:1216–22. 22. Herrmann N. Use of SSRIs in the elderly: obvious 8. Petersen RC, Thomas RG, Grundman M, Bennett D, beneﬁ ts but unappreciated risks. Can J Clin Pharmacol. Doody R, Ferris S, et al. Vitamin E and donepezil for 2000;7:91–5. the treatment of mild cognitive impairment. N Engl J 23. Teri L, Gallagher-Thompson D. Cognitive-behavioral Med. 2005;352:2379–88. interventions for treatment of depression in 9. Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, Alzheimer’s patients. Gerontologist. 1991;31:413–6. van Dyck CH, Weiner MF, et al. High-dose B vitamin 24. Teri L, Gibbons LE, McCurry SM, Logsdon RG, supplementation and cognitive decline in Alzheimer Buchner DM, Barlow WE, et al. Exercise plus behav- disease: a randomized controlled trial. J Am Med ioral management in patients with Alzheimer disease: Assoc. 2008;300:1774–83. a randomized controlled trial. J Am Med Assoc. 10. Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, 2003;290:2015–22. Nelson EB, Van Dyck C, et al. Docosahexaenoic acid 25. Zec RF, Burkett NR. Non-pharmacological and phar- supplementation and cognitive decline in Alzheimer macological treatment of the cognitive and behavioral disease: a randomized trial. J Am Med Assoc. symptoms of Alzheimer disease. NeuroRehabilitation. 2010;304:1903–11. 2008;23:425–38. 11. Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, 26. Teri L, Logsdon RG. Identifying pleasant activities Costantini LC. Study of the ketogenic agent AC-1202 for Alzheimer’s disease patients: the pleasant events in mild to moderate Alzheimer’s disease: a random- schedule-AD. Gerontologist. 1991;31:124–7. ized, double-blind, placebo-controlled, multicenter 27. Weiner MF, Teri L. Psychological and behavioral trial. Nutr Metab (Lond). 2009;10:31. management. In: Weiner MF, Lipton AM, editors. The 12. Roman MW. Axona (Accera, Inc): a new medical dementias: diagnosis, treatment and research. food therapy for persons with Alzheimer’s disease. Washington, D.C.: American Psychiatric Publishing, Issues Ment Health Nurs. 2010;31:435–6. Inc; 2003. p. 181–218. 13. Scheltens P, Kamphuis PJ, Verhey FR, Olde Rikkert 28. Chemerinski E, Petracca G, Manes F, Leiguarda R, MG, Wurtman RJ, Wilkinson D, et al. Ef ﬁ cacy of a med- Starkstein SE. Prevalence and correlates of anxiety in ical food in mild Alzheimer’s disease: a randomized, Alzheimer’s disease. Depress Anxiety. 1998;7:166–70. controlled trial. Alzheimers Dement. 2010;6:1–10. 29. Luxenberg JS. Clinical issues in the behavioural and 14. Hulme C, Wright J, Crocker T, Oluboyede Y, House psychological symptoms of dementia. Int J Geriatr A. Non-pharmacological approaches for dementia Psychiatry. 2000;15:5–8. that informal carers might try or access: a systematic 30. Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, review. Int J Geriatr Psychiatry. 2009;25:756–63. Breitner J, DeKosky S. Prevalence of neuropsychiat- 15. Desai AK, Grossberg GT. Diagnosis and treatment of ric symptoms in dementia and cognitive impairment: Alzheimer’s disease. Neurologic disorders update: cur- results from the Cardiovascular Health Study. J Am rent thinking and practices. Neurology. 2005;64:34–9. Med Assoc. 2002;288:1475–83. 16. Swanson KA, Carnahan RM. Dementia and comor- 31. Madhusoodanan S, Bogunovic OJ. Safety of benzodi- bidities: an overview of diagnosis and management. azepines in the geriatric population. Expert Opin Drug J Pharm Pract. 2007;20(4):296–317. Saf. 2004;3:485–93. 17. Martin BK, Frangakis CE, Rosenberg PB, Mintzer JE, 32. Ballard C, Creese B, Corbett A, Aarsland D. Atypical Katz IR, Porsteinsson AP, et al. Design of depression antipsychotics for the treatment of behavioral and 76 S. Hoover and M. Sano

psychological symptoms in dementia, with a particular 49. Sultzer DL, Levin HS, Mahler ME, High WM, focus on longer term outcomes and mortality. Expert Cummings JL. A comparison of psychiatric symp- Opin Drug Saf. 2011;10:35–43. toms in vascular dementia and Alzheimer’s disease. 33. Cummings JL. Cholinesterase inhibitors: a new class of Am J Psychiatry. 1993;156:1806–12. psychotropic compounds. Am J Psychiatry. 2000;157: 50. Aharon-Peretz J, Masiah A, Pillar T, Epstein R, 4–15. Tzischinsky OP, Lavie P. Sleep-wake cycles in multi- 34. Gleason OC. Delirium. Am Fam Physician. 2003; infarct dementia and dementia of the Alzheimer’s 67:1027–34. type. Neurology. 1991;41:1616–9. 35. Fick DM, Cooper JW, Wade WE, Waller JL, Maclean 51. Ala TA, Yang KH, Sung JH, Frey II WH. Hallucinations R, Beers MH. Updating the Beers criteria for poten- and signs of parkinsonism help distinguish patients tially inappropriate medication use in older adults: with dementia and cortical Lewy bodies from patients results of a U.S. panel of experts. Arch Intern Med. with Alzheimer’s disease at presentation a clinico- 2003;163:2716–24. pathological study. J Neurol Neurosurg Psychiatry. 36. Gilley DW, Wilson RS, Beckett LA, Evans DA. 1997;62:16–21. Psychotic symptoms and physically aggressive behav- 52. Boeve BF, Silber MH, Ferman TJ, Kokmen E, Smith ior in Alzheimer’s disease. J Am Geriatr Soc. 1997;45: GE, Ivnik RJ, et al. REM sleep behavior disorder and 1074–9. degenerative dementia—an association likely refl ecting 37. Tariot PN, Blazina L. The psychopathology of demen- Lewy body disease. Neurology. 1998;51:363–70. tia. In: Morris JC, editor. Handbook of dementing 53. McKeith I, Fairbairn A, Perry R, Thompson P, Perry E. illnesses, neurological disease and therapy. New York: Neuroleptic sensitivity in patients with senile dementia Marcel Dekker, Inc; 1994. p. 461–76. of Lewy body type. Br Med J. 1992;305:673–8. 38. Whitehouse PJ, Patterson MB, Strauss ME, 54. Lindau M, Almkvist O, Johansson SE, Wahlund LO. Geldmacher DS, Mack JL, Gilmore GC, et al. Cognitive and behavioral differentiation of frontal Hallucinations. Int Psychogeriatr. 1996;8:387–92. lobe degeneration of the non-Alzheimer’s type and 39. Schneider LS, Pierre N, Tariot PN, Dagerman KS, Alzheimer’s disease. Dement Geriatr Cogn Disord. Davis SM, Hsiao JK, et al. Effectiveness of atypical 1997;9:205–13. antipsychotics in patients with Alzheimer’s disease. 55. Mendez MF, Perryman KM, Miller BL, Cummings N Engl J Med. 2006;355:1525–38. JL. Behavioral differences between frontotemporal 40. Sink KM, Holden KF, Yaffe K. Pharmacological treat- dementia and Alzheimer’s disease: a comparison on ment of neuropsychiatric symptoms of dementia. J Am the BEHAVE-AD rating scale. Int Psychogeriatr. Med Assoc. 2005;293:596–608. 1998;10:155–62. 41. Nagaratnam N, Lewis-Jones M, Scott D, Palazzi L. 56. Whitehouse P, Frisoni G, Post S. Breaking the diagno- Behavioral and psychiatric manifestations in demen- sis of dementia. Lancet Neurol. 2004;3:124–8. tia patients in a community: caregiver burden and 57. Gauthier S. Advances in the pharmacotherapy of outcome. Alzheimer Dis Assoc Disord. 1998;12: Alzheimer’s disease. Can Med Assoc J. 2002;166: 330–4. 616–23. 42. Cohen-Mans fi eld J, Mintzer JE. Time for change: the 58. Logsdon RG, Pike KC, McCurry SM, Hunter P, role of nonpharmacological interventions in treating Maher J, Snyder L, et al. Early-stage memory loss behavior problems in nursing home residents with support groups: outcomes from a randomized con- dementia. Alzheimer Dis Assoc Disord. 2005;19: trolled clinical trial. J Gerontol B Psychol Sci Soc Sci. 37–40. 2010;65:691–7. 43. Mann AH, Graham N, Ashby D. Psychiatric illness in 59. Goldsilver PM, Gruneir MRB. Early stage dementia residential homes for the elderly: a survey in one group: an innovative model of support for individuals London borough. Age Aging. 1984;13(5):257–65. in the early stages of dementia. Am J Alzheimers Dis 44. Buchanan JA, Christenson AM, Ostrom C, Hofman Other Demen. 2001;16:109–14. N. Non-pharmacological interventions for aggression 60. Logsdon RG, McCurry SM, Teri L. Timelimited sup- in persons with dementia: a review of the literature. port groups for individuals with early stage dementia Behav Analyst Today. 2007;8:413–25. and their care partners: preliminary outcomes from a 45. Inouye SK. Delirium and other mental status prob- controlled clinical trial. Clin Gerontol. 2006;30:5–19. lems in the older patient (Chapter 26). In: Goldman L, 61. Zarit SH, Femia EE, Watson J, Rice-Oeschger L, Ausiello D, editors. Cecil medicine. 23rd ed. Kakos B. Memory club: a group intervention for peo- Philadelphia, PA: Saunders Elsevier; 2007. ple with early-stage dementia and their care partners. 46. Francis J. Delusions, delirium, and cognitive impair- Gerontologist. 2004;44:262–9. ment: the challenge of clinical heterogeneity. Journal 62. Gräßel E, Trilling A, Donath C, Luttenberger K. of the American Geriatric Society. 1992;40:844–9. Support groups for dementia caregivers—predictors 47. Fick DM, Agostini JV, Inouye SK. Delirium superim- for utilisation and expected quality from a family posed on dementia: A systematic review. Journal of caregiver’s point of view: a questionnaire survey the American Geriatric Society. 2002;50:1723–32. PART I. BMC Health Serv Res. 2010;10:219–26. 48. Flaherty JH. The evaluation and management of delir- 63. Kurz A, Hallauer J, Jansen S, Diehl J. Ef fi cacy of ium among older persons. Med Clin North Am. caregiver support groups for dementia. Der Nervenarzt. 2011;95:555–77. 2005;76:261–9. 5 After the Diagnosis of Dementia: Considerations in Disease Management 77

64. Thompson C, Spilsbury K. WITHDRAWN: Support 68. Jack Jr CR, Albert MS, Knopman DS, McKhann GM, for carers of people with Alzheimer’s type dementia. Sperling RA, Carrillo MC, et al. Introduction to the Cochrane Database Syst Rev. 2007:CD000454. recommendations from the National Institute on 65. Mittelman MS, Ferris SH, Shulman E, Steinberg G, Levin Aging-Alzheimer’s Association workgroups on diag- B. A family intervention to delay nursing home placement nostic guidelines for Alzheimer’s disease. Alzheimers of patients with Alzheimer disease: a randomized con- Dementia. 2011;7:257–62. trolled trial. J Am Med Assoc. 1996;276:1725–31. 69. Pul R, Dodel R, Stangel M. Antibody-based therapy 66. Weiner MW, Aisen PS, Jack Jr CR, Jagust WJ, in Alzheimer’s disease. Expert Opin Biol Ther. Trojanowski JQ, Shaw L, et al. The Alzheimer’s dis- 2011;11:343–57. ease neuroimaging initiative: progress report and 70. National Institutes of Health. Studies ﬁ nd possible future plans. Alzheimers Dement. 2010;6:202–11. new genetic risk factors for Alzheimer’s disease [Press 67. Aisen PS, Petersen RC, Donohue MC, Gamst A, Release]. http://www.nia.nih.gov/newsroom/2011/04/ Raman R, Thomas RG, et al. Clinical core of the studies-find-possible-new-genetic-risk-factors- Alzheimer’s disease neuroimaging initiative: progress alzheimers-disease (2011). and plans. Alzheimers Dementia. 2010;6:239–46. Sleep and Aging 6 Matthew R. Ebben

Abstract The purpose of this chapter is to discuss changes in sleep quality and architecture that occur as one ages. Normal age related changes in sleep architecture will be discussed ﬁ rst, followed by sleep and circadian rhythm disorders that increase in prevalence as we age. Finally, a short section at the end of this chapter discusses neurological disorders more frequently seen in older adults, and their impact on sleep.

Keywords Insomnia ¥ Geriatric ¥ Sleep architecture ¥ Circadian rhythms ¥ Treatment ¥ REM behavior disorder ¥ Apnea

There is a general perception that degradation of defining age chronologically. Some have argued sleep quality is a normal part of aging. In fact, prac- that subjective or physiological age and time from titioners who see geriatric patients on a regular basis death are more accurate ways of defining age; how- often hear complaints of sleep difficulties in their ever, chronological age is the most consistent patients. As we age, a number of age-related health definition for aging. Therefore, it is the one used problems are associated with difficulty sleeping. It within this chapter. is often difficult to differentiate sleep problems secondary to underlying health problems or medication effects from primary sleep disorders. This Changes in Sleep Architecture chapter will review the changes that occur in sleep as We Age quality as one ages and will address sleep disorders often seen in the older adults. The data discussed A number of studies have been conducted to look within this chapter is almost exclusively based on at changes in sleep architecture over the life span. One of the most consistent age-related changes M. R. Ebben, Ph.D. () in sleep architecture is a decline in delta or Department of Neurology and Neuroscience, slow-wave sleep (SWS). SWS is defi ned elec- Center for Sleep Medicine , New York Presbyterian trographically by low-frequency (0.5Ð2 Hz), Hospital, Weill Cornell Medical College , 425 East 61st Street , New York , NY 10065 , USA high-amplitude (>75 m V) waveforms [1 ] and is e-mail: [email protected] primarily confi ned to the fi rst half of the sleep

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 79 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_6, © Springer Science+Business Media, LLC 2013 80 M.R. Ebben period (as long as the person is not rebounding Table 6.1 Changes in sleep variables with aging from a period of sleep deprivation). Behaviorally, Sleep variable Change in % (or min) SWS is distinct from other stages of sleep because N1 ↑ of a higher arousal threshold. The decrease in N2 Ð SWS over the life span was originally described in SWS ↓ the 1970s and has been confi rmed by several stud- REM ↓ ies since that time [ 2Ð 6 ] . A recent comprehensive SE ↓ meta-analysis of 65 studies concluded that SWS WASO (min) ↑ declines at a rate of approximately 2% per decade KEY: N1= stage 1 sleep, N2 = stage 2 sleep, SWS = slow- of adult life, and plateaus at approximately 60 years wave sleep, REM = rapid eye movement sleep, SE = sleep of age [ 7 ] . There appears to be a gender difference, effi ciency, and WASO = wake after sleep onset. All variables are listed as a percentage of total sleep time, except with men showing a dramatic decrease in SWS. WASO, which is in minutes, and SE, which is the total sleep However, in women, delta sleep is preserved across time/time in bed the life span [ 8 ] . Generally, the EEG frequency of SWS is maintained in older adults, whereas the amplitude of the waveform decreases [2 ] . It is sleep and SWS. However, like SWS sleep, the thought that this decrease in amplitude of SWS is level of N1 sleep seems to be better preserved in a result of atrophy of brain tissue over time. woman than in men [8 ] . As the name implies, rapid eye movement Stage 2 sleep (N2) is de fi ned by an EEG signal (REM) sleep is defi ned by REMs, mixed fre- that contains both K-complexes (negative to posi- quency, low-voltage EEG (similar to the waking tive spikes with a duration of ³ 0.5 s) and sleep spin- state), and muscle atonia [ 1 ] . REM sleep at one dles (periods of relatively fast, synchronous EEG time was also called paradoxical sleep because it activity that looks like a spindle of yarn and is gen- is electrographically similar to waking. The erated by the thalamus). These two electrographic majority of REM sleep is typically present in the patterns are superimposed on a background of theta second half of the night. However, as we age, (4Ð7 Hz) activity [1 ] . N2 sleep makes up the major- there tends to be a shift in REM sleep to earlier in ity of the sleep period throughout the life span. the night, resulting in a slightly decreased latency Although the relative percentage of N2 sleep to REM sleep [ 7, 9] . Also, a decrease of approxi- changes very little over time, the landscape of this mately 0.6% per decade in percentage of REM sleep stage undergoes signi fi cant changes. Sleep sleep [7, 8 ] has been reported [10 ] , but this trend spindles and K-complexes become less numerous, toward decreased REM percentage has not been and the frequency of the spindles become slower as found in all studies [9 ] . we age (Table 6.1 ) [ 11 ] . Stage 1 sleep (now called N1 sleep) is a light, transitional stage of sleep between waking and stage 2 (N2) or REM sleep. It is de fi ned by mixed Insomnia in Older Adults frequency, low-voltage brain waves with slow rolling eye movements [1 ] . When awakened from Insomnia is one of the most prevalent health con- N1 sleep, individuals often report that they were cerns worldwide. Current estimates indicate that unaware that they were sleeping, which under- 6Ð15% of the population suffers from insomnia lines the transitional nature of N1 sleep. An [12 ] . According to the International Classi fi cation increased level of N1 sleep is often seen as a of Sleep Disorders [ 13 ] , insomnia is de fi ned as a marker for fragmentation of the sleep architec- complaint of diffi culty initiating or maintaining ture. Compared to the young, there is a mild to sleep, waking up too early, or experiencing sleep moderate increase in N1 sleep in the older adults, that is consistently not refreshing. The sleeping suggesting there is increased sleep fragmentation diffi culty should also be accompanied by daytime [7 ] . It is thought that the increase in N1 sleep may impairment, such as diffi culty concentrating, be, in part, due to the reduction in both REM memory diffi culties, fatigue, stomach problems, 6 Sleep and Aging 81

Fig. 6.1 The role of the 3Ps in the increase of insomnia effect of each of the three factors (predisposing, precipitat- severity over time. An illustration of the progression of ing, and perpetuating) described in the 3-P model. The insomnia over time. The severity of insomnia is an additive relative importance of these factors changes over time irritability, or reduced motivation. Studies inves- within the framework of the 3-P model (see tigating the impact of chronic insomnia demon- Fig. 6.1). The 3Ps in this model stand for predis- strated reduced quality of life, higher absenteeism, posing, precipitating, and perpetuating factors of impaired job performance, and higher health-care insomnia. Predisposing characteristics are genetic utilization [14, 15 ] . or underlying personality traits such as basal level In older adults, the prevalence of insomnia of anxiety or hyperarousal. Individuals with high appears to be even higher than in the general levels of anxiety or hyperarousal, for example, population. In the mid-1990s, a large-scale are at increased risk of developing insomnia epidemiological study was conducted that regardless of age [18 ] . These factors are consid- included nearly 7,000 individuals aged 65 and ered to be relatively stable over the life span and older. Over half of those surveyed complained of should not be dramatically increased with age. frequent dif fi culty sleeping [16 ] . Nearly a quarter Precipitating events are events that stimulate the of participants reported symptoms consistent with onset of insomnia. Baseline level of predisposing insomnia. Surprisingly, less than 20% reported factors will determine the magnitude of a precipi- little or no complaint of dif fi culty sleeping. When tating event necessary to cause the onset of insom- sleep quality in older compared to young adults nia. Precipitating events include factors such as was objectively investigated, there was a decrease health and emotional problems, or death of friends in total sleep time and an increase in wake time or family members. Factors such as these can after sleep onset [ 7 ] . However, when mood and induce periods of diffi culty sleeping [ 19 ] . As we health problems were controlled for, the preva- age, we are more likely to be exposed to precipitat- lence of insomnia was dramatically lower at 7%. ing factors; therefore, the likelihood of developing Once health or mood problems dissipate, symp- acute insomnia increases. A perpetuating event is toms of insomnia are also likely to disappear [17 ] . an event that causes the insomnia to continue This suggests that insomnia is commonly a symp- even after the precipitating event has passed. tom of concomitant health or mood problems, and Perpetuating activities commonly include mal- not vice versa. adaptive behaviors, such as prolonged time in bed, To better understand how insomnia progresses eating, using a computer or watching television over time, it is helpful to discuss this condition in bed, and drinking alcohol in an effort to help 82 M.R. Ebben

EXAMPLE: Into bed Out of bed

Fatigue Morning’s Time to Amount of Rating 6 7 8 9 10 11 Mid 1 2 3 4 5 6 7 8 9 10 11Noon 123456Date Fall asleep Sleep 1 Lo—10 Hi 1 C Mo 12/10 100 min 5 hours 3 C 1 = Benadryl, 50 mg Caffeine

Medication Asleep

Fatigue Morning’s Time to Amount of Rating 678910 11 Mid 1 2 3 4 5 6 7 8 9 10 11Noon 123456 Date Fall asleep Sleep 1 Lo—10 Hi

Medication 1 ______Dosage ______Medication 2 ______Dosage ______

Alcohol Day 1______2 ______3______4 ______5 ______6______7______

Fig. 6.2 A version of the City College of New York sleep ber prior to the black dot indicates when medications were log. Patients are instructed to complete this log upon awak- taken (if any were taken before bedtime). Medications ening in the morning. The black dot indicates the time the taken at other times of the day are listed below the chart. patient got into bed, and the black lines represent periods C indicates time of caffeine consumption. Daily alcohol con- of sleep. The black circle shows time out of bed. The num- sumption for each day is listed below medications [22 ] promote sleep. Acute insomnia becomes chronic included sleep restriction therapy, stimulus control, due to these perpetuating habits, practices, and cognitive therapy, and relaxation techniques. Sleep worrying. Older adults may be at greater risk for hygiene education is also commonly part of CBT-I engaging in some perpetuating activities like treatment; however, it has not been shown to spending too much time in bed because they are improve sleep quality when used in isolation of often retired and have more fl exible schedules. other techniques. Each of these treatments will be briefl y discussed below; for a more comprehensive review, please refer to Ebben and Spielman [22 ] . Treatment Approaches Sleep restriction therapy was originally developed by Spielman et al. [ 23 ] . It involves drasti- The fi rst line of treatment considered for insomnia cally reducing a patient’s time in bed in order to for the majority of Americans is typically pharma- help consolidate sleep. Typically, sleep logs are cotherapy [20 ] . Many of the benzodiazepines completed for a period of 2Ð4 weeks (see Fig. 6.2 ). prescribed for insomnia increase risk for falls. Based on the time in bed and the total sleep time This is particularly problematic for older adults documented on the sleep log, a new sleep/wake because they are already at a heightened risk for schedule is calculated. This new schedule only falls. In addition, treating insomnia with medica- provides enough time (or less) in bed to achieve tion is typically not as durable as non-pharmaco- the patient’s current sleep time. Once the patient logical treatments, such as cognitive behavioral begins the new schedule, they typically accumu- therapy for insomnia (CBT-I) [21 ] . late a sleep debt, which presumably helps them CBT-I is a general term that describes a host of consolidate their sleep. Once sleep is consolidated treatments that have been shown empirically to into this relatively short period of time, total sleep improved quality of sleep. These commonly time is slowly extended to satisfy the patient’s 6 Sleep and Aging 83 sleep need. Although this technique can be dif fi cult Relaxation techniques are treatments that for the patient to execute at fi rst, if performed cor- focus on tension in the muscles. Progressive mus- rectly, sleep restriction therapy can greatly improve cle relaxation (PMR) is the most common relax- sleep quality and daytime functioning. ation technique used for insomnia; however, Stimulus control therapy focuses on the role of EMG biofeedback is also occasionally used. conditioned wakefulness in maintaining insom- PMR is typically used at bedtime and involves nia. Often when individuals spend sleepless having the individual progressively tense then nights lying in bed, they condition themselves to relax muscles throughout the body starting with expect wakefulness in their bedroom environ- the head or toes. In general, this technique has ment. Once this occurs, commonly the individual been shown to improve quality of sleep [24 ] . will begin to spend more time in bed hoping it Interestingly, some data show that if this tech- will increase the likelihood that they will sleep nique is used in insomniacs without muscle ten- more; however, frequently the opposite occurs. sion, it can worsen their sleep [25 ] . When this conditioning pattern has developed, it is not uncommon for the patient to report improved sleep away from home. Emphasizing Circadian Rhythms in Aging this notion of conditioned insomnia is the fact that even during laboratory polysomnograms, The term circadian is derived from the Latin roots which involve numerous pieces of bothersome circa (meaning “about”) and diem (“day”). A cir- apparatus, individuals with conditioned wakeful- cadian rhythm is a rhythm that is approximately ness can achieve improved sleep quality. 24 h or 1 day long. The pacemaker, or master clock Therefore, the goal of stimulus control therapy is of mammalian circadian rhythms, is located in the to separate sleep from wakefulness activities. suprachiasmatic nucleus above the optic chiasm This is done by encouraging the patient to reserve [ 26 ] . Circadian rhythms are generally set or reset the bedtime for only sleep and sexual activity. by daytime light exposure, which naturally entrains Activities such as watching TV or listening to the the rhythm of the clock to a 24-h day. The human radio in bed, for example, should be eliminated. endogenous circadian rhythm (in the absence of The practice of cognitive therapy to treat light) in young and middle-age adults is typically insomnia differs little from its practice in treating longer than 24 h. Therefore, in controlled condi- other types of psychopathology. Often patients tions that exclude light, an individual tends to fall with insomnia develop erroneous associations asleep and wake-up a bit later each day. between their diffi culty sleeping and other prob- Studies in aged animals have shown a fl attening lems they are experiencing. For example, some and desynchronization of circadian rhythms, may begin to worry that without high-quality which can be restored by transplanting suprachi- sleep, they will completely lose their ability to asmatic tissue from younger animals [ 27 ] . In function during the day. However, most individu- humans, a reduction in period length and ampli- als with insomnia have maintained somewhat tude of circadian rhythms is seen in older adults normal daytime schedules, even after several compared to the young [ 28 ] . Clinically, it is not nights of poor quality sleep. The goal of the cog- uncommon to hear complaints from older adults nitive therapist is to replace the patient’s cata- regarding falling asleep too early and waking up strophic thinking with more realistic thoughts. too early. This condition is referred to as advanced This process often takes longer than behavioral sleep phase syndrome (ASPS). It is easy to con- techniques because many thought patterns are fuse this type of complaint with insomnia; more effectively approached indirectly (at least at however, it is important to differentiate circadian fi rst). Gaining permission from the patient to rhythm disorders from insomnia because the restructure their thought process requires a bond treatments for each disorder are different. between the patient and therapist, which takes Differentiating ASPS from insomnia is done time to develop. through a careful examination of the patient’s 84 M.R. Ebben sleep/wake pattern. For example, if a patient not the typical cognitive-behavioral treatments reports a long history (usually since childhood or reviewed previously in this chapter. A detailed adolescence) of diffi culty both falling asleep at review of the various treatment options for these night and waking up in the morning, there is a disorders is beyond the scope of this chapter; for very good chance they suffer from delayed sleep a thorough review on this topic, please refer to phase syndrome (DSPS). It is quite common for Zee [30 ] . insomniacs to report diffi culty falling asleep. However, it is much less common for insomnia sufferers to report diffi culty waking up in the Sleep-Disordered Breathing morning. This condition is frequently seen in (Sleep Apnea) teenagers and young adults, although it can also be present in older individuals. In other cases, the Apnea is a Latin term that means “without patient may report a history of falling asleep or breath.” Sleep-disordered breathing (SDB) is a getting sleepy early in the evening and then general name that includes two primary breathing waking up too early, unable to fall back to sleep. disorders that occur during sleep. These two These individuals may be suffering from ASPS. disorders are called obstructive sleep apnea This disorder has an estimated prevalence of (OSA) and central sleep apnea (CSA). OSA con- approximately 1% overall but is more frequently sists of a decrease or cessation in airfl ow second- seen in the older adults, with an estimated preva- ary to a collapse in the upper airway. Another lence of 7% in this age group [ 29 ] . It is not type of respiratory event included in the diagno- uncommon to hear patients with ASPS report sis of OSA is called hypopnea. This is a reduction bedtimes of 6 pm with wake times of 2 am. In in air fl ow accompanied by a decrease in blood addition to physiological changes in period length oxygen saturation [ 1 ] . CSA, as the name implies, of circadian rhythms such as core body tempera- refers to cessation of air fl ow secondary to lack of ture and melatonin that occur with age, behav- signaling to breathe from the higher brain areas ioral patterns such as a less social activities in the or “central centers.” evening and less light exposure in general may It is normal to have some respiratory events lead to the development ASPS. during sleep; however, having too many is prob- In both DSPS and ASPS, if the individual has lematic. The diagnosis of sleep apnea is deter- an adequate opportunity to sleep at their preferred mined by a sleep study or polysomnogram during time, total sleep time is generally within normal which sleep stages and respiratory events are limits and daytime sleepiness is usually not monitored. Apneas and hypopneas are typically reported. However, particularly in cases of DSPS, grouped into one index called the apnea-hypopnea daytime social activities can limit the person’s index or AHI, which is the total number of apneas ability to sleep into the late morning or early and hypopneas divided by the total hours of sleep. afternoon on a regular basis; as a result, they The typical range of AHI severity is as follows: often report daytime sleepiness. Patients with 5Ð15 mild, 15Ð30 moderate, and ³ 30 is severe ASPS are often bothered by the boredom of wak- [31 ] . The decrease in oxygen saturation associ- ing at a time when other friends and family mem- ated with the respiratory events also factors into bers are still sleeping. In addition, the early the severity of SDB. Typically, respiratory events bedtime limits their ability to take part social result in brief arousals from sleep, which can activities in the evening. DSPS and ASPS are cause daytime sleepiness. In fact, the majority of some of the most common circadian rhythm dis- adults with SDB complain of excessive daytime orders in both young and older adults; however, sleepiness [32 ] . numerous other circadian sleep disorders exist. OSA is a serious health problem and puts Generally, circadian rhythm disorders are patients at greater risk for hypertension, con- treated with a combination of bright light, mela- gestive heart failure, cardiac arrhythmia and tonin, and/or a customized sleep/wake schedule, ischemia, and cerebrovascular disease [ 33 ] . 6 Sleep and Aging 85

The prevalence of SDB in American adults is 4% It appears that RBD can also be a prodrome of for males and 2% for females [34 ] , and the preva- synucleinopathies. Estimates suggest there is a lence of moderate to severe apnea increases dra- mean interval of approximately 10 years from the matically with age. The Sleep Health Heart Study development of RBD to the diagnosis of a synu- found a prevalence of SDB of 20% in adults over cleinopathy [38 ] ; however, RBD has been shown the age of 60 [35 ] . to precede the onset of clinical symptoms in Treatment for SDB most commonly involves Parkinson’s disease by as long as fi ve decades the use of continuous positive airway pressure [38 ] . In one small study (n = 29), 38% of men (CPAP). CPAP is basically a medical quality air originally diagnosed with idiopathic RBD devel- compressor that blows air into the patient’s air- oped Parkinson’s disease later in life [ 39 ] . way causing a pneumatic splint. Once the appro- Withdrawal from alcohol or sedative medication, priate CPAP pressure is determined, the patient as well as the use of tricyclic antidepressants, has begins using the CPAP machine nightly during also been associated with the development of sleep. Use of CPAP typically causes a reduction RBD [40 ] . in clinical symptoms of OSA such as snoring and Treatment for RBD generally involves the excessive daytime sleepiness. It is also thought to nightly use of a low dose of clonazepam, which reduce the risk of the other disorders associated has been found effective in eliminating or with sleep apnea mentioned above. reducing RBD symptoms in 90% of cases [ 41 ] . However, once the medication is discontinued, the symptoms of RBD return. Other benzodiaz- REM Behavior Disorder epines are also occasionally used if the patient cannot tolerate the side effects of clonazepam. REM behavior disorder (RBD) is a condition that is de fi ned by increased motor activity during REM sleep. Dream mentation is thought to occur Common Neurologic Disorders That more frequently during periods of REM sleep. Affect Sleep During REM, voluntary muscles are inhibited through the inhibition of spinal motor neurons Alzheimer’s disease (AD) is a progressive neuro- [ 36 ] , thereby preventing movement during degenerative disorder that is often associated dreaming episodes. However, in individuals with with behavioral problems, particularly as the RBD, the inhibition of these muscles is absent or disease progresses. A common behavioral prob- incomplete. This disinhibition presumably allows lem referred to as sundowning represents agita- the person to act out their dreams. This may tion and wandering that is often exacerbated after involve violent actions such as kicking, punch- sundown. EEG fi ndings in AD are typically an ing, or screaming (the type of movement that exacerbation of the progression normally seen in occurs, most likely, depends on the dream content). elderly patients. This includes a decrease in REM RBD is more common in older males with an sleep and SWS, increased sleep fragmentation, estimated prevalence of approximately 0.5% in and a fl atting of phasic events such as K-complexes older adults [ 13] . In most cases, RBD develops and sleep spindles normally seen in N2 sleep after the age of 50. (reviewed in Petit et al. [42 ] ). There is growing evidence of the association Parkinson’s disease (PD) is a neuromuscular between RBD and synucleinopathies such as disorder that causes tremors, rigidity, stiffness, Parkinson’s disease, Lewy body disease, and bradykinesia, and coordination problems. In multiple systems atrophy (MSA). In fact, one addition to the higher incidence of RBD described study found that 69% of patients with MSA also above, a signifi cant percentage of PD patients had RBD [37 ] . Another study found that 33% of complain of sleep problems. In a study of 149 PD patients with Parkinson’s disease that under- patients with age-matched controls, 42% were went sleep studies were also found to have RBD. found to have sleep diffi culty compared to only 86 M.R. Ebben

12% in the control group [ 43 ] . The most common which can and should be differentiated from sleep problems reported were insomnia, night- insomnia because the treatments are different. mares, and excessive daytime sleepiness (EDS). ¥ REM behavior disorder (RBD) is a disorder It has been hypothesized that sleepiness in PD that is most common in older adult men and patients is partially related to the use of dopamine may be a prodrome for synucleinopathies. agonists. This theory was recently refuted by the ¥ RBD can be effectively controlled in 90% of Canadian Movement Disorders Group who found patients with the use of low-dose clonazepam. EDS was common in PD patients. In summary, there are a host of reasons for changes in our sleep as we age. These include References signifi cant changes in sleep architecture, as well as an increased frequency of a number of sleep 1. AASM. The AASM Manual for the Scoring of Sleep disorders, some of which can be attributed to and Associated Events: Rules, Terminology and Technical Speci fi cations. Darien: American Academy underlying health or mood disorders. Age-related of Sleep Medicine; 2007. behavioral changes, such as a lack of a defi ned 2. Feinberg I. Functional implications of changes in daily schedule (i.e., work schedule), also contribute sleep physiology with age. In: Gershon S, Terry RD, to sleep disorders such as insomnia or circadian editors. Neurobiology of aging. New York: Raven; 1976. p. 23Ð41. rhythm disorders. Disorders that result from behav- 3. Olivier-Martin R, Cendron H, Vallery-Masson J. ioral changes can frequently be treated successfully [Sleep in elderly subjects. Description, analysis of with behavior modifi cation and do not necessarily various data obtained in a rural population]. Ann Med need pharmacological intervention. A list of practi- Psychol. 1975;1:77Ð90. 4. Feinberg I, March JD, Fein G, Aminoff MJ. Log tioners trained in the use of cognitive-behavioral amplitude is a linear function of log frequency in treatments for sleep disorders can be found on the NREM sleep eeg of young and elderly normal sub- website of the American Academy of Sleep jects. Electroencephalogr Clin Neurophysiol. 1984;58: Medicine. In situations where the sleep disorder is 158Ð60. 5. Ehlers CL, Kupfer DJ. Effects of age on delta and secondary to another condition, treatment of the REM sleep parameters. Electroencephalogr Clin primary disorder is recommended fi rst before sleep Neurophysiol. 1989;72:118Ð25. symptoms are the target of intervention. 6. Lauer CJ, Riemann D, Wiegand M, Berger M. From early to late adulthood. Changes in EEG sleep of depressed patients and healthy volunteers. Biol Psychiatry. 1991;29:979Ð93. Clinical Pearls 7. Ohayon MM, Carskadon MA, Guilleminault C, Vitiello MV. Meta-analysis of quantitative sleep ¥ Deterioration of sleep quality is not necessar- parameters from childhood to old age in healthy individuals: developing normative sleep values across the ily a normal part of aging and is most often human lifespan. Sleep. 2004;27:1255Ð73. associated with physical or psychological 8. Redline S, et al. The effects of age, sex, ethnicity, and maladies. sleep-disordered breathing on sleep architecture. Arch ¥ Changes in sleep architecture as we age often Intern Med. 2004;164:406Ð18. 9. Dijk DJ, Duffy JF, Riel E, Shanahan TL, Czeisler CA. include a decrease in SWS and a shift of REM Ageing and the circadian and homeostatic regulation sleep earlier in the night. of human sleep during forced desynchrony of rest, ¥ Use of hypnotic medication for the treatment melatonin and temperature rhythms. J Physiol. of insomnia is often not recommended in older 1999;516(Pt 2):611Ð27. 10. Floyd JA, Janisse JJ, Jenuwine ES, Ager JW. Changes adults because of the increased risk of falls. in REM-sleep percentage over the adult lifespan. ¥ The fi rst line of treatment for insomnia in the Sleep. 2007;30:829Ð36. elderly should be cognitive behavioral therapy 11. Wauquier A. Aging and changes in phasic events for insomnia (CBT-I). during sleep. Physiol Behav. 1993;54:803Ð6. 12. Ohayon MM. Prevalence and comorbidity of sleep ¥ Older persons appear to be at greater risk for cer- disorders in general population. Rev Prat. 2007;57: tain circadian rhythm disorders such as ASPS, 1521Ð8. 6 Sleep and Aging 87

13. Medicine, A.A.o.S. The international classi fi cation of 29. Ando K, Kripke DF, Ancoli-Israel S. Delayed and sleep disorders. Diagnostic and coding manual. advanced sleep phase symptoms. Isr J Psychiatr Relat Westchester: American Academy of Sleep Medicine; Sci. 2002;39:11Ð8. 2005. 30. Zee P. Circadian rhythm sleep disorders. Prim 14. Kuppermann M, et al. Sleep problems and their cor- Psychiatr. 2006;13:58Ð67. relates in a working population. J Gen Intern Med. 31. The Report of an American Academy of Sleep 1995;10:25Ð32. Medicine Task Force. Sleep-related breathing dis- 15. Simon GE, VonKorff M. Prevalence, burden, and orders in adults: recommendations for syndrome treatment of insomnia in primary care. Am J defi nition and measurement techniques in clinical Psychiatry. 1997;154:1417Ð23. research. Sleep. 1999;22:667Ð89. 16. Foley DJ, et al. Sleep complaints among elderly per- 32. Partinen M, Guilleminault C. Daytime sleepiness and sons: an epidemiologic study of three communities. vascular morbidity at seven-year follow-up in obstruc- Sleep. 1995;18:425Ð32. tive sleep apnea patients. Chest. 1990;97:27Ð32. 17. Foley DJ, Monjan A, Simonsick EM, Wallace RB, 33. Shamsuzzaman AS, Gersh BJ, Somers VK. Blazer DG. Incidence and remission of insomnia Obstructive sleep apnea: implications for cardiac and among elderly adults: an epidemiologic study of vascular disease. JAMA. 2003;290:1906Ð14. 6,800 persons over 3 years. Sleep. 1999;22 Suppl 34. Young T, et al. The occurrence of sleep-disordered 2:S366Ð72. breathing among middle-aged adults. N Engl J Med. 18. Drake C, Richardson G, Roehrs T, Sco fi eld H, Roth T. 1993;328:1230Ð5. Vulnerability to stress-related sleep disturbance and 35. Gozal D. Morbidity of obstructive sleep apnea in hyperarousal. Sleep. 2004;27:285Ð91. children: facts and theory. Sleep Breath. 2001;5: 19. Bastien CH, Vallieres A, Morin CM. Precipitating fac- 35Ð42. tors of insomnia. Behav Sleep Med. 2004;2:50Ð62. 36. Pompeiano O. The control of posture and move- 20. Walsh J, Schweitzer P. Ten-year trends in the pharma- ments during REM sleep: neurophysiological and cologic treatment of insomnia. Sleep Med Rev. neurochemical mechanisms. Acta Astronaut. 1975;2: 1999;22:371Ð5. 225Ð39. 21. Edinger JD, Wohlgemuth WK, Radtke RA, Marsh 37. Plazzi G, et al. REM sleep behavior disorders in mul- GR, Quillian RE. Cognitive behavioral therapy for tiple system atrophy. Neurology. 1997;48:1094Ð7. treatment of chronic primary insomnia: a randomized 38. Claassen DO, et al. REM sleep behavior disorder controlled trial. JAMA. 2001;285:1856Ð64. preceding other aspects of synucleinopathies by up to 22. Ebben MR, Spielman AJ. Non-pharmacological treat- half a century. Neurology. 2010;75:494Ð9. ments for insomnia. J Behav Med. 2009;32:244Ð54. 39. Schenck CH, Bundlie SR, Mahowald MW. Delayed 23. Spielman AJ, Caruso LS, Glovinsky PB. A behavioral emergence of a parkinsonian disorder in 38% of 29 perspective on insomnia treatment. Psychiatr Clin older men initially diagnosed with idiopathic rapid North Am. 1987;10:541Ð53. eye movement sleep behaviour disorder. Neurology. 24. Nicassio PM, Boylan MB, McCabe TG. Progressive 1996;46:388Ð93. relaxation. EMG biofeedback and biofeedback pla- 40. Ancoli-Israel S, Ayalon L, Salzman C. Sleep in the cebo in the treatment of sleep-onset insomnia. Br elderly: normal variations and common sleep disor- J Med Psychol. 1982;55:159Ð66. ders. Harv Rev Psychiatry. 2008;16:279Ð86. 25. Hauri PJ, Percy L, Hellekson C, Hartmann E, Russ D. 41. Mahowald MW, Bundlie SR, Hurwitz TD, Schenck The treatment of psychophysiologic insomnia with CH. Sleep violenceÐforensic science implications: biofeedback: a replication study. Biofeedback Self polygraphic and video documentation. J Forensic Sci. Regul. 1982;7:223Ð35. 1990;35:413Ð32. 26. Moore RY, Eichler VB. Loss of a circadian adrenal 42. Petit D, Gagnon JF, Fantini ML, Ferini-Strambi L, corticosterone rhythm following suprachiasmatic Montplaisir J. Sleep and quantitative EEG in neurode- lesions in the rat. Brain Res. 1972;42:201Ð6. generative disorders. J Psychosom Res. 2004;56: 27. Gibson EM, Williams 3rd WP, Kriegsfeld LJ. Aging in 487Ð96. the circadian system: considerations for health, disease 43. Kumar S, Bhatia M, Behari M. Sleep disorders in prevention and longevity. Exp Gerontol. 2009;44:51Ð6. Parkinson’s disease. Mov Disord. 2002;17:775Ð81. 28. Weitzman ED, Moline ML, Czeisler CA, Zimmerman 44. Hobson DE, et al. Excessive daytime sleepiness and JC. Chronobiology of aging: temperature, sleep-wake sudden-onset sleep in Parkinson disease: a survey by rhythms and entrainment. Neurobiol Aging. 1982;3: the Canadian Movement Disorders Group. JAMA. 299Ð309. 2002;287:455Ð63. Medications and Cognition in Older Adults 7

Gregg L. Caporaso

Abstract The elderly patient is particularly susceptible to negative effects on cognition that can arise from certain medications. This may occur whether or not pre-existing cognitive impairment is present. Medications whose primary target is the central nervous system (e.g., antidepressants, antipsychotics, sedative-hypnotics) or those which are targeted at other primary systems (e.g., cardiovascular drugs, urinary anti-spasmodics) should be considered as contributing factors in the patient with confusion or memory decline. Steps that can be taken to reduce this risk include: coordination of medical care among the patient’s clinicians to avoid polypharmacy, judi- cious selection of appropriate medications, use of the lowest effective drug dose, and substitution of non-pharmacologic therapies whenever possible. This chapter addresses potential complications of medication use in older adults with cognitive decline.

Keywords Cognition • Elderly • Medications • Tricyclic antidepressants • Antipsychotics • Neuroleptics • Anticholinergics • Benzodiazepines • Opiates

Practicing clinicians cannot escape the irony that disease) and that this same population is elderly patients are more predisposed to medica- prescribed more medications, some of which may tion side effects (e.g., due to reduced renal clearance) impair cognition. It is therefore incumbent upon the and to cognitive disorders (e.g., Alzheimer’s clinician to recognize when cognitive problems might be due to medications or combinations of * Craig D, Passmore AP, Fullerton KJ, Beringer TR, medications, which medications are the most com- Gilmore DH, Crawford VL, McCaffrey PM, Montgomery A. mon offending agents, and how to treat these indi- Factors in ﬂ uencing prescription of CNS medications in viduals optimally, by either substituting safer drugs different elderly populations. Pharmacoepidemiol Drug or using non-pharmacological therapies. In addition Saf. 2003;12(5):383–7. to adverse motor effects such as impaired ﬁ ne motor G. L. Caporaso , M.D., Ph.D. ( ) coordination and imbalance, many medications Division of Neurology , Westchester Health Associates , Yorktown Heights , NY 10598 , USA prescribed to elderly patients can produce adverse

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 89 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_7, © Springer Science+Business Media, LLC 2013 90 G.L. Caporaso cognitive effects that impact attention, memory, and medications should be started at reduced doses executive functions. The scope of this potential in the elderly population, with upward titration problem is immense, with upward of one-third of proceeding slowly and cautiously. older adults taking psychotropic medications like antidepressants, anxiolytics, antipsychotics, and sedative–hypnotics. Many more elderly patients Medications that Can Affect Cognition are prescribed medications for non-neuropsychiatric conditions that can also negatively affect cogni- Though many medications have the potential for tion (e.g., antihistamines). affecting cognition, there are several classes of medications that are the most common offenders (Table 7.1 ). Rather than an exhaustive review of Clinical Assessment any potential problem drugs, this section will discuss those medications that the clinician is most History is always key in diagnosing the potential likely to encounter in a typical hospital or offi ce cause of cognitive decline. For example, progres- practice. In addition, toxic effects associated with sive cognitive decline of insidious onset is typical drug overdose will not be discussed so that the for Alzheimer’s disease whereas forgetfulness focus will be on cognitive and behavioral prob- after new treatment for hypertension might be lems that arise during normal prescribing prac- due to beta-blocker use. It should be kept in mind tice. Cognition-enhancing drugs such as those that the addition of a new medication may unmask used to treat Alzheimer’s disease (e.g., donepezil, an underlying incipient cognitive disturbance memantine) will be covered elsewhere in this such as neurodegenerative dementia or border- volume. One convenient way to approach these line cognitive function related to prior cerebro- various medications is by dividing them into neu- vascular disease. Indeed, preexisting dementia ropsychiatric drugs (i.e., drugs that are designed puts patients at 2–3 times the risk for developing to act on the nervous system) and systemic drugs delirium [ 1 ] . In obtaining a cognitive history, (i.e., drugs that primarily target tissues outside reports from a spouse, adult child, or caregiver the nervous system). are essential since cognitive impairment or behavioral changes may not be apparent to the patient. In this regard, a correlation between the addition Neuropsychiatric Drugs of a new medication or change in dose of an existing medication can be important in identifying an Antidepressants offending agent. Depression can produce cognitive impairment Laboratory assessment should be directed at (e.g., attentional defi cits that can resemble mem- potential effects of medications on metabolism ory loss, so-called pseudodementia) or worsen (e.g., hypokalemia related to diuretics, decreased cognition in patients with underlying cognitive serum albumin with resultant higher circulating impairment. Treatment of depression in patients drug levels), serum levels of some medications with or without cognitive impairment may there- (e.g., antiepileptic toxicity), or supervening med- fore have benefi ts on cognitive functioning in this ical conditions that can affect drug clearance or group [ 3 ] . However, positive effects on cognition potentiate drug effects (e.g., complete blood in the elderly can depend on the choice of antide- counts and urinalysis to diagnose urinary tract pressant [4 ] , and certain antidepressants have the infection). One must keep in mind that most potential to worsen cognition. elderly patients have reduced muscle mass and therefore lower serum creatinine values, so that a Tricyclic Antidepressants value within the normal laboratory range may As a group, tricyclic antidepressants (TCAs, actually represent impaired renal clearance in e.g., amitriptyline, nortriptyline, imipramine, these individuals [ 2] . Consequently, most clomipramine, desipramine, doxepin) are effective 7 Medications and Cognition in Older Adults 91

Table 7.1 Medications that can affect cognition (see text for discussion) Drugs that might impair Non-pharmacological Medical condition cognition Safer drug alternatives alternatives Depression Tricyclic SSRIs (e.g., ﬂ uoxetine, paroxetine, Counseling antidepressants (e.g., sertraline, citalopram, Psychotherapy amitriptyline, nortriptyline, escitalopram) Group therapy imipramine, desipramine, SNRIs (e.g., venlafaxine, Cognitive-behavioral clomipramine, doxepin) duloxetine) therapy Psychosis, High-potency antipsychotics Atypical antipsychotics Structured environment agitation (e.g., chlorpromazine, (e.g., risperidone, olanzapine, Regular daily routines haloperidol) quetiapine) Trained caregiver Insomnia Benzodiazepines (e.g., Z-drugs (e.g., zolpidem, zaleplon, Proper sleep hygiene alprazolam, triazolam, eszopiclone) (i.e., no late-day caffeine, temazepam, diazepam, Chloral hydrate no napping, regular lorazepam) Melatonin exercise, ﬁ xed bedtime/ Diphenhydramine awakening time) Parkinson’s Anticholinergics l -dopa – disease (e.g., trihexyphenidyl) Dopamine agonists (e.g., pramipexole, ropinirole) MAO-B inhibitors (e.g., selegiline, rasagiline) COMT inhibitors (e.g., tolcapone, entacapone) Epilepsy Phenobarbital Carbamazepine – Primidone Valproate Topiramate Levetiracetam Pain Opiates (e.g., morphine, Acetaminophen Biofeedback codeine, oxycodone, NSAIDs Physical therapy hydrocodone) Tramadol Acupuncture Topical agents Chiropractic therapy Motion sickness, Scopolamine Meclizinea Vestibular exercises vertigo Dimenhydrinatea Hypertension Beta-blockers (e.g., Diuretics (e.g., hydrochlorothiazide) Exercise propranolol, metoprolol) ACE inhibitors (e.g., captopril, Weight reduction lisinopril, ramipril) Angiotensin receptor antagonists (e.g., losartan) Urinary urge Oxybutynin M3 selective agents Scheduled toileting incontinence (e.g., tolterodine, trospium, Fluid restriction solifenacin, darifenacin) Caffeine avoidance ACE angiotensin-converting enzyme, COMT catechol-O -methyl-transferase, M3 muscarinic receptor, MAO-B monoamine oxygenase-B, SNRI serotonin–norepinephrine receptor uptake inhibitor, SSRI selective serotonin receptor uptake inhibitor a There are abundant data for scopalamine’s amnesic effects but less so for these other two agents listed

antidepressants but have anticholinergic effects [5 ] . Approximately 5–7% of geriatric inpatients that can worsen memory functioning in the who received a TCA may develop delirium [ 6, elderly. Given the cholinergic defi cits seen in 7 ] . In a mouse model of memory and learning, age-related illnesses such as Alzheimer’s dis- the TCAs amitriptyline and imipramine wors- ease, Parkinson’s disease, and dementia with ened memory and potentiated the effects of the Lewy bodies, it is not surprising that the elderly anticholinergic agent scopolamine, whereas the population may be especially sensitive to the neg- selective serotonin agent fl uoxetine had no effect ative cognitive effects of this class of medications on memory and could reverse scopolamine’s 92 G.L. Caporaso negative effects [ 8 ] . TCAs have been demon- Antipsychotics strated to have negative effects in the elderly on Antipsychotic drugs, or neuroleptics, are dop- measures of verbal memory [ 9– 12 ] . However, amine receptor antagonists used in the treatment low-dose imipramine (25 mg/day) was shown of hallucinations or delusions that might occur in not to worsen memory in patients with disorders such as schizophrenia or dementia. Alzheimer’s disease with or without depression They are also used to treat affective diseases [13 ] . In a large population-based study (N = 1,488 (e.g., bipolar disorder), Tourette’s syndrome, and patients), TCA use was not associated in the nausea. This group of medications carries the short- or long-term with cognitive de fi cits or risk of extrapyramidal side effects (EPS) includ- memory impairment [14 ] . ing parkinsonism (bradykinesia, rigidity, and tremors), dystonia, akathisia, and tardive dyski- Selective Serotonin- and Serotonin/ nesia. The older “conventional” or “high- Norepinephrine-Reuptake Inhibitors potency” antipsychotics (e.g., chlorpromazine, Selective serotonin-reuptake inhibitors (SSRIs, haloperidol) are less selective in their blockade e.g., fl uoxetine, sertraline, paroxetine, citalo- of dopamine receptor subtypes and are associ- pram, escitalopram) and serotonin/norepineph- ated with greater risk of EPS. The newer “atypi- rine-reuptake inhibitors (SNRIs, e.g., venlafaxine, cal” antipsychotics (e.g., risperidone, olanzapine, duloxetine, desvenlafaxine) are the most com- quetiapine) preferentially block serotonin monly prescribed antidepressants. Fortunately, 5-HT2A receptors more than dopamine D2 they do not seem to be associated with the nega- receptors and are believed to have a lower risk tive cognitive effects seen with TCAs [ 15 ] . of EPS [ 24 ] . Escitalopram improved cognition as well as It should be noted that the use of either con- mood in depressed elderly patients with memory ventional or atypical antipsychotics in the impairment [ 16] . Though sertraline seemed to elderly may be associated with increased mor- provide greater cognitive bene fi ts than fl uoxetine tality [25 ] and that the Food and Drug in elderly patients with depression [ 4, 17, 18 ] , Administration has issued advisories that cau- fl uoxetine appears to be comparable with parox- tion their use in this patient group [26 ]. The etine [ 19 ] , and fl uoxetine may provide some potential magnitude of this problem was high- bene fi ts for memory in nondepressed patients lighted by a recent study of the National Nursing with mild cognitive impairment [ 20] . Duloxetine Home Survey, which demonstrated that one and venlafaxine do not affect histaminergic or quarter of nursing home residents are prescribed cholinergic receptors and have been shown to antipsychotics, and of these, perhaps 40% are improve certain cognitive measures in older prescribed antipsychotics inappropriately [27 ] . depressed patients [21– 23] . Given their apparent Though antipsychotics are commonly used in safety in patients susceptible to cognitive impair- managing behavioral problems in the elderly, ment and their potential for improving cognition, their use cannot be endorsed in most patients. SSRIs and SNRIs should be considered preferred Indeed, many patients with Alzheimer’s disease treatments for depression in older patients. The can experience substantial bene fi ts in neuropsy- prescribing physician, though, should be aware chiatric symptoms, as well as cognition and of the risk, albeit small, of delirium induced by daily functioning, with treatment using approved serotonin agents as part of the serotonin syn- dementia agents such as donepezil [ 28 ] , rivastig- drome, which also encompasses myoclonus, mine [ 29 ] , or memantine [30 ] . Furthermore, rigidity, hyperre fl exia, tremors, and autonomic though many of the neuroleptics have been lability. The risk of this syndrome is increased shown to improve cognition in patients with when monoamine oxidase (MAO) inhibitors schizophrenia (e.g., executive function), there (and perhaps triptan migraine medications) are are fewer data on their effects in nonschizo- coadministered. phrenic elderly patients. 7 Medications and Cognition in Older Adults 93

Conventional Antipsychotics dementia without impacting cognition [ 45 ] . The The older neuroleptics such as chlorpromazine Clinical Antipsychotic Trials of Intervention exhibit anticholinergic activity, so one might pre- Effectiveness-Alzheimer’s Disease study group dict that they would detrimentally affect cogni- (CATIE-AD) randomized over 400 patients with tion in older individuals and in particular patients Alzheimer’s disease and psychosis or agitation to with Alzheimer’s disease. The results of studies antipsychotic medications (risperidone, olanzap- examining antipsychotic use in elderly demented ine, or quetiapine) or placebo [46 ] . When this patients have been mixed, with some studies group examined time to discontinuation as a pri- showing no effect on cognition [ 31– 33 ] and oth- mary study endpoint, they concluded that adverse ers demonstrating negative effects on cognition effects offset any advantages on neurobehavioral [34– 36] . One should interpret these studies with symptoms of antipsychotics compared to placebo caution, however, since dementia patients with [47 ] . In a subsequent analysis of antipsychotic psychotic symptoms or behavioral disturbances medication versus placebo, though, the authors have a worse prognosis than patients without indicated that treatment with olanzapine or ris- these problems, and they tend to experience more peridone (and perhaps quetiapine) improved cer- rapid cognitive decline [37, 38 ] . tain behavioral symptoms but had neither positive nor negative effects on cognition. Similar bene fi ts Atypical Antipsychotics on behavioral symptoms without cognitive dete- The newer generation of antipsychotics seems to rioration were seen with these three agents in confer neuropsychiatric and sometimes cogni- another smaller study of outpatients with tive benefi ts to elderly patients with psychosis, Alzheimer’s disease [ 48 ] . Aripiprazole is a new while being associated with fewer EPS [ 39 ] . agent used in the treatment of schizophrenia, However, the risk of EPS, as well as orthostatic bipolar disorder, and as an adjunctive to antide- hypotension and sedation, is not negligible, put- pressants for major depression. Several recent ting this group of patients at risk for falls and placebo-controlled studies have demonstrated its bone fractures. ef fi cacy in treating hallucinations and delusions Clozapine is a dibenzodiazepine with perhaps in patients with Alzheimer’s disease with little the lowest risk of EPS among neuroleptics. negative impact on cognition or safety [49– 51 ] . However, it carries a risk of agranulocytosis as However, head-to-head studies with other antip- high as 1% during the fi rst several months (requir- sychotics will be needed to test whether it really ing weekly monitoring of blood counts) and is safer than older agents. In summary, atypical roughly 0.01% after 1 year of use [ 40 ] . This agent antipsychotic agents may be useful in treating also possesses anticholinergic activity, which can psychosis, agitation, and aggression in some impair memory function, at least when studied in patients with dementia without harming cogni- patients with schizophrenia [ 41 ] . Olanzapine has tion, but the treatments must be individualized, been shown to worsen cognition in patients with and it would be prudent to start slowly with low Alzheimer’s disease, especially those with greater doses to minimize the chance of adverse effects. baseline impairment [ 42 ] . Compared with haloperidol, quetiapine had a wider range of bene fi ts Sedative–Hypnotics and Anxiolytics on psychiatric symptoms in patients with Insomnia occurs frequently in older patients and Alzheimer’s disease and improved memory and may have various causes, including a conse- daily functioning without producing signi fi cant quence of aging, sleep apnea, restless leg syn- EPS [43 ] . Quetiapine also showed neuropsychi- drome, or various parasomnias, such as periodic atric benefi ts without cognition deterioration in leg movement disorder. Overnight sleep studies an open-label pilot study of Alzheimer’s patients that monitor brain electrical activity, movements, [44 ] . Another small, open-label study using ris- and breathing are sometimes required for diag- peridone demonstrated improvement in psycho- nosing sleep disorders. Depression and anxiety sis, agitation, and aggression in patients with are among the most common causes of insomnia, 94 G.L. Caporaso so accurate diagnosis and directed therapy should effects, such as abuse and withdrawal symptoms be attempted before treating sleeplessness with upon discontinuation [ 53 ] . Two large epidemio- more generalized sleep aids. Dementia is often logical studies in older French men and women associated with inverted sleep–wake cycles that demonstrated an association between benzodiaz- result in daytime sleepiness and nighttime rest- epine use and cognitive decline [ 54, 55] , whereas lessness or wandering. a third did not [ 56] . Benzodiazepines can impair In managing insomnia, a trial of non-pharma- reaction time, attention, and memory [57 ] . cological therapy should be completed before Longer-acting agents are more likely to produce prescribing hypnotics or sedatives. This includes impairment [58 ] . Whenever the clinician makes counseling on good “sleep hygiene.” The patient a decision to stop benzodiazepines, they should should be told to avoid caffeinated beverages in be withdrawn gradually (i.e., dose tapered over the afternoon and evening, refrain from napping, one to several weeks) to lessen the risk of delir- get regular exercise, set regular bedtime and ium associated with drug withdrawal in the awakening hours, and restrict the bed at night for elderly [59 ] . sleeping and not watching television or reading. When treating anxiety, SSRIs or SNRIs should Such non-pharmacological interventions are be considered before prescribing benzodiaz- underutilized despite their effectiveness [ 52 ] . epines. In addition, buspirone has been shown to When needed, sleep aids should be used judi- be at least as effective as sertraline in treating ciously (e.g., only 1–2 nights/week when a patient anxiety in the elderly without signifi cant adverse really needs to catch up on sleep) and should not effects [60 ] . In healthy older subjects, buspirone be taken nightly. did not affect reaction time, psychomotor speed, Although they are still commonly prescribed or memory [ 61 ] . Nefazodone seems to be a safe for the treatment of anxiety, the use of short-acting choice in treating elderly patients with anxiety benzodiazepines (e.g., estazolam, triazolam, and comorbid depression [62 ] . temazepam) as sleep aids has largely been sup- The so-called Z-drugs are the most commonly planted by the development of non-benzodiaz- prescribed sleep aids in the elderly population. epines or “Z-drugs” (i.e., zolpidem, zaleplon, They are not without side effects and can produce eszopiclone) that also act as GABAA agonists, hallucinations, delirium, and amnesia [ 63– 65 ] . but which are believed to have fewer side effects. Most studies of these drugs have been conducted It should be noted that the perceived safety vis-à-vis in younger individuals, with some showing cog- reduced daytime sleepiness of the latter group of nitive impairment at commonly used doses [ 66 ] medications might be due to the fact they have and others showing no signifi cant effects [ 67– 69 ] . been unfairly compared to longer-acting benzo- Studies in the elderly have been limited. Following diazepines (e.g., nitrazepam) or inappropriate a single dose, zolpidem did not appear to affect doses of short-acting agents such as temazepam attention or memory in healthy elderly individu- (National Institute for Clinical Excellence, 2007 als [70 ] . Weeklong administration of zolpidem “Guidance on the use of zaleplon, zolpidem and also did not signi fi cantly impair psychomotor or zopiclone for the short-term management of cognitive functioning [ 71 ] . In contrast, another insomnia,” TA077). study demonstrated that older subjects experi- Benzodiazepines are more potent in elderly ence memory impairment the day following dos- patients due to target organ sensitivity, are cleared ing with zolpidem [72 ] . less effi ciently due to reduced hepatic clearance The antihistamine diphenhydramine is often and increased distribution volume, and can accu- prescribed as a sleep aid, especially by hospital mulate, resulting in cognitive impairment, psy- staff or taken by patients seeking over-the-coun- chomotor slowing, delirium, or sedation [2 ] . In ter remedies. It possesses anticholinergic activity the elderly, short-acting agents are preferred and and can induce delirium in elderly patients and high-potency benzodiazepines (e.g., alprazolam) can impair attention and memory [ 73– 75 ] . should be avoided due to increased risk of side Chloral hydrate can be an effective sleep aid in 7 Medications and Cognition in Older Adults 95 older patients that carries little risk of delirium disease with or without comorbid dementia [ 79 ] . but may increase the free concentrations of The absence of negative cognitive effects of certain other drugs (e.g., warfarin) due to dis- l-dopa seems to carry over into moderate or placement from plasma proteins [ 2 ] . Although severe Parkinson’s disease [80 ] . However, an trazodone is commonly prescribed as a sleep aid earlier study failed to show any cognitive bene fi t in elderly patients due to its perception as a “safe” of l-dopa in Parkinson’s patients [ 81 ] . In patients drug, a comprehensive review of the evidence for with early Parkinson’s disease, treatment either trazodone in insomnia identifi ed few trials that with l -dopa or the dopamine agonist bromocrip- were mostly performed in depressed patients, tine improved cognition whereas anticholinergic possible tolerance, and side effects that included therapy worsened it [82 ] . Addition of the daytime sedation, dizziness, and psychomotor MAO-B inhibitor selegiline to l -dopa treatment impairment [76 ] . Lastly, melatonin has been may help improve cognition in Parkinson’s shown to improve sleep quality and possibly cog- patients without dementia [ 83 ] . The newer nitive functioning in healthy elderly individuals MAO-B inhibitor rasagiline does not seem to be [77 ] . It also appears to be an effective sleep aid in associated with any signi fi cant cognitive or patients with dementia, reducing sleep latency behavioral worsening [84 ] . and prolonging sleep duration, though long-term In a randomized study of patients with early/ use may predispose to worsening affect [78 ] . In a mild Parkinson’s disease, the D2/D3 dopamine randomized, crossover study comparing mela- agonist pramipexole signifi cantly impaired ver- tonin and zolpidem in healthy older individuals, a bal memory, attention, and executive function prolonged-release formulation of melatonin did compared to l -dopa [ 85] . The same study group, not impact psychomotor functioning, memory, or however, showed that the D1/D2 dopamine ago- driving skills, whereas zolpidem negatively nist pergolide was comparable to l -dopa in its affected all three measures [72 ] . effects on cognition [ 86 ] . However, both pergolide and pramipexole might improve working Parkinson’s Disease Medications memory in medically naïve Parkinson’s patients Multiple classes of medications are used in treat- [87 ] . It should be noted that dopamine agonists ing Parkinson’s disease, including l -dopa, dop- such as pramipexole or ropinirole have been amine agonists (e.g., pramipexole, ropinirole), linked to impulse control disorders in patients MAO-B (monoamine oxidase inhibitor, class B) with Parkinson’s disease (e.g., pathological gam- and COMT (catechol O -methyltransferase) bling, compulsive sexual behavior, binge eating), enzyme inhibitors (which increase the bioavail- the risk being perhaps 2–3 times higher than in ability of dopamine), and anticholinergic agents patients not treated with dopamine agonists [ 88 ] . (e.g., trihexyphenidyl). It should be kept in mind In a small study of patients with advanced that cognitive dysfunction is common in patients Parkinson’s disease, treatment with tolcapone, a with Parkinson’s disease, either in the form of COMT inhibitor, resulted in improved scores for dementia with Lewy bodies, as a later complica- attention, verbal and visual-spatial memory, and tion of idiopathic Parkinson’s disease, or due to praxis [89 ] . depression, which occurs in more than half of The anticholinergic agent trihexyphenidyl is Parkinson’s patients during some point in their useful in treating tremors in Parkinson’s disease illness. As such, these patients may be particu- [ 90, 91] and may also be of use in patients with larly susceptible to untoward cognitive effects of tardive dyskinesia [ 92 ] . Trihexyphenidyl was medications described in this chapter. However, shown to worsen executive function in patients drugs used specifi cally to treat Parkinson’s dis- with Parkinson’s, an effect that is mediated by sub- ease might also have the potential for negatively cortical frontal circuits [93 ] . This medication was impacting cognition. also demonstrated to impair cognitive shifting and l -dopa did not seem to impair cognition after memory [94 ] . In a crossover study of patients with 3 months of treatment in patients with Parkinson’s drug-induced EPS, cognitive performance was 96 G.L. Caporaso better on the Parkinson’s medication amantadine levetiracetam improved attention and oral than in trihexyphenidyl [95 ] . Lastly, an uncon- fl uency and lamotrigine had a positive effect on trolled study of elderly patients with schizo- mood, but phenobarbital caused persistent cog- phrenia demonstrated a dose-dependent correlation nitive impairment [105 ] . Although it has not between global cognitive and memory impairment specifi cally been studied in the elderly, topira- and chronic use of trihexyphenidyl [96 ] . mate has been shown to impair cognitive speed, verbal fl uency, and short-term memory in Anticonvulsants patients with epilepsy, whereas levetiracetam Anticonvulsants or antiepileptic drugs (AEDs) are seems to lack cognitive side effects [106 ] . Other used primarily in treating seizure disorders but studies have demonstrated negative effects of also play an important role in the management of topiramate on verbal fl uency and attention in mood disorders, neuropathic pain syndromes (e.g., adults with migraines [107, 108 ] . trigeminal neuralgia), and migraine headaches. Since these drugs function to reduce neuronal irri- Opiates tability, such as cortical seizure foci, vis-à-vis The geriatric population is particularly suscepti- inhibiting neuronal excitability, they have the ble to musculoskeletal and rheumatologic ill- potential for impairing cognition, as well as other nesses associated with pain. Although studies brain and spinal cord functions such as balance [ 97 ] . directly addressing this issue are lacking, acet- At normal therapeutic doses, use of phenytoin, aminophen, nonsteroidal anti-in fl ammatory drugs valproate, or carbamazepine did not seem to affect (NSAIDs), tramadol, and topical agents (e.g., cognition signifi cantly in most adult patients, fentanyl patch or capsaicin lotion) are effective though their safety in the elderly is less well estab- therapies that only rarely produce cognitive lished [98 ] . Carbamazepine seemed to produce effects in elderly patients [109– 112 ] (for some fewer adverse effects on cognition compared to exceptions, see section on corticosteroids and phenytoin, primidone, or phenobarbital in a large NSAIDs). For more severe or intractable pain, study of veterans [ 99 ] , and a subsequent study in patients may be prescribed opiates (e.g., mor- the same population showed no difference between phine, codeine, oxycodone) or combination med- carbamazepine and valproate [100 ] . ications (e.g., acetaminophen–hydrocodone). In elderly patients on monotherapy for epi- Though any opiate may of course produce seda- lepsy (carbamazepine, phenytoin, or valproate), tion or cognitive impairment in patients of any increasing the dose of their AED to a higher age, one study of primary care patients with non- level within the normal dose range did not induce malignant pain found that problems with cogni- cognitive impairment or sedation [101 ] . A ran- tive functioning were more likely related to domized study comparing valproate and pheny- psychological health and pain control than with toin in elderly patients with new-onset epilepsy speci fi c opiate medications [113 ] . A review of found no signifi cant adverse cognitive effects postoperative pain management in elderly patients and no difference between the two drugs [ 102 ] . concluded that meperidine has consistently been However, a tolerability study of valproate in shown to be associated with an increased risk of non-epileptic patients with Alzheimer’s disease delirium whereas this has not been shown for demonstrated cognitive worsening at a dose of other commonly used opiates (e.g., morphine, 1,500 mg/day, though doses less than 1,000 mg/ fentanyl, hydromorphone) [ 114 ] . In using opi- day might be safe [ 103 ] . Carbamazepine was ates, it should be kept in mind that tolerance for a shown to be superior to placebo in treating agi- dose administered chronically may subsequently tation and aggression in demented nursing home be too high and result in delirium, sedation, or patients with no effects on cognition or func- cognitive impairment following another interven- tionality [104 ] . In a randomized, case–control tion to reduce absolute pain levels (e.g., spinal study of Alzheimer’s patients with seizures, nerve block, surgery). 7 Medications and Cognition in Older Adults 97

Anti-vertigo and Motion Sickness Agents either underlying cardiovascular pathology versus Anticholinergic and antihistaminergic agents are therapies used to treat them may be contribut- widely used to treat vertigo and motion sickness ing to cognitive worsening. With the possible (e.g., seasickness). Dimenhydrinate and mecliz- exception of beta-blockers (see below), antihy- ine are antihistamines that are effective in reliev- pertensives are not thought to affect cognition ing motion sickness and vertigo but which can signi fi cantly. A review of several randomized, produce psychometric slowing and sleepiness placebo-controlled studies and a recent meta- [115 ] . Although a case report noted memory loss analysis examining the effects of antihyperten- and confusion in an elderly woman taking mecl- sion medications on dementia suggested that izine, there have been no studies specifi cally these medications, and angiotensin-converting examining this drug’s or dimenhydrinate’s effects enzyme (ACE) inhibitors and diuretics in particular, on cognition in older patients [116 ] . may help prevent or slow the progression of Scopolamine is an anticholinergic medication dementia [121, 122 ] . used to treat motion sickness and has been associated with memory impairment. In a blinded Beta-Blockers placebo-controlled study, it was shown to worsen Although propranolol is also used to treat essen- cognition and behavior in a dose-dependent fash- tial tremor and prevent migraine headaches, the ion in patients with Alzheimer’s disease [ 117 ] . clinician is most likely to use beta-adrenergic It has also been demonstrated to worsen memory antagonists, or beta-blockers, in elderly patients in Parkinson’s patients without preexisting cog- with hypertension or cardiac disease. Beta- nitive impairment [118 ] . In a comparison between blockers may exert biological effects in the CNS healthy individuals of different ages, scopolamine either specifi cally via activity at downstream impaired memory and constructional praxis in receptors of central adrenergic pathways (e.g., old but not young subjects [119 ] . projections from the locus coeruleus) or nonspeci fi cally via neuronal membrane stabilization [123 ] . Lipophilic beta-blockers such as pro- Systemic Drugs pranolol and metoprolol cross the blood–brain barrier and accumulate in brain tissue compared Cardiovascular Drugs to hydrophilic agents like atenolol [124 ] . These Hypertension is a common risk factor for carotid differences in lipophilicity seem to correspond to atherosclerosis and cerebrovascular disease. the relative risk of CNS effects. Switching from a Ischemic changes in the brain may in themselves lipophilic beta-blocker to a less lipophilic agent produce cognitive impairment or dementia (e.g., was associated with improved sleep, concentra- “subcortical dementia,” Binswanger’s disease) or tion, and memory, and atenolol was less likely to contribute to the pathogenesis or potentiate the produce sleep disturbances than metoprolol effects of other dementias (e.g., Alzheimer’s dis- [ 125] . However, a comprehensive review of beta- ease). However, overaggressive lowering of blood blockers concluded they in general have minimal pressure in treating hypertension can also cause or absent effects on memory function, as well as cognitive changes. Elderly patients with a long in causing sleep disturbances, nightmares, or hal- history of hypertension can develop cervical or lucinations [126 ] . A large, randomized, controlled cerebral blood vessels with poor compliance that study of antihypertensives in elderly women require pressures greater than those considered failed to fi nd evidence of cognitive decline after normal in order to adequately perfuse the brain. 5 years of treatment with a diuretic and atenolol Hypoperfusion may also be a consequence of [ 127 ] . Elderly patients with hypertension ran- atrial fi brillation, congestive heart failure, myo- domized to the angiotensin receptor antagonist cardial infarction, or coronary artery bypass losartan experienced improved memory, but those grafting (CABG) [ 120 ] . As such, it can some- who received atenolol showed neither improved times be dif fi cult to gauge the extent to which nor worse memory function [128 ] . Another study 98 G.L. Caporaso compared propranolol to placebo in young or that H2 blocker use doubled the risk of developing middle-aged patients with hypertension and cognitive impairment [ 140] . Thus, it might be found little or no difference in performance on a prudent to periodically check serum B12 levels battery of cognitive tests [ 129] . A small study in (or sensitive surrogate markers such as methyl- hypertensive veterans demonstrated no decline in malonic acid and homocysteine) when using H2 cognitive performance with treatment using either blockers or proton-pump inhibitors in elderly propranolol or atenolol [ 130] . However, in a study patients. of cognitively impaired elderly patients, use of There have been numerous case reports beta-blockers was associated with a trend toward describing mental confusion in patients taking worsening memory [ 131 ] . the H2 blockers cimetidine, ranitidine, or famotidine. However, a randomized, placebo-controlled, Digoxin crossover of healthy elderly individuals showed Digoxin is a naturally occurring glycoside used no adverse effects of cimetidine on cognition, to improve cardiac output in patients with con- leading the authors to conclude that earlier case gestive heart failure. Altered mental state and reports might have been due to specifi c patient delirium can occur with toxic doses of digoxin sensitivities to this class of medications [ 141 ] . [132 ] and have even been reported with so-called A large cohort study, in contrast, suggested that therapeutic serum concentrations [ 133 ] . However, H2 blocker use was associated with higher risk of at therapeutic dosages, digoxin may actually cognitive impairment or decline in cognitive improve cognitive performance [134 ] . functioning [142 ] .

H2 Blockers and Proton-Pump Inhibitors Urinary Antispasmodics Histamine H2 receptor antagonists (e.g., cimeti- Urge urinary incontinence due to an overactive dine, ranitidine, famotidine, nizatidine) and or spastic bladder may be treated with medica- proton-pump inhibitors (e.g., omeprazole, lanso- tions that have the potential to produce cognitive prazole, esomeprazole, pantoprazole) are widely symptoms. Simple measures such as restricting prescribed for the treatment of acid-re fl ux disease fl uid intake, avoiding caffeine, or scheduling and peptic ulcer disease and to help reduce the frequent visits to the toilet can reduce the need gastric side effects of medications such as aspirin. for medical treatment in some patients. Others, Both classes of drug inhibit acid secretion from though, may be prescribed anticholinergic med- gastric parietal cells. Gastric acid is necessary for ications directed against muscarinic M3 recep- the release of vitamin B12 from ingested food, tors that decrease bladder detrusor muscle and H2 blockers may reduce B12 absorption activity (e.g., oxybutynin, tolterodine, trospium, [135, 136 ] . Since vitamin B12 de fi ciency can solifenacin, darifenacin). As with any anticho- cause cognitive impairment, dementia, or delir- linergics, these drugs can produce dry mouth, ium, prolonged inhibition of gastric acid secre- constipation, dizziness, and drowsiness. The tion may increase the risk of neurobehavioral risk for these agents to impair cognitive func- symptoms [137 ] . tioning is related to their ability to penetrate the A case–control study of elderly patients dem- brain and their interaction with muscarinic M1 onstrated an association between chronic use (at receptors [ 143 ] . In a study of healthy elderly least 12 months) of H2 blockers or proton-pump volunteers, solifenacin did not seem to affect inhibitors and vitamin B12 defi ciency [ 138 ] . cognition, whereas oxybutynin impaired several Another study showed that prolonged use of pro- measures of cognition [ 144 ] . After 3 weeks of ton-pump inhibitors, but not H2 blockers, was treatment, healthy elderly subjects experienced associated with vitamin B12 de fi ciency in the signi fi cant memory impairment on oxybutynin elderly, though the consequences of this on cog- in contrast to those on darifenacin, which nition were not examined [ 139 ] . A longitudinal showed no difference in memory compared to study of elderly African-Americans demonstrated the placebo group [ 145 ] . Darifenacin was found 7 Medications and Cognition in Older Adults 99 to have no effects on cognition in another trial have been mixed [158 ] , with most studies showing involving healthy elderly volunteers [146 ] . a possible protective effect [ 159– 165 ] and others Tolterodine was demonstrated to produce revers- providing no evidence for such protection [ 166, ible memory impairment in a single case report 167] or demonstrating a potential detrimental [ 147 ] but was found to have no effect on mem- effect [ 168, 169 ] . These diverse results likely ory in a 3-week crossover study compared to re fl ect differences in patient or subject groups, oxybutynin [ 143 ] . types and doses of NSAIDs taken, age at fi rst use, and length of therapy. Needless to say, a disap- Corticosteroids and NSAIDs pointment for those studying Alzheimer’s disease Corticosteroids and nonsteroidal anti- is that no prospective clinical trial has yet shown in fl ammatory drugs (NSAIDs) are used to treat that NSAID use prevents dementia. various conditions associated with infl ammation or pain (e.g., vasculitis, arthritis). Severe psychi- Hormonal Therapy atric symptoms, such as affective and psychotic There was initial enthusiasm that estrogen ther- conditions, may occur in upward of 5% of patients apy might help prevent cognitive decline and treated with corticosteroids [148 ] . Acute corti- dementia based on epidemiological studies of costeroid treatment, but not chronic treatment, estrogen-replacement therapy in younger women. seemed to induce memory impairment in patients However, no benefi ts have been demonstrated in with rheumatoid arthritis [149 ] . Steroid use has older, postmenopausal women [ 170, 171 ] . Indeed, likewise been associated with reversible demen- the large Women’s Health Initiative revealed that tia [150, 151] . It should be noted that too rapid postmenopausal estrogen therapy was associated withdrawal of corticosteroid therapy can also with signi fi cant risk of dementia (hazard ratio affect the brain [152 ] . 1.76), as well as negative effects on selective cog- Though non-neurological side effects of nitive measures such as verbal memory and lower NSAIDs are quite common (e.g., dyspepsia, brain volumes in the frontal lobe and hippocam- renal impairment), they infrequently can cause pus [ 172 ] . aseptic meningitis, disorientation, hallucinations, Testosterone levels in men decline with aging. and memory or attentional impairment, and the Evidence suggests that this drop might contribute elderly may be at increased risk [ 153 ] . A large to parallel cognitive decline and that testosterone randomized, placebo-controlled study of patients supplementation might prevent or be useful in with cardiovascular disease showed no differ- treating cognitive impairment, though neither ence in performance on multiple cognitive tasks the association nor the bene fi ts have been with long-term low-dose aspirin therapy [154 ] . strongly demonstrated in large-scale, rigorous Aspirin failed to prevent cognitive decline in trials [ 173– 175] . Treatment of elderly men with healthy older women participating in the low serum testosterone levels but no cognitive Women’s Health Study [ 155] . Neither naproxen impairment with exogenous testosterone (either nor celecoxib prevented cognitive decline com- alone or in combination with the 5-alpha pared to placebo in elderly non-demented sub- reductase inhibitor fi nasteride, which blocks jects with a family history of Alzheimer’s disease conversion of testosterone to dihydrotestoster- [156 ] . In contrast, a randomized, placebo-con- one) did not impact cognition [ 176 ] . Further, a trolled study of patients with subjective memory 6-month randomized, placebo-controlled trial of impairment demonstrated improvements in testosterone in older men with low normal serum executive functioning and memory, as well as testosterone levels failed to show any effects on increased cerebral metabolism on positron- cognition [ 177 ] . emission tomography (PET) imaging with cele- The long-term effects of antihormonal treat- coxib treatment [157 ] . ments for breast or prostate cancers on cognition The effects of long-term NSAID use on reduc- in the elderly are uncertain [178 ] . Treatment with ing the risk of cognitive decline and dementia the antiestrogen drug tamoxifen in women with 100 G.L. Caporaso breast cancer may be associated with cognitive dif fi culties later in life [179, 180 ] . However, the Summary selective estrogen receptor modulator raloxifene, which is used to treat osteoporosis and reduce the The clinician must be vigilant in identifying risk of breast cancer in postmenopausal women, medications that can cause or contribute to cogni- was shown to improve verbal memory versus tive impairment in the elderly. In this age of placebo [ 181 ] . Androgen deprivation in men polypharmacy, the potential for inappropriate or with prostate cancer seems to be associated with overprescribing has burgeoned, yet the increas- decline in some cognitive domains [ 182 ] . In ing use of electronic medical records might help elderly men being treated with androgen block- reverse this trend. Non-pharmacologic interven- ade for prostate cancer, no decline in cognition tions (e.g., counseling, structured environment, was noted after 12 weeks of therapy, and addition group activities) should be considered in treating of estrogen failed to improve verbal memory affective and behavioral disturbances, single compared to androgen blockade alone [183 ] . agents should be used whenever possible, and drugs with potential anticholinergic (i.e., TCAs) Cholesterol-Lowering Drugs or extrapyramidal (i.e., neuroleptics) side effects The 3-hydroxy-3-methyl-glutaryl-coenzyme-A should be eschewed. reductase inhibitors, or statins (e.g., lovastatin, pravastatin, simvastatin, atorvastatin, fl uvastatin, rosuvastatin), are effective in lowering levels of Clinical Pearls total cholesterol and low-density lipoprotein (LDL) and have been important treatments in • In prescribing any medications for elderly reducing the risk of coronary and cerebrovascular patients, follow the rule: “Start low, go slow.” disease. Statin therapy in elderly non-demented Elderly patients may require lower doses of a women was associated with lower risk of cogni- given medication than younger patients, so by tive impairment [184 ] . In the large Cardiovascular starting at the lowest possible dose and titrat- Health Study (N = 3,334 patients), cognitive ing upward slowly, you will be more likely to decline in the elderly was less in statin users, a identify the least amount of medication fi nding that seemed to be in part independent of required as well as minimize any potential lowering cholesterol levels [185 ] . It has been pro- side effects. posed that statins affect other non-lipid-related • Avoid polypharmacy and keep abreast of what pathways that could impact neurological disease medications are being prescribed by other and therefore cognition, but this has not yet been physicians. Increasing adoption of electronic adequately studied [186 ] . medical records, patient-centered medical Less is known about the cognitive effects of home (in which the multiple needs of a patient other cholesterol-lowering drugs on cognition. are coordinated through a primary/personal Treatment with gem fi brozil in elderly patients physician), and electronic prescribing are with hypertriglyceridemia and stroke risk factors ways to help reduce the number of medica- improved cognitive scores and cerebral blood fl ow tions for a given patient and prevent deleteri- after several months compared to placebo [ 187 ] . ous interactions and side effects. Severe niacin defi ciency can produce dementia • When possible, select medications that may (i.e., pellagra), and dietary niacin intake was found be used to treat more than one of the patient’s to be inversely related to risk of cognitive decline medical conditions in order to reduce the and Alzheimer’s disease [ 188 ] . However, the patient’s number of medications. For example, effects on cognition in the elderly of high-dose the SNRI duloxetine can be used to treat niacin used to treat hypercholesterolemia (usually depression as well as painful diabetic neurop- 500–2,000 mg/day) have not been examined. athy, or propranolol might be a good choice of 7 Medications and Cognition in Older Adults 101

antihypertensive for a patient with essential 10. Meyers BS, Mattis S, Gabriele M, Kakuma T. Effects tremor. of nortriptyline on memory self-assessment and performance in recovered elderly depressives. Psychophar- • Before prescribing sleep aids in elderly macol Bull. 1991;27(3):295–9. patients, especially those with cognitive 11. Young RC, Mattis S, Alexopoulos GS, Meyers BS, impairment, try promoting healthy sleep habits, Shindledecker RD, Dhar AK. Verbal memory and so-called good sleep hygiene. That is, instruct plasma drug concentrations in elderly depressives treated with nortriptyline. Psychopharmacol Bull. the patient or caregiver to set regular awaken- 1991;27(3):291–4. ing and sleep times, avoid caffeine in the after- 12. Branconnier RJ, DeVitt DR, Cole JO, Spera KF. noon and evening, and restrict the bed for Amitriptyline selectively disrupts verbal recall from sleep and not reading or watching television. secondary memory of the normal aged. Neurobiol Aging. 1982;3(1):55–9. In addition, recommend that the patient avoid 13. Teri L, Rei fl er BV, Veith RC, Barnes R, White E, napping and get regular exercise. McLean P, Raskind M. Imipramine in the treatment of • Every attempt should be made to manage behav- depressed Alzheimer’s patients: impact on cognition. ioral problems in patients with dementia using J Gerontol. 1991;46(6):P372–7. 14. Podewils LJ, Lyketsos CG. Tricyclic antidepressants non-pharmacological means. Simple measures and cognitive decline. Psychosomatics. 2002;43(1): such as a structured home environment (e.g., 31–5. regular routines for meals, sleep, and social 15. Knegtering H, Eijck M, Huijsman A. Effects of anti- activities) can sometimes reduce the likelihood depressants on cognitive functioning of elderly patients. A review. Drugs Aging. 1994;5(3):192–9. of behavioral outbursts or confrontations with- 16. Savaskan E, Muller SE, Bohringer A, Schulz A, out having to resort to sedating medications. Schachinger H. Antidepressive therapy with escitalopram improves mood, cognitive symptoms, and identity memory for angry faces in elderly depressed patients. Int J Neuropsychopharmacol. 2008;11(3): References 381–8. 17. Finkel SI, Richter EM, Clary CM, Batzar E. 1. Francis J. Delirium in older patients. J Am Geriatr Comparative ef fi cacy of sertraline vs. fl uoxetine in Soc. 1992;40(8):829–38. patients age 70 or over with major depression. Am 2. Thompson II TL, Moran MG, Nies AS. Drug therapy: J Geriatr Psychiatry. 1999;7(3):221–7. Psychotropic drug use in the elderly ( fi rst of two 18. Newhouse PA, Krishnan KR, Doraiswamy PM, parts). N Engl J Med. 1983;308(3):134–8. Richter EM, Batzar ED, Clary CM. A double-blind 3. Reynolds 3rd CF, Perel JM, Kupfer DJ, Zimmer B, comparison of sertraline and fl uoxetine in depressed Stack JA, Hoch CC. Open-trial response to antide- elderly outpatients. J Clin Psychiatry. 2000;61(8): pressant treatment in elderly patients with mixed 559–68. depression and cognitive impairment. Psychiatry Res. 19. Cassano GB, Puca F, Scapicchio PL, Trabucchi M. 1987;21(2):111–22. Paroxetine and fl uoxetine effects on mood and cogni- 4. Doraiswamy PM, Krishnan KR, Oxman T, Jenkyn tive functions in depressed nondemented elderly LR, Coffey DJ, Burt T, Clary CM. Does antidepres- patients. J Clin Psychiatry. 2002;63(5):396–402. sant therapy improve cognition in elderly depressed 20. Mowla A, Mosavinasab M, Pani A. Does fl uoxetine patients? J Gerontol A Biol Sci Med Sci. 2003;58(12): have any effect on the cognition of patients with mild M1137–44. cognitive impairment? A double-blind, placebo-con- 5. Bartus RT, Dean 3rd RL, Beer B, Lippa AS. The trolled, clinical trial. J Clin Psychopharmacol. cholinergic hypothesis of geriatric memory dysfunc- 2007;27(1):67–70. tion. Science. 1982;217(4558):408–14. 21. Bymaster FP, Dresh fi eld-Ahmad LJ, Threlkeld PG, 6. Cole JO, Branconnier R, Salomon M, Dessain E. Shaw JL, Thompson L, Nelson DL, Hemrick- Tricyclic use in the cognitively impaired elderly. J Luecke SK, Wong DT. Comparative affi nity of Clin Psychiatry. 1983;44(9 Pt 2):14–9. duloxetine and venlafaxine for serotonin and nor- 7. Livingston RL, Zucker DK, Isenberg K, Wetzel RD. epinephrine transporters in vitro and in vivo, human Tricyclic antidepressants and delirium. J Clin serotonin receptor subtypes, and other neuronal Psychiatry. 1983;44(5):173–6. receptors. Neuropsychopharmacology. 2001;25(6): 8. Kumar S, Kulkarni SK. In fl uence of antidepressant 871–80. drugs on learning and memory paradigms in mice. 22. Trick L, Stanley N, Rigney U, Hindmarch I. A dou- Indian J Exp Biol. 1996;34(5):431–5. ble-blind, randomized, 26-week study comparing the 9. Hoff AL, Shukla S, Helms P, Aronson TA, Logue C, cognitive and psychomotor effects and ef fi cacy of Ollo C, Cook B. The effects of nortriptyline on cogni- 75 mg (37.5 mg b.I.D.) venlafaxine and 75 mg tion in elderly depressed patients. J Clin (25 mg mane, 50 mg nocte) dothiepin in elderly Psychopharmacol. 1990;10(3):231–2. patients with moderate major depression being 102 G.L. Caporaso

treated in general practice. J Psychopharmacol. decline in dementia? Prospective study with necropsy 2004;18(2):205–14. follow up. BMJ. 1997;314(7076):266–70. 23. Raskin J, Wiltse CG, Siegal A, Sheikh J, Xu J, Dinkel 37. Chui HC, Lyness SA, Sobel E, Schneider LS. JJ, Rotz BT, Mohs RC. Effi cacy of duloxetine on cog- Extrapyramidal signs and psychiatric symptoms pre- nition, depression, and pain in elderly patients with dict faster cognitive decline in Alzheimer’s disease. major depressive disorder: an 8-week, double-blind, Arch Neurol. 1994;51(7):676–81. placebo-controlled trial. Am J Psychiatry. 2007; 38. Lopez OL, Wisniewski SR, Becker JT, Boller F, 164(6):900–9. DeKosky ST. Psychiatric medication and abnormal 24. Miller CH, Mohr F, Umbricht D, Woerner M, behavior as predictors of progression in probable Fleischhacker WW, Lieberman JA. The prevalence of Alzheimer disease. Arch Neurol. 1999;56(10):1266–72. acute extrapyramidal signs and symptoms in patients 39. Jeste DV, Rockwell E, Harris MJ, Lohr JB, Lacro J. treated with clozapine, risperidone, and conventional Conventional vs. newer antipsychotics in elderly antipsychotics. J Clin Psychiatry. 1998;59(2):69–75. patients. Am J Geriatr Psychiatry. 1999;7(1):70–6. 25. Wang PS, Schneeweiss S, Avorn J, Fischer MA, 40. Alvir JM, Lieberman JA, Safferman AZ, Schwimmer Mogun H, Solomon DH, Brookhart MA. Risk of JL, Schaaf JA. Clozapine-induced agranulocytosis. death in elderly users of conventional vs. atypical Incidence and risk factors in the United States. N Engl antipsychotic medications. N Engl J Med. 2005; J Med. 1993;329(3):162–7. 353(22):2335–41. 41. Goldberg TE, Greenberg RD, Grif fi n SJ, Gold JM, 26. US Department of Health and Human Services. Public Kleinman JE, Pickar D, Schulz SC, Weinberger DR. Health Advisory: Deaths with Antipsychotics in The effect of clozapine on cognition and psychia- Elderly Patients with Behavioral Disturbances. Food tric symptoms in patients with schizophrenia. Br and Drug Administration Web site. J Psychiatry. 1993;162:43–8. 27. Stevenson DG, Decker SL, Dwyer LL, Huskamp HA, 42. Kennedy J, Deberdt W, Siegal A, Micca J, Degenhardt Grabowski DC, Metzger ED, Mitchell SL. E, Ahl J, Meyers A, Kaiser C, Baker RW. Olanzapine Antipsychotic and benzodiazepine use among nursing does not enhance cognition in non-agitated and non- home residents: fi ndings from the 2004 national nurs- psychotic patients with mild to moderate Alzheimer’s ing home survey. Am J Geriatr Psychiatry. 2010; dementia. Int J Geriatr Psychiatry. 2005;20(11): 18(12):1078–92. 1020–7. 28. Cummings JL, McRae T, Zhang R. Effects of donepe- 43. Savaskan E, Schnitzler C, Schroder C, Cajochen C, zil on neuropsychiatric symptoms in patients with Muller-Spahn F, Wirz-Justice A. Treatment of behav- dementia and severe behavioral disorders. Am ioural, cognitive and circadian rest-activity cycle dis- J Geriatr Psychiatry. 2006;14(7):605–12. turbances in Alzheimer’s disease: haloperidol vs. 29. Figiel G, Sadowsky C. A systematic review of the quetiapine. Int J Neuropsychopharmacol. 2006;9(5): effectiveness of rivastigmine for the treatment of behav- 507–16. ioral disturbances in dementia and other neurological 44. Scharre DW, Chang SI. Cognitive and behavioral disorders. Curr Med Res Opin. 2008;24(1):157–66. effects of quetiapine in Alzheimer disease patients. 30. Wilcock GK, Ballard CG, Cooper JA, Loft H. Alzheimer Dis Assoc Disord. 2002;16(2):128–30. Memantine for agitation/aggression and psychosis in 45. Rainer MK, Masching AJ, Ertl MG, Kraxberger E, moderately severe to severe Alzheimer’s disease: a Haushofer M. Effect of risperidone on behavioral and pooled analysis of 3 studies. J Clin Psychiatry. 2008; psychological symptoms and cognitive function in 69(3):341–8. dementia. J Clin Psychiatry. 2001;62(11):894–900. 31. Burton LC, German PS, Rovner BW, Brant LJ. 46. Schneider LS, Tariot PN, Dagerman KS, Davis SM, Physical restraint use and cognitive decline among Hsiao JK, Ismail MS, Lebowitz BD, Lyketsos CG, nursing home residents. J Am Geriatr Soc. 1992; Ryan JM, Stroup TS, Sultzer DL, Weintraub D, 40(8):811–6. Lieberman JA. Effectiveness of atypical antipsychotic 32. Woerner MG, Alvir JM, Kane JM, Saltz BL, drugs in patients with Alzheimer’s disease. N Engl Lieberman JA. Neuroleptic treatment of elderly J Med. 2006;355(15):1525–38. patients. Psychopharmacol Bull. 1995;31(2):333–7. 47. Sultzer DL, Davis SM, Tariot PN, Dagerman KS, 33. Steele C, Lucas MJ, Tune L. Haloperidol versus thior- Lebowitz BD, Lyketsos CG, Rosenheck RA, Hsiao idazine in the treatment of behavioral symptoms in JK, Lieberman JA, Schneider LS. Clinical symptom senile dementia of the Alzheimer’s type: preliminary responses to atypical antipsychotic medications in fi ndings. J Clin Psychiatry. 1986;47(6):310–2. Alzheimer’s disease: phase 1 outcomes from the 34. Devanand DP, Sackeim HA, Brown RP, Mayeux R. A CATIE-AD effectiveness trial. Am J Psychiatry. pilot study of haloperidol treatment of psychosis and 2008;165(7):844–54. behavioral disturbance in Alzheimer’s disease. Arch 48. Rocca P, Marino F, Montemagni C, Perrone D, Neurol. 1989;46(8):854–7. Bogetto F. Risperidone, olanzapine and quetiapine in 35. Brown JW, Chobor A, Zinn F. Dementia testing in the the treatment of behavioral and psychological symp- elderly. J Nerv Ment Dis. 1993;181(11):695–8. toms in patients with Alzheimer’s disease: prelimi- 36. McShane R, Keene J, Gedling K, Fairburn C, Jacoby nary fi ndings from a naturalistic, retrospective study. R, Hope T. Do neuroleptic drugs hasten cognitive Psychiatry Clin Neurosci. 2007;61(6):622–9. 7 Medications and Cognition in Older Adults 103

49. De Deyn P, Jeste DV, Swanink R, Kostic D, Breder C, 63. Roehrs T, Merlotti L, Zorick F, Roth T. Sedative, Carson WH, Iwamoto T. Aripiprazole for the treat- memory, and performance effects of hypnotics. ment of psychosis in patients with Alzheimer’s dis- Psychopharmacology (Berl). 1994;116(2):130–4. ease: a randomized, placebo-controlled study. J Clin 64. Toner LC, Tsambiras BM, Catalano G, Catalano MC, Psychopharmacol. 2005;25(5):463–7. Cooper DS. Central nervous system side effects asso- 50. Mintzer JE, Tune LE, Breder CD, Swanink R, Marcus ciated with zolpidem treatment. Clin Neuropharmacol. RN, McQuade RD, Forbes A. Aripiprazole for the 2000;23(1):54–8. treatment of psychoses in institutionalized patients 65. Stone JR, Zorick TS, Tsuang J. Dose-related illusions with Alzheimer dementia: a multicenter, randomized, and hallucinations with zaleplon. Clin Toxicol (Phila). double-blind, placebo-controlled assessment of three 2008;46(4):344–5. fi xed doses. Am J Geriatr Psychiatry. 2007;15(11): 66. Mintzer MZ, Grif fi ths RR. Selective effects of zolpi- 918–31. dem on human memory functions. J Psychopharmacol. 51. Streim JE, Porsteinsson AP, Breder CD, Swanink R, 1999;13(1):18–31. Marcus R, McQuade R, Carson WH. A randomized, 67. Troy SM, Lucki I, Unruh MA, Cevallos WH, Leister double-blind, placebo-controlled study of aripiprazole CA, Martin PT, Furlan PM, Mangano R. Comparison for the treatment of psychosis in nursing home patients of the effects of zaleplon, zolpidem, and triazolam on with Alzheimer disease. Am J Geriatr Psychiatry. memory, learning, and psychomotor performance. 2008;16(7):537–50. J Clin Psychopharmacol. 2000;20(3):328–37. 52. Bain KT. Management of chronic insomnia in elderly 68. Verster JC, Volkerts ER, Schreuder AH, Eijken EJ, persons. Am J Geriatr Pharmacother. 2006;4(2): van Heuckelum JH, Veldhuijzen DS, Verbaten MN, 168–92. Paty I, Darwish M, Danjou P, Patat A. Residual effects 53. Bogunovic OJ, Green fi eld SF. Practical geriatrics: use of middle-of-the-night administration of zaleplon and of benzodiazepines among elderly patients. Psychiatr zolpidem on driving ability, memory functions, and Serv. 2004;55(3):233–5. psychomotor performance. J Clin Psychopharmacol. 54. Paterniti S, Dufouil C, Alperovitch A. Long-term ben- 2002;22(6):576–83. zodiazepine use and cognitive decline in the elderly: 69. Boyle J, Trick L, Johnsen S, Roach J, Rubens R. Next- the epidemiology of vascular aging study. J Clin day cognition, psychomotor function, and driving- Psychopharmacol. 2002;22(3):285–93. related skills following nighttime administration of 55. Lagnaoui R, Begaud B, Moore N, Chaslerie A, Fourrier eszopiclone. Hum Psychopharmacol. 2008;23(5): A, Letenneur L, Dartigues JF, Moride Y. Benzodiazepine 385–97. use and risk of dementia: a nested case-control study. 70. Allain H, Bentue-Ferrer D, Tarral A, Gandon JM. J Clin Epidemiol. 2002;55(3):314–8. Effects on postural oscillation and memory functions 56. Dealberto MJ, McAvay GJ, Seeman T, Berkman L. of a single dose of zolpidem 5 mg, zopiclone 3.75 mg Psychotropic drug use and cognitive decline among and lormetazepam 1 mg in elderly healthy subjects. A older men and women. Int J Geriatr Psychiatry. randomized, cross-over, double-blind study versus 1997;12(5):567–74. placebo. Eur J Clin Pharmacol. 2003;59(3):179–88. 57. Brooks JO, Hoblyn JC. Neurocognitive costs and 71. Fairweather DB, Kerr JS, Hindmarch I. The effects of benefi ts of psychotropic medications in older adults. acute and repeated doses of zolpidem on subjective J Geriatr Psychiatry Neurol. 2007;20(4):199–214. sleep, psychomotor performance and cognitive func- 58. Larson EB, Kukull WA, Buchner D, Rei fl er BV. tion in elderly volunteers. Eur J Clin Pharmacol. Adverse drug reactions associated with global cogni- 1992;43(6):597–601. tive impairment in elderly persons. Ann Intern Med. 72. Otmani S, Demazieres A, Staner C, Jacob N, Nir T, 1987;107(2):169–73. Zisapel N, Staner L. Effects of prolonged-release 59. Foy A, Drinkwater V, March S, Mearrick P. Confusion melatonin, zolpidem, and their combination on psy- after admission to hospital in elderly patients using chomotor functions, memory recall, and driving skills benzodiazepines. Br Med J (Clin Res Ed). in healthy middle aged and elderly volunteers. Hum 1986;293(6554):1072. Psychopharmacol. 2008;23(8):693–705. 60. Mokhber N, Azarpazhooh MR, Khajehdaluee M, 73. Agostini JV, Leo-Summers LS, Inouye SK. Cognitive Velayati A, Hopwood M. Randomized, single-blind, and other adverse effects of diphenhydramine use in trial of sertraline and buspirone for treatment of hospitalized older patients. Arch Intern Med. 2001; elderly patients with generalized anxiety disorder. 161(17):2091–7. Psychiatry Clin Neurosci. 2010;64(2):128–33. 74. Basu R, Dodge H, Stoehr GP, Ganguli M. Sedative- 61. Hart RP, Colenda CC, Hamer RM. Effects of bus- hypnotic use of diphenhydramine in a rural, older pirone and alprazolam on the cognitive performance adult, community-based cohort: effects on cognition. of normal elderly subjects. Am J Psychiatry. 1991; Am J Geriatr Psychiatry. 2003;11(2):205–13. 148(1):73–7. 75. McEvoy LK, Smith ME, Fordyce M, Gevins A. 62. Cassidy EL, Lauderdale S, Sheikh JI. Mixed anxiety Characterizing impaired functional alertness from and depression in older adults: clinical characteristics diphenhydramine in the elderly with performance and management. J Geriatr Psychiatry Neurol. 2005; and neurophysiologic measures. Sleep. 2006;29(7): 18(2):83–8. 957–66. 104 G.L. Caporaso

76. Mendelson WB. A review of the evidence for the 89. Gasparini M, Fabrizio E, Bonifati V, Meco G. ef fi cacy and safety of trazodone in insomnia. J Clin Cognitive improvement during tolcapone treatment Psychiatry. 2005;66(4):469–76. in Parkinson’s disease. J Neural Transm. 1997; 77. Peck JS, LeGoff DB, Ahmed I, Goebert D. Cognitive 104(8–9):887–94. effects of exogenous melatonin administration in 90. Hokendorf H. Combination therapy of extrapyrami- elderly persons: a pilot study. Am J Geriatr dal disease with trihexyphenidyl and l-dopa: an elec- Psychiatry. 2004;12(4):432–6. tromyographic study with specifi c reference to 78. Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol tremor. J Int Med Res. 1979;7(1):19–28. EM, Hoogendijk WJ, Van Someren EJ. Effect of 91. Koller WC. Pharmacologic treatment of parkinso- bright light and melatonin on cognitive and noncog- nian tremor. Arch Neurol. 1986;43(2):126–7. nitive function in elderly residents of group care 92. Wirshing WC, Freidenberg DL, Cummings JL, facilities: a randomized controlled trial. JAMA. 2008; Bartzokis G. Effects of anticholinergic agents on 299(22):2642–55. patients with tardive dyskinesia and concomitant 79. Molloy SA, Rowan EN, O’Brien JT, McKeith IG, drug-induced parkinsonism. J Clin Psychopharmacol. Wesnes K, Burn DJ. Effect of levodopa on cognitive 1989;9(6):407–11. function in Parkinson’s disease with and without 93. Bedard MA, Pillon B, Dubois B, Duchesne N, dementia and dementia with Lewy bodies. J Neurol Masson H, Agid Y. Acute and long-term administra- Neurosurg Psychiatry. 2006;77(12):1323–8. tion of anticholinergics in Parkinson’s disease: 80. Morrison CE, Borod JC, Brin MF, Halbig TD, Olanow specifi c effects on the subcortico-frontal syndrome. CW. Effects of levodopa on cognitive functioning in Brain Cogn. 1999;40(2):289–313. moderate-to-severe Parkinson’s disease (MSPD). J 94. Van Spaendonck KP, Berger HJ, Horstink MW, Neural Transm. 2004;111(10–11):1333–41. Buytenhuijs EL, Cools AR. Impaired cognitive 81. Radbill R, Rosenberg G, Schwartz A. Effects of shifting in parkinsonian patients on anticholinergic levodopa therapy in Parkinson’s disease. II. therapy. Neuropsychologia. 1993;31(4):407–11. Measurement of behavioural changes. Can Med 95. Fayen M, Goldman MB, Moulthrop MA, Luchins Assoc J. 1974;111(11):1218–22. DJ. Differential memory function with dopaminer- 82. Cooper JA, Sagar HJ, Doherty SM, Jordan N, gic versus anticholinergic treatment of drug-induced Tidswell P, Sullivan EV. Different effects of dop- extrapyramidal symptoms. Am J Psychiatry. 1988; aminergic and anticholinergic therapies on cognitive 145(4):483–6. and motor function in Parkinson’s disease. A follow- 96. Heinik J. Effects of trihexyphenidyl on MMSE and up study of untreated patients. Brain. 1992;115(Pt CAMCOG scores of medicated elderly patients with 6):1701–25. schizophrenia. Int Psychogeriatr. 1998;10(1):103–8. 83. Portin R, Rinne UK. The effect of deprenyl (selegi- 97. Meador KJ. Cognitive side effects of medications. line) on cognition and emotion in parkinsonian Neurol Clin. 1998;16(1):141–55. patients undergoing long-term levodopa treatment. 98. Drane DL, Meador KJ. Epilepsy, anticonvulsant Acta Neurol Scand Suppl. 1983;95:135–44. drugs and cognition. Baillieres Clin Neurol. 1996; 84. Elmer L, Schwid S, Eberly S, Goetz C, Fahn S, 5(4):877–85. Kieburtz K, Oakes D, Blindauer K, Salzman P, Oren 99. Smith DB, Mattson RH, Cramer JA, Collins JF, S, Prisco UL, Stern M, Shoulson I. Rasagiline- Novelly RA, Craft B. Results of a nationwide veter- associated motor improvement in PD occurs without ans administration cooperative study comparing the worsening of cognitive and behavioral symptoms. J effi cacy and toxicity of carbamazepine, phenobarbi- Neurol Sci. 2006;248(1–2):78–83. tal, phenytoin, and primidone. Epilepsia. 1987;28 85. Brusa L, Bassi A, Stefani A, Pierantozzi M, Peppe A, Suppl 3:S50–8. Caramia MD, Boffa L, Ruggieri S, Stanzione P. 100. Prevey ML, Delaney RC, Cramer JA, Cattanach L, Pramipexole in comparison to l-dopa: a neuropsycho- Collins JF, Mattson RH. Effect of valproate on cogni- logical study. J Neural Transm. 2003;110(4):373–80. tive functioning. Comparison with carbamazepine. The 86. Brusa L, Tiraboschi P, Koch G, Peppe A, Pierantozzi department of veterans affairs epilepsy cooperative M, Ruggieri S, Stanzione P. Pergolide effect on study 264 group. Arch Neurol. 1996;53(10):1008–16. cognitive functions in early-mild Parkinson’s dis- 101. Read CL, Stephen LJ, Stolarek IH, Paul A, Sills GJ, ease. J Neural Transm. 2005;112(2):231–7. Brodie MJ. Cognitive effects of anticonvulsant 87. Costa A, Peppe A, Dell’Agnello G, Caltagirone C, monotherapy in elderly patients: a placebo-con- Carlesimo GA. Dopamine and cognitive functioning trolled study. Seizure. 1998;7(2):159–62. in de novo subjects with Parkinson’s disease: effects 102. Craig I, Tallis R. Impact of valproate and phenytoin of pramipexole and pergolide on working memory. on cognitive function in elderly patients: results of a Neuropsychologia. 2009;47(5):1374–81. single-blind randomized comparative study. Epilepsia. 88. Weintraub D, Koester J, Potenza MN, Siderowf AD, 1994;35(2):381–90. Stacy M, Voon V, Whetteckey J, Wunderlich GR, 103. Profenno LA, Jakimovich L, Holt CJ, Porsteinsson Lang AE. Impulse control disorders in Parkinson A, Tariot PN. A randomized, double-blind, placebo- disease: a cross-sectional study of 3090 patients. controlled pilot trial of safety and tolerability of two Arch Neurol. 2010;67(5):589–95. doses of divalproex sodium in outpatients with 7 Medications and Cognition in Older Adults 105

probable Alzheimer’s disease. Curr Alzheimer Res. type and age-matched controls. A dose-response 2005;2(5):553–8. study. Arch Gen Psychiatry. 1987;44(5):418–26. 104. Tariot PN, Erb R, Podgorski CA, Cox C, Patel S, 118. Dubois B, Danze F, Pillon B, Cusimano G, Lhermitte Jakimovich L, Irvine C. Effi cacy and tolerability of F, Agid Y. Cholinergic-dependent cognitive defi cits carbamazepine for agitation and aggression in in Parkinson’s disease. Ann Neurol. 1987;22(1): dementia. Am J Psychiatry. 1998;155(1):54–61. 26–30. 105. Cumbo E, Ligori LD. Levetiracetam, lamotrigine, 119. Zemishlany Z, Thorne AE. Anticholinergic chal- and phenobarbital in patients with epileptic seizures lenge and cognitive functions: a comparison between and Alzheimer’s disease. Epilepsy Behav. 2010; young and elderly normal subjects. Isr J Psychiatry 17(4):461–6. Relat Sci. 1991;28(3):32–41. 106. Gomer B, Wagner K, Frings L, Saar J, Carius A, 120. de la Torre JC. How do heart disease and stroke Harle M, Steinhoff BJ, Schulze-Bonhage A. The become risk factors for Alzheimer’s disease? Neurol infl uence of antiepileptic drugs on cognition: a Res. 2006;28(6):637–44. comparison of levetiracetam with topiramate. 121. Poon IO. Effects of antihypertensive drug treatment Epilepsy Behav. 2007;10(3):486–94. on the risk of dementia and cognitive impairment. 107. Romigi A, Cervellino A, Marciani MG, Izzi F, Pharmacotherapy. 2008;28(3):366–75. Massoud R, Corona M, Torelli F, Zannino S, Uasone 122. Shah K, Qureshi SU, Johnson M, Parikh N, Schulz E, Placidi F. Cognitive and psychiatric effects of PE, Kunik ME. Does use of antihypertensive drugs topiramate monotherapy in migraine treatment: an affect the incidence or progression of dementia? open study. Eur J Neurol. 2008;15(2):190–5. A systematic review. Am J Geriatr Pharmacother. 108. Kececi H, Atakay S. Effects of topiramate on neuro- 2009;7(5):250–61. physiological and neuropsychological tests in 123. Koella WP. CNS-related (side-)effects of beta-block- migraine patients. J Clin Neurosci. 2009;16(12): ers with special reference to mechanisms of action. 1588–91. Eur J Clin Pharmacol. 1985;28(Suppl):55–63. 109. Menefee LA, Frank ED, Crerand C, Jalali S, Park J, 124. Neil-Dwyer G, Bartlett J, McAinsh J, Cruickshank Sanschagrin K, Besser M. The effects of transdermal JM. Beta-adrenoceptor blockers and the blood- fentanyl on driving, cognitive performance, and bal- brian barrier. Br J Clin Pharmacol. 1981;11(6): ance in patients with chronic nonmalignant pain 549–53. conditions. Pain Med. 2004;5(1):42–9. 125. Cove-Smith JR, Kirk CA. CNS-related side-effects 110. Blumstein H, Gorevic PD. Rheumatologic illnesses: with metoprolol and atenolol. Eur J Clin Pharmacol. treatment strategies for older adults. Geriatrics. 1985;28(Suppl):69–72. 2005;60(6):28–35. 126. McAinsh J, Cruickshank JM. Beta-blockers and cen- 111. Ng KF, Yuen TS, Ng VM. A comparison of postop- tral nervous system side effects. Pharmacol Ther. erative cognitive function and pain relief with fenta- 1990;46(2):163–97. nyl or tramadol patient-controlled analgesia. J Clin 127. Applegate WB, Pressel S, Wittes J, Luhr J, Shekelle Anesth. 2006;18(3):205–10. RB, Camel GH, Greenlick MR, Hadley E, Moye L, 112. Kunig G, Datwyler S, Eschen A, Schreiter Gasser U. Perry Jr HM, et al. Impact of the treatment of iso- Unrecognised long-lasting tramadol-induced delir- lated systolic hypertension on behavioral variables. ium in two elderly patients. A case report. Results from the systolic hypertension in the elderly Pharmacopsychiatry. 2006;39(5):194–9. program. Arch Intern Med. 1994;154(19):2154–60. 113. Brown RT, Zuelsdorff M, Fleming M. Adverse 128. Fogari R, Mugellini A, Zoppi A, Derosa G, Pasotti effects and cognitive function among primary care C, Fogari E, Preti P. In fl uence of losartan and atenolol patients taking opioids for chronic nonmalignant on memory function in very elderly hypertensive pain. J Opioid Manag. 2006;2(3):137–46. patients. J Hum Hypertens. 2003;17(11):781–5. 114. Fong HK, Sands LP, Leung JM. The role of postop- 129. Perez-Stable EJ, Halliday R, Gardiner PS, Baron erative analgesia in delirium and cognitive decline in RB, Hauck WW, Acree M, Coates TJ. The effects of elderly patients: a systematic review. Anesth Analg. propranolol on cognitive function and quality of life: 2006;102(4):1255–66. a randomized trial among patients with diastolic 115. Manning C, Scandale L, Manning EJ, Gengo FM. hypertension. Am J Med. 2000;108(5):359–65. Central nervous system effects of meclizine and 130. Palac DM, Cornish RD, McDonald WJ, Middaugh dimenhydrinate: evidence of acute tolerance to DA, Howieson D, Bagby SP. Cognitive function in antihistamines. J Clin Pharmacol. 1992;32(11): hypertensives treated with atenolol or propranolol. 996–1002. J Gen Intern Med. 1990;5(4):310–8. 116. Molloy DW. Memory loss, confusion, and disorien- 131. Gliebus G, Lippa CF. The in fl uence of beta-blockers tation in an elderly woman taking meclizine. J Am on delayed memory function in people with cogni- Geriatr Soc. 1987;35(5):454–6. tive impairment. Am J Alzheimers Dis Other Demen. 117. Sunderland T, Tariot PN, Cohen RM, Weingartner 2007;22(1):57–61. H, Mueller 3rd EA, Murphy DL. Anticholinergic 132. Portnoi VA. Digitalis delirium in elderly patients. sensitivity in patients with dementia of the Alzheimer J Clin Pharmacol. 1979;19(11–12):747–50. 106 G.L. Caporaso

133. Eisendrath SJ, Sweeney MA. Toxic neuropsychiatric 148. Lewis DA, Smith RE. Steroid-induced psychiatric effects of digoxin at therapeutic serum concentra- syndromes. A report of 14 cases and a review of the tions. Am J Psychiatry. 1987;144(4):506–7. literature. J Affect Disord. 1983;5(4):319–32. 134. Laudisio A, Marzetti E, Pagano F, Cocchi A, 149. Coluccia D, Wolf OT, Kollias S, Roozendaal B, Bernabei R, Zuccala G. Digoxin and cognitive per- Forster A, de Quervain DJ. Glucocorticoid therapy- formance in patients with heart failure: a cohort, induced memory de fi cits: acute versus chronic pharmacoepidemiological survey. Drugs Aging. effects. J Neurosci. 2008;28(13):3474–8. 2009;26(2):103–12. 150. Varney NR, Alexander B, MacIndoe JH. Reversible 135. Salom IL, Silvis SE, Doscherholmen A. Effect of steroid dementia in patients without steroid psycho- cimetidine on the absorption of vitamin B12. Scand sis. Am J Psychiatry. 1984;141(3):369–72. J Gastroenterol. 1982;17(1):129–31. 151. Sacks O, Shulman M. Steroid dementia: an over- 136. Force RW, Nahata MC. Effect of histamine h2-re- looked diagnosis? Neurology. 2005;64(4):707–9. ceptor antagonists on vitamin B12 absorption. Ann 152. Gupta VP, Ehrlich GE. Organic brain syndrome in Pharmacother. 1992;26(10):1283–6. rheumatoid arthritis following corticosteroid with- 137. Wolters M, Strohle A, Hahn A. Cobalamin: a critical drawal. Arthritis Rheum. 1976;19(6):1333–8. vitamin in the elderly. Prev Med. 2004;39(6): 153. Hoppmann RA, Peden JG, Ober SK. Central nervous 1256–66. system side effects of nonsteroidal anti-in fl ammatory 138. Valuck RJ, Ruscin JM. A case-control study on drugs. Aseptic meningitis, psychosis, and cognitive adverse effects: H2 blocker or proton pump inhibitor dysfunction. Arch Intern Med. 1991;151(7):1309–13. use and risk of vitamin B12 defi ciency in older 154. Price JF, Stewart MC, Deary IJ, Murray GD, adults. J Clin Epidemiol. 2004;57(4):422–8. Sandercock P, Butcher I, Fowkes FG. Low dose aspi- 139. Dharmarajan TS, Kanagala MR, Murakonda P, rin and cognitive function in middle aged to elderly Lebelt AS, Norkus EP. Do acid-lowering agents adults: randomised controlled trial. BMJ. 2008; affect vitamin B12 status in older adults? J Am Med 337:a1198. Dir Assoc. 2008;9(3):162–7. 155. Kang JH, Cook N, Manson J, Buring JE, Grodstein 140. Boustani M, Hall KS, Lane KA, Aljadhey H, Gao S, F. Low dose aspirin and cognitive function in the Unverzagt F, Murray MD, Ogunniyi A, Hendrie H. women’s health study cognitive cohort. BMJ. The association between cognition and histamine-2 2007;334(7601):987. receptor antagonists in African Americans. J Am 156. Martin BK, Szekely C, Brandt J, Piantadosi S, Geriatr Soc. 2007;55(8):1248–53. Breitner JC, Craft S, Evans D, Green R, Mullan M. 141. Oslin DW, Katz IR, Sands LP, Bilker W, DiFilippo Cognitive function over time in the Alzheimer’s dis- SD, D’Angelo K. Examination of the cognitive ease anti-in fl ammatory prevention trial (adapt): effects of cimetidine in normal elderly volunteers. results of a randomized, controlled trial of naproxen Am J Geriatr Psychiatry. 1999;7(2):160–5. and celecoxib. Arch Neurol. 2008;65(7):896–905. 142. Hanlon JT, Landerman LR, Artz MB, Gray SL, 157. Small GW, Siddarth P, Silverman DH, Ercoli LM, Fillenbaum GG, Schmader KE. Histamine2 receptor Miller KJ, Lavretsky H, Bookheimer SY, Huang SC, antagonist use and decline in cognitive function Barrio JR, Phelps ME. Cognitive and cerebral meta- among community dwelling elderly. Pharma- bolic effects of celecoxib versus placebo in people with coepidemiol Drug Saf. 2004;13(11):781–7. age-related memory loss: randomized controlled study. 143. Kay GG, Ebinger U. Preserving cognitive function Am J Geriatr Psychiatry. 2008;16(12):999–1009. for patients with overactive bladder: evidence for a 158. Szekely CA, Zandi PP. Non-steroidal anti- differential effect with darifenacin. Int J Clin Pract. infl ammatory drugs and Alzheimer’s disease: the 2008;62(11):1792–800. epidemiological evidence. CNS Neurol Disord Drug 144. Wesnes KA, Edgar C, Tretter RN, Bolodeoku J. Targets. 2010;9(2):132–9. Exploratory pilot study assessing the risk of cogni- 159. Andersen K, Launer LJ, Ott A, Hoes AW, Breteler tive impairment or sedation in the elderly following MM, Hofman A. Do nonsteroidal anti-infl ammatory single doses of solifenacin 10 mg. Expert Opin Drug drugs decrease the risk for Alzheimer’s disease? Saf. 2009;8(6):615–26. The Rotterdam study. Neurology. 1995;45(8): 145. Kay G, Crook T, Rekeda L, Lima R, Ebinger U, 1441–5. Arguinzoniz M, Steel M. Differential effects of the 160. Rich JB, Rasmusson DX, Folstein MF, Carson KA, antimuscarinic agents darifenacin and oxybutynin Kawas C, Brandt J. Nonsteroidal anti-infl ammatory ER on memory in older subjects. Eur Urol. drugs in Alzheimer’s disease. Neurology. 1995;45(1): 2006;50(2):317–26. 51–5. 146. Lipton RB, Kolodner K, Wesnes K. Assessment of 161. Sturmer T, Glynn RJ, Field TS, Taylor JO, Hennekens cognitive function of the elderly population: effects CH. Aspirin use and cognitive function in the elderly. of darifenacin. J Urol. 2005;173(2):493–8. Am J Epidemiol. 1996;143(7):683–91. 147. Womack KB, Heilman KM. Tolterodine and 162. Stewart WF, Kawas C, Corrada M, Metter EJ. Risk memory: dry but forgetful. Arch Neurol. 2003;60(5): of Alzheimer’s disease and duration of NSAID use. 771–3. Neurology. 1997;48(3):626–32. 7 Medications and Cognition in Older Adults 107

163. Szekely CA, Thorne JE, Zandi PP, Ek M, Messias E, 176. Vaughan C, Goldstein FC, Tenover JL. Exogenous Breitner JC, Goodman SN. Nonsteroidal anti- testosterone alone or with fi nasteride does not in fl ammatory drugs for the prevention of Alzheimer’s improve measurements of cognition in healthy older disease: a systematic review. Neuroepidemiology. men with low serum testosterone. J Androl. 2007; 2004;23(4):159–69. 28(6):875–82. 164. Vlad SC, Miller DR, Kowall NW, Felson DT. 177. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, Protective effects of NSAIDS on the development Aleman A, Lock TM, Bosch JL, Grobbee DE, van of Alzheimer disease. Neurology. 2008;70(19): der Schouw YT. Effect of testosterone supplementa- 1672–7. tion on functional mobility, cognition, and other 165. Waldstein SR, Wendell CR, Seliger SL, Ferrucci L, parameters in older men: a randomized controlled Metter EJ, Zonderman AB. Nonsteroidal anti- trial. JAMA. 2008;299(1):39–52. infl ammatory drugs, aspirin, and cognitive function 178. Mitsiades N, Correa D, Gross CP, Hurria A, Slovin in the Baltimore longitudinal study of aging. J Am SF. Cognitive effects of hormonal therapy in older Geriatr Soc. 2010;58(1):38–43. adults. Semin Oncol. 2008;35(6):569–81. 166. Hanlon JT, Schmader KE, Landerman LR, Horner 179. Paganini-Hill A, Clark LJ. Preliminary assessment RD, Fillenbaum GG, Pieper CF, Wall Jr WE, of cognitive function in breast cancer patients treated Koronkowski MJ, Cohen HJ. Relation of prescrip- with tamoxifen. Breast Cancer Res Treat. 2000; tion nonsteroidal antiinfl ammatory drug use to cog- 64(2):165–76. nitive function among community-dwelling elderly. 180. Castellon SA, Ganz PA, Bower JE, Petersen L, Ann Epidemiol. 1997;7(2):87–94. Abraham L, Greendale GA. Neurocognitive perfor- 167. Henderson AS, Jorm AF, Christensen H, Jacomb PA, mance in breast cancer survivors exposed to adju- Korten AE. Aspirin, anti-in fl ammatory drugs and vant chemotherapy and tamoxifen. J Clin Exp risk of dementia. Int J Geriatr Psychiatry. 1997; Neuropsychol. 2004;26(7):955–69. 12(9):926–30. 181. Jacobsen DE, Samson MM, Emmelot-Vonk MH, 168. Saag KG, Rubenstein LM, Chrischilles EA, Wallace Verhaar HJ. Raloxifene improves verbal memory in RB. Nonsteroidal antiinfl ammatory drugs and cogni- late postmenopausal women: a randomized, double- tive decline in the elderly. J Rheumatol. 1995;22(11): blind, placebo-controlled trial. Menopause. 2010; 2142–7. 17(2):309–14. 169. Breitner JC, Haneuse SJ, Walker R, Dublin S, Crane 182. Nelson CJ, Lee JS, Gamboa MC, Roth AJ. Cognitive PK, Gray SL, Larson EB. Risk of dementia and ad effects of hormone therapy in men with prostate can- with prior exposure to NSAIDS in an elderly commu- cer: a review. Cancer. 2008;113(5):1097–106. nity-based cohort. Neurology. 2009;72(22):1899–905. 183. Matousek RH, Sherwin BB. A randomized controlled 170. Lethaby A, Hogervorst E, Richards M, Yesufu A, trial of add-back estrogen or placebo on cognition in Yaffe K Hormone replacement therapy for cognitive men with prostate cancer receiving an antiandrogen function in postmenopausal women. Cochrane and a gonadotropin-releasing hormone analog. Database Syst Rev. 2008;(1):CD003122. Psychoneuroendocrinology. 2010;35(2):215–25. 171. Greendale GA, Huang MH, Wight RG, Seeman T, 184. Yaffe K, Barrett-Connor E, Lin F, Grady D. Serum Luetters C, Avis NE, Johnston J, Karlamangla AS. lipoprotein levels, statin use, and cognitive function Effects of the menopause transition and hormone use in older women. Arch Neurol. 2002;59(3):378–84. on cognitive performance in midlife women. 185. Bernick C, Katz R, Smith NL, Rapp S, Bhadelia R, Neurology. 2009;72(21):1850–7. Carlson M, Kuller L. Statins and cognitive function 172. Coker LH, Espeland MA, Rapp SR, Legault C, in the elderly: the cardiovascular health study. Resnick SM, Hogan P, Gaussoin S, Dailey M, Neurology. 2005;65(9):1388–94. Shumaker SA. Postmenopausal hormone therapy 186. Willey JZ, Elkind MS. 3-hydroxy-3-methylglutaryl- and cognitive outcomes: the women’s health initia- coenzyme a reductase inhibitors in the treatment of tive memory study (WHIMS). J Steroid Biochem central nervous system diseases. Arch Neurol. Mol Biol. 2010;118(4–5):304–10. 2010;67(9):1062–7. 173. Moffat SD. Effects of testosterone on cognitive and 187. Rogers RL, Meyer JS, McClintic K, Mortel KF. brain aging in elderly men. Ann N Y Acad Sci. Reducing hypertriglyceridemia in elderly patients 2005;1055:80–92. with cerebrovascular disease stabilizes or improves 174. Fuller SJ, Tan RS, Martins RN. Androgens in the eti- cognition and cerebral perfusion. Angiology. 1989; ology of Alzheimer’s disease in aging men and pos- 40(4 Pt 1):260–9. sible therapeutic interventions. J Alzheimers Dis. 188. Morris MC, Evans DA, Bienias JL, Scherr PA, 2007;12(2):129–42. Tangney CC, Hebert LE, Bennett DA, Wilson RS, 175. Warren MF, Serby MJ, Roane DM. The effects of Aggarwal N. Dietary niacin and the risk of incident testosterone on cognition in elderly men: a review. Alzheimer’s disease and of cognitive decline. J Neurol CNS Spectr. 2008;13(10):887–97. Neurosurg Psychiatry. 2004;75(8):1093–9. Assessment of Depression and Anxiety in Older Adults 8

Dimitris N. Kiosses

Abstract Late-life depression and anxiety may contribute to detrimental consequences for patients and their families. They impair functioning, negatively affect quality of life, disrupt interpersonal relationships and increase utilization of medical services. Further, late-life depression is associated with increased morbidity, mortality and is the most common psychiatric diagnosis in attempted or completed suicides. This chapter explores diagnostic considerations and provides clinical pearls for the accurate assessment of the most common depression and anxiety disorders in older adults.

Keywords Depression • Anxiety • Assessment • Diagnosis • Suicide • Disability

and 14% of home-care recipients have major Epidemiology of Late-Life Depression depression [1– 3] . The percentages are even greater in milder forms of depression including The prevalence of late-life depression increases dysthymia. as we move from the community to medical set- Despite its detrimental consequences, late-life tings, home care, and nursing homes. Three per- depression is underdiagnosed and undertreated. cent of older adults in the community, 5–8% of Factors which contribute to underdiagnosis and medical outpatients, 11% of medical inpatients, undertreatment of geriatric depression likely approximately 12% of nursing home residents, include the following. (a) Similarities of depression symptoms with those of medical illnesses. (b) Many older depressed adults do not report D. N. Kiosses , Ph.D. () depressed mood but rather lack of interest or Department of Psychiatry , Weill-Cornell Institute pleasure in activities. of Geriatric Psychiatry, Weill Medical College of Cornell (c) Aging stereotypes. University , 21 Bloomingdale Road, White Plains , (d) Primary care settings, where most of the New York , NY 10605 , USA e-mail: [email protected] depressed older adults are treated, are busy

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 109 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_8, © Springer Science+Business Media, LLC 2013 110 D.N. Kiosses

and emphasize medical rather than mental health problems [ 4 ] . In primary care, almost Diagnosis of Clinical Depression half of high utilizers receive no antidepressant and Anxiety treatment and 1/3 receive inadequate treatment [ 4, 5 ] . Even when antidepressants are Diagnosis of Clinical Depression prescribed, adherence rates are discouraging, ranging from 25 to 60% [ 5 ] . There are different types of clinical depression highlighted in the DSM-IV [ 16 ] , while some of them may be updated in the DSM-V. Major Suicide depressive disorder (MDD), dysthymic disorder, depressive disorder NOS, and adjustment disor- Suicide is devastating for the victims’ families, der of depressed mood and anxiety are the most friends, and communities. Suicide rates increase common diagnoses of clinical unipolar depres- with age, with white older men at greatest risk. sion. Differential diagnosis is based on the sever- Although there has been a decrease in suicide ity and duration of symptoms as well as on the rates in older adults in recent years, rates may precipitants of the onset of depression. As we signi fi cantly rise again because of the aging of review the symptoms of different types of depres- baby boomers, a cohort with increased suicide sion, it is evident that MDD is the most severe. In rates [6 ] . When compared with suicide attempts the following section, the most common depres- of young adults, attempts of older adults are more sive and anxiety disorders will be described and determined and use more lethal means, including certain diagnostic considerations will be high- the use of fi rearms or hanging. Psychiatric ill- lighted. The detailed descriptions of diagnoses nesses in general, but mood disorders and major follow the DSM-IV. The DSM-5 is expected to depression in particular, are the most prominent be released in May 2013. risk factors for suicide. Other risk factors include poor physical health, disability, recent loss, and Major Depressive Disorder lack of social connectedness [ 7– 9 ] . Assessment MDD is characterized by the presence of one or of these risk factors is important during the more major depressive episodes (MDEs) and the assessment of depression. absence of any hypomanic or manic episode. A MDE is diagnosed when either depressed mood or loss of interest or pleasure (anhedonia) is present Epidemiology of Late-Life Anxiety for at least 2 weeks, every day, most of the day [ 16 ] . In addition, the patient may experience fi ve Late-life anxiety contributes to decreased sense or more of the following symptoms: (a) depressed of well-being, reduced satisfaction, and increased mood, (b) lack of interest or pleasure in activities, disability [ 10 ] . Even though reported prevalence (c) signi fi cant weight loss or weight gain or appe- rates of diagnosable anxiety in older adults vary tite disturbances (in older adults, most commonly greatly in the community (2–19%), the best esti- weight loss and decreased appetite), (d) sleep dis- mate is about 10%, while this rate increases in turbances, i.e., insomnia or hypersomnia, (e) psy- medically ill populations [ 10 ] . Comorbid anxiety chomotor agitation or retardation, (f) fatigue or is common in late-life depression, with reports loss of energy, (g) feelings of worthlessness or estimating its prevalence up to 65% [ 10 ] and it is excessive or inappropriate guilt, (h) concentration associated with lower response to antidepressant diffi culties or indecisiveness, and (i) recurrent medication treatment, longer time to response or thoughts of death, recurrent suicidal ideation, or a remission, and shorter time to recurrence once suicide attempt or a specifi c plan for committing remission is achieved [11– 15 ] . suicide (DSM-IV) [ 16 ] . To diagnose an episode of 8 Assessment of Depression and Anxiety in Older Adults 111 major depression, clinically signifi cant distress or other medical illnesses. As older adults frequently impairment in social, occupational, or other suffer from medical illnesses, it may be dif fi cult important areas of functioning is required [ 16 ] . to differentiate whether these symptoms are Within the diagnosis of MDD, there are different features of depression or other medical illnesses. degrees of severity denoted in the last digit of the Second, due to aging stereotypes, lack of interest DSM-IV diagnosis [ 16 ] . Specifi cally, (1) refers to or pleasure may be incorrectly perceived as a nor- mild severity, (2) to moderate, (3) to severe with- mal part of aging. This is a very critical issue as out psychotic features, (4) to severe with psychotic many depressed older adults do not exhibit or features, whereas (5) and (6) refer to partial or full report depressed mood, but rather lack of interest remission. or pleasure.

Psychotic Depression Adjustment Disorder with Anxiety Major depression with psychotic features is a and/or Depressed Mood severe disorder, which is characterized by delu- Adjustment disorder refers to the development of sions or hallucinations and is associated with emotional and behavioral symptoms as a response slow recovery, poor outcomes, and increased dis- to a stressor occurring within 3 months of the ability and mortality [ 17– 19 ] . Delusions are more onset of the symptoms [16 ] . Usual stressors of frequent than hallucinations, and compared to adjustment disorder in older adults include poor delusions in dementia, delusions in psychotic physical health and disability, socioeconomic depression are systematized and mood congruent deprivation, and placement to a long-term care [4 ] . Usual delusional themes include guilt, perse- facility [4, 20 ] . Based on DSM-IV [16 ] , the cution, hypochondriasis, nihilism, and jealousy. symptoms are clinically signi fi cant, may cause marked distress (more than expected from the Dysthymia exposure to that stressor) and signi fi cant impair- Dysthymic disorder is a chronic depression of ment in social or occupational functioning. milder intensity than major depression. Adjustment disorder may occur with anxiety, Specifi cally, depressed mood is present for most depressed mood, or both. of the day, not every day but for most days than not, for at least 2 years and should not be absent for longer than 2 months [ 16 ] . Contrary to the Cognitive Defi cits Associated diagnosis of major depression, lack of interest or with Depression pleasure is not a cardinal symptom of dysthymia. As mentioned above, late-life depression may be In addition to depressed mood, the patient may accompanied by cognitive diffi culties. Poor con- experience two or more of the following symp- centration is a common symptom of depression. toms: (a) poor appetite or overeating (in older Moreover, nondemented depressed elders may adults, most commonly poor appetite), (b) insom- present with disturbances in processing speed nia or hypersomnia, (c) low energy or fatigue, (d) and executive functioning [ 21, 22 ] . To evaluate low self-esteem, (e) poor concentration or the etiology of cognitive dif fi culties in late-life dif fi culty making decisions, and (f) feelings of depression, a thorough neuropsychological hopelessness [16 ] . Once again, clinically examination is strongly recommended. signi fi cant distress or impairment in social, occu- Some older adults display symptoms of pational, or other important areas of functioning dementia that are due to depression. As soon as is required for diagnosis [16 ] . depression remits, their cognitive functioning A close examination of the symptoms of major may reach their premorbid functioning. This depression and dysthymia may explain why late- clinical picture is referred as “pseudodementia” life depression is underdiagnosed. First, fatigue, or “reversible dementia.” The causes of “pseudo- loss of energy, concentration dif fi culties, weight dementia” are not clearly understood; in some loss, and sleep disturbances may be symptoms of cases, depression may contribute to cognitive 112 D.N. Kiosses impairment whereas in others, cognitive de fi cits clinically signi fi cant distress or disruption in may be the result of a progressive subclinical functioning [25 ] . dementia that is exacerbated by depression [4, The provisional diagnostic criteria for depres- 23] . Despite their return to almost normal sion of AD mainly differ from DSM-IV criteria cognitive functioning, older adults with “pseudo- of MDD in the following ways: (a) the duration dementia” may develop irreversible dementia at of cardinal symptoms (in DSM-IV, the symptoms a rate of 9–25% per year (approximately 40% must be there nearly every day, most of the day, within 3 years) [ 4, 23 ] . Further research is while in provisional criteria, the symptoms may needed to understand “pseudodementia” and its have shorter duration), (b) the number of symp- consequences. toms required for the diagnosis (5 in DSM-IV vs. 3 in provisional criteria), and (c) description of Depression in Alzheimer’s Disease anhedonia (“lack of pleasure in DSM-IV” vs. Some depressive symptoms may be similar to “decreased positive affect or pleasure in response symptoms of Alzheimer’s disease (AD). For to social contacts or activities” in provisional cri- example, diminished social activity and lack of teria) [24, 25 ] . interest, which are symptoms of depression, are prevalent in AD. The overlap of symptoms between depression and AD may complicate the Diagnosis of Anxiety diagnosis of depression in AD [ 24 ] . Further, research suggests that depression in AD may be In a recent review of cognitive therapy of anxiety different from other depressive disorders [24 ] . disorders, Clark and Beck highlight the following In 2002, the NIMH organized a workshop de fi nitions of fear and anxiety: “Fear is a primi- with a group of investigators of depression and tive automatic neuropsychological state of alarm AD to facilitate the development of provisional involving the cognitive appraisal of imminent diagnostic criteria for depression of AD [ 24, 25 ] . threat or danger to the safety and security of an The goals of the development of these criteria individual,” whereas “Anxiety is a complex cog- were to assist clinicians in diagnosing depression nitive, affective, physiological, and behavioral in AD and to provide a target for research on the response system (i.e., threat mode) that is acti- mechanism and treatment of depression and AD vated when anticipated events or circumstances [25 ] . The criteria required three (or more) of the are deemed to be highly aversive because they are following symptoms to be present during the perceived to be unpredictable, uncontrollable same 2-week period and represent a change from events that could potentially threaten the vital previous functioning: at least one of the symp- interests of an individual” [ 26 ] . Therefore, fear toms is either (1) depressed mood or (2) decreased and anxiety have a protective value of helping us positive affect or pleasure. The symptoms were: deal with actual threats. However, in anxiety dis- (a) clinically signifi cant depressed mood, (b) orders, the patient’s perceived threats may not be decreased positive affect or pleasure, (c) social accurate, last longer than expected, while the isolation or withdrawal, (d) disruption in appe- threshold for perceived threats is lowered and, tite, (e) disruption in sleep, (f) psychomotor therefore, the patient becomes hypersensitive to changes (agitation or retardation), (g) irritability, external stimuli. As a result, the response could (h) fatigue or loss of energy, (i) feelings of worth- be excessive compared to the severity of the per- lessness, hopelessness, or excessive or inappro- ceived threat, while anxiety feels uncontrollable priate guilt, and (j) recurrent thoughts of death, and signi fi cantly impairs functioning. Therefore, suicidal ideation, and plan or attempt [24 , 25 ] . in the assessment of anxiety, the clinician has to These criteria must be present in an individual evaluate the evidence for a realistic threat and the diagnosed with Dementia of the Alzheimer’s appropriateness and excessiveness of the patient’s Type and the symptoms are believed to cause response to the perceived threat. 8 Assessment of Depression and Anxiety in Older Adults 113

Generalized anxiety disorder (GAD) and pho- sweating, (c) trembling or shaking, (d) sensations bias are the most common anxiety disorders in of shortness of breath or smothering, (e) feeling older adults [10, 27, 28 ] , even though a number of choking, (f) chest pain or discomfort, (g) nau- of older adults may experience clinically sea or abdominal stress, (h) feeling dizzy, signifi cant anxiety without any specifi c diagnosis unsteady, lightheaded, or faint, (i) derealization [10 ] . The following section highlights the diag- (feelings of unreality) or depersonalization (being noses of GAD, phobias, and panic disorder. detached from oneself), (j) fear of losing control or going crazy, (k) fear of dying, (l) paresthesias Generalized Anxiety Disorder (numbness or tingling sensations), and (m) chills The critical features of GAD as described in or hot fl ushes” [16 ] . Panic disorder may be diag- DSM-IV [ 16 ] are (a) excessive and diffi cult to nosed in the presence or absence of agoraphobia, control anxiety or worry (apprehensive expecta- which is characterized by anxiety and avoidance tion), for more days than not, for at least of places or situations in the event of having a 6 months; (b) at least three or more of the follow- panic attack. ing symptoms: (1) restlessness, (2) being easily fatigued, (3) concentration dif fi culties, (4) irritability, (5) muscle tension, and (6) sleep distur- Diagnostic Considerations bances [ 16 ] . Similar to other diagnoses in DSM-IV, the symptoms must be severe enough Rule out Other Diagnoses to cause clinically signi fi cant distress or impair- The clinician needs to evaluate whether other ment in social, occupational, or other important mental disorders exist. For example, ruling out areas of functioning [16 ] . Bipolar I and II disorders is critical because the pharmacological or psychological treatment of Speci fi c Phobia bipolar depression differ from that of unipolar Speci fi c Phobia is characterized by “marked and depression. Geriatric bipolar disorder is relatively persistent fear that is excessive and unreason- rare in the community and its point prevalence able, cued by the presence or anticipation of a rate is less than 0.5% [ 29 ] . However, 17% of speci fi c object or situation (e.g., fl ying, heights, older adults in psychiatric emergency rooms have animals, receiving an injection, seeing blood)” bipolar disorder [ 29, 30 ] . Compared to young [ 16 ] . The patient recognizes that his or her fear is adults, fewer older bipolar patients have a diag- excessive and unreasonable and avoids the pho- nosis of substance abuse and more have a cogni- bic situation, as the exposure of the stimulus tive disorder diagnosis (i.e., dementia, amnesia, “almost invariably provokes an immediate anxi- and cognitive disorder NOS) [28 ] . ety response” [16 ] . Bipolar I is characterized by the occurrence of manic episodes, with or without MDEs [ 16 ] . Panic Disorder However, Bipolar I older patients usually have As described in DSM-IV, panic disorder is char- had one or more MDEs. Manic episode is de fi ned acterized by recurrent unexpected panic attacks; as “a distinct period of abnormally and persis- one of the attacks has been followed by at least tently elevated, expansive, or irritable mood, last- 1 month of persistent concern about having addi- ing at least 1 week (or any duration if hospitalization tional attacks, worry about the implications or is necessary)” [ 16 ] . During this period, the patient consequences of the attack, or a signi fi cant experiences three or more of the following symp- change in behavior related to the attacks [ 16 ] . toms (four if mood is only irritable): (a) in fl ated Panic attacks are defi ned as “an intense period of self-esteem or grandiosity, (b) decreased need for fear or discomfort, in which four (or more) of the sleep (e.g., patient feels rested after only 3 h of following symptoms developed abruptly and sleep), (c) more talkative than usual or pressured reached a peak within 10 min: (a) palpitations, speech, (d) fl ights of ideas or racing thoughts, (e) pounding heart, or accelerated heart rate; (b) distractibility, (f) psychomotor agitation or 114 D.N. Kiosses increase in goal-directed activities, and (g) exces- benzodiazepines may cause depression [ 4 ] . As sive involvement in pleasurable activities that noted in DSM-IV, the symptoms of depression have a high potential for painful consequences must not be “due to the direct physiological (e.g., buying sprees, sexual indiscretions, or fool- effects of a substance (e.g., a drug of abuse, a ish business investments) [ 16 ] . The patient has medication) or a general medical condition (e.g., signifi cant impairment in occupational, interper- hypothyroidism).” Treatment recommendations sonal, or social functioning [ 16 ] that may require highlight that the medical condition may need to hospitalization. Because of the severity of the be treated fi rst; however, there are cases that manic episodes, early-onset Bipolar I disorder has depression may not remit unless antidepressant been usually diagnosed before an older adult pres- medication treatment is prescribed [4 ] . ents with psychiatric problems, while late-onset Bipolar I disorder occurs only in a small minority of geriatric bipolar cases [ 31 ] . Assessment of Depression Bipolar II is characterized by the occurrence and Anxiety of MDEs and at least one hypomanic episode [16 ] . Hypomanic episode is of lesser severity and Accurate Diagnosis of Depression duration than a manic episode and is defi ned as “a distinct period of persistently elevated, expan- During the fi rst interview with the depressed sive, or irritable mood, lasting throughout at least older adult, the clinician must obtain the follow- 4 days, that is clearly different from the usual ing information: present history of depression, nondepressed mood” [16 ] . During this period, onset of the current episode, precipitants of the the patient experiences three or more of the same current episode, past history of depression, symptoms described in the manic episode (four if current or past suicidal ideation, family history mood is only irritable) [ 16 ] . According to the of depression and suicide attempts, history of DSM-IV criteria, the hypomanic episode does antidepressant medication and psychotherapeu- not include psychotic features and is not severe tic treatments and outcomes, medical history, enough to cause signifi cant impairment in occu- and list of psychiatric and nonpsychiatric pational, interpersonal, or social functioning, or medications. to necessitate hospitalization [16 ] . The clinician should evaluate the onset of current and past depression episodes, explore any Substance Abuse events that preceded these episodes, and evaluate Use of alcohol, drug, or prescription medication the coping mechanisms that the patient used to needs to be evaluated. The clinician shall evaluate deal with potential stressors. Helpful questions the amount and frequency of alcohol consump- include: What were the precipitants of the epi- tion, the use of possible illicit drugs and prescrip- sodes of depression? What were the most critical tion medication. Special attention must be placed stressors that the patient experienced before the on the possible abuse of prescription medications onset of depression? What were the coping mech- as some of them may be addictive (e.g., medica- anisms that the patient utilized? Which coping tions for the treatment of anxiety or pain). mechanisms were successful or unsuccessful? As the clinician explores past and current Evaluation of Medical Conditions depressive episodes, he should evaluate the and Medications patient’s previous response to antidepressants or Certain medical conditions and medications may psychotherapies. The patient should also be asked cause depression. Speci fi cally, medical condi- to produce a list of all antidepressant medications tions, including thyroid abnormalities, de fi ciency (i.e., highest dosages, duration, and treatment of vitamin B12, lymphomas, and pancreatic can- response for each medication), a list of previous cer, are often associated with depression [ 4 ] . and current psychotherapeutic treatment (i.e., Moreover, steroids, anti-Parkinsonian drugs, and type of treatment, for example, cognitive 8 Assessment of Depression and Anxiety in Older Adults 115

behavioral therapy, behavioral therapy, or prob- The clinician should gather detailed informa- lem solving therapy; frequency and duration of tion about past and recent suicide attempts. The treatment; and treatment response), and a list of patient may describe the sequence of events, as any other treatments (e.g., electroconvulsive ther- well as severity and duration of the suicide apy). These lists may help the clinician to deter- ideation that contributed to the suicide attempt. mine adequacy and response to antidepressant The goal of the clinician is to understand risky treatment. Finally, psychiatric hospitalizations, situations, to illuminate the hopeless thoughts reasons for admissions, inpatient psychiatric that contributed to suicide ideation or suicide treatments, and follow-up treatments should be attempts, and to explore potential positive discussed in detail. thoughts that have prevented the patient from Sometimes the patient’s depression may not be harming or killing himself or herself. Access to easily recognized. Loss of interest and pleasure or fi rearms or to other potential lethal means (for depressed mood are cardinal symptoms of clinical example, lethal doses of medicaiton) must be depression. At least one of these two symptoms is evaluated during the interview of a patient at required for the diagnosis of major depression. risk of suicide. In certain cases, to avoid risky Therefore, a patient may suffer from depression access to fi rearms, the clinician may propose even though he or she does not report depressed that fi rearms be removed from the patient’s resi- mood. In fact, many older adults report loss of dence. Finally, the clinician may decide to hos- interest or pleasure, as well as physical symptoms, pitalize the patient if, after the evaluation, the in the absence of depressed mood. It is also clinician believes that the patient is a threat to important to recognize that depressed older adults himself or herself. In addition to suicide ide- may not necessarily use the words “depressed” or ation, the clinician should also evaluate whether “sad,” but rather “blue,” “helpless,” “hopeless,” the patient is a threat to hurt others, or whether “apathetic,” “disinterested,” or “unmotivated.” The there is a history of violent outbursts and physi- clinician needs to evaluate the patient’s words cal abuse. carefully and assess whether these words refl ect clinical depression. Depression vs. Normal Fluctuation Assessment of Past or Present Suicide of Mood Ideation Since hopelessness is associated with suicide Clinical depression is different from the normal ideation, the clinician should evaluate the degree “ups and downs” of everyday life in severity, of hopelessness and suicide ideation in past and duration, and its effect on the patient’s function- current episodes of depression. Important ques- ing. Normal fl uctuation of mood is usually not tions include: What makes you feel hopeless? prolonged, is not as severe, and does not Have you recently felt (or have you ever felt) that signi fi cantly impair functioning. Impairment in life is not worth living? What parts of life are not functioning is required for the diagnosis of clini- worth living? What parts of life are worth living? cal depression. Signs and symptoms of hopeless- How strong is your wish to live? Have you ever ness, worthlessness, or excessive guilt are wished you were dead? Describe recent events associated with clinical depression and are not that made you feel that life was not worth living typically part of normal mood fl uctuations. or that you wished you were dead? Any speci fi c event or stressor that precipitated these feelings? What went through your mind? Have you ever Complicated Grief thought of hurting or killing yourself? If yes, have you thought about a specifi c plan? What One of the most diffi cult situations in assessing kept you from doing anything to harm or kill depression and recommending treatment is when yourself? Has there been a family history of sui- the sadness is associated with grief. In general, if cide attempts? the older adult’s functioning is signifi cantly 116 D.N. Kiosses impaired, psychotherapeutic or medication treat- make the differential diagnosis include: (a) How ment is recommended. Because of the stigma convinced are you that you have cancer? (b) Do attached to mental illness, the clinician needs to you feel relieved that the physicians have address the issue tactfully, recognizing that it con fi rmed that there is no evidence of cancer? is expected to experience sadness after the loss (c) Do you see any alternative explanation for of a loved one. Grief stricken patients may also your pain other than cancer? Nondelusional experience an exaggerated sense of guilt when depressed patients usually recognize that their they feel pleasure, which may reinforce the thoughts are exaggerated but they may not be vicious cycle of depression. able to reduce its effect [ 4 ] . In addition to astute questioning, the Delusional Assessment Scale for psychotic depression may help the clinician mea- Accurate Diagnosis of Anxiety sure the intensity of delusional beliefs [32 ] . Disorders: Productive Anxiety vs. Unnecessary Worrying The Use of Formal Measures in the Assessment of Depression and Anxiety Patients with anxiety disorders often present for Certain questionnaires may be helpful in identi- the treatment of anxiety with the expectation of fying symptoms of depression and anxiety. These complete elimination of their anxiety symptoms. measures are not necessarily used to diagnose The clinician should discuss the potential benefi t clinical depression but rather help the clinician of anxiety to help the patient recognize that the identify symptoms of depression and assess their goal of treatment may not be the elimination of severity. Both clinician-administered and self- anxiety per se, but rather learning techniques to report measures may be administered. Clinician- effectively deal with excessive and uncontrolla- administered rating scales include Hamilton ble anxiety or worrying. Moderate levels of anxi- Rating Scale for Depression, Montgomery- ety may also be a motivating factor and become a Asberg Depression Rating Scale [ 33 ] ; both may productive force. be used for patients with mild cognitive impair- The interview may illuminate areas of worry- ment. Depression in patients with dementia may ing, degree and duration of worrying, and its be evaluated with the Cornell Scale for Depression impact on the patient’s functioning. It is impor- in Dementia [ 34 ] , a measures which calculates a tant for the clinician to understand the patient’s composite score based on reports from both the fears and explore his or her “catastrophic” pre- patients and their caregivers. Self-report ques- dictions that are the basis for their anxiety or tionnaires include the Beck Depression Inventory worrying. Finally, patients with anxiety may [35 ] and Geriatric Depression Scale [ 36 ] . either avoid situations that produce anxiety (for Measures that may capture anxiety symptoms example, a patient may avoid going out because also include self-report (e.g., Beck Anxiety he is concerned that he may have an anxiety Inventory [ 37] ) or clinician administered (e.g., attack) or focus extensively (obsess) on situations Hamilton Scale for Anxiety [38 ] ). that trigger anxiety (for example, a patient is obsessively worried about his or her health). Involvement of Caregiver Differentiating Obsessive Anxiety and Overvalued Ideas from Delusions The clinician should encourage the participation The clinician should assess whether the patient’s of an available and willing caregiver in the assess- obsessive concerns, anxiety, or overvalued ideas ment process. The caregiver may be a spouse, are reaching psychotic proportions. For example, partner, child, sibling, other family member, or an a patient believes that she has cancer in the aide. If the patient does not think that the involve- absence of any medical data to support her con- ment of caregiver is necessary or helpful, the viction. Questions that may help the clinician therapist may try to understand the reasons for 8 Assessment of Depression and Anxiety in Older Adults 117 the patient’s reluctance (e.g., beliefs that this may ing, the clinician may administer instruments that be burdensome to the caregiver, tension between evaluate a patient’s functioning and disability the patient and the caregiver, caregiver is not such as the Philadelphia Multiphasic Assessment involved signifi cantly in the patient’s care, etc.). Instrument (MAI) [ 40] , or the World Health The clinician may explore whether these reasons Organization Disability Assessment Schedule II may contribute to or affect patient’s depression. (WHODAS II) [41 ] . Caregiver participation in the assessment process may prove to be important and at times necessary. The caregiver may help in identifying Clinical Pearls periods of depression, illuminate the patient’s behavior when he or she is depressed, and high- • Clinical depression is different from the light patient’s cognitive, physical, and functional normal fl uctuation of depressed mood in the limitations. This is particularly important in severity of symptoms, their duration, and most patients with cognitive impairment, as obtaining importantly, the patient’s impairment in his or information from a collateral source is necessary her everyday functioning. when patients are not good historians, have • Depressed older adults may exhibit lack of advanced cognitive impairment or may lack interest or pleasure and physical symptoms insight into their dif fi culties. rather than depressed mood. This is one of the reasons late-life depression is underrecognized. • The clinician should be aware that the patient Assessment of Disability may not report sadness or depression per se, but may report “discouragement,” “lack of energy,” Depression may contribute to disability and dis- “blue feeling,” or “lack of motivation.” ability may precipitate the onset of depression. • Depressed elders may display “dementing” Furthermore, recent research demonstrated that symptoms during their depression; sometimes, improving functioning and reducing disability these symptoms subside when the depression mediated a reduction in depression [ 39 ] . Because remits. This phenomenon is called “pseudode- of the reciprocal relationship of depression and mentia” or “reversible dementia.” Depression disability, a careful assessment of patient’s may also be a prodromal state of dementia. depression, disability, and everyday functioning • A thorough neuropsychological examination is strongly recommended. Specifi cally, the clini- is recommended for depressed elders who cian should evaluate the patient’s physical and present with cognitive dif fi culties. functional limitations and assess their perfor- • Treatment for complicated grief is recom- mance in activities of daily living. Activities of mended when the patient’s functioning is daily living may be divided into instrumental signi fi cantly impaired. activities of daily living (e.g., taking medication, • The clinician should thoroughly evaluate walking a short distance, shopping for groceries, hopelessness given its strong correlation with using the telephone, paying bills, doing house- suicide risk, past and present suicide ideation work and handyman work, doing laundry, prepar- and attempts, and family history of suicide. ing meals) or basic activities of daily living (e.g., Risky access to fi rearms or to other potential bathing, eating, combing hair). The clinician may lethal means must be evaluated during the explore whether the patient was performing these interview of a patient at risk of suicide. activities before the onset of their depression, • In the assessment of anxiety, the clinician has whether depression has affected the patient’s per- to evaluate the evidence for a realistic threat formance in activities of daily living, or whether and the appropriateness and excessiveness the patient is able to perform these activities with of the patient’s response to the perceived or without help. In addition to careful question- threat. 118 D.N. Kiosses

17. Meyers BS, Klimstra SA, Gabriele M, Hamilton M, References Kakuma T, Tirumalasetti F, Alexopoulos GS. Continuation treatment of delusional depression of 1. Katon W, Schulberg H. Epidemiology of depression older adults. Am J Geriatr Psychiatry. 2001;9:415–22. in primary care. Gen Hosp Psychiatry. 1992;14(4): 18. Maj M, Pirozzi R, Magliano L, Fiorillo A, Bartoli L. 237–47. Phenomenology and prognostic signifi cance of delu- 2. Bruce ML, McAvay GJ, Raue PJ, Brown EL, Meyers sions in major depressive disorder: a 10-year prospec- BS, Keohane DJ, Jagoda DR, Weber C. Major depression tive follow-up study. J Clin Psychiatry. 2007;68(9): in elderly home health care patients. Am J Psychiatry. 1411–7. 2002;159(8):1367–74. 19. Vythilingam M, Chen J, Bremner JD, Mazure CM, 3. Katz IR. On the inseparability of mental and physical Maciejewski PK, Nelson JC. Psychotic depression health in aged persons: lessons from depression and and mortality. Am J Psychiatry. 2003;160(3):574–6. medical comorbidity. Am J Geriatr Psychiatry. 1996; 20. Wilson KC, Chen R, Taylor S, McCracken CF, 4:1–6. Copeland JR. Socio-economic deprivation and the 4. Alexopoulos GS, Kelly Jr RE. Research advances in prevalence and prediction of depression in older geriatric depression. World Psychiatry. 2009;8: community residents. The MRC-ALPHA study. Br 140–9. J Psychiatry. 1999;175:549–53. 5. Pampallona S, Bollini P, Tibaldi G, Kupelnick B, 21. Lockwood KA, Alexopoulos GS, Kakuma T, van Munizza C. Patient adherence in the treatment of Gorp WG. Subtypes of cognitive impairment in depression. Br J Psychiatry. 2002;180:104–9. depressed older adults. Am J Geriatr Psychiatry. 6. Conwell Y, Van Orden K, Caine E. Suicide in older 2000;8:201–8. adults. Psychiatr Clin North Am. 2011;34(2):451–68. 22. Kindermann SS, Kalayam B, Brown GG, Burdick 7. Rubenowitz E, Waern M, Wilhelmson K, Allebeck P. KE, Alexopoulos GS. Executive functions and P300 Life events and psychosocial factors in elderly sui- latency in elderly depressed patients and control sub- cides—a case-control study. Psychol Med. 2001;31(7): jects. Am J Geriatr Psychiatry. 2000;8:57–65. 1193–202. 23. Alexopoulos GS, Meyers BS, Young RC, Mattis S, 8. Duberstein PR, Conwell Y, Conner KR, Eberly S, Kakuma T. The course of geriatric depression with Caine ED. Suicide at 50 years of age and older: per- “reversible dementia”: a controlled study. Am ceived physical illness, family discord and fi nancial J Psychiatry. 1993;150:1693–9. strain. Psychol Med. 2004;34(1):137–46. 24. Olin JT, Katz IR, Meyers BS, Schneider LS, Lebowitz 9. Conwell Y, Duberstein PR, Hirsch JK, Conner KR, BD. Provisional diagnostic criteria for depression of Eberly S, Caine ED. Health status and suicide in the Alzheimer disease: rationale and background. Am J second half of life. Int J Geriatr Psychiatry. 2009; Geriatr Psychiatry. 2002;10(2):129–41. Review. 25(4):371–9. Erratum in: Am J Geriatr Psychiatry 2002 May- 10. Ayers CR, Sorrell JT, Thorp SR, Wetherell JL. Jun;10(3):264. Evidence-based psychological treatments for late-life 25. Olin JT, Schneider LS, Katz IR, Meyers BS, anxiety. Psychol Aging. 2007;22:8–17. Alexopoulos GS, Breitner JC, Bruce ML, Caine ED, 11. Lenze EJ. Comorbidity of depression and anxiety in Cummings JL, Devanand DP, Krishnan KR, Lyketsos the elderly. Curr Psychiatry Rep. 2003;5:62–7. CG, Lyness JM, Rabins PV, Reynolds 3rd CF, Rovner 12. Driscoll HC, Karp JF, Dew MA, et al. Getting better, BW, Steffens DC, Tariot PN, Lebowitz BD. Provisional getting well: understanding and managing partial and diagnostic criteria for depression of Alzheimer dis- non-response to pharmacological treatment of non- ease. Am J Geriatr Psychiatry. 2002;10(2):125–8. psychotic major depression in old age. Drugs Aging. 26. Clark DA, Beck A. Cognitive therapy of anxiety dis- 2007;24:801–14. orders. New York: The Guilford Press; 2010. 13. Andreescu C, Lenze EJ, Dew MA, et al. Effect of 27. Beekman AT, Bremmer MA, Deeg DH, Van Balkom comorbid anxiety on treatment response and relapse AM, Snut JH, De Beurs E, et al. Anxiety disorders in risk in late-life depression: controlled study. Br later life: a report from the Longitudinal Aging Study J Psychiatry. 2007;190:344–9. Amsterdam. Int J Geriatr Psychiatry. 1998;13: 14. Greenlee A, Karp JF, Dew MA, et al. Anxiety impairs 717–26. depression remission in partial responders during 28. Kessler RC, Berglund P, Demler O, Jin R, Merikangas extended treatment in late-life. Depress Anxiety. KR, Walters EE. Lifetime prevalence and age-of- 2010;27:451–6. onset distributions of DSM-IV disorders in the 15. Andreescu C, Lenze E, Mulsant B, et al. High worry National Comorbidity Survey Replication. Arch Gen severity is associated with poorer acute and mainte- Psychiatry. 2005;62:593–602. nance effi cacy of antidepressants in late-life depres- 29. Sajatovic M, Chen P. Geriatric bipolar disorder. sion. Depress Anxiety. 2009;26:266–72. Psychiatr Clin North Am. 2011;34(2):319–33. 16. American Psychiatric Association. Diagnostic and 30. Depp CA, Lindamer LA, Folsom DP, et al. Differences statistical manual of mental disorders, fourth edition, in clinical features and mental health service use in text revision (DSM-IV-TR). Washington, DC: bipolar disorder across the lifespan. Am J Geriatr American Psychiatric Association; 2000. Psychiatry. 2005;13(4):290–8. 8 Assessment of Depression and Anxiety in Older Adults 119

31. Sajatovic M, Blow FC, Ignacio RV, et al. New-onset version. In: Brink TL, editor. Clinical gerontology: a bipolar disorder in later life. Am J Geriatr Psychiatry. guide to assessment and intervention. New York: The 2005;13(4):282–9. Haworth Press; 1986. p. 165–73. 32. Meyers BS, English J, Gabriele M, Peasley-Miklus 37. Beck AT, Steer RA. Beck anxiety inventory manual. C, Heo M, Flint AJ, Mulsant BH, Rothschild AJ, San Antonio, TX: The Psychological Corporation STOP-PD Study Group. A delusion assessment Harcourt Brace & Company; 1993. scale for psychotic major depression: reliability, 38. Hamilton M. The assessment of anxiety states by validity, and utility. Biol Psychiatry. 2006;60(12): rating. Br J Med Psychol. 1959;32:50–5. 1336–42. 39. Alexopoulos GS, Raue PJ, Kiosses DN, Mackin RS, 33. Montgomery SA, Asberg M. A new depression scale Kanellopoulos D, McCulloch C, Areán PA. Problem- designed to be sensitive to change. Br J Psychiatry. solving therapy and supportive therapy in older adults 1979;134:382–9. with major depression and executive dysfunction: 34. Alexopoulos GS, Abrams RC, Young RC, Shamoian effect on disability. Arch Gen Psychiatry. 2011;68(1): CA. Cornell Scale for depression in dementia. Biol 33–41. Psychiatry. 1988;23(3):271–84. 40. Lawton MP, Moss M, Fulcomer M, Kleban MH. A 35. Beck AT, Steer RA, Brown GK. Manual for Beck research and service oriented multilevel assessment Depression Inventory II (BDI-II). San Antonio, TX: instrument. J Gerontol. 1982;37(1):91–9. Psychology Corporation; 1996. 41. Ustun B. WHODAS-II disability assessment schedule. 36. Sheikh JI, Yesavage JA. Geriatric Depression Scale In: NIMH Mental Health Research Conference. 2000. (GDS): recent evidence and development of a shorter Washington, DC. Neuropsychological Assessment and Management of Older Adults 9 with Multiple Somatic Symptoms

Greg J. Lamberty and Kimberly K. Bares

Abstract Older adults frequently present with somatic concerns that need to be evaluated with a clear understanding of their history and context. While it is tempting to dismiss physical complaints as normal consequences of the aging process, such symptoms warrant the neuropsychologist’s attention. This chapter reviews defi nitions, clinical presentations, assessment strategies, provision of feedback, consultation with colleagues, and treatment approaches that can be used with older adults. Rather than succumbing to therapeutic nihilism, neuropsychologists are encouraged to look into an increasingly broader range of intervention techniques that may bene fi t their older patients and assist their referral sources. Finally, a number of clinical “pearls” are offered to assist those in working with older patients that present with signi fi cant somatoform concerns.

Keywords Neuropsychological assessment ¥ Somatization ¥ Somatoform symptoms ¥ Intervention ¥ Complementary and alternative medicine ¥ Interview ¥ Empirically supported treatment

need to be evaluated with a clear understanding Traditional Views of Somatoform of their history and context. Complaints about Symptoms physical symptoms have traditionally been regarded as normal consequences of the aging Perhaps more than any group of individuals process; one only needs to progress through the referred for neuropsychological assessment, aging process to appreciate that basic fact. older adults present with somatic concerns that Symptoms such as pain, fatigue, sleep dif ﬁ culty, and motor slowing are common and often related G. J. Lamberty, Ph.D. ( ) ¥ K. K. Bares, Ph.D. to generally lowered levels of activity, weight Minneapolis VA Health Care System , Minneapolis , MN , USA gain, and increased levels of neuropsychiatric e-mail: [email protected] ; [email protected] symptoms. Certainly, such symptoms warrant

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 121 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_9, © Springer Science+Business Media, LLC 2013 122 G.J. Lamberty and K.K. Bares attention to rule out treatable medical conditions, effectively with patients in the assessment con- but medical symptoms must be distinguished text and subsequently making effective treatment from the reporting of abnormally large numbers recommendations [ 2 ] . of pain, gastrointestinal, pseudoneurological, and This chapter will provide an overview of how sexual symptoms described in the criteria for somatic symptoms have been conceptualized in somatization disorders [1 ] . While the diagnostic older adults and will provide guidance in making validity of the Diagnostic and Statistical Manual the important distinctions between “normal” pre- (DSM) criteria have been widely criticized [2 ] , sentations and those suggesting a somatic symp- the clinical reality is that “normalcy” in older tom disorder (the new term to be introduced in adults may well involve more complaints of pain DSM-V). We will also discuss a range of treat- and discomfort than that seen in younger adult ment options for effectively managing patients samples [3, 4 ] . with a high level of somatoform symptomatol- There is great variability in the prevalence of ogy, particularly considering the increased likeli- the various DSM somatoform disorders, particu- hood of cognitive dysfunction seen in aging larly somatization disorder, which prompted populations in general. researchers to modify criteria for somatization disorder in a way that more accurately refl ected the common and troubling presentations seen in Somatoform Disorders in DSM-V many clinical settings. The reported prevalence of somatization disorder as described in the Somatoform disorders were fi rst introduced as an DSM-IV is very low (0.2Ð2%) [ 1 ] , but rates of offi cial diagnostic category in 1980 with the pub- clinically signi fi cant somatoform symptomatol- lication of the DSM-III [ 13 ] . Hysteria was the ogy have been reported to be as high as 20Ð30% “neurotic” disorder that somatization replaced of all patients seen in some medical clinic set- from the second DSM [ 14 ] and was based on the tings [5Ð 8 ] . Early epidemiologic studies on the presumption that multiple physical symptoms DSM-based somatoform diagnoses did not typi- were the product of underlying psychic confl icts. cally examine differences in these presentations Rather than relying on underlying psychody- across the lifespan. Several reviews have failed to namic origins, the DSM-III focused on specifi c indicate greater prevalence of somatoform disor- criteria that were thought to be descriptive of a ders with increasing age, though the association distinct syndrome, as originally described in between somatoform symptoms and neuropsy- Briquet’s famous monograph from the mid-nine- chiatric disorders (especially depression) is par- teenth century [ 15] . This afforded many advan- ticularly high in older patients [ 9Ð 11 ] . In other tages for researchers of some disorders (e.g., words, the presentation of multiple medically schizophrenia, depression), while the lack of a unexplained symptoms as a clinically relevant proposed biological mechanism for somatization syndrome is not observed to be more common in disorder relegated it to an apparently less com- older individuals, despite a general tendency to pelling status where researchers were concerned. experience physical symptoms more commonly. As noted above, it was clear that somatization An important clinical challenge with older disorder, as defi ned in DSM-III, was rare. patients continues to be the ability to distinguish Nevertheless, it was also the case that patients in between symptoms that relate directly to physi- many settings were presenting with medically cal disorders or disease processes and those that unexplained symptoms that were problematic are related to what have become known in popu- and resistant to treatment. As a result, more clini- lar parlance as “mind–body” disorders [ 12 ] . cally relevant conceptualizations such as abridged With a greater overall tendency of older patients somatization or multisomatoform disorder [16, 17 ] to report symptoms, this can be particularly evolved to account for the observation that challenging. Finally, the importance of under- patients with large numbers of medically unexplained standing these dynamics is essential for working symptoms comprised a substantial percentage of 9 Neuropsychological Assessment and Management of Older Adults with Multiple Somatic Symptoms 123

primary care and specialty clinic (e.g., neurology) thoughts, feelings, and behaviors that relate to the visits. Over time, problems with the DSM-IV symptoms (Criterion B). Finally, the condition classi fi cation scheme for somatoform disorders must be chronic (>6 months; Criterion C). These have been identi fi ed, and calls for change have criteria are much less exclusive than those for issued forth [ 18Ð 21] . The reasons for these calls somatization disorder, but the essential nature of are numerous and include concerns about the “… a chronic and disabling condition related to an dualistic nature of the diagnoses, problems with individual’s concerns or preoccupation with patients’ acceptance of the diagnoses, lack of physical symptoms seems to capture the essence ability to exclude physical causes of some symp- of the presentations so frequently seen clinically. toms, restrictiveness of the diagnostic criteria, Simple somatic symptom disorder (SSSD) is, and general problems with reliability and validity…” as the name suggests, a more basic version of ( [2 ] ; p. 14). CSSD that requires only 1 month symptom dura- In DSM-V, Somatoform Disorders will be tion and only one Criterion B symptom (i.e., renamed Somatic Symptom Disorders, a change thoughts, feelings, or behaviors associated with which is described on the American Psychiatric the symptom). In circumstances when a clinical Association’s DSM-V Development web site. The problem is less severe or more acute, SSSD might basic rationale for the change is described below: be more appropriate and representative of a dif- Because the current terminology for somatoform ferent presentation. A common example might disorders is confusing and because somatoform involve such diffi culties following a hospitaliza- disorders, psychological factors affecting medical tion or surgical procedure. condition, and factitious disorders all involve pre- Generally speaking, the DSM-V conceptual- sentation of physical symptoms and/or concern about medical illness, the work group suggests ization of somatic symptom disorders represents renaming this group of disorders somatic symptom an effort to make the category and diagnoses disorders. In addition, because of the implicit more relevant and clinically useful. The proposed mindÐbody dualism and the unreliability of assess- changes refl ect a more pragmatic approach to ments of “medically unexplained symptoms,” these symptoms are no longer emphasized as core fea- mindÐbody problems. Rather than forcing dualis- tures of many of these disorders. Since somatiza- tic distinctions, the SSD category represents a tion disorder, hypochondriasis, undifferentiated clinical reality in which patients often struggle to somatoform disorder, and pain disorder share cer- deal with pain, neuropsychiatric symptoms, and tain common features, namely, somatic symptoms and cognitive distortions, the work group is pro- behavior patterns that interfere with more opti- posing that these disorders be grouped under a mal functioning. How this applies to work with common rubric called complex somatic symptom older patients is considered below. disorder. ( http://www.dsm5.org/ProposedRevisions/ Pages/SomatoformDisorders.aspx . Downloaded on February 28, 2011) [22 ] . Dif fi culties in Characterizing the Complex somatic symptom disorder (CSSD) Physical Complaints of Older Patients is proposed as a diagnosis that subsumes several DSM-IV diagnoses including somatization disor- Neuropsychologists who are less familiar with der, undifferentiated somatoform disorder, hypo- issues confronting older adults may be inclined chondriasis, pain disorder associated with both to over- or underestimate the role of somatic psychological factors and a general medical con- symptoms in a given patient’s health status. dition, and pain disorder associated with psycho- There are a number of ways to assure that infor- logical factors. Like the modifi ed versions of mation about a patient is objective, though care somatization disorder that emerged after publica- must be taken in all phases to make proper tion of DSM-III, CSSD requires one or more determinations. somatic symptoms that cause signifi cant disrup- In instances where records are available for tion or distress (Criterion A) as well as excessive review, the neuropsychologist should be able to 124 G.J. Lamberty and K.K. Bares obtain a reasonably objective sense of dif fi culties colleagues or others their age. There is a certain confronting the patient. This often presupposes charm and sensibility to this approach, though that the referral source has expertise with older obviously the astute neuropsychologist should patients, which may or may not be the case. The not be lulled into assumptions of normalcy sim- number of physicians specializing in geriatrics is ply because a patient takes a stoic approach to very small, and the offset between the number of reporting his symptoms. Older patients who specialists and the number of patients over the affect a more stoic presentation are often charac- age of 65 is likely to increase in dramatic fashion terized by a different dynamic than the younger over the next two decades ( http://www.american- somatizing patient. With the older patient, medi- geriatrics.org/fi les/documents/Adv_Resouces/ cal history and general psychological adjustment PayReform_fact5.pdf. ) [ 23 ] . This means that is important to assess to look beyond stereotypes older patients will probably be referred by an of “not wanting to be a burden.” Some of these expanding and diverse base of practitioners, many claims are fairly transparent, and within a brief of whom may have an incomplete sense of issues period of time it becomes clear that either (1) the confronting the elderly. The appropriateness of patient has multiple medical issues that account dementia referrals can vary widely because of for his symptoms or (2) emotional or psychologi- this variability in practitioners’ expertise. cal distress is exerting some infl uence on the Practically speaking, this means that record patient’s experience and reporting of symptoms. review, no matter how extensive, cannot replace It is also important to get a sense of the natural the clinical interview and observation for an history of current symptoms, as well as a general appreciation of an individual’s appearance and history of health and medical problems over the behavior and how this squares with his self- years. The likelihood of a complex somatic symp- report. tom disorder is obviously much higher in an indi- A thorough clinical interview is an essential vidual with a long history of engagement with the part of the assessment process as well as an medical fi eld. important source of information about somatic Interviews with collateral sources are valu- concerns. Many popular neuropsychology texts able, particularly in cases where cognitive also discuss the importance of behavioral obser- dif fi culties might interfere with a patient’s ability vations within the interview process and how to provide a thorough and descriptive history. they ultimately inform the conclusions and rec- When patients minimize their symptoms, family ommendations made in neuropsychological members can provide a clearer sense of what reports [24Ð 26 ] . Careful observation of the older kinds of problems are apparent to them. The same patient will afford insights into factors such as can be true in instances when the older patient is gait, mobility, pain behaviors, affect, orientation, focused on physical complaints. Of course, the and speed of processing. It is important to note neuropsychologist must be mindful of the vari- differences between the patient’s self-report of ous roles played by friends and family members symptoms and whether such things are apparent and how that might impact their reporting of what in his behavioral presentation. Lamberty [ 2 ] they observe in the patient or know about their noted two general patterns of behavior in soma- history. As always, the forensic implications of tizing patients—stoic and expressive. The out- an evaluation need to be considered in cases ward appearance in these examples is strikingly where guardianship or estate matters loom. different, despite the fact that the overall level of The cautions offered regarding the report of self-reported symptomatology in both kinds of somatic symptoms are basically the same for presentations can be similar. complaints about cognitive diffi culties. Recent work Many older adults employ a generalized nor- has drawn comparisons between somatoform malizing strategy wherein they present them- syndromes and similar presentations that focus selves as “no worse off” than any of their primarily on reports of cognitive dysfunction. 9 Neuropsychological Assessment and Management of Older Adults with Multiple Somatic Symptoms 125

Cognitively oriented analogs of somatic symptom cooperate. As an exam wears on and failure expe- disorders have been suggested and have evocative riences mount, there is increased likelihood that names like “cogniform disorder” [27 ] and “neu- performance will decline and become less repre- rocognitive hypochondriasis” [28 ] , though these sentative of actual abilities. The spectrum of how presentations are basically two sides of the same this presents is broad and includes decreased coin. Neuropsychologists encounter many patients attentional focus and carelessness on one end, all that present with such a focus. Just as with physi- the way to rejection of tasks and refusal to con- cal concerns, it is important to appreciate age- tinue on the other. The parallels with pediatric related cognitive diffi culties in older patients. assessment in this regard are substantial and can Accounting for age-related cognitive complaints sometimes be navigated by a skilled evaluator. is a regular part of the assessment process for neu- Regardless, it is dif fi cult to know with certainty ropsychologists, so the risk of misattributing cog- the impact that waning attention or investment in nitive diffi culties should be lower than it is when performance may have on the patient’s overall attempting to determine the nature of physical performance. As with the clinical interview, care- complaints. In other words, neuropsychologists ful observation of behaviors during testing is also are better equipped to empirically assess cogni- important in interpreting performances that may tive diffi culties than they are somatic concerns. be atypical for reasons that do not involve cognitive dif fi culties alone. Behaviors such as frequent sighing, moaning, pain behaviors, crying, and Understanding the Role of Physical agitation are obviously notable and possibly sug- Discomfort in the Examination gestive of challenges to the validity of an assess- Process ment, no matter what they are motivated by. The ability to thoroughly assess personality Older patients often fi nd the neuropsychological and psychopathology in a typical neuropsycho- evaluation process overwhelming and intimidat- logical evaluation for the older adult is often per- ing. The prospect of having one’s cognitive func- ceived to be limited. Asking patients to complete tioning assessed can awaken fears about whether lengthy personality inventories such as the or not there are major de fi cits, degenerative MMPI-2 [29 ] after 2Ð3 h of testing is typically changes in the brain, or impending major changes thought to place an unrealistic burden on a patient in the ability to live independently. In this con- who might be experiencing diffi culties with text, aches and pains that complicate everyday motor control, fatigue, and emotional exhaustion. life can become magni fi ed and serve as signi fi cant Instead, more focused symptom measures such obstacles to the successful completion of a neu- as the Beck Depression Inventory-II [30 ] or the ropsychological examination. Older patients fre- Geriatric Depression Scale [ 31 ] are often quently present with limited mobility, arthritic employed to get a sense of whether there is nota- pain, fatigue, and visual and hearing limitations ble neuropsychiatric symptomatology or, even secondary to a range of age-related changes. more basically, distress. Scales speci fi cally devel- Most neuropsychologists are prepared for these oped for use with older adults have typically lim- basic obstacles and can alter the examination pro- ited the amount of somatic symptomatology cesses accordingly. Common adaptations include assessed, presumably to avoid over diagnosing tables that accommodate wheelchairs, enlarged disorders such as depression that have a signi fi cant type protocols, magni fi ers, sound ampli fi ers, somatic component [31 ] . Nevertheless, to the allowing for extra time and breaks, and generally extent that good measures of somatoform symp- shortened testing protocols. Beyond these basic tomatology are thought to be important in the physical adaptations, neuropsychologists and diagnostic differential, consideration should be psychometrists need to be prepared to work with given to lengthier measures, such as the MMPI-2. the anxiety, reticence, and outright refusal to Lamberty [ 2] noted that few instruments allow 126 G.J. Lamberty and K.K. Bares the extensive assessment of somatoform features that the MMPI-2 and its various subscales do. Treatment Approaches with Older Speci fi cally, elevations on scales 1 and 3 are Adults prototypical indicators of a high level of somatoform symptomatology, as is an elevation on scale As theoretical conceptualizations and diagnostic RC1 (somatic complaints) from the MMPI-2-RF criteria for somatoform disorders have evolved [32 ] . In addition, the commonly used FBS valid- over time, so too have clinical treatment ity scale [ 33 ] is often signi fi cantly elevated in approaches expanded to better address the com- individuals whose primary issues involve report- plex psychiatric and medical needs of patients ing of physical discomfort or concerns about cog- with these conditions. Historically, treatment nitive diffi culties. The use of more extensively interventions consisted of intensive psychother- validated measures allows clinicians a greater apy aimed at developing insight into psychic level of certainty with regard to the effects of trauma thought to underlie the expression of psy- such symptoms on general cognitive performance chological pain as physical symptoms. In such as a function of the literature examining these discovery, it was believed that patients would fi nd relationships. relief from and resolution of their somatic ail- Finally, many neuropsychologists struggle ments due to increased self-awareness and will- with the prospects of providing feedback to ingness to confront psychological issues more patients in cases where the results will be, frankly, directly. These strategies were met with limited diffi cult to hear. In some ways, talking about success, leading to a broadly held belief that indi- somatoform symptoms with older patients is viduals with somatoform conditions are, nearly facilitated by the reality that many are legiti- by defi nition, incapable of insight and unlikely to mately fearful of the prospects of having a benefi t from psychological interventions. dementing disorder. This sets up one of a few rea- Somatizing patients became viewed as inconve- sonable “good news/bad news” scenarios con- nient and bothersome at best, or exasperating and fronted by neuropsychologists. In the event that draining of time and costly services at worst [ 34 ] . an older patient’s dif fi culties upon testing are More recently, approaches in the fi eld of health thought to be due to variable effort, or that they psychology have begun to bridge the mind/body are actually performing within normative expec- gap between medical illness and psychological tations, there should be some solace in knowing functioning. Additionally, much focus has been that their cognitive functioning is actually rea- directed at reducing national health-care costs sonably sound and not a great cause for concern. and fi nding empirically supported, cost-effective This also provides a good basis for a discussion treatments for consumers of medical care. These about the issue of mindÐbody problems. Most factors have resulted in renewed interest in pro- patients are receptive to respectful feedback about viding appropriate treatment interventions for how anxiety, stress, and depression symptoms individuals with somatoform conditions who are can impact cognitive effi ciency. Intellectually, often heavy consumers of health-care services. most anyone can understand that “unseen” fac- Goals of treatment have appropriately shifted tors can in fl uence cognitive or mental function- from symptom elimination and insight to symp- ing and that there are many different ways that tom management, improving quality of life and these problems might be treated. Again, older daily functioning, and decreasing service patients are often receptive to approaches that do utilization. not involve additional medications or surgical In this section, we will highlight important procedures. The remainder of this chapter focuses treatment considerations in providing care to on a range of treatment options that are thought older adults with somatoform disorders. to represent some of the better options for work- Empirically supported treatment approaches ing with older adults struggling with mindÐbody will be reviewed, and suggestions will be made symptoms and issues. for other psychotherapeutic strategies that may 9 Neuropsychological Assessment and Management of Older Adults with Multiple Somatic Symptoms 127 hold promise in working with these patients patients and can interfere with thoughtful consid- more effectively. Challenges specifi c to treating eration of mental health referrals. Therapists may older somatizing patients are presented, with an be unwilling to accept patient referrals and may eye toward how those obstacles might be over- discontinue interventions prematurely when come. Finally, practical recommendations are patients are not cooperative or are otherwise made regarding the important consultative role aversive in session. Thus, providers (both referral neuropsychologists can play in helping medical sources and mental health clinicians) will bene fi t colleagues work more effectively with these from acknowledging and attending to counter- patients. transference reactions. These reactions often mirror a patient’s emotional state and can inform clinicians of the frustration, anger, and hostility Treatment Considerations that the patients feel in not getting the medical attention and relief they are seeking. Additionally, It is helpful to acknowledge the many challenges case consultation with peers and treatment teams involved in engaging somatizing patients in non- can be used to get support and generate ideas medical treatments. Ironically, the fi rst stumbling about how to proceed in helpful ways. block may be a medical provider’s hesitation to Even when providers are open to referring for make a referral or a mental health clinician’s hes- mental health services, many patients will vehe- itation to accept one. As noted above, there is a mently protest such a referral, as they are symp- broad skepticism about the capacity of somatiz- tom-driven and seeking medical solutions. By ing patients to bene fi t from therapy. This may this logic, they assume that mental health provid- stem from clinical training that stresses the ers who do not prescribe medications or order importance of capacity for insight and a willing- medical tests could not possibly help with their ness to consider one’s role in the development medical problems. If patients do follow through and maintenance of problems. Because the pres- with a mental health referral, they may present ence of somatoform conditions typically pre- with a clear goal of convincing clinicians of the sumes a lack of conscious awareness of symptom legitimacy of their physical symptoms, with production, with little or no insight into the con- much focus on the failures of the medical system dition, providers may conclude that there is little to properly diagnose and treat them. They may be use in pursuing psychological treatment for these keenly attuned to any language that implies that individuals. However, it may be helpful to keep their symptoms are “all in their heads.” in mind that there are many other patient groups So, how do medical and mental health provid- where insight, in and of itself, is neither a prereq- ers bridge this gap? Drawn from the fi eld of uisite nor a goal of therapy. For example, patients addictions, motivational interviewing (MI) holds with traumatic brain injuries with clearly promise for facilitating readiness for therapeutic decreased insight may still be benefi cially referred intervention and meaningful lifestyle change. for psychosocial intervention strategies. Likewise, First described in 1983, MI is a simple yet elegant individuals with deeply entrenched delusional counseling stance that meets patients where they belief systems are sometimes able to benefi t from are in their understanding of problems and readi- therapeutic strategies to decrease and manage ness to explore options for improving their lives. their distress more effectively and increase qual- The approach involves clinician-guided collab- ity of life. orative conversations during which patients’ per- We should also acknowledge that patients with sonal goals, values, and reasons for wanting medically unexplained symptoms are particularly things to be different are elicited. MI is increas- challenging for health-care providers to work ingly used by primary care providers and has with. Countertransference reactions such as dis- shown to be effective in preparing patients to like, anger, and exasperation may cause medical commit to behavior change not only in alcohol providers to limit/discontinue contact with these and drug abuse but also in individuals with 128 G.J. Lamberty and K.K. Bares chronic illnesses such as heart disease, obesity, others), 34 published studies involving 3,922 and even psychosis [35 ] . patients were examined [37 ] with CBT (group or With a somatizing patient, a provider using individual therapy) as the primary intervention in MI would inquire about how somatic conditions 13 of those studies. Positive outcomes were noted impact an individual’s life and how things would in 85% of the studies (11 of 13), as de fi ned by be different if physical concerns were less promi- treatment groups faring better on at least one out- nent. Frequent validation and refl ection of con- come measure relative to controls. Similar concerns conveys understanding and acceptance. clusions were drawn by Sumathipala [ 38 ] who Clinicians listen actively and probe for “change examined six previous review articles spanning talk,” (e.g., comments from patients suggesting a hundreds of patients treated with CBT for soma- wish to resume former activities). Patients are toform disorders. In general, signifi cant benefi cial encouraged to explicitly state what they would effects were noted both for individual and group like to be different in their lives, and what that CBT in reducing physical complaints and mood suggests about their personal values and future disturbances while improving quality of life. goals. Ambivalence is common and validated CBT was also noted to be more effi cacious than genuinely. Any inquiries from patients about how antidepressant treatments. Caution was raised, change is possible are used as opportunities to however, about the lack of data on long-term out- discuss treatment options. Typically, over the come in the majority of studies reviewed. course of 2Ð3 guided conversations in which cli- Unfortunately, neither of these recent compre- nicians actively listen, elicit personal values, hensive reviews included meta-analytic proce- explore ambivalence, and highlight change talk, dures or speci fi cally examined age cohort patients may begin to feel more empowered to differences in response to CBT, illustrating the improve their quality of life, even if pain or other need for future studies in this regard. somatic concerns persist. Clinically, we have observed that older patients When providers and patients are committed to require some modi fi cations to CBT due to age- explore treatments for somatic conditions, there related changes in their capacity to process and are a number of empirically supported and poten- remember written material and to think fl exibly tially promising treatment interventions that may when challenged to reframe their cognitions. This be of bene fi t. We describe several below. can usually be minimized by meeting with patients more frequently, slowing the pace of sessions, explaining concepts in more basic terms, Cognitive–Behavioral Therapies and repeating/reviewing new information. One must also exercise caution to not invalidate CognitiveÐbehavioral therapy (CBT) is perhaps patient’s beliefs as “irrational,” which quickly the most studied psychotherapeutic intervention undermines trust and triggers defensive reactions. with demonstrated effectiveness for somatoform This can usually be addressed by resuming an conditions. These approaches are based on the empathic, refl ective stance, and perhaps shifting notion that irrational thoughts and perceptions the focus from changing cognitions to changing strongly infl uence mood states and behavior, behaviors that stand in the way of their preferred resulting in the development and maintenance of lifestyles. depression, anxiety, and other psychosocial problems [36 ] . As such, CBT interventions help patients to examine and change unhelpful cogni- Physical and Complementary/ tions, thereby in fl uencing mood and behavior in a Alternative Interventions positive manner. In a recent review of randomized controlled treatments for patients with vari- Patients with somatoform symptoms are gener- ous somatic conditions (e.g., somatization ally disinclined to seek assistance in mental disorder, medically unexplained symptoms, and health settings [2 ] . Rather, they are more likely to 9 Neuropsychological Assessment and Management of Older Adults with Multiple Somatic Symptoms 129 see themselves as seeking relief from physical “trace” or observe changes in body awareness symptoms, suggesting greater receptiveness to (e.g., move ankle, notice sensation in foot). The physically oriented rather than psychologically authors characterized this intervention as both oriented interventions. As such, treatment recom- behavioral and psychodynamic in its goal to re- mendations for approaches such as mindfulness- experience and integrate bodily self-awareness. based stress reduction, yoga, and other exercise However, its description suggests reasonable practices may be more bene fi cial for some membership among a group of mindfulness- patients. Contemporary mindfulness-based inter- based approaches. Results showed that patients in ventions developed out of traditional Far Eastern the functional relaxation intervention (n = 11) medicine practices that have acknowledged for reported signi fi cant declines on the Symptom centuries that the mind and body are intimately Checklist-90 (SCL-90, [ 44 ] ) Somatization, related. Mindfulness-based strategies involve Anxiety, and Global Severity Index scales and on focused attention to bring body and mind percep- a cardiovascular complaints scale compared with tions into greater awareness while assuming a those in the medical care-as-usual group (n = 11), nonjudgmental, observer stance. In doing so, who showed no signifi cant changes. Results sug- individuals may be able to move toward greater gested ef fi cacy of this somatically oriented mind- acceptance of negative feelings (both physical fulness technique in reducing body complaints and emotional) that detract from contentment and and psychological distress. Again, the study was appreciation of the present moment [ 39 ] . An not speci fi cally targeted to older adults and increasing body of literature is available to sup- requires replication in larger samples, but may port the benefi ts of mindfulness-based approaches show promise for our older patients with frequent in managing a wide variety of medical ailments chest pain complaints. including chronic pain, cancer, fi bromyalgia, Yoga comprises a number of mind/body prac- migraine headache, and morbid obesity [ 40Ð 42 ] . tices including physical postures, controlled Success with these patient groups suggests the breathing, meditation, and relaxation. With regu- promise of similar benefi t for somatoform lar practice, yoga is thought to improve the func- patients. Strategies of mindfulness may include tional balance of various organ systems and to mindful breathing, body scan, mindful sitting, relieve muscular and nervous tension, leading to standing, and walking, and mindful listening to improved general health and sense of well-being sounds and thoughts [ 39 ] . These techniques are [45 ] . In a recent review article on yoga and mind- particularly adaptable for older patients who may fulness, Salmon et al. [ 46 ] pointed out positive have decreased mobility and pain tolerance that outcomes (reduced symptoms, improved quality interferes with more active physical interventions of life, or emotional well-being) in randomized such as physical therapy and exercise. trials of yoga with several patient groups includ- In a randomized clinical trial conducted in ing diabetes, chronic back pain, irritable bowel Germany, an intervention termed “functional syndrome, fi bromyalgia, chronic pancreatitis, relaxation” was evaluated for its ability to reduce lymphoma, and in healthy older adults. Because somatic complaints and emotional distress in several of the yoga postures, or asanas , involve patients with recurrent nonspecifi c chest pain kneeling, stretching, and twisting, older patients [43 ] . The authors noted that although chest pain may require modifi cations to accommodate their is a frequent complaint to cardiologists, no evi- physical capabilities and pain tolerance. dence of structural or other cardiac abnormality Fortunately, yoga is easily adapted and, in fact, is found in 50% of cases after extensive and costly encourages a stance of “start where you are,” evaluation, and three-quarters of those individu- allowing participants to accept their current mind/ als seek further medical attention. Functional body state and to work patiently within their pres- relaxation used in this study involved guiding ent limitations. patients through a series of small muscle move- Older adults may also fi nd bene fi t in regular ments while exhaling. Patients were then asked to physical exercise or perhaps the social support 130 G.J. Lamberty and K.K. Bares afforded by attending exercise classes. Peters SSRIs. In a smaller meta-analysis of 11 random- et al. [ 47 ] conducted a randomized controlled ized controlled studies using antidepressants to study of aerobic exercise in a large sample treat somatoform pain disorder and psychogenic ( n = 228) of patients ranging from 9 to 73 years pain, patients treated with antidepressants with persistent medically unexplained symptoms. showed signifi cantly decreased pain intensity All participants were scheduled to attend 20 1-h with a moderate effect size relative to patients sessions of either aerobic exercise or stretching, treated with placebo [ 49 ] . Onghena and Van the control condition. Measures of health-care Houdenhove [50 ] also noted moderate to large use and symptoms, emotional state, and perceived effect sizes for treatment of chronic pain patients disability were completed before, during, and with antidepressants in a meta-analysis of 39 6 months after training. Results showed that pri- studies. It also has been shown that antidepres- mary care consultations and prescriptions were sants that act on both serotonergic and nora- signifi cantly reduced in the 6 months following drenergic receptors (tricyclics and SNRIs) may training for both groups, with no particular benefi t have more analgesic effects than other antide- of aerobic training over the stretching control pressants [51 ] . group. The extent of reduction in medical care While the impact of medication treatment was dependent on the number of sessions with older somatizing patients has not been attended. The authors suggested that these posi- extensively studied, psychiatric consultation with tive outcomes may have been resulted from group a geriatric psychiatrist is recommended, espe- support from fellow sufferers and counseling by cially when patients have multiple health condi- physiotherapists, resulting in reduced reliance on tions and medications that can complicate general practitioners and medications for symp- medication management. Typically, a “start low tom management. and go slow” dosing approach is taken, as older patients may experience (or anticipate) side effects which prompt them to quickly discon- Psychotropic Medications tinue psychotropic medications before any bene fi t can be appreciated. Again, many older somatiz- Systematic reviews and meta-analytic studies ing patients will resist a referral to psychiatry, provide good support for bene fi cial effects of both because of a preference for medical solu- antidepressant medications in the treatment of tions and their greater generational perceived somatoform disorders. While no meta-analysis stigma of being seen by a mental health provider. has been done that examines treatment benefi t This may be lessened by assurances that they are speci fi cally for older patients, many samples in not being abandoned by their medical providers the available meta-analyses include older adults and will continue to be seen for follow-up care with medically unexplained illnesses and and renewals of psychotropics. A similar chronic pain issues. In one meta-analysis of 94 approach was found ef fi cacious by Hoedeman placebo-controlled studies, patients taking anti- et al. [ 52 ] who showed improved health outcomes depressants showed more than three times in somatizing patients whose psychiatrists sent a greater improvement in medically unexplained consultation letter to the patient’s primary care symptoms compared to placebo controls [ 48 ] . providers about diagnosis and treatment options Benefi ts were seen both for tricyclic antidepres- to be incorporated into their medical treatment sants (76% of studies with positive outcomes) plans. In an older study, Smith et al. [ 53 ] used a and selective serotonin reuptake inhibitors crossover randomized controlled design to evalu- (SSRIs; 47% of studies with positive outcomes), ate the effi cacy of psychiatric consultation in though there were an insuffi cient number of reducing medical costs of somatizing patients. studies with SSRIs in this meta-analysis to con- After psychiatrists consulted with the patients’ clude that tricyclics were of greater benefi t than primary care providers, quarterly health-care 9 Neuropsychological Assessment and Management of Older Adults with Multiple Somatic Symptoms 131 charges declined by 53% in the treatment group against the problem rather than each other and to and were signi fi cantly lower than controls. After develop ways to limit the problem’s infl uence in the control group crossed over, their quarterly their lives. By developing these broader narra- medical charges declined by 49%. They con- tives, patients often begin to view themselves as cluded good benefi t from psychiatric consulta- more than a sick person, with greater self-effi cacy tion to physicians in reducing costs, without and hope to be able to live more contentedly. affecting health status or patient satisfaction with Family members, by extension, may also experi- health care. ence decreased caregiving stress and have renewed energy to continue to support their loved ones in helpful ways. Family Psychoeducation and Therapy

Clinicians often hear from exasperated spouses Primary Care Interventions and family members of older somatizing patients, imploring clinicians to “do something” to relieve Neuropsychologists are uniquely suited to objec- the patients’ suffering or worries and, in turn, tively assess brain dysfunction as well as psycho- lessen caregiver burden. To date, no studies are logical conditions that may in fl uence cognitive available that speak to the effi cacy of family performance and daily functioning. In providing interventions in working with patients with feedback to referral sources, we also have the somatoform conditions. However, our clinical opportunity to serve an important consultative experience has suggested that couple/family role regarding how to work more effectively with interventions are sometimes just as or more effec- an older somatically focused patient. Some prac- tive in reducing somatic complaints, and quality tical recommendations include the following: of life than are individual interventions. Family ¥ Determine a single “go-to” provider (e.g., counseling offers the opportunity for concerns to PCP, nurse practitioner) with whom the patient be aired and validated, reassurances to be pro- can establish a collaborative alliance. This vided, and coping strategies to be explored. helps to reduce overlapping providers and Behavioral approaches such as pleasant-event opportunities for “splitting,” or pitting of one scheduling (e.g., weekly brunch) can reduce provider against another regarding treatment loneliness and boredom and increase opportuni- approaches. ties for physical activity, while distracting patients ¥ Plan regularly scheduled appointments to from physical discomfort and worries. Family reduce emergency calls or visits. members can be encouraged to reinforce positive ¥ Explicitly state that the goal of medical con- healthy behaviors, while reducing inadvertent tacts is functional restoration and maintenance reinforcement of somatic complaints. Narrative of health and well-being, not to fi nd a cure for therapy approaches such as those developed by conditions or to eliminate all somatic worries. White and Epston [ 54 ] invite participants to ¥ Proactively ask about new symptoms and cur- develop a richer narrative, or story, about an rent life stressors at each visit, making a point individual’s life and capabilities, while naming to acknowledge and validate distress, while and externalizing the problem (e.g., “the providing reassurance that grave conditions fi bromyalgia”) as separate from the person. have been ruled out. Narrative therapy stresses that “the person is not ¥ Limit medical testing and referrals to special- the problem; the problem is the problem.” Patients ists that patients may seek for reassurance, but and family members are interviewed to focus on are not medically indicated. “exceptions” to the problem (e.g., “when did you ¥ Avoid opiates, anticholinergic medications, not allow the fi bromyalgia to get in your way this and polypharmacy whenever possible, to week?”). They are also encouraged to team up reduce potential clouding of cognition. 132 G.J. Lamberty and K.K. Bares

¥ Initiate brief conversations about the mindÐ body connection, how chronic physical condi- Clinical Pearls tions often take a toll on mood, sleep, and quality of life. ¥ Always attempt to obtain thorough clinical ¥ Monitor for depression, anxiety, and substance records regarding the patient’s health con- abuse issues, and seek psychiatric consulta- cerns. Be mindful of whether or not the records tion/referral when indicated. come from experienced geriatric clinicians. ¥ Characterize referrals for mental health ser- ¥ Carefully observe patient behaviors that sug- vices as one of many available tools in medi- gest diffi culties with pain, mobility, affect, and cine to address their complex needs. Reassure general cognition. Attend to the context in patients that they will continue to be followed which these behaviors are emitted. for regular medical care. ¥ Consider information from family members and other collateral sources judiciously, but be aware of the relationship with the informant Summary and the clinical context and how that might impact the nature of the report. Many clinical challenges exist for neuropsychol- ¥ Understand that over- and underestimating the ogists and others providing services to older impact of somatic symptoms results from not patients with somatoform symptoms. In this adhering to the fi rst three suggestions. chapter, we have highlighted traditional and ¥ Be prepared for older patients to struggle with emerging schemes for describing somatic symp- completing the neuropsychological evaluation tom disorders, as well as the dif fi culties inherent process secondary to a range of physical, per- in identifying these problems in patients whose ceptual, and emotional challenges. baseline often involves physical symptomatology ¥ Do not underestimate the importance of stan- related to normal aging. Physical concerns can dardized assessment of somatic and emotional impact the assessment process, and it is important symptoms, even if older patients have limited to have strategies for dealing with behaviors and stamina. complaints that can limit the ability to conduct a ¥ Take advantage of the opportunity to reinforce complete assessment. In an era that emphasizes an understanding of the complexity of mindÐ empirically supported treatments, it is important body relationships, while sharing encouraging to consider treatments that have been proven news about a lack of cognitive fi ndings in a effective, even if the evidence base with more positive way. specifi c groups of patients have not yet been ¥ Familiarize yourself with empirically sup- extensively studied. Promising treatments that ported treatments like MI and CBT, but under- involve mindfulness-based approaches appear stand that they can sometimes be impacted by particularly well suited for somatizing patients cognitive limitations in older patients. given their emphasis on acceptance and increased ¥ Be aware of and open to complementary and awareness. Further, many complementary and alternative approaches like mindfulness medi- alternative approaches appeal to somatizing tation and yoga that can be preferable to psy- patients because of a seeming lack of focus on chologically oriented therapies for somatizing psychological and emotional material. patients. Neuropsychologists are in a unique position to ¥ Work closely with family members to rein- evaluate, consult with, and recommend effective force a better understanding of the interrelat- interventions for their older patients. Careful edness of stressors, somatic symptoms, and attention to the patient’s needs and a collaborative the range of treatments that can be used to approach can improve outcomes in these chal- lessen the impact of these symptoms. lenging patients, and this should be the goal of all ¥ Work collaboratively with older patients’ pri- neuropsychologists working with older adults. mary care providers to maximize the bene fi t 9 Neuropsychological Assessment and Management of Older Adults with Multiple Somatic Symptoms 133

of your consultation, minimize the overuse of 16. Escobar JI, Burnam MA, Karno M, Forsythe A, medications, improve therapeutic recommen- Golding JM. Somatization in the community. Arch Gen Psychiatry. 1987;44:713Ð8. dations, and improve patients’ and families’ 17. Kroenke K, Spitzer RL, deGruy III FV, Hahn SR, overall adjustment and quality of life. Linzer M, Williams JB, et al. Multisomatoform disorder. An alternative to undifferentiated somatoform disorder for the somatizing patient in primary care. Arch Gen Psychiatry. 1997;54:352Ð8. References 18. Engel CC. Explanatory and pragmatic perspectives regarding idiopathic physical symptoms and related 1. American Psychiatric Association. Diagnostic & sta- syndromes. CNS Spectr. 2006;11:225Ð32. tistical manual of mental disorders, 4th edition, text 19. Kirmayer LJ, Groleau D, Looper KJ, Dao MD. revision. Washington, DC: American Psychiatric Explaining medically unexplained symptoms. Can J Association; 2000. Psychiatry. 2004;49:663Ð72. 2. Lamberty GJ. Understanding somatization in the 20. Mayou R, Kirmayer LJ, Simon G, Kroenke K, Sharpe practice of clinical neuropsychology. New York: M. Somatoform disorders: time for a new approach in Oxford University Press; 2008. DSM-V. Am J Psychiatry. 2005;162:847Ð55. 3. McCarthy LH, Bigal ME, Katz M, Derby C, Lipton 21. Sharpe M, Carson A. “Unexplained” somatic symp- RB. Chronic pain and obesity in the elderly: results toms, functional syndromes, and somatization: do we from the Einstein aging study. J Am Geriatr Soc. need a paradigm shift? Ann Intern Med. 2001;134: 2009;57:115Ð9. 926Ð30. 4. Helme RD, Gibson SJ. The epidemiology of pain in 22. American Psychiatric Association. DSM-5 develop- elderly people. Clin Geriatr Med. 2001;17:417Ð31. ment. Somatoform disorders. 2012. http://www.dsm5. 5. Barsky AJ, Orav EJ, Bates DW. Somatization increases org/ProposedRevisions/Pages/SomatoformDisorders. medical utilization and costs independent of psychiat- aspx . 28 Feb 2011. ric and medical comorbidity. Arch Gen Psychiatry. 23. The Demand for Geriatric Care and the evident 2005;62:903Ð10. Shortage of Geriatrics Healthcare Providers. The 6. Carson AJ, Ringbauer B, Stone J, McKenzie L, American Geriatric Society, 2012. http://www.ameri- Warlow C, Sharpe M. Do medically unexplained cangeriatrics.org/ ﬁ les/documents/Adv_Resouces/ symptoms matter? A prospective cohort study of 300 PayReform_fact5.pdf . new referrals to neurology outpatient clinics. J Neurol 24. Axelrod BN. Neuropsychological report writing. In: Neurosurg Psychiatry. 2000;68:207Ð10. Vanderploeg RD, editor. Clinician’s guide to neurop- 7. Escobar JI, Waitzkin H, Silver RC, Gara M, Holman sychological assessment. 2nd ed. Mahwah: Erlbaum; A. Abridged somatization: a study in primary care. 2000. p. 245Ð73. Psychosom Med. 1998;60:466Ð72. 25. Lezak MD, Howieson DB, Loring DW, Hannay HJ, 8. Fink P, Hansen MS, Sondergaard L. Somatoform dis- Fischer JS. Neuropsychological assessment. 4th ed. orders among ﬁ rst-time referrals to a neurology ser- New York: Oxford University Press; 2004. vice. Psychosomatics. 2005;46:540Ð8. 26. Strauss E, Sherman EMS, Spreen O. A compendium 9. Drayer RA, Mulsant BH, Lenze EJ, Rollman BL, of neuropsychological tests: administration, norms, Dew MA, Kelleher K, Karp JF, Begley A, Schulberg and commentary. 2nd ed. New York: Oxford University HC, Reynolds CFIII. Somatic symptoms of depres- Press; 2006. sion in elderly patients with medical comorbidities. 27. Delis DC, Wetter SR. Cogniform disorder and cogni- Int J Geriatr Psychiatry. 2005;20:973Ð82. form condition: proposed diagnoses for excessive 10. Lobo-Escolar A, Saz P, Marcos G, Quintanilla MÁ, cognitive symptoms. Arch Clin Neuropsychol. 2007; Campayo A, Lobo A, ZARADEMP Workgroup. 22:589Ð604. Somatic and psychiatric comorbidity in the general 28. Boone KB. Fixed belief in cognitive dysfunction elderly population: results from the ZARADEMP despite normal neuropsychological scores: neurocog- project. J Psychosom Res. 2008;65:347Ð55. nitive hypochondriasis? Clin Neuropsychol. 2009;23: 11. Sheehan B, Banjeree S. Review: somatization in the 1016Ð36. elderly. Int J Geriatr Psychiatry. 1999;14:1044Ð9. 29. Butcher JN, Dahlstrom WG, Graham JR, Tellegen AM, 12. Sarno JE. The divided mind: the epidemic of mind- Kaemmer B. MMPI-2, Minnesota multiphasic person- body disorders. New York: Harper; 2006. ality inventory—2: manual for administration and scor- 13. American Psychiatric Association. Diagnostic and ing. Minneapolis: University of Minnesota Press; 1989. statistical manual of mental disorders. 3rd ed. 30. Beck AT, Steer RA, Brown GK. Beck depression Washington, DC: Author; 1980. inventory. 2nd ed. San Antonio: The Psychological 14. American Psychiatric Association. Diagnostic and Corporation; 1996. statistical manual of mental disorders. 2nd ed. 31. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Washington, DC: Author; 1968. Adey MB, Leirer VO. Development and validation of 15. Briquet P. Traite« clinique et the«rapeutique de a geriatric depression screening scale: a preliminary l’Hysterie. Paris: Bailliere; 1859. report. J Psychiatr Res. 1983;17:37Ð49. 134 G.J. Lamberty and K.K. Bares

32. Ben-Porath YS, Tellegen A. MMPI-2-RF (Minnesota 43. Lahmann C, Loew TH, Tritt K, Nickel M. Ef fi cacy of Multiphasic Personality Inventory-2 Restructured functional relaxation and patient education in the Form): manual for administration, scoring, and inter- treatment of somatoform heart disorders: a random- pretation. Minneapolis: University of Minnesota ized, controlled clinical investigation. Psychosomatics. Press; 2008. 2008;49:378Ð85. 33. Lees-Haley PR, English LT, Glenn WJ. A Fake Bad 44. Derogatis LR. The SCL-90-R. Baltimore: Clinical Scale on the MMPI-2 for personal injury claimants. Psychometric Research; 1975. Psychol Rep. 1991;68:203Ð10. 45. Nayak NN, Shankar K. Yoga: a therapeutic approach. 34. Hahn SR, Kroenke K, Spitzer RL, et al. The diffi cult Phys Med Rehabil Clin N Am. 2004;15:783Ð98. patient: prevalence, psychopathology, and functional 46. Salmon P, Lush E, Jablonski M, Sephton SE. Yoga impairment. J Gen Intern Med. 1996;11:1Ð8. and mindfulness: clinical aspects of an ancient mind/ 35. Rollnick S, Miller WR, Butler CC. Motivational inter- body practice. Cogn Behav Pract. 2009;16:59Ð72. viewing in health care: helping patients change behav- 47. Peters S, Stanley I, Rose M, Kaney S, Salmon P. A ior. New York: The Guilford Press; 2008. randomized controlled trial of group aerobic exer- 36. Greenberger D, Padesky CA. Mind over mood: change cise in primary care patients with persistent, unex- how you feel by changing the way you think. New plained physical symptoms. Fam Pract. 2002;19: York: The Guilford Press; 1995. 665Ð74. 37. Kroenke K. Ef fi cacy of treatment for somatoform dis- 48. O’Malley PG, Jackson JL, Santoro J, Tomkins G, Balden orders: a review of randomized controlled trials. E, Kroenke K. Antidepressant therapy for unexplained Psychosom Med. 2007;69:881Ð8. symptoms and symptom syndromes. J Fam Pract. 38. Sumathipala A. What is the evidence for the ef fi cacy 1999;48:980Ð90. of treatments for somatoform disorders? A critical 49. Fishbain DA, Cutler RB, Rosomoff HL, Rosomoff review of previous intervention studies. Psychosom RS. Do antidepressants have an analgesic effect in Med. 2007;69(9):889Ð900. psychogenic pain and somatoform pain disorder? A 39. Kabat-Zinn J. Full catastrophe living: using the wis- meta-analysis. Psychosom Med. 1998;60:503Ð9. dom of your body and mind to face stress, pain, and 50. Onghena P, Van Houdenhove B. Antidepressant- illness. 15th anniversary edition reissue. New York: induced analgesia in chronic non-malignant pain: a Bantam Dell; 2009. meta-analysis of 39 placebo-controlled studies. Pain. 40. Bonadonna R. Meditation’s impact on chronic illness. 1992;49:205Ð19. Holist Nurs Pract. 2003;17:309Ð19. 51. Fallon BA. Pharmacotherapy of somatoform disor- 41. Carlson L, Speca M, Faris P, Patel K. One year pre- ders. J Psychosom Res. 2004;56:455. post intervention follow-up of psychological, immune, 52. Hoedeman R, Blankenstein AH, Krol B, Koopmans endocrine and blood pressure outcomes of mindful- PC, Groothoff JW. The contribution of high levels of ness-based stress reduction (MBSR) in breast and somatic symptom severity to sickness absence dura- prostate cancer outpatients. Brain Behav Immun. tion, disability and discharge. J Occup Rehabil. 2007;21:1038Ð49. 2010;20:264Ð73. 42. Sephton S, Salmon P, Weissbecker I, Ulmer C, Floyd 53. Smith GR, Monson RA, Ray DC. Psychiatric consul- A, Hoover K, Studts J. Mindfulness meditation allevi- tation in somatization disorder: a randomized con- ates depressive symptoms in women with fi bromyalgia: trolled study. N Engl J Med. 1986;314:1407Ð13. results of a randomized clinical trial. Arthritis Rheum. 54. White M, Epston D. Narrative means to therapeutic 2007;57:77Ð85. ends. New York: W.W. Norton; 1990. Driving Evaluation in Older Adults 1 0 Kevin J. Manning and Maria T. Schultheis

Abstract Individuals increasingly maintain active driver status later into life. The prevalence of age-related medical conditions (e.g., dementia) negatively affects the cognitive, visual, and physical abilities deemed necessary for safe driving. Thus, clinicians are increasingly called upon to comment on an older patient’s ability to remain an active driver. The current chapter aims to provide the clinician with a practical understanding of the literature on driving research that has been conducted in older drivers. We introduce concepts and challenges inherent in conducting driving research, and provide a review of the literature on the effects of healthy aging and neurological disease on driving performance. Special focus on cognition and driving is meant to help translate empirical studies into clinical applications. Finally, guidelines are provided for the clinician faced with evaluating driving capacity of an older adult.

Keywords Older drivers • Driving evaluation • Alzheimer’s disease and driving

Introduction

In today’s fast-paced society, there is often an emphasis on autonomy and mobility. It is not K. J. Manning , M.S. () Department of Psychology , Drexel University , surprising that our society is highly dependent 3141 Chestnut Street, PSA Building, Room 218 , on automobiles, and recent statistics indicate Philadelphia , PA 19104 , USA that individuals maintain active driver status and e-mail: [email protected] stay on the road later into life [ 1] . As a result, the M. T. Schultheis , Ph.D. number of drivers on the road over the age of 65 Department of Psychology and Department of Biomedical continues to progressively increase [ 2] . Advanced Engineering , Drexel University , 3141 Chestnut Street, PSA Building, Room 218 , Philadelphia , PA 19104 , USA age and the prevalence of age-related medical e-mail: [email protected] conditions (e.g., dementia) have been shown to

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 135 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_10, © Springer Science+Business Media, LLC 2013 136 K.J. Manning and M.T. Schultheis negatively affect the cognitive, visual, and physical between cognition and driving in healthy aging. abilities deemed necessary for safe driving. As a The third section focuses on the characteriza- result, clinicians are increasingly called upon to tion of the older driver with neurological disease comment on an older patient’s ability to remain or compromise. Since the focus of this chapter an active driver. The clinical recommendation is on clinical driving evaluations, we limit our to cease or limit driving can have negative review to Alzheimer’s disease, Parkinson’s dis- ramifi cations on everyday activities (i.e., getting ease, and mild cognitive impairment (MCI). The to work, opportunity to engage in social activi- interested reader is urged to consult Schultheis ties, access to medical appointments/needs), sense et al. [5 ] for a review of additional age-related of autonomy, and is even associated with poor neurological disease or injury (e.g., stroke) that health and depression [3 , 4 ] . Clinicians are chal- is known to effect driving performance. The lenged to evaluate the safety of the older driver in fi nal section includes a discussion of the clinical society while balancing the patient’s needs for application of this research to clinical neuropsy- mobility and quality of life. chology and aims to provide helpful guidelines The current chapter aims to provide the clini- for the clinician faced with evaluating driving cian with a practical understanding of the litera- capacity of an older adult. ture on driving research that has been conducted in older drivers. To accomplish this, we have sectioned the chapter into four main topics. The Considerations in Driving Research fi rst section introduces some key concepts and challenges inherent in conducting driving The relationship between driving performance research, and it is meant to provide a reference and driving outcome can be conceptualized as an framework for the subsequent discussions. The imaginary triangle or iceberg (see Fig. 10.1 ). second section provides a review of the litera- Rizzo and colleagues [6 ] illustrate this point fi rst ture on the effects of healthy aging on driving raised by Heinrich et al. [ 7 ] and Maycock [8 ] . performance. By providing a description of At the tip of the iceberg, above the “waterline,” common crash statistics and driving errors of are driving errors that produce accidents. For older drivers free of neurological compromise, example, running a red light is obviously dan- we aim to provide the clinician with an under- gerous and concerning to individual drivers and standing of “typical” driving behaviors in older society at large, despite the fact that crashes are adults. This section also includes a summary of relatively rare events [ 9 ] . A greater portion of the our current understanding of the relationship iceberg is “below the waterline” and includes

Fig. 10.1 Driving performance and driving outcome 10 Driving Evaluation in Older Adults 137 behaviors less obvious to individual drivers and examination (BTW), (b) performance on instru- society. This portion is comprised of driving mented vehicles, (c) performance on driving sim- errors that increase crash risk or result in near ulators, (d) self-reported driving behaviors, (e) crashes. These more frequently occurring driv- crash statistics, or (f) documented crash involve- ing errors range in crash-risk severity. For exam- ment (i.e., DMV reports). Despite the fact that all ple, errors such as “texting” while driving are of these factors have been used to de fi ne “driving more related to accidents than errors related to performance,” there are signi fi cant differences driving with one hand on the steering wheel. across these methods (i.e., subjective vs. objec- Two main areas of driving research have evolved tive measures, real-world vs. simulated driving). in investigating driving errors. The fi rst aims at A summary of the pros and cons to each of these elucidating the relationship between speci fi c approaches is summarized in Table 10.1 . In this driving errors of varying severities and crash risk chapter, we have reviewed studies using any of or crash involvement. A second aim is to under- these various methods to assess driving perfor- stand driver characteristics that are related to a mance. In our own research, we have endorsed a high likelihood of committing driving errors. multimethod approach, which commonly From a clinical application perspective, under- includes simultaneous measurement of more than standing how driver characteristics such as age one of these outcome measures. and cognition contribute to these driving errors It should be noted that the BTW driving evalu- may aid clinicians in detecting individuals who ation is the most “clinically” useful method of may be at greater risk for driving diffi culties. evaluating driving performance. The BTW is an An important consideration in driving research on-road evaluation, commonly conducted by a is the variability in how driving outcome or driving specialist (e.g., occupational therapist) in driving performance is defi ned in a laboratory. a dual-controlled vehicle, and, together with the There is a lack of consistency on how this very driving specialist’s off-road clinical evaluation, complex behavior is quanti fi ed. Most studies comprises a clinical driving evaluation. BTW have employed one of the following measures for evaluations can vary signi fi cantly since there are defi ning driving performance: (a) behind-the-wheel no state or federally mandated guidelines and

Table 10.1 Methods of driving assessment Measures Description Driving performance pro(s) Driving performance con(s) Behind-the-wheel On-road test conducted Direct measurement of driving Subjective rating based on exam (BTW) by a driving specialist on the road clinical judgment who observes and directs Quanti fi able measurement Unable to safely measure the driving of the examinee challenging driving scenarios Instrumented Instrumentation (e.g., Direct measurement of driving Unable to safely measure vehicle cameras, sensors) is directly on the road challenging driving scenarios linked to vehicle inputs Quanti fi able measurement Expensive to implement (e.g., steering, braking) Objective measurement Virtual reality Mode of implementation Quanti fi able measurement Questionable if results from driving simulation varies from low- fi delity Objective measurement simulated driving can be inexpensive computer-based Allows safe presentation translated to the real world to full immersion programs of challenging driving scenarios Risk of simulation sickness Crash statistics Data gathered from collisions Very strong clinical relevance Infrequent events and possible contributing Usually does not account for factors accidents that are not reported to the authorities Data collected after the fact Self-report Self-report of driving history Easily obtained Limitations of self-report include (e.g., nonreported accidents, information over- and underestimation of violations, driving frequency) events 138 K.J. Manning and M.T. Schultheis they are unique per setting/evaluator. In the important caveats to this fi nding. One is that crash majority of the cases, the individual being evalu- risk increases as driving exposure (i.e., annual ated is commonly guided through identifi ed miles driven) decreases. Thus, older adults who routes while driving behaviors are observed, and drive less than 2,000 miles annually, approxi- a pass/fall determination is typically rendered at mately 13% of all older drivers, have one of the the end of the drive. A large percentage of indi- largest crash rates [10 ] . Second, whereas older viduals will successfully pass this evaluation, drivers are not at an overall increased crash risk, raising issues of sensitivity since BTW evalua- they are more likely to be involved in certain tions may not pick up on more subtle diffi culties types of crashes compared to younger and middle- that could render an older diver unsafe. aged drivers. Evidence suggests that drivers aged There are two existing literatures of driving 65 and above are signi fi cantly more likely to be research—studies conducted with a clinical/ involved in crashes at intersections, stop signs, medical focus and studies conducted with a trans- while turning against oncoming traf fi c and chang- portation research focus. Arguably, these two ing lanes [ 9, 12– 14] . These crashes that involve areas of research should inform each other; how- confl ict with oncoming traffi c or direct moving ever, too often this is not the case. The majority traffi c fl ow can result in signifi cant injuries of the studies examining driving performance of and have been viewed as “high-risk” involvement. the healthy older driver have been conducted by A closer evaluation of the speci fi c errors provides transportation researchers and are typically not insight into these commonly seen accidents in published in journals that are commonly accessed older adults. by clinicians. This literature is substantial and contains important information for understand- Driving Errors in Healthy Older Adults ing aging and driving behaviors, regardless of the Stopping errors and errors involving the right of presence of neurological compromise. By con- way elevate crash risk at intersections and stop trast, the literature on driving in neurologically signs. Bao and Boyle [15 ] compared the driving compromised older adults (i.e., drivers with performance of 60 younger, middle-aged, and dementia) is smaller and typically focuses on older adults at rural expressway intersections clinical contributions to driving performance controlled by a stop sign. All participants were (i.e., cognitive and physical changes) and the licensed drivers screened to ensure safe driving development of clinical measures for predicting records. Driving performance was measured with driving performance. an on-road instrumented vehicle, enabling the precise calculation of stopping pro fi les based on time and distance from stop signs. Overall, high Characterization of the Healthy Older crash risk was noted in older (n = 20; age range Driver 65–80) and younger drivers (n = 20; age range 18–21) who were signifi cantly more likely to run Crash Rates of the Healthy Older Driver stop signs compared to middle-aged (n = 20; age A common misconception surrounding older range 35–55) adults. Fully missed stop signs drivers is that they have a greater likelihood of rarely occurred, and the majority of accidents at being involved in automobile crashes compared stop signs occur after drivers stop at least once to other age groups in the general population. before entering the intersection [ 16 ] . Bao and Empirical evidence does not support this wide- Boyle also analyzed stopping behavior and found spread claim [ 10, 11] . In fact, when the crash that older drivers demonstrated a dangerous brak- rates of 47,500 drivers of various ages were coming profi le compared to middle-aged adults. pared after adjusting for annual miles driven, the Older adults braking was best characterized as majority of older drivers had lower crash rates sudden; they began breaking closer to the stop than all other age groups [ 10 ] . There are two sign and progressed faster from the initial brake 10 Driving Evaluation in Older Adults 139 press to maximum breaking, resulting in a short impairment, including memory, attention, per- stop. Described in further detail below, work ceptual and visuospatial ability, information using driving simulation has demonstrated that processing speed, and abilities falling under the sudden stopping in older adults with Alzheimer’s broad domain of executive functioning (e.g., disease signifi cantly increases crash risk at inter- working memory, planning). In the following sections [17 ] . section, we provide a concise review of recent Errors in judgment or attention are related to studies that investigate different aspects of driv- increased crash risk in older drivers while turning ing performance in older adults free of neuro- or changing lanes. Braitman et al. [ 18 ] reviewed logical compromise. For a larger review of the police crash reports and photographs of accident literature on driving and cognition in older scenes and conducted telephone interviews with adults, consult Anstey et al. [20 ] and Mathias at-fault drivers involved in intersection crashes. and Lucas [ 21 ] . Participants were grouped according to age: driv- Dawson et al. [22 ] administered a BTW exam to ers ages 70–79 (n = 78), 80 and older (n = 76), and 111 healthy older adult drivers (age range = 65–89) a group of middle-aged drivers 35–54 (n = 73). and 80 middle-aged drivers (age range = 40–64). Findings confi rmed that crashes that occurred All participants were screened for neurological when the driver failed to yield the right of way disorders and cognitive complaints. Rather than increased with age and more often occurred when simply dichotomize performance on the BTW the driver was turning left (i.e., against oncoming exam into “pass” or “fail,” results of the exam traffi c). Compared to middle-aged and the oldest were coded into 15 different categories of driving drivers, drivers ages 70–79 failed to evaluate the errors based upon the Iowa Department of correct speed of the oncoming vehicle. That is, Transportation’s Drive Test Scoring Standards. they saw the other vehicle, but misjudged whether Results clearly illustrated older adults had a pro- there was adequate time to proceed. On the con- pensity towards signifi cantly more errors per trary, the oldest drivers reported failing to see the drive on 7 out of the 15 categories including other vehicle involved in the accident. Likewise, speed control, turning, lane changes, lane obser- failure to see another vehicle or inability to judge vance, parallel parking, railroad crossing, and its oncoming speed is often cited as a reason for starting the car and pulling away from the curb. accidents following a lane change [19 ] . Furthermore, older drivers committed signi- To summarize, older drivers are not at an over- fi cantly more high crash-risk driving errors than all increased crash risk compared to younger middle-aged drivers (such as entering an inter- drivers. However, older drivers are more likely to section during a red light). Age correlated with commit driving errors that increase their crash worse performance in the oldest group, but not risk at intersections and stop signs, and while in middle-aged adults. The strongest predictor changing lanes or turning against oncoming of driving in the older-aged cohort was a com- traf fi c. These errors include sudden stopping, posite measure of eight cognitive tests, including misjudging speed and distance of other vehicles, tests of visual and verbal memory, construc- and failure to see other vehicles on the road. tional praxis, visual perception, working memory, and verbal fl uency. Specifi cally, for every one Cognition and Driving in Healthy Older standard deviation decrease in a cognitive func- Adults tion composite measure in healthy older drivers, Many researchers have attempted to examine there were 3.6 more driving errors observed after the relationship between cognition and specifi c adjusting for age, sex, and education. driving errors. Findings indicate that numerous The Salisbury Eye Evaluation and Driving speci fi c cognitive abilities are signi fi cantly Study is a longitudinal study of vision, cognition, associated with various driving performance and driving of older adults on Maryland’s Eastern measures in healthy older adults free of cognitive Shore that investigated factors associated with a 140 K.J. Manning and M.T. Schultheis frequent antecedent to crashes: lane changes [ 23 ] . protect the older driver from errors” (p. 243) [ 26 ] . There are three major strengths of this work: (1) Although the sample consisted of community- large sample of cognitively intact licensed commu- dwelling older adults, participants had an average nity-dwelling adults (n = 981; average Mini-Mental MMSE of 24.9 ± 4.3 and possibly met clinical State Exam (MMSE) = 27.6 ± 2.2 [24 ] ; average age criteria for MCI or dementia, limiting the gener- 77.8 ± 5.2), (2) each participant was administered a alizability of the fi ndings. Other investigators comprehensive visual exam and fi ve common neu- have also provided evidence for the importance ropsychological tests of executive functioning, of intact executive functions in the safe driving of visuospatial abilities, and memory, and (3) driving cognitively healthy older adults [28 ] as well as performance was measured with the use of dual older adults with dementia (i.e., Alzheimer’s dis- cameras and a driving monitoring system within ease and Parkinson’s disease). each participant’s vehicle for a period of 5 days. Results confi rmed that older drivers often fail to check for traf fi c before changing lanes. Taking total Driving in Older Adults lane changes into consideration, failure rates ranged with Neurological Disease from 16 to 24%, with drivers who most often changed lanes demonstrating the highest failure The Older Driver with Alzheimer’s rate. Furthermore, fi ndings revealed susceptibility Disease: Crash Rates and Routine to distraction, and higher-order visuospatial skills Driving Ability are important in lane-changing behavior. Worse performance on measures of visuoconstruction and Despite early work suggesting older adults with auditory divided attention predicted a higher inci- Alzheimer’s disease (AD) had an increased risk dence of lane-changing errors after accounting for of crashes compared to age-matched controls age and gender. [29 ] , more recent investigations have found no Freund and colleagues have used virtual reality relationship between a diagnosis of dementia and driving simulation as an objective tool to provide crash risk [ 30, 31] . Although crash rates may not older adults with clinical driving recommenda- differ between healthy older adults and adults tions [25, 26] . Based upon driving errors mea- with AD, the groups signi fi cantly differ on driv- sured during simulation, Freund and Colgrove ing errors committed. Dawson et al. [ 32 ] admin- [25 ] classifi ed 108 older drivers (age range istered a BTW exam to 40 licensed drivers with 61–96) as safe ( n = 35), unsafe ( n = 47), or mild AD (mean MMSE = 26.5 ± 2.9) and 115 restricted (n = 26). Safe drivers made no “hazard- older adult drivers free of cognitive impairment. ous errors” during simulated driving (e.g., crashes Errors from the BTW were coded into 15 catego- or running red lights), whereas restricted drivers ries including, among others, traffi c signals, stop committed at least one error and unsafe drivers at signs, turns, lane change, speed, and parking. least two. Of several screening measures, Trail Considering individual error types, older adults Making Test B was the only measure that with AD made more driving errors compared to signifi cantly differed among the three groups, healthy older adults in only 1 out of 15 catego- and a simple test of clock drawing correlated the ries: lane changes. However, when total driving strongest with total simulated driving errors errors were tallied, adults with AD made ( r = 0.68) and pedal confusion (i.e., confusing the signi fi cantly more errors (42.00 ± 12.84) than gas for the brake) [26, 27 ] . The authors hypothe- healthy older adults (33.18 ± 12.22), including sized that executive functioning may be espe- signi fi cantly more high crash-risk errors. cially relevant to driving in older adults “because Longitudinal studies of older drivers demon- executive functioning is a critical component of strate that a diagnosis of dementia, per se, does safe driving, and in the presence of executive not universally impact the ability of individuals dysfunction, the automatized and procedural with Alzheimer’s disease to pass a clinical driving skills learned over decades of daily living do not evaluation [33, 34 ] . Ott et al. [34 ] conducted a 10 Driving Evaluation in Older Adults 141 longitudinal study of drivers with Alzheimer’s individual measures of visuoconstruction, work- disease spanning 3 years using the BTW. Greater ing memory, and verbal fl uency. severity of dementia determined by a Clinical Following up their earlier work, Uc, Rizzo, Dementia Rating (CDR) [ 35 ] , increased age, and Anderson, Shi, and Dawson [ 31 ] further demon- lower education was associated with higher rates strated the benefi ts of virtual reality simulation in of BTW failure at follow-up. However, only 22% measuring driving performance in older adults of individuals with mild Alzheimer’s disease with Alzheimer’s disease. They studied 61 driv- (CDR = 1.0) failed the exam at follow-up and ers with AD (average age 73.5 ± 8.5) and 115 were judged as unsafe drivers. This failure rate healthy older adults (average age 69.4 ± 6.7). All was even less in the group of individuals consid- participants underwent a crash simulation; ered to have questionable dementia or severe specifi cally, after a segment of uneventful driv- MCI (CDR = 0.5). Therefore, despite evidence ing, each driver suddenly encountered a lead that, as a group, older drivers with AD commit vehicle stopped at an intersection, creating the more high crash-risk driving errors than healthy potential for a collision with the lead vehicle or older adults [ 32 ] , many older drivers with AD are another vehicle following closely behind the able to safely maintain routine driving over sev- driver. Contrary to their earlier fi ndings with eral years when tested with the BTW [ 34 ] . As incursion vehicles [17 ] , crash rates did not differ noted, the BTW, the current clinical gold stan- between individuals with AD (5%) and healthy dard of driving evaluations, does not allow for the older adults (3%). However, individuals with AD administration of challenging driving scenarios were more likely to engage in sudden vehicle [36 ] . The ability to older drivers with AD to adapt slowing, which signi fi cantly increased the risk of to novel driving situations (e.g., another vehicle being struck from behind [31 ] . Furthermore, sud- suddenly swerves in front of the vehicle) is com- den slowing was associated with multiple cogni- promised compared to older adults without neu- tive abilities, but a brief measure of executive rodegenerative disease. functioning (Trail Making Part B) was associated with the greatest increase in risk of unsafe behavior. These fi nding suggested that with each 30-s The Older Driver with Alzheimer’s prolongation on Trail Making Part B, the risk of Disease: Driving and Cognition abrupt slowing increased by 31%. There has been only one meta-analytic attempt Virtual reality simulation proves a useful tool to to summarize the literature on neuropsychologi- investigate challenging driving scenarios. Rizzo cal tests and driving performance in adults with et al. [17 ] studied 18 participants with mild to AD [37 ] . In their meta-analysis, Reger et al. [ 37 ] moderate AD (mean age 73) and 12 healthy older categorized studies into three categories based on adults (mean age 70) using virtual reality driving driving outcome: BTW, nonroad tests (e.g., vir- simulation. Each participant drove an uneventful tual reality driving simulation), and caregiver virtual route for 15 min before reaching a fi nal report. Cognitive performance was grouped into intersection that triggered an illegal incursion by six domains: mental status, attention, visuospa- another vehicle. Optimal response in order to tial abilities, memory, executive functions, and avert a crash required the driver to release the language. Results can be interpreted using accelerator, apply the brake, and make a steering Cohen’s [38 ] classi fi cation of r = 0.10, 0.30, and correction. Findings revealed that participants 0.50, as small, moderate, and large effects. committed a safety error while driving on Overall, tests of visuospatial abilities demon- uneventful segments of the virtual environment. strated the strongest performance with driving However, 6 of the 18 subjects with AD crashed as outcome in adults with AD ( r = 0.29 with BTW, a result of intersection incursion vehicle com- r = 0.31 with nonroad tests, and r = 0.19 with pared to 0 control participants. Overall, cognitive caregiver report). No relationship was found performance was associated with crashes, as were between tests of executive functioning and the 142 K.J. Manning and M.T. Schultheis

BTW (r = −0.06), whereas a mild–moderate rela- received a BTW exam rated on 17 different tionship was found between executive function- parameters including physical control, response ing and nonroad tests ( r = 0.22). Given fi ndings to other drivers, lane discipline, roundabout man- from Uc et al. [31 ] and other work demonstrating agement, braking, and merging. Based on these the importance of executive functioning tests dis- parameters, a driving specialist rated participants criminating safe and unsafe older drivers with as “safe” or “unsafe.” Out of the 154 PD patients, AD [39 ] , results of the Reger et al. [ 37 ] meta- 50 (32.5%) were judged as unsafe to drive analysis should be interpreted with caution, and because of concerns over road safety. additional studies are clearly needed. Overall, these results suggest that individuals with PD commit more driving errors compared to age-matched peers. Error types include dif fi culty The Older Driver with Parkinson’s maintaining lane positions, turning, failing to Disease: Driving Errors and Routine check blind spots, reduced usage of side- and Driving Ability rear-view mirrors, and dif fi culty navigating stop signs and intersections. However, when crash Compared to healthy older adults, evidence sug- risk is compared in PD subjects and healthy older gests that older adults with Parkinson’s disease adults, there are no signi fi cant differences (PD) are more likely to commit driving errors between groups on total high crash-risk errors. involving lane changes, failing to check blind Analysis of driving frequency suggests PD spots, reduced usage of side- and rear-view mir- patients do not limit their driving compared to rors, backing out of a space, and indecisiveness at age-matched peers. Older adults with PD average intersections [ 40, 41] . Uc et al. [ 42 ] compared the as many miles per week and make as many trips BTW performance of 84 older adults with PD and as do healthy older adults [ 40 ] . Furthermore, the 182 healthy older drivers. Similar to their work majority of PD participants are able to maintain with other populations [22, 31] , BTW perfor- routine driving ability when tested with the BTW, mance was classifi ed into 15 different error cate- at least in early in the course of their illness. gories, and total safety errors were tallied as well as serious driving errors. Individuals with PD had an average illness duration of 5.9 ± 5.0 years, a The Older Driver with Parkinson’s mean Hoehn and Yahr stage of 2.2 ± 0.59, and did Disease: Driving and Cognition not signifi cantly differ from the healthy group on age. Drivers with PD committed more errors than Neuropsychological measures of attention, visual healthy adults while at stop signs, turning, and spatial ability, memory, and executive functioning maintaining lanes. Furthermore, when total errors are important in the assessment of driving perfor- were tallied, the PD group committed signifi cantly mance in PD [6, 40] . Grace and colleagues [ 40 ] more safety errors (41.6 ± 14.6) than the cogni- investigated the BTW driving performance of 21 tively healthy adults (32.9 ± 12.3). However, the PD subjects, 21 healthy older adults, and 20 AD PD group did not commit more high-crash risk subjects. PD participants had mild levels of errors compared to healthy adults. impairment as evidenced by a mean MMSE of The majority of older adults with PD are able 28.1 ± 1.6, a mode Hoehn and Yahr stage of 2.0, to pass clinical driving evaluations. Singh and and a mean Unifi ed Parkinson’s Disease Rating colleagues [43 ] analyzed data on 154 PD patients Scale motor section of 28.4 ± 7.7. Participants referred to a clinical driving assessment service were classifi ed as “safe,” “marginally safe,” or over a 15-year period. Participants had a mean “unsafe” as a result of the BTW exam, and total duration of illness of 5.9 years, a mean Hoehn driving errors were tallied. Results of global safety and Yahr stage of 1.9, and the average age was ratings are consistent with fi ndings from Singh 67.6 years (standard deviations were not reported). et al. [ 43] described above, where the majority As part of the driving assessment, each individual of drivers with PD were characterized as “safe.” 10 Driving Evaluation in Older Adults 143

In the study by Grace et al. [40 ] , no PD driver was differ between groups when rated on the Hoehn characterized as “unsafe,” 67% (14/21) of PD par- and Yahr scale but was signi fi cantly different ticipants were characterized as “safe,” and 33% when rated with the CDR. (7/21) were characterized as “marginally safe.” Review of the literature on PD and driving However, driving performance differences suggests the clinician should consider clinical between groups were statistically signifi cant; and cognitive risk factors when evaluating fi tness 100% of the healthy older adult group was charac- to drive in patients with PD. Important clinical terized as “safe,” and PD drivers (7.6 ± 4.2) did factors include disease duration and severity, commit more errors than the healthy adult group motor performance, visual acuity, and contrast (3.7 ± 2.7). Cognitive performances were also sta- sensitivity. Neuropsychological measures of tistically different between groups defi ned by attention, visual spatial ability, memory, and driving safety ratings. When compared to the executive functioning can inform driving recom- healthy control group, PD participants character- mendations and identify those in need of further ized as “marginally safe” drivers performed evaluation [44 ] . signifi cantly worse on measures of verbal learning and memory, visuospatial ability, working memory, and fi nger tapping. The neuropsychological Characterization of the Older Driver performance of drivers with PD labeled as “safe” with Mild Cognitive Impairment did not signi fi cantly differ from the healthy adult group. Comparisons of “safe” and “marginally The research on the driving performance of older safe” PD drivers confi rm the importance of visu- adults with MCI is less developed that than of ospatial abilities and working memory in discrim- older adults with AD and PD. Briefl y, MCI is a inating the two groups. Amick et al. [44 ] reported term that broadly de fi nes an intermediate stage of that performance on Trail Making Test, Rey objective cognitive decline thought to be associ- Complex Figure Copy Test, and the Useful Field ated with higher risk of dementia [ 47, 48 ] . Wadley of View Divided Attention Subtest, a measure of et al. [ 49 ] investigated the BTW performance of visual attention [ 45] , distinguished 14 safe PD 46 adults with MCI (mean age = 71.30 ± 7.79) and and 11 marginally safe PD drivers tested BTW. 59 cognitively healthy older adults (mean Analysis of the neuropsychological perfor- age = 67.07 ± 6.72) with MCI de fi ned using mance of 84 PD participants revealed that visual Petersen criteria [ 50 ] . However, it was noted that processing speed and attention, motion percep- the MCI participants performed comparably to tion, visuoconstruction, visual memory, and gen- the cognitively healthy older adults on the eral cognition were signi fi cant predictors of total Dementia Rating Scale [ 51 ] with average scores error counts on the BTW after adjusting for age (DRS) of 132.60 ± 8.49 and 137.48 ± 6.26, respec- and education [ 42 ] . Far visual acuity and contrast tively. It is notable that 43 of the MCI partici- sensitivity (i.e., the ability to see objects that do pants were characterized as amnesic MCI, and not stand out from their background) were also the majority of these participants were described signifi cant predictors of total driving errors. as free of cognitive impairments in domains other Devos and colleagues [ 46 ] compared the clinical than memory. characteristics and cognitive performance of 29 Wadley and colleagues [ 49 ] recorded fi ve adults with PD who “passed” a virtual reality BTW error types: turning, lane control, gap judg- driving simulation and 11 adults with PD who ment, steering steadiness, and maintaining proper “failed” the simulation. Those adults with PD speed in MCI subjects. Driving outcome was who failed the evaluation were older and had lon- de fi ned using two methods: (1) as the total errors ger disease duration, worse contrast sensitivity, across the fi ve error types, and (2) the driving worse motor performance on the UPDRS, and specialist’s ratings of (A) “evaluator took control worse performance on the Rey Complex Figure of the car,” (B) “unsafe,” (C) “unsatisfactory,” (D) Copy Test. Disease severity did not signi fi cantly “not optimal,” and (E) “optimal.” Results revealed 144 K.J. Manning and M.T. Schultheis that overall mean errors did not differ between a clinical practice parameter on patients with adults with MCI and cognitively healthy older dementia and their families who seek advice on adults. When groups were compared on the driv- driving [ 54 ] . Iverson et al. [ 54 ] urge clinicians to ing specialist’s ratings, a higher proportion of consider risk factors for decreased driving ability adults with MCI were judged as demonstrating (history of crashes/citations, reduced driving mile- “not optimal” performance on left turns, lane age, self-reported avoidance, aggressive personal- control, and an overall global rating of driving ity characteristics) and to use the CDR scale and performance. These authors discuss two major informant report as the primary methods of deter- implications of their fi ndings. First, driving abili- mining the driving risk of the older patient with ties in individuals with MCI, while “less than dementia. We concur that consideration of risk optimal,” were not impaired. No drivers received factors and family concerns are extremely impor- “unsafe” or “unsatisfactory” driver ratings, nor tant in conducting clinical driving evaluations. did the evaluator ever take control of the vehicle. However, Iverson et al. [ 54 ] fail to address the The authors bring this point by summarizing, “It contributions of cognition and do not address how appears that individuals with MCI are less likely clinicians may best evaluate when cognitive per- than cognitively normal peers to seamlessly performance begins to impede on driving perfor- form certain routine driving maneuvers” (p. 92, mance. We purport that neuropsychological italicized added) [ 49 ] . Second, they speculate that assessment can make a valuable contribution to executive functions are important cognitive abili- clinical driving evaluations, and whenever possi- ties affected in MCI that may underlie less than ble, a comprehensive cognitive assessment should optimal driving performance. This interpretation be included in the driver evaluation process. is consistent with evidence that executive func- Presented below are recommendations for clinical tioning abilities are signi fi cantly impaired even in neuropsychologists, and other clinicians, involved adults who meet criteria for pure amnesic MCI in evaluations of driving safety. [52 ] . Future research is needed to further investigate the impact of executive dysfunction on driving performance and better understand changes Clinical Neuropsychological in driving ability among individuals with MCI. Considerations on Driving

The gold standard for driving assessment remains Application to Clinical the clinical driving evaluation, of which the BTW Neuropsychology examination is a critical component [ 55 ] . Driving simulation, while of great potential use, remains Clinical neuropsychologists are often called upon in its infancy as a clinical tool. When specifi cally to comment on the driving abilities of older adults. evaluating driving capacity, the clinical neurop- The recommendation to cease or continue driving sychological evaluation can serve as guide to entails signifi cant responsibility, both to the patient inform whether further evaluation of driving and society. Despite the ample literature on the ability is warranted. It is also important to recog- relationship between cognitive performance and nize that what constitutes a suffi cient clinical driving, it remains challenging for clinicians to neuropsychological evaluation may not consti- translate the statistically signi fi cant relationships tute adequate neuropsychological assessment in between cognition and driving into clinically driving ability. Although limited, research can meaningful outcomes for older adults. Presently, provide direction for the selection of neuropsy- there are no neuropsychological practice parame- chological measures to be administered. Speci fi c ters or guidelines as to what constitutes a neces- cognitive domains associated with driving per- sary and suf fi cient assessment battery for formance have been identifi ed in the literature determining vehicle-driving fi tness [ 53 ] . Recently, and include varying types of attention (i.e., the American Academy of Neurology has updated divided attention, sustained attention), information 10 Driving Evaluation in Older Adults 145

Table 10.2 Neuropsychological measures empirically related to crash rates or behind-the-wheel performance in older adults Cognitive domain Neuropsychological measure Study sample(s) Attention Useful ﬁ eld of view [31 , 45 , 67 – 69 ] AD, HC Cancelation task [70 , 71 ] HC Processing speed Symbol Digits Modalities Test [72, 73 ] PD Trail Making Part A [32 , 74 ] AD Executive functions Brief Test of Attention [23 , 75 ] HC Clock drawing [76 ] HC Mazes [39 , 71 ] HC, AD Paper folding task [67 , 77 ] HC Stroop color-word Test [78 ] HC Tower of London test [78 , 79 ] HC Trail Making Part B [31 , 69 , 70 , 74 ] AD, HC Wisconsin Card Sorting Test [78 , 80 ] HC Visuospatial Judgment of Line Orientation [31 , 81 ] AD Block design [22 , 82 ] HC Complex Figure Copy [22 , 31 , 32 ] AD, HC Beery–Buktenica Test of Visual Motor Integration [23 , 83 ] HC Motor-Free Visual Perception Test [68 , 69 , 76 ] HC Memory Benton Visual Retention Test [31 , 32 , 71 , 84 ] HC, AD Complex Figure Recall [22 , 31 ] AD, HC Hopkins Verbal Learning Test [40 , 85 ] PD Motor Purdue Pegboard [73 , 86 ] PD Note : References to the driving literature are in bold. AD Alzheimer’s disease, HC cognitively healthy older adults, PD Parkinson’s disease

processing speed and reaction time, working performance and daily functioning. Furthermore, memory, visual spatial learning and memory, clinicians do not always have the luxury of visual scanning, judgment, inhibition, problem- lengthy evaluations. solving, and spatial perception. Table 10.2 Mr. Smith is a 72-year-old retired machine provides examples of empirically supported operator with 12 years of education, who under- neuropsychological measures associated with went a clinical driving evaluation following com- driving ability as defi ned by crash rates or BTW plaints of his own worsening driving performance. performance. This is not meant as a systematic review of the literature or a comment on the History of Present Illness strength of the relationship between neuropsy- • Mr. Smith’s family fi rst noticed symptoms of chological tests and driving performance. Instead, depression and anxiety in 2001 when he was Table 10.2 is provided to guide the clinician in 65 years old. test selection of neuropsychological assessment • Mr. Smith’s wife fi rst noticed dif fi culties with of driving ability. his memory in 2005 when Mr. Smith was 69 years old. These diffi culties were not noticeable to Mr. Smith’s two children, but he Case Example was prescribed Aricept by his internist. • Mr. Smith underwent a neurological evaluation Cases encountered in clinical practice are often in August 2007 following periods of increased far from “classic” and straightforward. Clinicians confusion while his wife was hospitalized for a asked to comment on the functional performance lengthy illness. The neurologist reported an of patients are often challenged by the relation- MMSE of 25/30 and diagnosed “MCI, possible ship (or lack thereof) between objective cognitive worsened by underlying depression.” 146 K.J. Manning and M.T. Schultheis

• Medical history was signi fi cant for hyperten- • “Tendency to the drift to the left,” but was “not sion, hypothyroidism, hypercholesterolemia, unsafe” and was “aware of other vehicles in coronary artery disease (with a stent placed in the left lane.” 2005), prostate cancer (surgery in 2003), and • He drove “55 in a 65-mph zone” but had a “good type II diabetes successfully managed with response to vehicles merging from the right.” medication. • Mr. Smith passed his driving evaluation, and it • MRI of the brain, completed in September was recommended that he only drive on local 2007, revealed “diffuse atrophy” and a “few familiar roads and to familiar destinations and foci of increased T2 signal within the supraten- restrict his driving to daylight off-peak hours torial white matter secondary to chronic small only. vessel ischemia.” • While his wife remained hospitalized, Mr. Case Assessment Smith lived alone and performed his own Results of Mr. Smith’s clinical driving evalua- daily activities. However, he reported his tion, notable for impairments on off-road cogni- driving had become more cautious, and he tive measures but safe on-road driving, clearly had struck a curb. Mr. Smith asked his neu- demonstrates that cognitive impairment does not rologist to refer him for a clinical driving always equal driving impairment. In order to gain evaluation. a comprehensive picture of the cognitive abilities of patients, multimethod assessment is important. Clinical Driving Evaluation: Off-Road If a decision was made for Mr. Smith to relin- Assessment quish his driving privileges solely on the basis of • Cognitive dif fi culties included poor divided the few off-road cognitive measures adminis- attention, decreased short-term memory, and tered, it is obvious this decision would have been impaired mental fl exibility (see Table 10.3 ). premature. Multiple abilities should be assessed • Binocular visual acuity was 20/20. Depth per- under each cognitive domain. For example, there ception, peripheral vision, and basic reaction is empirical support for the useful fi eld of view time were judged to be within normal limits. (UFOV) and its strong relationship to driving ability in older adults [ 56 ] . However, neither the Clinical Driving Evaluation: On-Road UFOV nor any other measure alone will explain Assessment all the variance in driving performance [57, 58 ] . • Mr. Smith was “very nervous/cautious initially As noted, Table 10.2 provides examples of empir- and too slow.” ically supported cognitive measures. • With cues to “drive closer to posted speed limits,” Mr. Smith’s “speed improved as [he] relaxed.” Additional Risk Factors • Mr. Smith required “minimal verbal reminders There are additional risk factors for driving on multilane curved roads for lane placement.” errors besides age and cognition. Other medical

Table 10.3 Case example: Results of Mr. Smith’s off-road assessment September 2007 Measure Raw score Percentile Description Trail Making Part A 54″ 10 Low average Trail Making Part B 537″ <1st Impaired WAIS-R Digit Symbol 18/93 7th Borderline WAIS-R Picture Completion 11/20 9th Low average Motor-Free Visual Perceptual Test—Revised 24/36 – Impaired * (MVPT-R) * Note : All normative data are based on Heaton et al. [ 87 ] or Wechsler [88 ] besides MVPT-R, which is based on recommendations of the American Medical Association [89 ] 10 Driving Evaluation in Older Adults 147 conditions, often comorbid in older adults, can aware of the fact that older drivers typically impact driving. In Mr. Smith’s case, there was a described self-limiting their driving in certain complicated cardiovascular history along with scenarios. For example, older drivers often diabetes, in addition to the identi fi ed cognitive describe not driving during heavy traf fi c or in problems. Age-related changes and diseases poor weather conditions. However, empirical evi- affecting vision (e.g., reduced contrast sensitiv- dence does not support these claims; evidence ity, cataracts), respiratory diseases (e.g., sleep suggests older drivers do not regulate their driv- apnea), and musculoskeletal conditions (e.g., ing as much as they report [64 ] . Clinicians should arthritis) are but a few. therefore obtain information from collateral The clinician should also carefully consider sources. Consultation with a knowledgeable the potential impact of medications on driving spouse or other family member, ideally someone performance [59, 60 ] . LeRoy and Morse [61 ] , in who drives with the patient, is a must. conjunction with the National Highway Traffi c Safety Administration, analyzed the medication Sensitive Functional Assessment use of 33,519 individuals involved in a traf fi c Sensitive functional assessment, in conjunction accident and 100,000 controls who had not with thorough cognitive assessment, is essential to crashed. Results suggested the side effects of the development of evidence-based driving guide- individual medications and combinations can lines for older adults. The BTW exam does not impair cognitive functioning and lead to unsafe typically involve challenging driving scenarios; it driving. Mr. Smith’s current medications at the has been argued that the BTW exam only assesses time of his driving evaluation included several driving performance associated with automatized examples of the medication classes associated procedural driving, and not driving skills depen- with increased likelihood of accidents: dent on higher cognitive abilities. Figure 10.2 • Clopidogrel (antiplatelet; 69% increased like- illustrates the diffi culty with using the BTW as the lihood of accidents) sole measure of driving performance. Greater • Escitalopram (SSRI; 59% increased likeli- emphasis on incorporating the literature from hood of accidents) driving research into clinical practice may help • Ranitidine (H2 blocker; 55% increased likelihood of accidents) • Levothyroxine (thyroid hormone; 29% increased likelihood of accidents) • Lisinopril (angiotensin-converting enzyme inhibitor; 23% increased likelihood of accidents) The reader is referred to Looco and Staplin [62 ] for a comprehensive review on the impact of polypharmacy on the older driver. Insight into cognitive impairment and awareness of functional ability is another risk factor. For example, when tested on a BTW exam and asked to gauge their performance, older adults with MCI tend to overestimate their driving ability [ 63] . What is remarkable in Mr. Smith’s case is that he requested the driving evaluation. In the majority of cases, there is a reluctance to raise the issue of driving by patients and, subsequently, the burden of inquiring about changes in driving in Fig. 10.2 Do clinical behind-the-wheel exams lack sen- on the treating clinician. It is also important to be sitivity to cognitive impairment? 148 K.J. Manning and M.T. Schultheis illuminate the relationship between cognitive Clinicians should also be familiar with inter- functioning and driving performance. For exam- ventions for older drivers who do not need to ple, Uc et al. [31 ] investigated the effect of sud- relinquish their driving privileges but require denly stopped lead vehicles on the virtual reality modi fi cation of their driving habits. These inter- driving performance of older healthy adults and ventions include driving education (i.e., refresher adults with AD. Results revealed AD patients were course). There is moderate evidence that driving more likely to engage in sudden vehicle slowing, education improves behavior and awareness which signi fi cantly increased the risk of being in older drivers [ 66 ] . Driving education may struck from behind [ 31 ] . Multiple cognitive abili- allow older drivers to successfully maintain safe ties were associated with sudden vehicle slowing, driving for extended periods of time. but time on Trail Making Part B had the strongest Neuropsychologists should be familiar with association with performance. In each 30-s pro- the work of driving specialists in their area who longation on Trail Making Part B, the risk of conduct clinical driving evaluations (see addi- abrupt slowing increased by 31%. Given his tional resources below for help fi nding a driver signifi cant impairment on Trails B, it is intrigu- specialist in your area). Knowledge of the driving ing to speculate on Mr. Smith’s reaction to a vehi- specialist’s clinical examination will enable a cle suddenly stopping in front of him on the frank discussion with patients as what they can actual road. Whereas not available in the case of expect from further evaluations. Finally, the cli- Mr. Smith, empirically validated driving simula- nician should be familiar on state laws on manda- tion may prove a useful tool in clinical driving tory reporting, which vary considerably. For examinations. example, in Pennsylvania, state law requires all health-care personnel authorized to diagnose or Interventions and Recommendations treat disorders to report within 10 days the full Potential driving cessation should be discussed name and address of any patient who has been as early as possible with the older patient. This diagnosed as having a condition that could impair is especially true for adults with a neurodegen- his or her ability to safely operate a motor vehi- erative illness who will eventually cease driving. cle. However, not all states require mandatory In the case of progressive disorders (i.e., demen- medical reporting and instead temper their rec- tia), it is benefi cial to have an ongoing dialogue ommendations (e.g., Arkansas’ guidelines about driving ability and to consider that multi- include “We do encourage unsafe driver’s to be ple driving evaluations may be required during reported to our offi ce”). An excellent resource the course of the disease. Clinicians, especially that includes a review of state guidelines and neuropsychologists, have a responsibility to descriptions of driving assessment methods is the counsel and educate the patient and his or her “Physician’s Guide to Assessing and Counseling family on the impact of relinquishing a driver’s Older Drivers” sponsored by the National license. Inclusion of family members in this Highway Traffi c Safety Administration and avail- counseling process can serve to alleviate com- able free from their website ( http://www.nhtsa. mon communication strains between patients gov/Senior-Drivers ). and family members about this sensitive topic. It Driving is a complex behavior. To date, there is important to recall that one robust fi nding in remains much controversy about which clinical the literature is the relationship between driving tools or methods are the best predictors of driving cessation and depression and loss of autonomy. capacity. One important contribution that a clin- Practical considerations include fi nding alter- ical neuropsychologist can contribute to this pro- nate transportation to doctors’ appointments, cess is to support the evaluation of driving work, and other activities outside the home. A capacity at multiple levels. The literature pro- useful review of interventions for older adults vides support that using a combination of mea- who have ceased driving is included in Windsor sures can provide the best data for making and Anstey [65 ] . recommendations. As clinical neuropsychologist, 10 Driving Evaluation in Older Adults 149 the most commonly requested contribution is the and should not serve as a substitute for a com- identi fi cation of the cognitive impairments that prehensive driving evaluation. may impede driving performance. As clinicians • Be familiar with age-related medical condi- specializing in brain–behavior relationship, we tions (i.e., dementia, stroke, seizures) that should recognize the complexity of this behavior affect driving. Communication with the treat- and promote the evaluation of other domains ing physician (i.e., neurologist, cardiologist) affecting driving (i.e., vision, motor, psychologi- can help educate colleagues of the need to cal, and driving history). The integration of data consider driving capacity. from these various areas is a unique contribution • Be on the lookout for medication effects . Given that neuropsychologist can provide to patients the high number of medications commonly and their families. used by older adults, clinicians should consider the effect (individual or combined) of medications on driving behavior. Medications Clinical Pearls altering cognition, alertness, increasing fatigue, drowsiness, or altering sleep patterns • Know the law . State laws vary in their require- may warrant consideration. ments for reporting and assessing drivers. • Potential driving cessation should be dis- Clinicians are strongly encouraged to be cussed as early as possible. It is often familiar with their individual state require- bene fi cial to include signi fi cant others or ments (additional resources listed below). additional family members in this dialogue as • Ask about driving. Clinicians should be aware they may provide additional insight into driv- that driving cessation is often a topic of ing performance. con fl ict. Too often, older adults do not raise • Familiarize yourself with transportation the issue for fear of complete loss of driving options. Clinicians have a responsibility to privileges. Family members are also con fl icted counsel and educate the patient and his or her and in many cases are unsure about how to family on the impact of relinquishing a driv- handle/raise the discussion. Clinicians can er’s license. Being prepared with appropriate help minimize this con fl ict by including ques- referrals (i.e., medical transportation services) tions about driving performance in their regu- or community information (i.e., transit sched- lar checkups or appointments. ules) can help adults begin to explore/plan • Know what cognitive domains are most rele- alternate methods of transportation. vant. Although there is not a specifi c pattern or • Consider interventions. Interventions can defi ned group of tests that 100% predict driv- benefi t individuals who do not need to relin- ing performance, general domains of cognition quish their driving privileges but require relevant to driving are identi fi ed in the litera- modifi cation of their driving habits. These ture. Neuropsychological test selection should interventions can range from structured be based upon empirical evidence with multiple approaches (i.e., improving fi eld of view) to abilities assessed under the domains of atten- more practical recommendations, such as tion, information processing speed, working restricting or limiting driving. memory, executive functions, visual-spatial abilities, visual spatial learning, and memory. • Be familiar with the clinical driving evalua- Appendix A. Additional Resources tion process . This includes identifying referral procedures and locations offering BTW evalu- • National Highway Traf fi c Safety Administration ations with Certifi ed Driving Rehabilitation – Guidelines and strategies for working with Specialist (CDRS) accreditation. The neurop- older drivers; statistics on older driver’s sychological evaluation should serve as guide traf fi c safety ( http://www.nhtsa.gov/Senior- to inform further evaluation of driving ability Drivers ) . 150 K.J. Manning and M.T. Schultheis

• Association for Driver Rehabilitation Specialists middle-aged drivers. Accid Anal Prev. 1990;22(5): – Includes a directory for locating a driver spe- 499–508. 15. Bao S, Boyle L. Driver performance at two-way stop- cialist in your area (http://www.aded.net ). controlled intersections on divided highways. • The Handbook for the Assessment of Driving Transport Res Rec J Transport Res Board. 2008;2069: Capacity (2009). Schulthies, MT., Deluca, J. 26–32. and Chute, DL. Elsevier Publishers. 16. Retting RA, Weinstein HB, Solomon MG. Analysis of motor-vehicle crashes at stop signs in four US cities. • CanDrive J Safety Res. 2003;34:485–9. – Website for driving research with older 17. Rizzo M, McGehee DV, Dawson JD, Anderson SN. adults; includes publications and other Simulated car crashes at intersections in drivers with resources ( http://www.candrive.ca/ ) . Alzheimer disease. Alzheimer Dis Assoc Disord. 2001;15(1):10–20. 18. Braitman KA, Kirley BB, Ferguson S, Chaudhary NK. Factors leading to older drivers’ intersection crashes. Traf fi c Inj Prev. 2007;8(3):267–74. References 19. Sen B, Najm WG, Smith JD. Analysis of lane change crashes, performed by John A. Volpe National 1. Fildes BN. Future directions for older driver research. Transportation System Center, Cambridge, MA. Traf fi c Inj Prev. 2008;9:387–93. Washington DC: Department of Transportation, 2. Dobbs BM. Aging baby boomers: a blessing or chal- Administration NHTS; 2003. lenge for driver licensing authorities. Traffi c Inj Prev. 20. Anstey KJ, Wood J, Lord S, Walker JG. Cognitive, 2008;9:379–86. sensory and physical factors enabling driving safety 3. Martolli RA, de Leon CFM, Glass TA, Williams CS, in older adults. Clin Psychol Rev. 2005;25(1):45–65. Cooney LM, Berkman LF. Consequences of driving 21. Mathias JL, Lucas LK. Cognitive predictors of unsafe cessation: decreased out-of-home activity levels. driving in older drivers: a meta-analysis. Int J Gerontol B Psychol Sci Soc Sci. 2000;55:S334–40. Psychogeriatr. 2009;21(4):637–53. 4. Oxley J, Whelan M. It cannot be all about safety: the 22. Dawson JD, Uc EY, Anderson SW, Johnson AM, Rizzo bene fi t of prolonged mobility. Traf fi c Inj Prev. M. Neuropsychological predictors of driving errors in 2008;9:367–78. older adults. J Am Geriatr Soc. 2010;58(6):1090–6. 5. Schultheis M, DeLuca J, Chute D, editors. Handbook doi:10.1111/j.1532-5415.2010.02872.x . for the assessment of driving capacity. New York: 23. Munro CA, Jefferys J, Gower EW, et al. Predictors of Academic; 2009. lane change errors in older drivers. J Am Geriatr Soc. 6. Rizzo M, Uc EY, Dawson J, Anderson S, Rodnitzky 2010;58:457–64. R. Driving diffi culties in Parkinson’s disease. Mov 24. Folstein MF, Folstein SE, McHugh PR. “Mini mental Disord. 2010;25 Suppl 1:S136–40. state”: a practical method for grading the cognitive 7. Heinrich HW, Petersen D, Roos N. Industrial accident state of patients for the clinician. J Psychiatr Res. prevention. New York: McGraw-Hill; 1980. 1975;12:189–98. 8. Maycock G. Accident liability: the human perspec- 25. Freund B, Colgrove LA. Error speci fi c restrictions for tive. In: Rothengatter ET, Vaya EC, editors. Traf fi c older drivers: promoting continued independence and and transport psychology: theory and application. public safety. Accid Anal Prev. 2008;40(1):97–103. Oxford: Pergamon; 1997. p. 65–76. 26. Freund B, Gravenstein S, Ferris R, Burke BL, Shaheen 9. McGwin Jr G, Brown D. Characteristics of traf fi c E. Drawing clocks and driving cars. J Gen Intern Med. crashes among young, middle-aged, and older drivers. 2005;20(3):240–4. Accid Anal Prev. 1999;31:181–98. 27. Freund B, Colgrove LA, Petrakos D, McLeod R. In 10. Langford J, Methorst R, Hakamies-Blomqvist L. my car the brake is on the right: pedal errors among Older drivers do not have a high crash risk-a replica- older drivers. Accid Anal Prev. 2008;40(1):403–9. tion of low mileage bias. Accid Anal Prev. 2006;38: 28. Zook NA, Bennett TL, Lane M. Identifying at-risk 574–8. older adult community-dwelling drivers through 11. Hakamies-Blomqvist L, Raitanen T, O’Neill D. Driver neuropsychological evaluation. Appl Neuropsychol. ageing does not cause higher accident rates per km. 2009;16:281–7. Transport Res F Traf fi c Psychol Behav. 2002;5: 29. Friedland RP, Koss E, Kumar A, et al. Motor vehicle 271–4. crashes in dementia of the Alzheimer type. Ann 12. Ryan GA, Legge M, Rosman D. Age related changes Neurol. 1988;24(6):782–6. in drivers’ crash risk and crash type. Accid Anal Prev. 30. Carr DB, Duchek J, Morris JC. Characteristics of 1998;30(3):379–87. motor vehicle crashes of drivers with dementia of the 13. Hakamies-Blomqvist LE. Fatal accidents of older Alzheimer type. J Am Geriatr Soc. 2000;48(1):18–22. drivers. Accid Anal Prev. 1993;25(1):19–27. 31. Uc EY, Rizzo M, Anderson SW, Shi Q, Dawson JD. 14. Cooper PJ. Differences in accident characteristics Unsafe rear-end collision avoidance in Alzheimer’s among elderly drivers and between elderly and disease. J Neurol Sci. 2006;251(1–2):35–43. 10 Driving Evaluation in Older Adults 151

32. Dawson JD, Anderson SW, Uc EY, Dastrup E, Rizzo of driving performance. J Geriatr Psychiatry Neurol. M. Predictors of driving safety in early Alzheimer dis- 2009;22(2):87–94. ease. Neurology. 2009;72(6):521–7. 50. Petersen RC. Mild cognitive impairment as a diagnos- 33. Duchek JM, Carr DB, Hunt L, et al. Longitudinal tic entity. J Intern Med. 2004;256:183–94. driving performance in early-stage dementia of the 51. Jurica PJ, Leitten CL, Mattis S: DRS-2: Dementia Alzheimer type. J Am Geriatr Soc. 2003;51(10): Rating Scale-2. Professional Manual. Lutz, FL, 1342–7. Psychological Resources, 2004. 34. Ott BR, Heindel WC, Papandonatos GD, et al. A lon- 52. Brandt J, Aretouli E, Neijstrom E, et al. Selectivity of gitudinal study of drivers with Alzheimer’s disease. executive function de fi cits in mild cognitive impair- Neurology. 2008;70:1171–8. ment. Neuropsychology. 2009;23(5):607–18. 35. Hughes CP, Berg L, Danziger WL, Coben LA, Martin 53. Hopewell CA. Driving assessment issues for prac- RL. A new clinical scale for the staging of dementia. ticing clinicians. J Head Trauma Rehabil. 2002;17: Br J Psychiatry. 1982;140:566–72. 48–61. 36. Boyle L, Lee JD. Using driving simulators to assess 54. Iverson DJ, Gronseth GS, Reger MA, Classen S, driving safety. Accid Anal Prev. 2010;42:785–7. Dubinsky RM, Rizzo M. Practice parameter update: 37. Reger MA, Welsh RK, Watson GS, Cholerton B, Baker evaluation and management of driving risk in demen- LD, Craft S. The relationship between neuropsycho- tia. Neurology. 2010;74:1316–24. logical functioning and driving ability in dementia: a 55. Korner-Bitensky N, Bitensky J, Sofer S, Man-Son- meta-analysis. Neuropsychology. 2004;18(1):85–93. Hing M, Gelinas I. Driving evaluation practices of 38. Cohen J. A power primer. Psychol Bull. 1992;112: clinicians working in the United States and Canada. 155–9. Am J Occup Ther. 2006;60:428–34. 39. Ott BR, Festa EK, Amick MM, Grace J, Davis JD, 56. Clay OJ, Wadley VG, Edwards JD, Roth DL, Roenker Heindel WC. Computerized maze navigation and on- DL, Ball KK. Cumulative meta-analysis of the rela- road performance by drivers with dementia. J Geriatr tionship between useful fi eld of view and driving per- Psychiatry Neurol. 2008;21(1):18–25. formance in older adults: current and future 40. Grace J, Amick MM, D’Abreu A, Festa EK, Heindel implications. Optom Vis Sci. 2005;82(8):724–31. WC, Ott BR. Neuropsychological defi cits associated 57. Bedard M, Weaver B, Darzins P, Porter MM. with driving performance in Parkinson’s and Predicting driving performance in older adults: we are Alzheimer’s disease. J Int Neuropsychol Soc. 2005; not there yet! Traf fi c Inj Prev. 2008;9(4):336–41. 11(6):766–75. 58. Langford J. Usefulness of off-road screening tests to 41. Cordell R, Lee HC, Granger A, Vieira B, Lee AH. licensing authorities when assessing older driver Driving assessment in Parkinson’s disease—a novel fi tness to drive. Traf fi c Inj Prev. 2008;9(4):328–35. predictor of performance? Mov Disord. 2008;23(9): 59. Lot fi pour S, Vaca F. Commentary: polypharmacy and 1217–22. older drivers: beyond the doors of the emergency 42. Uc EY, Rizzo M, Johnson AM, Dastrup E, Anderson department for patient safety. Ann Emerg Med. SW, Dawson JD. Road safety in drivers with Parkinson 2007;49:535–7. disease. Neurology. 2009;73(24):2112–9. 60. Ray WA, Thapa PB, Shorr RI. Medications and the 43. Singh R, Pentland B, Hunter J, Provan F. Parkinson’s older driver. Clin Geriatr Med. 1993;9(2):413–38. disease and driving ability. J Neurol Neurosurg 61. LeRoy AA, Morse ML. Multiple medications and Psychiatry. 2007;78:363–6. vehicle crashes: analysis of databases. Washington, 44. Amick MM, Grace J, Ott BR. Visual and cognitive pre- DC: Department of Transportation, Administration dictors of driving safety in Parkinson’s disease patients. NHTS; 2008. Arch Clin Neuropsychol. 2007;22(8):957–67. 62. Lococo KH, Staplin L. Literature review of polyphar- 45. Ball K, Owsley C, Sloane ME, Roenker DL, Bruni macy and older drivers: identifying strategies to col- JR. Visual attention problems as a predictor of vehicle lect drug usage and driving functioning among older crashes in older drivers. Invest Ophthalmol Vis Sci. drivers. Washington, DC: US Department of 1993;34(11):3110–23. Transportation, Administration NHTS; 2006. 46. Devos H, Vandenberghe W, Nieuwboer A, Tant M, 63. Okonkwo O, Grif fi th HR, Vance DE, Marson DC, Baten G, De Weerdt W. Predictors of fi tness to drive Ball K, Wadley V. Awareness of functional diffi culties in people with Parkinson disease. Neurology. in mild cognitive impairment: a multidomain assess- 2007;69(14):1434–41. ment approach. J Am Geriatr Soc. 2009;57:978–84. 47. Flicker C, Ferris SH, Reisberg B. Mild cognitive 64. Blanchard RA, Myers A, Porter MM. Correspondence impairment in the elderly: predictors of dementia. between self-reported and objective measures of driv- Neurology. 1991;41(7):1006–9. ing exposure and patterns in older drivers. Accid Anal 48. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Prev. 2010;42:523–9. Tangalos EG, Kokmen E. Mild cognitive impairment: 65. Windsor TD, Anstey KJ. Interventions to reduce the clinical characterization and outcome. Arch Neurol. adverse psychosocial impact of driving cessation on 1999;56(3):303–8. older adults. Clin Interv Aging. 2006;1:205–11. 49. Wadley VG, Okonkwo O, Crowe M, et al. Mild cogni- 66. Kua A, Korner-Bitensky N, Desrosiers J, Man-Son-Hing tive impairment and everyday function: an investigation M, Marshall S. Older drivers retraining: a systematic 152 K.J. Manning and M.T. Schultheis

review of evidence of effectiveness. J Safety Res. reasoning and spatial abilities. J Exp Psychol Learn 2007;38:81–90. Mem Cogn. 1989;15:507–13. 67. De Raedt R, Ponjaert-Kristoffersen I. Predicting at- 78. Daigneault G, Joly P, Frigon J. Executive functions in fault car accidents of older drivers. Accid Anal Prev. the evaluation of accident risk of older drivers. J Clin 2001;33:809–19. Exp Neuropsychol. 2002;24:221–38. 68. Staplin L, Gish KW, Wagner EK. MaryPODS revis- 79. Shallice T. Speci fi c impairments of planning. Philos ited: updated crash analysis and implications for Trans R Soc Lond B Biol Sci. 1982;298:199–209. screening program implementation. J Safety Res. 80. Grant DA, Berg E. A behavioral analysis of degree of 2003;34(4):389–97. reinforcement and ease of shifting to new responses in 69. Ball KK, Roenker DL, Wadley VG, et al. Can high- a Weigl-type card-sorting problem. J Exp Psychol. risk older drivers be identi fi ed through performance- 1948;38:404–11. based measures in a department of motor vehicle 81. Benton AL, Varney N, Hamsher K. Visuospatial setting? J Am Geriatr Soc. 2005;54:77–84. judgment: a clinical test. Arch Neurol. 1978;35: 70. Richardson ED, Martolli RA. Visual attention and 364–7. driving behaviors among community-living older 82. Wechsler D. Wechsler Adult Intelligence Scale. 3rd persons. J Gerontol A Biol Sci Med Sci. 2003;58: ed. San Antonio: Psychological Corporation; 1997. M832–6. 83. Beery K, Buktenica N, Beery N. Beery-Buktenica 71. Whelihan WM, DiCarlo MA, Paul RH. The relation- Developmental Test of Visual-Motor Integration. ship of neuropsychological functioning to driving Upper Saddle River: Pearson; 2010. competence in older persons with early cognitive 84. Benton Sivian A. Benton Visual Retention Test. 5th decline. Arch Clin Neuropsychol. 2005;20:217–28. ed. Upper Saddle River: Pearson; 1991. 72. Smith A. Symbol digits modalities test. Los Angeles: 85. Brandt J, Benedict RH. Hopkins Verbal Learning Western Psychological Services; 1982. Test—Revised. Professional manual. Lutz: 73. Worringham CJ, Wood J, Kerr GK, Silburn PA. Psychological Assessment Resources; 2001. Predictors of driving assessment outcome in 86. Instrument L. Grooved pegboard user instructions. Parkinson’s disease. Mov Disord. 2005;21:230–5. Lafayette: Lafayette Instrument; 2002. 74. War Department, Adjutant General’s Of fi ce. Army 87. Heaton RK, Miller SW, Taylor MJ, Grant I. Revised Individual Test Battery. Manual for directions and comprehensive norms for an expanded halstead- scoring. Washington, DC: War Department, Adjutant reitan battery: demographically adjusted neuropsy- General’s Of fi ce; 1944. chological norms for African American and Caucasian 75. Schretlen D, Bobholz J, Brandt J. Development and adults. Lutz: Psychological Assessment Resources; psychometric properties of the brief test of attention. 2004. Clin Neuropsychol. 1996;10:80–9. 88. Wechsler D. Wechsler Adult Intelligence Scale. 76. Oswanski MF, Sharma OP, Raj SS, et al. Evaluation of Revised edition. San Antonio: Psychological two assessment tools in predicting driving ability of Corporation; 1981. senior drivers. Am J Phys Med Rehabil. 2007;86: 89. Carr DB, Schwartzberg JG, Manning L, Sempek J. 190–9. Physician’s guide to assessing and counseling older 77. Salthouse TA, Mitchell DJ, Skovronek E, Babcock drivers. 2nd ed. Washington, DC: Administration RL. Effects of adult age and working memory on NHTS; 2010. Environmental Design for Cognitive Decline 1 1

Rosemary Bakker

Abstract Cognitive decline, especially substantial changes associated with Alzheimer’s disease and other dementias, signi fi cantly changes how individuals interact with their home environment. The nature and extent of these changes are highly individual and in constant fl ux, and are in fl uenced by neuropathology, normal age-related changes in physical and mental functions, medications, as well as specifi cs in the patient’s home environment. One consistent observation is that sensitivity to the environment increases sharply with the onset of dementia. As a clinician, it is important to understand the functional challenges that the typical unadapted home presents to a dementia patient, and the guiding principles for a dementia- friendly living space. Equipped with this information, clinicians can serve as a frontline resource, advising patients and their families about practical home management strategies to enhance safety, performance of daily skills, and quality of life.

Keywords Dementia home safety • Falls • Activities of daily living • Wandering • Smart home technology • Memory aides • Alzheimer’s caregiving • Agitation • Monitoring

Environmental design is an underutilized yet smart home technologies) will be explored that effective treatment option in helping patients with can help patients and their caregivers lead safer cognitive decline maintain function with fewer and more satisfactory lives. Environmental design behavioral problems [ 1 ] . In this chapter, key design cannot stand alone as a therapeutic modality; solutions (e.g., memory aides, interior design, and therefore, the importance of the psychosocial environment, with guidelines on how caregivers can R. Bakker , M.S., ASID. (*) best elicit cooperation and trust from their loved Division of Geriatrics, Department of Medicine , ones, will be addressed. Table 11.1 highlights Weill Cornell Medical College , 525 E. 68th Street , environment-related changes in function and per- Box 39 , New York , NY 10065 , USA e-mail: [email protected] ception commonly associated with dementia.

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 153 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_11, © Springer Science+Business Media, LLC 2013 154 R. Bakker

Table 11.1 Environment-related changes of function and perception in dementia patients Visual/spatial Hearing Problems with visual/spatial perception if foreground and Inability to focus due to excessive background noise background are not color contrasted (e.g., reduced food intake can occur if food and plate are the same color) Perceptual distortion caused by highly patterned fl ooring, Confusion or agitation in noisy environments seating, or wall covering Inability to recognize their own image (e.g., in the mirror Loss of ability to interpret sounds accurately; underlying or in a bare re fl ective window) hearing disorders can also predispose a person toward auditory misperceptions (e.g., sound of telephone perceived as small dog barking) Visual misinterpretations in low lighting Problems with object recognition with similarly shaped objects (e.g., waste basket mistaken for toilet bowl) Mobility Memory/judgment Dif fi culty in walking caused by changes in gait and Problems with sequential tasks balance, especially if area carpets and door sills are present Stair climbing diffi culties Problems with short-term memory (e.g., forgetting food – lack of handrails cooking on stove) – only one handrail, if patient has a one-side Inability to focus weakness due to a stroke Way fi nding issues and getting lost, even within the home – risers and steps in the same color Inappropriate judgment (e.g., putting clothes in the microwave to dry) Forgetting they cannot walk unassisted Forgetting to use their walker or inability to learn how to use it Restricted access due to narrow doorways or lack of stair alternatives during wheelchair usage in the late stages

Caregiver Challenges Unusual Behaviors

Fluctuation in Skills and Behaviors Patients may engage in unusual or unsafe behaviors that are particularly challenging to cope with, Patient skills, behavior, and memory can fl uctuate like hoarding or wandering. Mistaken perceptions from day to day or even within a single day, mak- can occur in low-light levels and in shadowy ing it diffi cult for individuals or families to know areas, sometimes leading to calls to the police due how to intervene. Robert C took his wife for test- to “strangers in the room.” Low-stress thresholds ing as he could no longer cope with her changes are common and seemingly minor events, such as in memory and judgment; she was regularly the noise of a loud television or dishwasher, can fl ooding the apartment, forgetting that the bath act as a trigger for an extreme reaction. It is not water was running. An accomplished cook for surprising that more than 40% of caregivers of 50 years, she had recently roasted a frozen persons with cognitive decline rate the emotional chicken in the oven without removing the plastic stress of caregiving as high or very high [2 ] , and wrapping. Yet he reports, there are days when she that 34% of caregivers report needing more help still seems “normal.” with keeping the person safe at home [3 ] . 11 Environmental Design for Cognitive Decline 155

Lack of Insight the interventions are too restrictive, not allowing for meaningful participation by the patient. For Patients with cognitive decline often have limited example, if a patient forgets a couple of steps in insight that there is anything wrong, making it the bathing process due to problems with sequen- diffi cult for the clinician or family member to tial tasks, the caregiver may take over all steps, openly discuss dementia or safety issues for fear which often causes resentment on both sides. of upsetting the patient. For example, the patient may not remember that he or she has been leaving the stove on or getting lost on the way home from Finding Out What Works a shopping excursion. As a clinician, you may need to broach performance of daily activities Clinicians should stress to caregivers that design gently, noting any resistance, and get permission and behavioral strategies need to be individualized from the patient to speak privately with the care- and continually reassessed; strategies that are giver later on, if necessary. effective for some may only work brie fl y or not at all in different situations. Throughout this chapter, individualized approaches to challenging situa- Cognitive Decline or Poor Design? tions will be highlighted, to illustrate the wide variety of responses in this population. When a patient has impaired function, it is commonly assumed that the problem is cognitive decline rather than the interaction between the Ongoing Safety and Design Issues patient and the environment. Consider the following example: On a very hot summer day, the Caregivers should keep in mind that providing author reported to the assisted-living staff that for the safety of their loved ones is an ongoing her mother was in her room—agitated and with- challenge as the disease progresses. As one care- out air conditioning; the staff replied that her giver recently remarked, “Even when you think Alzheimer’s had progressed and she could no you have resolved a problem, you have no clue as longer operate her air conditioner. Upon further to what is going to hit you in the face the next investigation, however, the lack of function was day.” To help reduce challenging behaviors when not due to dementia. Rather, her mother simply adapting the home environment, changes should could not read the lettering on the air condition- be phased in gradually whenever possible, and er’s control panel because the font was too small caregivers should be instructed to observe how and the contrast between the font and the back- the person responds and switch course when and ground color too low. She was not able to under- if necessary. If the caregiver is planning on keep- stand the problem, but she did express her ing their loved one at home for as long as possi- frustration over the poor design as the discussion ble, consideration should be given to increasing ensued. “Why do they do that? Why do they make the home’s accessibility (e.g., wider doorways, your brain work so hard?” Applying an On/Off ramps, walk-in showers, etc.). label in a large black font against a white background quickly restored her function—and her well-being. The Environment as a Therapeutic An environment that is suited for individuals Modality with cognitive impairments does not happen spontaneously, it takes understanding and plan- Reducing Environmental Triggers ning. Without understanding the environment’s of Agitation effect on a patient’s behavior, many caregivers blame declining abilities on the disease and may It is common for caregivers to report that their not engage in preventive measures. In some cases, loved ones are easily agitated, but when the 156 R. Bakker patient’s behavior is explored in greater detail, tear the room apart. Ron G removed the knobs there is usually a speci fi c event preceding the agi- and installed child safety covers on the stove tation that acts as a trigger for that behavior. If a before he went to work so that his mother would patient presents with a new history of agitation, not cook when he was not at home; this is a ask the caregiver to think back to the activity or common home safety recommendation. Left conversation that took place prior to the behavior. alone all day, his mother became so agitated that For example, if a caregiver states that their loved she dismantled the stove and emptied the kitchen one becomes agitated during bathing, ask them to cabinets onto the fl oor and countertops. Ron G document exactly when the agitation begins. Was was overwhelmed by this severe reaction and felt the patient uncomfortable while disrobing, fear- he had no choice but to place her in a nursing ful of getting into or out of the bathtub, anxious home. This outcome may have been prevented, or when the water was turned on, or when their body at least postponed, if he had been warned of the was washed? Caregivers can be advised to keep a potential for negative outcomes and had been journal and document the behavioral incidents. If able to monitor the situation. the cause is external, whether it is precipitated by environmental factors or by caregiver interaction, the caregiver can then act to change or modify the Memory Aides for Earlier Stages trigger(s) and the associated agitation [4– 7 ] . Common triggers for agitation include envi- In the early to mid stages, depending on the extent ronmental factors and caregiver interaction, of the cognitive loss, reminder signs with simple including: language, large-sized text, and personalized • Noise images, act as an “external brain,” giving needed • Room temperature instruction for daily living. The image and text • Standard bathing techniques used must be customized for the person and large • Lack of stimulation enough to capture their attention, or the interven- • Overstimulation tion will not be effective [ 4] . Here are a few • Denial of access successful examples: • Tasks too complicated for person’s current 1. Cecilia G remembered to brush her teeth if abilities simple instructions were placed in her direct • Caregiver tone of voice view: • Caregiver behavior (e.g., controlling) (a) Put toothpaste on toothbrush. (b) Brush teeth. 2. Arlene S identi fi ed her room when a photo of Monitoring the Effects of Interventions herself from her earlier days was placed on the door. But for Ed T, a former corn researcher, it It is not always clear if a person can safely engage was a dried corn arrangement, not a personal in an activity, and balancing risk and freedom is portrait, which enabled him to recognize his an ongoing challenge for caregivers. At some apartment door. point, the caregiver may need to set certain items or areas of the household off-limits. Most standard home safety checklists recommend denying Finding Lost Items access to “safety hazards” but do not mention that sometimes the solution causes a new prob- Losing and searching for belongings is a com- lem. Patient A may simply walk away if they can mon and frustrating activity; organizational strat- no longer turn the stove on (after removal of the egies may be helpful for those experiencing mild knobs) or open a newly locked cabinet door, but cognitive decline. For example, a patient may be patient B may become so frustrated that they able to learn to place their keys in one location, attempt to remove the lock or the door or even especially if it is visually easy to identify, as in a 11 Environmental Design for Cognitive Decline 157 bright red bowl on an uncluttered foyer table. may see a stranger and not themselves in the mirror A sign (text and icon) reminding the patient to or think that their own refl ection in a dark window place the keys in the bowl can help reinforce the at night is a stranger. And some may see frighten- new behavior. Electronic fi nder devices can also ing shapes, like a crouching person in a large reduce distressing time spent on fi nding objects. houseplant in dim lighting, or animals in a swirling, The patient may not be able to learn how to use patterned fabric or carpet. Others have diffi culty the device or may misplace the device, but differentiating reality from representation. They caregivers have successfully used locator devices may perceive people in photographs as real and for some patients with good results [5 ] . As one refuse to undress or even get upset if the photo- caregiver said, “I used to get so anxious when graph does not respond when spoken to. If a violent I visited my dad, as we would spend a lot of time TV show is on, they may think the event is actually searching for his keys and then we would both be happening right in their room. The person may in a bad mood. Now, when I visit, I use the loca- become so frightened that they call the police. tor device, which I keep on my key ring and The following interventions can reduce or within minutes, I fi nd his keys. Now we spend eliminate the misperceptions, depending on the more time on enjoyable activities.” cause: • Remove wastebaskets from bathrooms. • Remove or cover mirrors. Visual Misperceptions and Visual • Turn photographs around (or remove, if Dysfunction necessary). • Close blinds or drapes early at night. Problems with Depth Perception • Increase light levels. • Control TV viewing. Many patients experience visual dysfunction • Replace patterned furnishings. when there is lack of contrast, causing signifi cant problems with depth perception. Lack of contrast makes it harder or impossible to identify objects Lighting and Function that are set against a background of similar col- ors. For example, a patient may walk right past a Appropriate lighting can improve overall quality white toilet on a white wall and continue to search of life for people with dementia, though this is for the toilet, but a color-contrasted toilet seat can often overlooked. It can reduce the environmen- enhance object recognition and may help the per- tal misperceptions that occur in low-light condi- son remain continent for a longer period of time tions. Appropriate lighting can also signifi cantly [6 ] . Patterned carpeting or carpets with dark con- improve visual function due to age-associated trasting borders also be diffi cult for patients with visual loss [ 7 ] . Mark P regularly led the congre- visuospatial dif fi culties; some individuals may gation during prayer service, but when he began not perceive the fl oor to be level and may attempt stumbling over words, everyone thought it was to jump or step over patterns or borders. due to the progression of his dementia. But after a new overhead light was installed, his reading skills went back to normal. Misperception and the Environment

Some individuals have difﬁ culty differentiating Mobility and Falls objects, especially those that have similar shapes, such as a patient who mistakes the wastebasket Patients with dementia fall two to three times (oval shape) for the toilet bowl (oval shape). Others more often than individuals without cognitive may be unable to recognize themselves in a mirror impairments [ 8] . Patients experience not only or misperceive what’s there. For example, he or she normal age-related vision and mobility changes 158 R. Bakker

Table 11.2 Common dementia-related risk factors for • Monitor high fall areas with sensors or weight- falls sensitive chair, bed, or fl oor pads to alert Inability to housekeep, maintain a home, or hoarding caregiver when person attempts to transfer or behavior can create mounds of clutter and other home use stairs independently when it is no longer hazards safe to do so. Reduced attention and/or depth perception can make certain objects, like doorsills and low tables, less noticeable and are common causes for tripping Lowered stress thresholds and becoming easily agitated; Challenges with Stair Climbing storming off or possibly striking out and losing balance Fear of falling and, consequently, not walking much , At some point, the individual may have diffi culty which further increases fall risk; reduced exercises leads to weakened muscles and stiff joints climbing stairs, especially if there are no Impaired memory and judgment can cause risky handrails. One-sided handrails can be problematic behaviors, such as descending steep stairs in the dark, for an individual with weakness on the side as the searching for a mother or adult child the person believes handrail (e.g., due to a stroke). Risers and steps is still in his/her care that are similar in color can also pose a challenge. Changes in perception and balance can cause problems, If the patient is unsure of their step or becomes such as knowing where to place one’s feet going up or down stairs, walking with a shuf fl e, and getting one’s agitated when climbing stairs, a 2-in. strip of foot caught on area rugs or doorsills, or holding onto bright tape applied along the edge of the step may unsteady furniture help them better distinguish the tread from the riser [9 ] . When it is too dangerous for someone to use the stairs without supervision, the caregiver needs to limit access. A monitoring device, such as a motion sensor, should be used. A motion that increase fall risk but also dementia-related sensor with a remote alert can notify the care- challenges increase the incidence of unsafe situa- giver, even in another room, when the patient tions. Table 11.2 lists common dementia-related approaches the staircase. Advance notice may risk factors for falls. give the caregiver the time they need to be at the patient’s side to offer assistance. A baby monitor may or may not work, depending on the amount Strategies to Reduce Falls of noise a person makes walking across a room. Denying access to the stairs using gates or locked There are a variety of environmental strategies to doors may be necessary at times, but it should be employ depending on the patient’s fall risk fac- done with caution and frequent monitoring, espe- tors. Below is a list of key interventions: cially when the person is accustomed to using the • Remove area carpets and doorsills, especially stairs freely. Child safety gates are speci fi cally if patient shuf fl es. designed for children, not for the strength or • Clear clutter (crates and baskets can be used to height of an adult. Some individuals may simply store clutter outside of walkways if patient is turn around and walk away when faced with a upset at removal). child safety gate, but others may attempt to open • Remove low tables, especially glass. the gate, or worse, climb over it. • Provide for accessibility: – Ramps – Walk-in showers Electric Stair Lifts – Bath and shower chairs – Use compensatory measures: Sometimes people ask if a patient with dementia – Highlight edges of steps for better visibility can use an electric stair chair lift. There is little – Color contrast seating, bedding, and toilet research on this topic, but problems with fear of seat to fl oor falling should be expected, as most patients have 11 Environmental Design for Cognitive Decline 159 little or no experience with using a “chair” that patient’s temperament, the stage of the disease, automatically moves up and down the stairs. their environment, and, of course, the product or Step-by-step instructions before starting the chair strategy employed. For example, a patient may lift could help reduce fears. It may also be a good become very agitated by locked doors, refuse to idea for the caregiver to walk behind the person carry a tracking device like a cell phone, or wear and offer support, telling their loved one that they a special monitoring device on their wrist. Further, are safe, and they will not fall. GPS and other tracking devices do not work in all environments. Since no single strategy will work in all situations, it is best to recommend that the Wandering caregiver try several to see which ones work best for their situation. Combining several strategies Wandering and getting lost are serious problems for is preferred for backup safety; for example, using patients with dementia, especially since it happens both an ID bracelet as well as a monitoring device so unpredictably. A patient can wander off unex- that alerts the caregiver to an open door. pectedly, even when the caregiver thinks they are Pilot studies of a nighttime home wandering safe. It is not unusual that someone with dementia monitoring system, consisting of room and bed may leave their home in an effort to get to a job they occupancy sensors, door alarms with remote no longer have, or they may go searching for some- alerts, and a communication panel at the care- one they truly believe is still in their care, such as a giver’s bedside showed potential for improved child who is now fully grown. They may leave home caregiver well-being and quality of sleep [ 10 ] , desperately searching for their “real” home because reduced injuries, and unattended home exits by they no longer recognize where they are living. The persons with dementia [11 ] . Redirecting an indi- patient may pace and constantly move about, vidual’s attention from leaving home to a pre- increasing their chances of getting lost. Finally, they ferred activity is a powerful preventive tool. Many may become agitated and storm off; they may be patients have decreased initiation but can partici- bored, disturbed by too much noise, or upset by side pate if someone else can initiate the activity for effects from certain medications. them. Going outside when the weather permits What makes wandering diffi cult is that most can also reduce “cooped up” feelings and associ- people are so accustomed to leaving home when- ated agitation. Refer to the section on wandering ever they wish, and individuals with dementia are at ThisCaringHome.org for prevention strategies; no exception. At some point in the disease, the there are also reviews and descriptions of elec- patient will get lost if they go out alone, and we can- tronic devices that can help fi nd the patient if they not predict when that moment will come. Wandering wander and cannot fi nd their way home. typically occurs during the middle stages of AD, when many other disease symptoms are present. However, caregivers have brought their loved ones Chair and Bed Transfers in for testing only after a serious wandering episode, stating that there was no warning that there was any- Assisting an adult in the sit-to-stand transfer is thing to be concerned about. It can be a shocking one of the most dif fi cult and dangerous tasks for way to learn that the dementia process has begun. a caregiver, putting them at risk for injury [ 12 ] . There has been little research on which wan- Caregivers, especially novice caregivers, often dering solutions work best in different situations provide more physical help than is needed, not and environments, so trying to fi nd the best knowing how else to proceed, and physical sup- strategies to deal with wandering can be chal- port is usually not performed in an ergonomically lenging. How well any intervention works correct manner [ 13 ] . Dif fi culties with transfer- depends on a number of factors, including the ring are usually due to a combination of factors, 160 R. Bakker including furniture design, the individual’s health, out of bed and stand, as it offers a stable surface memory, and response to the caregiver (e.g., to hold onto and push off from, it can also help many patients do not respond favorably to a care- with balance. To use a bed handle safely, the per- giver’s request to get up from a chair or bed). son still needs good upper body strength and the ability to stand and bear weight. The bed handle should attach securely to the bed frame. Chairs

For most people with adequate strength and func- Impact of Memory Issues on Transfers tion, it is much easier to get up from an ergo- nomic chair (not too low or deep, with an opening Although it may be hard to imagine, people with under the seat, and side arms) than from a sofa or dementia sometimes forget how to get out of a chair an easy chair, because the necessary body move- or bed, therefore providing instructions may be ments are much easier on the joints and muscles. helpful. Gloria T had been physically helping her Even individuals with Parkinson’s disease who husband to get up from his chair and bed, but was are rigid and frequently lean forward can get in experiencing signi ﬁ cant back problems. The author and out of a good chair, especially if they rock recommended that her husband be assessed for back and forth and rise on the count of three. function to see if he still had adequate ability to help Motorized, lift-up chairs can be extremely with transferring. A physical therapist’s assessment helpful when the person has severely limited showed that he had adequate transfer function and movement or refuses to sleep in bed, as the chair taught Gloria T “coaching” techniques to replace can be put in a reclining position. Caregivers her physical assistance. She now offers simple step- should be forewarned that a lift chair is best used by-step instructions, including visual cueing, like with a caregiver present, as the controls are typi- tapping the edge of the seat or bed, and physical cally dif ﬁ cult for persons with dementia to use. cues, like placing one hand on his lower back and A fall could occur if a person attempts to climb one on his shoulder to gently guide him forward. out of a chair that is in the reclining position. The caregiver’s attitude and physical approach is an Additionally, some patients become frightened important aspect of the person’s willingness to get when the chair starts to move without warning, so up. Approaching the patient with a positive attitude the caregiver should tell the person what is going and offering an inviting reason to get up can provide to happen before they lower or raise the chair, needed encouragement. To reduce feelings of intim- even if they think the person will not understand. idation and “power struggles,” the caregiver should be advised to be at eye level with the patient (e.g., sit next to patient or kneel down at bedside) while Beds inviting the patient to an enjoyable activity.

A mattress with the appropriate degree of ﬁ rmness will be comfortable for the patient to sleep on and Meal Preparation, Cooking, easier to push off from when getting out of bed. and Dining For many individuals, the most suitable bed height for a comfortable transfer is 18 in. Before Organizational Strategies and Cues attempting to help a person out of bed, instruct the caregiver to give a good reason to get up. In Although many patients may no longer be able to addition, a warm, gentle voice can do wonders. cook a full meal, most can participate in a limited The right type of bed handle can help a person get way with the proper instruction and kitchen 11 Environmental Design for Cognitive Decline 161

organization. It is hard for anyone to fi nd items in should be advised to frequently assess the patient’s a cluttered environment, especially, if the storage cooking skills and judgment, for example: areas are not well marked. Patients in the early • Do they still know which cookware is safe to stages or their caregivers can be advised to group use or do they put plastic containers on lit burn- similar items together (e.g., breakfast foods ers or metal containers in the microwave? items). If the patient forgets to look inside the • Might an electric teakettle be placed on a hot cupboards or drawers, signs and pictures can be burner? put up on the outside to help him locate objects • Do they know that paper plates that are safe to behind closed doors or drawers. If this does not use in the microwave oven are not safe in the work, a cupboard door can be removed. The most toaster oven? used items can also be left on the countertop, in see-through containers, labeled in large letters to help alert the patient as to their contents. Gregg T Eating and Nutritional Status was able to prepare his breakfast on his own, but only when his wife set out all ingredients before- Nutritional status can be affected by a myriad of hand and left simple instructions. factors, including lighting, table and tableware, food choice and appearance, cueing, and tablemates (for those living in a facility). Often, eating chal- Cooking Challenges lenges can be overcome with a bit of trial and error. Inadequate lighting and lack of color contrast Use of cooking appliances when an individual’s can lead to reduced nutritional intake [15 ] . memory is impaired is a major safety concern • High contrast between the dinnerware and the [14 ] . Devices that automatically turn off appli- tabletop is now included in design regulations ances left on inadvertently can proactively help for dementia specifi c units in some assisted- to avert crises and extend a patient’s ability to living and nursing home residences. cook, as long as the patient still has good stove • Printed tablecloths decorated with fruit may skills and judgment. For example, Jon B installed cause the cloth to be picked at instead of the a device to turn off the stove for his wife’s night- actual food; therefore, plain tablecloths and time cup of tea. He felt she was safe cooking placemats are recommended. independently but wanted assurance that if she • A person’s food or liquid intake can be inade- were to forget and leave the stove on, it would quate if the drinking glass or utensils cannot automatically shut off after a set period of time be easily grasped; built-up handles and appro- (he chose 3 min, long enough for the kettle to priate-sized glasses are the key. boil). Alternatively, cooking appliances are avail- • Choice of food items, texture, portion, and able that may be safer to use for a certain sub- arrangement are critical for encouraging appe- group of patients, including electric teakettles tite. Some individuals will refuse to eat from a that automatically turn off after the water boils plate piled high with food or if more than one and microwaves with easy one-button cooking. food is served at one time. Not everyone, however, will be able to use a • Many patients have changes in olfactory and new appliance or learn a new way of cooking, no taste perceptions; unusual fl avor combinations matter how minor. Caregivers who have replaced or excessive desire for sweets are not uncom- a gas stove with an electric stove are sometimes mon [16 ] . Caregivers report that their loved shocked to discover that their loved one cannot one’s appetites have increased when they learn how to use it. Smart devices and safer added sauces to dishes, including salsa, honey household appliances can be very helpful, but mustard, maple syrup, or ketchup. The choice they do not replace caregiver oversight. Caregivers of fl avors and their combination is very 162 R. Bakker

individual so it is important that the caregiver a color-contrasted bath mat in the tub for a full experiment to see what the patient responds to immersion (so the person can judge the depth most favorably. of the tub to reduce fear of drowning). • Verbal cueing (e.g., “place the fork in your hand”) and physical cueing (placing a fork in their hand) may encourage greater independence. Toileting • Some individuals who can no longer manipu- late utensils may be able to eat independently Some individuals become incontinent simply if fi nger foods are offered (e.g., baked fries or because they cannot fi nd the bathroom. They may fi sh sticks). A key to success is to serve only not be able to distinguish the bathroom door from foods that require like utensils at a given time, the surrounding doors, or they may have com- otherwise confusion can occur over which pletely forgotten the bathroom’s location [4 ] . If food items require the use of a utensil. they are in the early to mid stage, the patient may be able to fi nd the bathroom using the following techniques: Hygiene • Placing a large sign on the door. • Painting the door a bright color. Bathing and Agitation • Leaving the light on in the bathroom or hallway. Another common problem is forgetting to use Bathing a person with dementia is one of the most toilet tissue. Increased odor and infection risk are stressful activities for a caregiver. It can also be an key concerns. Reminder notes and verbal prompts emotionally demanding experience for the patient, can be helpful for some, but do not work for who may be stressed by fear of running water, dis- everyone. Bidet toilet seats have been used as a comfort in a cold drafty room, embarrassment at substitute for paper in Continental Europe and being seen undressed, fear of falling (especially Asia for many years. There are separate units or when moving in or out of the tub), or confusion due those that attach to an existing toilet, with push to memory problems. The person may think he or button controls for washing and drying, allowing she has already bathed, or may be simply over- the user to wash after each use. Bidet toilet seats whelmed by the bathing process itself, no longer can increase the person’s cleanliness, but they are understanding what to do or how to do it. Dementia- expensive, and they require a caregiver present as friendly bathing techniques can be highly effective operating new controls and a new way to toilet in reducing bathing agitation. In the video, Bathing would be beyond the skills of most patients with Without a Battle, nursing home residents who previ- cognitive loss. ously yelled, hit, and cursed during a standard bath are shown relaxing and thanking the aide for their help after the aide had received specialized training Dressing [ 17, 18 ] . If a patient refuses to bathe or experiences agitation during bathing, consider referring the Patients with cognitive decline commonly experi- caregiver to techniques such as: ence clothing and dressing problems [ 19] . For • Warming up the room before the bath (feeling example, the individual may no longer be able to cold can be a stressor). organize and sort clothing and, therefore, leave • Using a specially designed bathing privacy piles of clothing scattered about or mix dirty out fi t (lack of privacy can be a stressor). clothes with clean clothes. At some point, dress- • Using a handheld shower and avoiding spraying ing may require more skills than the patient pos- water onto the head and facial area (overly sensi- sesses. For example, they may forget the order in tive areas in many patients with dementia). which to put on various clothing items, they may • Placing a color-contrasted towel on the bath wear too little or too many layers of clothing, or chair for enhanced depth perception and using they may refuse/forget to change clothing when 11 Environmental Design for Cognitive Decline 163 needed. Often, the patient may resist help and Home “Behavioral” Systems become terribly agitated when the caregiver tries to intervene. Here are a few simple strategies that These monitoring systems work by using discreet have helped other caregivers in similar situations: wireless sensors placed in key locations around • Label drawers with words or pictures of the the home, like the bedroom, kitchen, medication content (e.g., blouses, pants, underpants). areas, and bathroom. The sensors keep track of • Leave out the clothes to be worn that day, in the patient’s normal routines and send the desig- the order in which they are to be worn either nated caregiver(s) alerts regarding unusual situa- on a wall hook or on the bed. tions or departures from the norm. For example, • Buy two or three of the same clothing item. depending on the system, the caregiver can When the patient is bathing, the caregiver can receive alerts if the person opens the outside door quickly swap the dirty set for the fresh. at 5:00 am instead of their usual 10:00 am time, or gets out of bed at night and does not return. Pilot studies show these systems can be helpful Smart Devices and Monitoring for the right person, who can still live safely on Systems their own, but need daily monitoring and some backup support to do so [20– 22 ] . In the last decade, there has been a signi fi cant increase in the availability of home monitoring products to help extend independent living for Conclusion those with cognitive decline. These systems allow caregivers to monitor the activity of a fam- Clinicians can serve as a valuable resource to ily member who is living alone, so they can patients and their caregivers by providing them with check in on them from a remote location and advice and information on how to avoid excess dis- offer support as needed. Smart devices can be ability through dementia-appropriate design. By used “off the shelf” for speci fi c activities or understanding the environment’s effect on a per- entire home systems can be installed. Monitoring son’s behavior, caregivers have the opportunity to can help to identify problems as they occur so create a therapeutic environment that promotes that the caregiver can intervene before they more positive outcomes, allowing them and the per- become a full-blown crisis. For example, there son they care for lead safer, more satis fi ed lives. are medication reminders that attach to a standard phone line and will send the caregiver an alert if the person does not remove pills from a Clinical Pearls medication box. There are also devices that detect extreme changes in room temperature and • Caregivers should keep in mind that providing can send the caregiver an alert if the home is too for the safety of their loved ones is an ongoing hot or too cold. Dan G visited his mother in challenge as the disease progresses. Wisconsin in early winter and was alarmed to • Reminder signs can act as an “external” brain discover how cold the home was. His mother had for those in the earlier stages helping a person inadvertently turned off the furnace switch and function more independently. Use simple lan- was not cognizant that there was any problem. A guage, large-sized text, and/or photographs. monitoring device could have detected the drop • Usually there is a speci fi c event preceding agita- in temperature and sent the son an alert; then the tion that acts as a trigger for that behavior (e.g., son could have called a neighbor to check in on noise, cold interior temperature, water fl owing the mother and turn the furnace back on. onto the face during a shower.) Advise the care- Fortunately, the son visited his mother before giver to fi nd the “trigger” when the person is any serious problems occurred. agitated so that he or she can act to change or 164 R. Bakker

modify the trigger(s) and the associated 7. Torrington JM, Tregenza PR. Lighting for people with agitation. dementia. Lighting Res Technol. 2007;39(1):81–97. 8. Tinetti ME, Speechley M, Ginter SF. Risk factors for • Before denying access to appliances, rooms, falls among elderly persons living in the community. or exit and entrance doors, monitoring tech- N Engl J Med. 1988;319(26):1701–7. nologies (e.g., motion sensors, remote door 9. Hurley A, Gauthier M, Horvath K, Harvey R, Smith alarms, automatic turn off devices) should be S, Trudeau S, Cipolloni PB, Hendricks A, Duffy M. Promoting safer home environments for persons with tried fi rst whenever possible. If locks need to Alzheimer’s disease: the home safety/injury model. be installed (e.g., cabinets, front door) or the J Gerontol Nurs. 2004;30:43–51. stove knobs removed, advise the caregiver to 10. Spring H, Rowe M, Kelly A. Improving caregivers’ monitor the person’s reaction, as some patients well-being by using technology to assist in managing nighttime activity in persons with dementia. Res become agitated when access is denied. Gerontol Nurs. 2009;2(1):39–48. • Interventions should be frequently reassessed 11. Rowe M, Kelly A, Horne C, Lane S, Campbell J, since strategies may not continue to be effec- Lehman B, Phipps C, Keller M, Benito AP. Reducing tive as the symptoms of the disease progress dangerous nighttime events in persons with dementia by using a nighttime monitoring system. Alzheimers or if the environment changes. Dement. 2009;5(5):419–26. • Salient interior features and household items 12. Patient care ergonomics resource guide: safe patient should be color-contrasted from their back- handling and movement. Patient Safety Center of ground to enhance function (e.g., increase food Inquiry. Tampa, FL: Veterans Health Administration and Department of Defense; 2001 (rev 8/31/05). http:// intake by using a strongly contrasting plate color www.visn8.va.gov/patientsafetycenter/ to the food, reduce tripping on stairs by high- resguide/ErgoGuidePtOne.pdf. Accessed 29 Mar 2012. lighting the edges of steps with 2-in. color tape). 13. Daikoku R, Saito Y. Differences between novice and • To reduce environmental misperception, pat- experienced caregivers in muscle activity and perceived exertion while repositioning bedridden patients. terns should be kept to a minimum and light- J Physiol Anthropol. 2008;27(6):333–9. ing levels should be abundant and glare free, 14. Safety at home. Alzheimer’s Association National with no dark areas in a room. Of fi ce. 2005. http://www.alz.org/national/documents/ brochure_homesafety.pdf. Accessed 29 Mar 2012. 15. Calkins MP, Brush JA. Designing for dining: the secret of happier mealtimes. J Dement Care. 2002;10(2):24–6. References 16. Piwnica-Worms K, Omar R, Hailstone JC, Warren JD. Flavour processing in semantic dementia. Cortex. 2010;46(6):761. 1. Gitlin LN, Hauck WW, Dennis MP, Winter L. 17. Barrick AL, et al. Bathing without a battle: creating a Maintenance of effects of the home environmental better bathing experience for persons with Alzheimer’s skill-building program for family caregivers and indi- disease and related disorders (CD-ROM). Chapel Hill, viduals with Alzheimer’s Disease and related disorders. NC: University of North Carolina; 2003. J Gerontol A Biol Sci Med Sci. 2005;60: 368–74. 18. Barrick AL, Rader J, Hoeffer B, Sloane P, Biddle S, 2. Alzheimer’s Association Alzheimer’s disease facts editors. Bathing without a battle: person-directed care and fi gures, Alzheimer’s & dementia (6). http://www.alz. of individuals with dementia, Springer series on geri- org/documents_custom/report_alzfacts fi gures2010. atric nursing. 2nd ed. New York: Springer; 2008. pdf . Accessed 29 Mar 2012. 19. Cohen-Mans fi eld J, Creedon M, Malone T, Parpura- 3. Caregiving in the U.S. National Alliance for Gill A, Dakheel-Ali M, Heasly C. Dressing of cogni- Caregiving and AARP. 2004. http://www.caregiving. tively impaired nursing home residents: description org/data/04 fi nalreport.pdf. Accessed 29 Mar 2012. and analysis. Gerontologist. 2006;46(1):89–96. 4. Calkins M. Design for dementia. J Healthcare Design. 20. Kinney J, Kart C, Murdoch L, Conley C. Striving to 1991;3:159–71. provide safety assistance for families of elders: the 5. Jones K. Enabling technologies for people with demen- SAFE house project. Dementia. 2004;3(3):351–70. tia: report of the assessment study in England. 2004. 21. Topo P. Technology studies to meet the needs of peo- http://www.enableproject.org/download/Enable%20 ple with dementia and their caregivers: a literature -%20National%20Report%20-%20UK.pdf . Accessed review. J Appl Gerontol. 2009;28:5–37. 29 Mar 2012. 22. Buettner L, Yu F, Burgener S. Technology innova- 6. Dunne TE, Neargarder SA, Cipolloni PB, Cronin- tions: evidence supporting technology-based inter- Golmb A. Visual contrast enhances food and liquid ventions for people with early-stage Alzheimer’s intake in advanced Alzheimer’s disease. Clin Nutr. disease. J Gerontol Nurs. 2010;36(10):15–9. 2004;23:533–8. 11 Environmental Design for Cognitive Decline 165

innovative ways to learn research-based strategies that Additional Resources reduce caregiver stress and enhance the safety and well-being of loved ones with Alzheimer’s disease or ThisCaringHome.org, a project of Weill Cornell Medical other types of dementia. College, is multimedia web site that offers caregivers Prevention of Cognitive Decline 1 2 Jose Gutierrez and Richard S. Isaacson

Abstract Effective strategies to prevent cognitive decline in the context of normal aging, mild cognitive impairment, and dementia are imperative. Existing studies have provided some clues into the puzzle of prevention, yet it is rare that the evidence is unquestionable. Speciﬁ c dietary changes rich in vegetables, fruits, and ﬁ sh and low in carbohydrates and saturated fat are advisable, with particular emphasis in patients at risk of developing Alzheimer’s disease (AD) or vascular dementia. Patients should remain active physically and mentally. Physical exercise is among the best of all potential interventions against AD. There is no evidence that hormonal supplementation can decrease the incidence of dementia. Some agents that are touted as having cognitive protective effects should only be used under physician supervision. AD patients should be considered for medical therapy unless contraindicated. Promising novel therapies include active and passive immunization against Ab peptides and gamma secretase inhibitors to reduce Ab production. In this chapter, we review strategies used to prevent age related cognitive decline.

Keywords Alzheimer’s disease prevention ¥ Delay of cognitive decline ¥ Vitamins ¥ Fish oil ¥ Dementia ¥ Cholinesterase inhibitors ¥ Curcumin ¥ Cognitive exercises

J. Gutierrez , M.D., MPH. Introduction Department of Neurology , Neurological Institute, Columbia University , 710 West 168th Street, 6th Floor , New York , NY 10032 , USA The prevention of cognitive decline and dementia e-mail: [email protected] is a complex area in which multiple prior inter- R. S. Isaacson , M.D. () ventions have failed to show a consistent effect. Department of Neurology , Clinical Research Building, The importance of studying preventive measures University of Miami Miller School of Medicine , for cognitive decline and dementia is directly 1120 NW 14th Street, Suite 1339 , Miami , FL 33136 , USA e-mail: [email protected] proportional to the magnitude of the dementia

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 167 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_12, © Springer Science+Business Media, LLC 2013 168 J. Gutierrez and R.S. Isaacson epidemic that our society faces. Cognitive decline progression from MCI to dementia. Tertiary encompasses a continuum of changes ranging for prophylaxis refers to the treatment of dementia normal aging in the mildest expression to demen- that encompasses either gaining of function, sta- tia on the more severe presentation; there is sub- bilization of the decline, or slowing of the pro- jectivity in the de fi nition of each category. gression. Since the most prevalent of the Advancing age is accompanied by the decline of dementias is AD, the majority of the interven- cognitive abilities such as perceptual speed, rea- tions and strategies reviewed will be related to soning, episodic memory, and working memory AD and, to a lesser degree, vascular dementia. [1 ] . The early stages of pathologic cognitive A large body of evidence exists in the literature, decline, often referred as mild cognitive impair- and a detailed, critical analysis of each reference ment (MCI) or cognitive impairment without has been attempted when possible. We emphasized dementia, pertain to cognitive decline “greater the level of evidence available in order to preserve than expected” for age and educational level and the scienti fi c rigor. However, methodological het- no more than mild functional impairment in car- erogeneity in populations studied, study designs, rying activities of daily living that does not qual- case defi nitions, and outcome evaluations has ify for the diagnosis of dementia [ 2 ] . Dementia is resulted in confl icting evidence that precludes a de fi ned as a progressive global deterioration of fi rm conclusion on many of the prevention strate- cognitive abilities in multiple domains severe gies reviewed and discussed. When reading the enough to interfere with daily living [3 ] . More results of observational and experimental studies, precise de fi nitions are discussed elsewhere in this it is important to keep in mind that statistical volume. signi fi cance is not equivalent to clinical relevance The challenge posed by MCI and dementia to and that the opposite is also true. society is not insignifi cant: Ten percent of persons older than 65 years and about 50% of those older than 85 years have Alzheimer’s disease An Overview of Cognitive Decline (AD), the most common form of adult onset dementia [4 ] . By 2050, the prevalence of AD in The normal cognitive process requires complex the USA is expected to triple. This increment is neural networks localized in different part of the largely attributed to the aging of the “baby brain such as the medial temporal lobes including boomer generation.” The risk of dementia nearly the hippocampus and the entorhinal cortex and doubles with every 5 years of age. The US the frontoparietal cortices [7 ] Memory, attention, Medicare economic cost of caring for people executive functions, perception, language, and with dementia in 2008 was 91 billion dollars, and psychomotor functions are components of the it is expected to nearly double by 2015 [ 5 ] . Of no cognitive process [ 8 ] . The dysfunction in any of less importance is the untold economic and emo- these components in the context of neurodegen- tional impact on families and friends. eration has a pathological substrate in a corre- The prevention of cognitive decline emerges sponding brain area accounting for its processing. as the main way to offset the demographic tran- The pathological changes vary depending on the sition of our aging society and the concomi- type of dementia. Since AD is the hallmark of the tant challenge that it represents. If the onset of neurodegenerative diseases associated with AD can be delayed by 5 years, the expected dementia and also the most studied, many clini- prevalence would decrease by more than 1 million cal trials have been exclusively focused on AD. cases after 10 years and more than 4 million cases The early pathological changes in AD involve after 50 years [6 ] . In this chapter, we review strat- the deposition of A b42 aggregates and related egies used to prevent cognitive decline at differ- tau accumulation in vulnerable brain areas such ent levels. Primary prophylaxis refers to avoidance as the hippocampus and the entorhinal cortex. of age-associated cognitive decline. Secondary The activity of gamma and beta secretases is prophylaxis refers to prevention or slowing of thought to be an important rate-limiting step in 12 Prevention of Cognitive Decline 169 the pathology of AD. The Ab and tau aggregates and vitamin B12 (cobalamin) generally come progress to plaques and tangles that are eventually from meat, poultry, seafood, and eggs as well as widespread in the brain. After decades of accu- enriched cereals. The major source of folates is mulation, synaptic dysfunction and neuronal loss the green leafy vegetables [ 14] . Thiamine, appear to play a major role in driving the cogni- ribofl avin, and niacin function in major biochem- tive de fi cit [7 ] . Oxidative damage, excessive glu- ical pathways in the metabolism of glucose, taminergic activity, energy failure, infl ammation, amino acids, and fatty acids, while the coen- and apoptosis seem to be signi fi cant contributors zymes of vitamin B12, folate, and vitamin B6 to neuronal loss and progressive cognitive dys- interact together in the metabolism of homo- function [9Ð 13 ] . The degeneration of some cysteine, a risk factor for vascular disease and regions is associated with neurotransmitter dementia [ 15, 16 ] . The exploration of these vita- defi ciencies that are part of neuronal circuits mins in the context of cognition is related to their important for cognition (e.g., degeneration of the antioxidant and anti-infl ammatory properties basal forebrain is associated with decrements in along with their role in nucleotide synthesis and acetylcholine-mediated neuronal activity nerve functions [14 ] . involved in memory). An important interaction occurs between vita- Multiple genetic, clinical, and environmental min B12, folate, and pyridoxine that could medi- risk factors have been associated with the occur- ate some effects in cognitive decline. All three rence of AD. Vascular risk factors like diabetes vitamins are major determinants of homocysteine mellitus (DM), hypertension (HTN), dyslipidemia levels, and high levels can be deleterious due to (Dys), and smoking are attractive targets from a neurotoxic and vasotoxic effects on brain vascu- public health perspective due to their high preva- lature and normal cognitive functioning [ 17Ð 19 ] . lence, their relative ease to treat, and the multiple Longitudinal studies have explored the interac- other diseases associated with these factors. The tion between folate, vitamin B6, and B12 and contribution of each risk factor seems additive to cognitive decline. Folate levels are associated the occurrence and severity of the disease. with different degrees of cognitive decline inde- The prevention of cognitive decline involves pendent of the homocysteine and vitamin B lev- multiple strategies directed at different stages of els [ 19Ð 21 ] . Future studies attempting to evaluate the pathophysiological process. Examples are Ab the effects of B vitamins and folate supplementa- and tau aggregation inhibitors, antioxidants, anti- tion should control for homocysteine levels to infl ammatory compounds, cognitive enhancers further clarify this interaction. Trials of combined or facilitators, neuroprotective agents, or some vitamin supplementation are challenging to inter- combination of these approaches. The failure of pret due to various covariates that make it diffi cult recent trials to prevent cognitive decline and the to isolate an effect [2, 14 ] . complexity of the cascade leading to AD suggest that pleiotropic interventions may be more likely Vitamin B1 (Thiamine) to succeed, although no evidence so far exists to Animal models have shown that rats with low support this statement [7 ] . thiamine diet have impaired cognitive performance when compared with controls fed with adequate thiamine supplementation [ 22 ] , and Vitamins and Minerals repetitive episodes of thiamine defi ciency can cause worsening of cognitive performance and B Vitamins severe brain damage [ 23, 24 ] . Thiamine de fi ciency has been associated with bloodÐbrain barrier Vitamin B1 (thiamine) and vitamin B2 (ribofl avin) (BBB) dysfunction and intracellular edema in exist in a variety of food sources, including animal models, revealing pathological changes enriched and whole grain cereals, organ meats, that could derail the normal functioning of the milk, and vegetables. Vitamin B6 (pyridoxine) brain [14 ] . 170 J. Gutierrez and R.S. Isaacson

In a non-randomized controlled trial (RCT), of pyridoxine for the prevention or treatment of Meador et al. [25 ] found that older individuals cognitive decline [2, 3, 27, 32 ] . supplemented with 3Ð8 g/day of oral thiamine showed statically signifi cant improvement in the Vitamin B12 (Cobalamin) ADAS in the initial months with slowing of the In rats with nucleus basalis magnocellularis cognitive decline rate during 11Ð13 months after lesions (mimicking a hypocholinergic state), the the trial stopped. The small sample and open supplementation of cobalamin had no effect on design are concerns in this trial. Mimori et al. movements and did not improve memory [33 ] . In [26 ] showed that higher blood levels of thiamine observational studies, high methylmalonic acid after supplementation with an oral form were level, a more specifi c marker for vitamin B12 associated with improvement in scores on the de fi ciency, was associated with a faster rate of Mini-Mental State Examination (MMSE) in an cognitive decline, especially in APOE e 4 carries open design trial. Low thiamine levels have not [34 ] . The administration of cobalamin was asso- been consistently associated with higher preva- ciated with improvement on a12-word list learn- lence of AD [ 14 ] , and there is currently not ing test at 15 min, and a trend was found for enough evidence at this point to recommend thia- improvement on other cognitive measures in an mine supplementation for the prevention or treat- RCT of cognitively impaired individuals with ment of cognitive decline [2, 3, 27 ] . B12 de fi ciency [ 35, 36 ] . In uncontrolled trials, there is con fl icting evidence on the effects of Vitamin B2 (Ribofl avin) cobalamin supplementation in normal and cogni- Godwin et al. showed that individuals at the bot- tively impaired patients. In most of the studies tom decile of ribo fl avin dietary intake had worse where cobalamin supplementation was associ- cognitive performance in some domains com- ated with cognitive improvement, the cobalamin pared to the upper deciles [ 28 ] , and Lee et al. was administered via parenteral route. Dietary found that MMSE scores increased as ribofl avin intake of cobalamin has not been associated to intake increased in women but not in men [ 29 ] . the presence AD in cross-sectional studies [ 14 ] . However, low ribo fl avin serum levels have not The heterogeneity of the trials, cognitive out- been associated with the presence of AD. There comes, and populations studied contribute to the is no RCT speci fi cally designed to evaluate the inconsistency of the fi ndings. The supplementa- effects of ribofl avin in cognitive decline or tion of cobalamin for the prevention or treatment dementia. Ribo fl avin supplementation is not rec- of cognitive decline is not supported at this point ommended for AD prevention or treatment [ 2, 3, [2, 3, 27, 32 ] . However, vitamin B12 levels are 27, 30 ] . part of the workup for reversible causes of dementia as well as other neurological diseases, and Vitamin B6 (Pyridoxine) defi ciencies should be a target of clinical In rodents, the supplementation of pyridoxine did intervention. not improve cognition or learning functions. When analyzing the linear doseÐresponse rela- Folate tionship, low pyridoxine was associated with In amyloid precursor protein (APP) mutant worse motor skills [14 ] . In high-dose supplemen- mice model, Kruman et al. [ 37 ] showed that the tation trials in humans [ 14 ] , it was shown that amount of deposition of A b amyloid did not pyridoxine was associated with improved long- differ among folate-defi cient mice vs. a control term memory, but threats to validity make con- group. However, the cornus ammonis (CA) 3 clusions based on these trials uncertain. Mizrahi region of the hippocampus in folate-de fi cient et al. found an association of low pyridoxine mice had at least 20% fewer neurons compared dietary intake with AD; however, the recall bias to controls, suggesting susceptibility of this for dietary exposure among patients with demen- region to folate de fi ciency independent of A b tia limits interpretation of this data [ 31 ] . There is production or deposition. Apolipoprotein E currently not enough evidence to support the use gene (ApoE)-defi cient mice, a model thought 12 Prevention of Cognitive Decline 171 to be at increased susceptibility to oxidative recognition, and verbal ability [41 ] . Sommer et al. damage, were fed with folate-free diet in one showed, in a very small sample, that very high group and folate-supplemented diet in the other doses of folate supplementation (20 mg/day) can one. The folate-supplemented group showed be associated with worsening cognitive functions signifi cant decrement in the amount of oxida- [ 42] . Recent systematic reviews and meta-analysis tive by-products when challenged with iron, do not support the use of folate with or without an oxidizing substance [ 14, 38 ] . These results vitamin B supplements for the prevention or suggest that the oxidative potential of ApoE treatment of cognitive decline in the short term de fi ciency could be alleviated with folate supple- [2, 3, 27, 32, 43 ] . Long-term administration of mentation. In a diet-induced hyperhomocystei- folate supplements to healthy and cognitively nemia rat model, the investigators evaluated impaired individuals has not yet been systematically the impact of folate supplementation on the studied. Folate levels are part of the dementia homocysteine-induced endothelial dysfunction workup and should be supplemented if indicated. [29 ] . They found that the folate supplementation reduced endothelial nitric oxide synthetase activity and glucose transporter protein-1 activity, Vitamins C and E suggesting that folate supplementation could offset the oxidative potential of homocysteine The protective factors of antioxidants are the pro- at the endothelial level. posed mechanism of action of vitamin C for the Observational studies have shown confl icting prevention of cognitive decline. It has been data in regards of dietary intake of folate and the observed that higher levels of ascorbic acid (vita- presence of AD. Tucker et al. investigated the min C) are associated with better cognitive per- association of dietary intake and several vitamins formance in a cohort study [ 44 ] . Vitamin E is and found that high dietary folate offered inde- considered a powerful antioxidant available in pendent protection against cognitive [21 ] , while oily food. In adults over 65 year of age, it was Morris et al. showed that high folate intake from shown that individuals in the upper tercile of vita- food or supplements was associated with faster min E consumption (data obtained by a food cognitive decline in a cohort of aging individuals questionnaire) had better cognitive performance [39 ] . Despite these con fl icting fi ndings, most of than the lower tercile [ 45 ] . Wengreen et al. stud- the cross-sectional and caseÐcontrol studies sug- ied the dietary intake of vitamins C and E in indi- gest that lower levels of serum folate or higher viduals older than 65 followed on average for prevalence of folate de fi ciency is found in patients 7 years and found that the higher intake of vita- with AD [14 ] . min E and C was associated with higher MMSE In human studies, one RCT showed cognitive scores and that the low intake of these vitamins benefi t of folate supplementation in demented, and carotene was associated with higher rate of cognitively impaired, and normal subjects, but no decline in MMSE [ 46 ] . However, trials examin- clinical bene fi t was reported [14 ] . Fioravanti et al. ing the combination of vitamins E and C supple- showed that folate supplementation improved mentation have failed to consistently demonstrate cognitive scores in aged patients with cognitive signi fi cant improvements, and at this time, there impairment and low folate levels. Of interest, is no evidence to support the prescription of vita- initial cognitive status did not correlate with ini- min C and vitamin E or their combination for pre- tial folate levels [ 40 ] . Bryan et al. studied women venting the cognitive decline [32, 47 ] . of all ages without cognitive impairment and reported that folate supplementation improved cognition in the older women. Unfortunately, the Chromium dietary intake of these women could potentially be an interaction that was not controlled for since Metabolic syndrome is associated with insulin dietary intake of folate and other vitamins were resistance and secondary hyperinsulinemia. The correlation with speed of processing, recall and receptor for insulin transport across the BBB 172 J. Gutierrez and R.S. Isaacson becomes saturated with the fl ush of plasmatic vegetables, and they provide the plant with its insulin, thus creating a hypoinsulinimic state in color that attracts pollinators and repels insect the brain. Hypoinsulinemia is associated with attacks [9 ] . They are found in high concentrations increased rate of Ab aggregation. Peripheral in berries, onions, dark chocolate, broccoli, hyperinsulinemia has also been associated with apples, tea, red wine, purple grape juice, soybean, worse cognitive performance among AD and and tomatoes [ 53] . Below we will discuss the non-AD patients [48 ] . more conspicuous members of the phenolic fam- Chromium is an essential trace mineral used ily that have been studied to date. in insulin receptor signaling, and it is thought to amplify the insulin action [ 49] . At doses of 200Ð 1,000 mcg, it has been shown to improve insulin Berries resistance in diabetic patients [ 50, 51 ] . Krikorian et al. [ 49 ] randomly assigned 26 patients to Berries are thought to be rich in antioxidants, and receive chromium supplementation vs. placebo their consumption is hypothesized to provide and followed them for 12 weeks with examina- neuroprotection against the oxidative and tion on multiple cognitive tests. No effects were in fl ammatory process associated with aging. seen on fasting insulin or fasting glucose, but a Strawberries, blueberries, blackberries, cranber- reduced rate of intrusion errors was found in the ries, and raspberries are fruits with high antioxi- active group. Functional magnetic resonance dant capacity due to the high content of imaging (fMRI) data showed that individuals in anti-in fl ammatory anthocyanins and/or proantho- the active arm had increased activation in multi- cyanidins ( fl avonoid compounds) [14, 54, 55 ] . ple regions of the brain including the thalamus Anthocyanins can cross the BBB and block and the frontal cortex; however, areas of activa- 5 ¢-deiodinase activity and stimulate T3 transport tion did not correspond to the improved cognitive into rat brains [ 56 ] . In blueberry-fed rats, histo- performance. This suggests that chromium could pathology and cognitive test results suggest a have functions independent on its effects on protective effect compared with controls. metabolism that should be further explored. Blueberry extract was associated with increased Chromium supplementation shows promising precursor cells (increased neurogenesis) in the results but not enough to unequivocally deter- dentate gyrus in rats that also performed better on mine an association with AD or cognitive decline cognitive testing [57 ] . Strawberry extract supple- [2 ] . Larger and better designed studies should be mentation in animal experiments has been asso- undertaken to strengthen the current evidence. ciated with improved biochemical markers in the brain suggestive of neuroprotection; however, an association with cognitive performance has not Polyphenolic Compounds been reported [ 14 ] . In vitro studies suggest that (Flavonoids) various berry extracts can protect the deleterious effects of Ab -induced oxidative damage [58 ] . One of the most well-studied hypothesis underly- Human studies are lacking to recommend berries ing AD causation has been A b -mediated neuro- extracts for the prevention of cognitive decline; degeneration. Several phenolic compounds, such however, inclusion of berries in the diet has a as wine-related myricetin (MYR), curcumin, nor- theoretical bene fi t and is recommended as part of dihydroguaiaretic acid (NDGA), and rosmarinic a balanced diet. acid (RA), have been shown to possess strong anti-Ab aggregation properties in vitro and in vivo [52 ] . Flavonoids are also part of the poly- Curcumin phenol family, phytochemicals thought to have important antioxidative, antiviral and anticarci- Hamaguchi et al. showed that RA, CUR, and nogenic properties [14 ] . They are ubiquitous in MYR inhibit the aggregation of A b monomers to 12 Prevention of Cognitive Decline 173

Ab oligomers and from oligomers to Ab deposi- is the preservation of debrin, a vital component tion [52 ] . Curcumin is a potent antioxidant and for the adequate synaptic function. Other an effective anti-infl ammatory compound. pleiotropic mechanisms in which DHA can affect Curcumin can inhibit the formation of Ab oli- the progression of cognitive decline are anti- gomers and fi brils, bind plaque, and reduce infl ammatory activity, neuroprotection, neuro- plaque burden [59 ] . In another animal model of genesis, antioxidant, metabolic enhancer, and dementia, curcumin (20 mg/kg p.o. daily for weak amyloid aggregation inhibitor [7 ] . 14 days) successfully attenuated Streptozotocin In animal models, it has been shown that STZ-induced memory de fi cits. Higher levels of depleting DHA from the system was associated brain AChE activity and oxidative stress were with cognitive impairment, but replacing DHA observed in STZ-treated animals, which were prevented pathological changes similar to those signi fi cantly attenuated by curcumin [60 ] . Other seen in AD [ 64, 65] . A small trial of DHA in MCI animal studies raise the possibility that curcumin and AD groups was associated with a slower rate may act as a metal chelator, have anti-apoptotic of cognitive decline [ 66, 67 ] . A recent random- or immunomodulator properties, or promote neu- ized, double-blind, placebo-controlled study with rogenesis [7 ] . 485 subjects (aged 55 and older) called the In human studies, one of the main challenges “Memory Improvement with Docosahexaenoic using curcumin is its poor bioavailability [61 ] . In Acid Study” (MIDAS) aimed at evaluating the a pilot study, a small RCT evaluated the pharma- effects of 900 mg/day of algae-based DHA in cokinetics and effects of curcumin supplementa- healthy older adults with age-related cognitive tion in humans [ 62 ] . The preliminary results decline [ 66, 67] . The study found that DHA taken showed promising MMSE changes without major for 6 months improved memory and learning in side effects, yet the short period of follow-up and healthy, older adults with mild memory the lack of cognitive decline in the placebo group complaints. limit the interpretation of the data. The risks asso- A combination of DHA and choline showed ciated with curcumin administration are uncer- improvement in delayed memory after 12 weeks tain, and further studies are warranted in regard of follow-up compared to placebo [ 68 ] . In a to safety and effi cacy. In the trial by Baum et al. recent RCT, 402 patients with AD were given [62 ] , gastric, neurological, and pulmonary symp- DHA or placebo and followed for 18 months. toms were reported at an equal rate among The primary outcomes were changes in ADAS- patients taking placebo and those on active treat- cog and clinical dementia rating (CDR) obtained ment. Four clinical trials have studied curcumin every 6 months until the end of the follow-up for AD treatment (two with no signifi cant differ- period. Secondary outcomes were MMSE and ences in cognitive function; no results yet from MR brain volume measurements. The active arm the other two); however, there is no clinical trial did not show any signi fi cant difference in the pri- evidence for AD prevention [ 62, 63 ] . The mary or secondary outcomes when compared risk:bene fi t ratio of curcumin supplementation with the placebo group in a model adjusted for should be discussed in detail with patients and covariates. However, in a subgroup analysis based caregivers. on APOE genotype, subjects without an APOE e4 allele who received DHA showed slower progression of cognitive decline as documented by Docosahexaenoic Acid (DHA) the ADAS-cog and MMSE compared with APOE e 4-negative patients in the placebo group. No DHA is a long-chain 22-carbon omega-3 polyun- signi fi cant differences were observed in the CDR saturated fatty acid with six double bonds. It is and the brain volumes [69 ] . The APOE e 4-status found abundantly in marine algae, fatty fi sh, and interaction on the effectiveness of DHA had fi sh oil [ 7 ] . The main proposed mechanism of already been documented by Whalley et al. [ 70 ] action of DHA in the context of cognitive decline in nondemented patients in whom erythrocyte 174 J. Gutierrez and R.S. Isaacson membrane DHA content was positively associ- Mediterranean diet was suggested based on the ated with cognitive performance. progressive lower risk for developing dementia Recent systematic reviews of RCT and obser- or MCI in the middle and the upper score tertile vational studies published for DHA supplemen- when compared with the bottom tertile (21% and tation have failed to identify unequivocal evidence 47% risk reduction, respectively) [ 74, 75 ] . suggestive of a protective effect of DHA on cog- Another prospective cohort showed that high nitive decline [ 2, 27, 32 ] , although the associa- adherence to Mediterranean diet was associated tion of DHA with slower cognitive decline seems with better cognitive performance and episodic to be somewhat consistent across studies [ 3 ] . memory test results over time, but did not show Taken together, these data suggest DHA supple- any protective effect for the development of mentation may have a potential role in the pre- AD [76 ] . vention of cognitive decline and that its effect Due to methodological diffi culties with the may be more evident in APOE e4-negative adjustment for covariates associated with a patients. Early supplementation as well as the healthier diet, such as education, exercise, and long-term effects of DHA warrants further less prevalent cardiovascular risk factors, the fi nal investigation. impact of the Mediterranean diet on cognition is still debatable. Some authors have suggested that the late onset of a healthier diet might not reverse Diet a lifelong exposure to detrimental factors. It is generally thought that the earlier the healthy diet The fi rst suggestion that diet could provide pro- is introduced, the better it is for cognition as well tective effects against cognitive decline and as for other cardiovascular risks that are also dementia came from the Mediterranean basin known to contribute to the occurrence of AD and where lower prevalence of cognitive decline and cognitive decline [ 71 ] . Since no well-designed other neurodegenerative disease was observed. RCT has proven the ef fi cacy of Mediterranean Since then, multiple studies have investigated the diet vs. other type of diet, the evidence available “Mediterranean diet” as well as other dietary pat- is low to systematically recommend Mediterranean terns [71 ] . In general, a balanced and healthy diet diet for the prevention of cognitive decline [ 2 ] . should provide adequate amount of vitamins, On the other hand, it seems that the Mediterranean minerals, and elemental components necessary to diet contains a healthy combination of ingredi- function. As it has been discussed above, these ents that could potentially lead to a better health elements could provide protection against the overall. neurodegeneration associated with AD and cog- Gu et al. [77 ] proposed a different approach to nitive decline from various perspectives includ- the evaluation of diet and the risk for cognitive ing high supply of natural fi sh oil, vitamins, and decline/AD. Since there was concern that a polyphenols [5, 13 ] . Mediterranean diet might have a low prevalence The traditional Mediterranean diet is rich in in local communities not in the Mediterranean fruits, vegetables, whole grains, olive oil, cheese basin, nutrients and dietary patterns were evalu- and yogurt, low-to-moderate consumption of ated with various statistical analyses to obtain wine, and fi sh or seafood products. Variation components of the diet associated with lower risk might occur according to the country or region of developing AD. It was shown that a dietary studied, but the core elements and the proportions pattern consisting of greater intake of salad dress- are relatively similar [72 ] . Several scores and ing, nuts, fi sh, tomato, poultry, cruciferous vege- outcome scales have been created to assess adher- tables, fruit, and dark and green leafy vegetables ence to the Mediterranean diet [ 73 ] . In a recent was associated with lower risk of AD and nega- prospective cohort study, a higher Mediterranean tively correlated with intake of high-fat dairy, red diet score was associated with better cognition. meat, organ meat, and butter. Based on the In this same cohort, a doseÐresponse effect of previous results, a healthy diet rich in vegetables, 12 Prevention of Cognitive Decline 175 fruits, grains, and fi sh and nut oils is recom- studies showing marginal improvement in cogni- mended [1, 3, 5] . As discussed by several authors, tion while others fail to reproduce any signi fi cant fragmenting ingredients in the diet has failed effect [13, 82 ] . A small RCT showed that ginkgo to produce robust evidence. To date, it has been extract was associated with marginal improve- methodologically diffi cult to measure diet comment in the clinical dementia rating scale (CDR) ponents and to determine if a particular compo- when adjusting for medication adherence [ 83 ] . nent has more effects than the others. The clinical signi fi cance of this marginal improvement in cognitive testing in conjunction with a higher incidence of stroke and TIA in the treat- Other Supplements or Diet-Related ment arm could have confounded the results. Items A recent meta-analysis [ 84 ] on nine trials using standardized formulation of ginkgo biloba in the Garlic treatment of dementia showed statistically signifi cant improvement in cognitive scales with Garlic is high in antioxidants and organosulfurs. no signifi cant benefi t in activities of daily living An extract preparation has been associated with performance. In the Alzheimer’s dementia sub- decrement in blood pressure and cholesterol lev- group analysis, ginkgo biloba supplementation els. It is speculated that garlic may have a double was associated with statistically signifi cant benefi t by lowering cardiovascular risk factors changes in cognitive scales as well as in the activ- and their impact on the development of AD as ities of daily living performance. The high vari- well as supplying important antioxidants that ability of study designs hampers the generalization counteract the ongoing neurodegenerative pro- of these results. Ideally, a well-powered, blinded cess. It has been shown in animal models that RCT should be performed to provide better qual- garlic can reduce homocysteine [ 78 ] . In vitro ity evidence to evaluate the value of ginkgo biloba studies demonstrated that garlic extract can supplementation in the context of cognitive inhibit Ab and caspase enzymes that promote the decline/dementia. deposition of amyloid [ 79 ] . Budoff et al. [ 80 ] showed that garlic can also decrease the levels of homocysteine in humans, although it is unclear if Alcohol its effect was independent of that attributable to concurrent statin therapy the subjects were receiv- Low-to-moderate alcohol consumption has been ing. More studies are needed to clarify the effi cacy associated with decrease risk of dementia in some of garlic extract as preventive measure for cogni- observational studies [ 85, 86 ] . It is hypothesized tive decline. that alcohol exerts its benefi t through the improvement of the lipid pro fi le, although the content of fl avonoids in red wine could also contribute [ 9, Ginkgo Biloba 52] . A recent meta-analysis of 23 observational studies showed that small amounts of alcohol can Ginkgo biloba contains fl avonoids and terpenes be protective against dementia and AD but did that have been suggested to have pleiotropic not impact the rate of cognitive decline or the actions that can affect infl ammation and oxida- incidence of vascular dementia [ 85 ] . The hetero- tive processes in the human body [ 81 ] . It is geneity of the studies included in the analysis approved in some European countries for the prevents a fi rm conclusion on the applicability of treatment of cerebrovascular insuffi ciency and the fi ndings. Thus, the systematic recommenda- cognitive decline, although in the USA, it is sold tion of alcohol consumption for the prevention of as a supplement [ 1 ] . Short-term supplementation cognitive decline is not supported with the cur- has provided confl icting results, with some rent state of evidence. 176 J. Gutierrez and R.S. Isaacson

Caffeine these effects may be explained by counteracting age-related decreased arousal [ 97, 98 ] . Caffeine has been used by civilization since The relationship between AD and caffeine has ancient times. Its popularity has granted its sta- been more elusive to grasp. A retrospective cohort tus as the more popular and most consumed study suggested a protective effect of caffeine behaviorally acting substance around the world intake at midlife against the subsequent develop- [ 87] . Caffeine is an antagonist of adenosine ment of AD [99 ] . In prospective studies, Ritchie receptors A 1 and A 2A, although it can also inter- et al. showed a protective effect of caffeine in act with other enzymes and receptors like women consuming more than three cups of cof-

GABAA or 5 ¢ nucleotidase at higher levels [88 ] . fee per day [100 ] , and van Gelder et al. showed

In animal models, antagonist of A2A receptors that men also benefi tted from caffeine intake. In like caffeine decreased the levels in cerebrospi- his prospective cohort, it was shown that men nal fl uid and serum of Ab peptides and counter- who drank more than three coffee cups per day acted its noxious effects at the neuronal levels had slower cognitive decline when compared [89, 90 ] . Inhibition of phosphodiesterase is with those drinking less than three cups per day thought to be a potential mechanism to convey and non-coffee drinkers [101 ] . Another prospec- neuroprotection [91 ] . The activation of A2A tive cohort analysis showed that cognitive perfor- receptors has been associated with long-term mance was strongly associated with caffeine potentiation in striatal and hippocampal syn- intake, with no gender differences in its protec- apses essential for memory processing. The tive effects. However, caffeine intake was also excessive or insuffi cient activation of these strongly associated with age, IQ, and social class, receptors results in aberrant synaptic functioning thus education confounding effects could not be [ 91Ð 93] . Caffeine can act as normalizer of aber- ruled out [ 102] . Finally, Boxtel et al. were not rant memory performance rather than enhancing able to reproduce any of the above-mentioned this process, especially in conditions with exces- fi ndings and demonstrated no associations sive endogenous adenosine stimulation such as between longtime caffeine intake and cognitive fatigue and stress [ 91, 94 ] . performance [103 ] . In the context of heteroge- In humans, caffeine reaches a peak in plasma neous studies and results, it is dif fi cult to strongly 45Ð120 min after oral ingestion and has a half-life recommend caffeine intake as an effective mea- that ranges from 2.5 to 4.5 h [88 ] . Caffeine facili- sure against cognitive decline; however, it seems tates learning on tasks in which information is safe to say that caffeine can provide a boost in presented passively, but it has not proven effective memory performance and has been shown to be for those tasks that involve intentional learning. protective in some populations. The caffeine effect on memory tasks seems to have an inverted U shape curve, with improvement seen during mild-to-moderate complexity Cardiovascular Risk Profi le tasks but impaired performance for high complexity tasks [8 ] . Caffeine confers a boost for Although age is the single most important risk cognitive performance among fatigued individuals, factor for the development of dementia, cardio- and it might also improve cognitive functioning vascular risk factors seem to be strongly associ- with chronic consumption, although its acute ated with cognitive decline and dementia and effect is more evident in non-usual consumers carry the great advantage of being modifi able. [ 95, 96] . Caffeine appears to have a differential Traditional risk factors like hypertension, diabe- effect across the age span. In older populations, tes, dyslipidemia, and smoking are believed to the administration of caffeine is more effective for convey risk for vascular disease. Vascular disease improving attention, psychomotor performance, is associated with cerebral hypoperfusion, oxida- and cognitive functioning, possibly offsetting tive stress, neurodegeneration, and cognitive the decline associated with age. A large part of decline [104 ] . The clinical expression of vascular 12 Prevention of Cognitive Decline 177 disease can manifest as either mild cognitive developing AD [ 2, 117, 118 ] . Trials and meta- symptoms or a full-blown dementia that may be analysis investigating the effects of cholesterol attributable to an AD process, mixed AD/vascu- lowering medications (statins) have failed to lar pathology, or vascular disease alone [ 105 ] . demonstrate protective effects of statins on the There is general agreement that the pure cases of subsequent risk of developing AD [ 2, 119Ð 121 ] . AD account for less than 20% of all the cases and It is possible that the large number of covariates that AD with various components of vascular dis- to control in these trials such as concomitant risk ease are much more common than AD alone factors, education, diet content, levels of exercise, [106Ð 108] . The amount of AD pathology neces- and genetic predisposition, might partially sary to produce clinical dementia seems to be less account for the lack of clear bene fi t. Regardless, when concurring with the presence of vascular cardiovascular risk factors should be aggressively risk factors [105 ] . The cumulative presence of treated in populations with or without cognitive vascular disease has a biological gradient in the decline to reduce cardiovascular mortality. severity of cognitive decline moderated by covariates like age, gender, and race [ 109Ð 111 ] . This is dif fi cult to disentangle, as it would be unethical Diabetes and Insulin Resistance to perform an RCT to evaluate the effects of controlling for risk factors in some but not other Several investigators have claimed that insulin subjects. resistance is a risk factor for cognitive decline [106 ] . Insulin facilitates cognition when given concomitantly with glucose to support metabo- Hypertension and lism. Defects in insulin signaling are associated Hypercholesterolemia with increased deposition of Ab and hyperphos- phorylated tau. Insulin-degrading enzyme (IDE) It seems that a lifetime exposure to cardiovascu- is a protease involved in the degradation of insular risk factors can be associated with higher odds lin and Ab . In patients with hyperinsulinemia, for dementia, suggestive of a time period where insulin can saturate IDE and subsequently exposure is more fundamental for subsequent increase the AB serum levels [ 122 ] . Patients with risk. The interaction of the risk exposure and time diabetes have lower hippocampal and prefrontal of onset varies according to each risk factor. volumes when compared with nondiabetic con- There is evidence that higher levels of systolic trols [ 123] . The progression of dementia in pressure in midlife are associated with higher patients with stroke and diabetes was more prom- risk of dementia later in life, but lower levels of inent when compared to patients without stroke systolic pressure later in life can also be associ- without diabetes [124 ] . Diagnosed and undiag- ated with dementia [ 112 ] . The same effect has nosed diabetes have been associated with lower been described for cholesterol levels [113 ] . MMSE scores in a population-based sample In primary prevention trials of cardiovascular [125 ] . Although diabetes has been strongly asso- disease, con fl icting evidence exists about the ciated with the presence of AD [126Ð 128 ] , less is effect on controlling risk factors and the incidence known about its treatment and the effects on of dementia. While treatment of hypertension dementia incidence [125, 129 ] . The treatment of with calcium channel blockers and ACE inhibi- diabetes should be a priority in all patients for its tors showed reduction in all cardiovascular out- multiple deleterious consequences. comes and halved the risk to develop AD [ 114 ] , other trials using diuretics and beta-blockers or angiotensin receptor blockers did not reproduce Smoking the fi ndings [115, 116 ] . Recent meta-analyses have not found a signifi cant effect in the treat- Initial observational studies suggested that smoking ment of hypertension with the subsequent risk of could be associated with lower risk for developing 178 J. Gutierrez and R.S. Isaacson

Alzheimer’s disease in carriers of APOE e 4 down the rate of decline as early as 4 months [130, 131] . Former smokers had a decreased risk after the intervention. [140, 141 ] . Promoting for developing dementia with increasing numbers exercise should be part of a holistic strategy to of pack-per-year smoked. This was suggestive of a promote healthy lifestyles in patients and should doseÐeffect relationship of higher exposure to be advised in patients with cognitive decline or nicotine and lower incidence of dementia [ 130, AD unless contraindicated or not practical to 132 ] . The interaction between APOE e 4 status and implement. Tailoring of the physical exercise and smoking exposure has been a matter of debate and routines to the patient’s needs and capacities is that remains unclear. However, it is generally advisable. accepted that smokers have higher risk of develop- There is uncertainty regarding secondary pro- ing dementia and that there is a doseÐeffect gradi- phylaxis with treatment of cardiovascular risk ent with higher odds for heavier smokers [ 133 ] . factors. Heterogeneous defi nitions of MCI and Additionally, smoking can accelerate atrophy varying methodologies in conversion studies and degenerative changes resulting from neu- confound our understanding of the impact of ronal loss [ 134, 135] . In a recent meta-analysis of these risk factors on the progression of MCI to prospective studies, Anstey et al. showed that dementia. Even assuming a stable and reproduc- current smokers had an increased risk of ible defi nition of MCI, no strong association has Alzheimer’s disease compared with former smok- been found with the presence of cardiovascular ers at baseline. Current smokers also shower risk factors [ 142 ] . To date, no strategy has been greater decline in cognitive abilities, but the successful to halt the progression of MCI to groups were not different regarding risk of vascu- dementia [ 106] . As mentioned above, general lar dementia or other dementias. The authors recommendations to engage in a healthy life concluded that elderly smokers have increased should be applied to patients with MCI. risks of dementia and cognitive decline [ 136 ] . A In summary, it would be unethical to advise recent systematic review found low-quality evi- against treating cardiovascular risk factors in the dence to unequivocally support the association of absence of evidence toward preventing cognitive tobacco use and dementia, although it was cate- decline or dementia. The development of cere- gorized as a risk factor [ 2 ] . There is no question brovascular disease is a well-known consequence that all smokers should be encouraged to quit. In of uncontrolled risk factors, and the incidence of the case of patients with cognitive decline and stroke is strongly associated with cognitive prob- dementia, it should be even further emphasized. lem or dementia [143Ð 146 ] . It is safe to say that addressing the cardiovascular profi le should be a priority in patients with cognitive dysfunction, Physical Exercise dementia, or those at risk of developing either.

Physical exercise is thought to exert its protective effects on cognition through the improvement of Cognitive Engagement cardiovascular disease, as well as decreasing amyloid throughout the brain (e.g., frontal lobes The term “cognitive reserve” has been applied in and hippocampus) [ 5, 137 ] . Additionally, exer- the literature to describe the general idea that the cise induces brain neurotrophic factors that are greater number of neurons or advance neuropsy- used in repair processes [5, 137 ] . In observational chological competence (intelligence) can protect studies, it has been demonstrated that there is an individual from developing clinically evident lower prevalence of dementia in people who cognitive decline or dementia [ 147 ] . A more exercise regularly compared with those who do comprehensive defi nition of cognitive reserve not [138, 139] . Interventional studies have dem- involves neurocomputational fl exibility where onstrated that people who become physically the end goal is adaption. It proposes that high active can improve their cognition and can slow brain-reserve individuals have a larger repertoire 12 Prevention of Cognitive Decline 179 of strategies to resolve complex tasks as well as No training effects on everyday functioning were redundant neuronal networks to carry out the detected in the second year of follow-up [ 153 ] . same activities. As such, when a particular net- A 5-year follow-up of the same population showed work malfunctions, other networks can be used that compared with the control group, cognitive- to conduct the same strategy, or if not possible, trained subjects had improved cognitive abilities other strategies can be used to solve the same speci fi c to the abilities trained that persisted after tasks [ 148 ] . Environmental enrichment has been the intervention was stopped [ 154 ] . associated with neurotrophic and nerve growth A computer-based cognitive training RCT factors, increased synaptogenesis, and synaptic aimed at improving aural language processing plasticity [147 ] . was linked to improvement in targeted cognition and non-trained cognitive function in the active group compared to controls [ 155 ] . In individuals Cognitive Training with MCI, unimodal memory training might not be enough [ 156, 157] . A small study indicated Longitudinal studies assessing the association that multimodal intervention might be more of mental activities and the incidence of demen- effective in patients with MCI [ 158 ] . The multi- tia have shown that engaging in highly complex domain cognitive training approach has also been mental activities is a protective factor against tested in patient with dementia with encouraging the development of dementia, with a dose- results [156 ] . However, longer follow-up is dependent effect observed in some studies needed to investigate whether effects of cognitive [149, 150 ] . A systematic review of observational training are sustained. Based on previous results, studies evaluated 22 population-based cohorts it seems advisable for individuals at risk for and showed that education attainment, cognitive developing dementia to engage in cognitive train- lifestyle activities, and occupational complexity ing programs as part of a formal multimodal ther- conferred protection against the subsequent apeutic approach. development of dementia [ 151 ] . An older trial found that individuals who received cognitive training had a favorable in fl uence on everyday Social Engagement coping and on memory performance [ 152 ] . The ACTIVE trial published in 2002 was a It has been well documented that individuals with major study in this fi eld that randomized 2,832 reduced social networks are more risk for devel- patients to four groups and three intervention oping cognitive decline compared with those who arms: 10-session group training for memory (ver- have more broad social interactions. Activities bal episodic memory; n = 711), reasoning (ability that exposed the individual to interact with others to solve problems that follow a serial pattern; and create bonding are considered protective n = 705), or speed of processing (visual search and against cognitive decline [ 5 ] . A few critics have identi fi cation; n = 712) or a no-contact control challenged the notion that this is a predictive group (n = 704). The results showed signi fi cant association, suggesting that the retraction from improvement in 87% of processing speed, 74% of social networks might precede the onset of cogni- reasoning, and 26% of memory-trained partici- tive symptoms during midlife and could be a sign pants and demonstrated reliable cognitive improve- of premature non-cognition symptoms of neuro- ment immediately after the intervention period. degeneration [159 ] . Other dif fi culties in isolating Booster training signifi cantly enhanced training social engagement effects on the risk of dementia gains in processing speed and reasoning interven- have been the multiple covariates associated with tions (speed booster, 92%; no booster, 68%; rea- both such as exercise and cognitive reserve. It soning booster, 72%; no booster, 49%), which seems reasonable to advise engagement in social were maintained at the second year of follow-up. activities as tolerated to promote healthy aging. 180 J. Gutierrez and R.S. Isaacson

Depression ef fi ciently and in speed of information processing. However, women tend to have smaller hippo- One of the reversible causes of cognitive impair- campal volumes, decrease glucose metabolism in ment that all aged adults with cognitive com- areas concerned with cognition, and greater plaints should be assessed for is depression. It age-adjusted prevalence of dementia [165 ] . can be diffi cult to isolate depression from demen- Observational studies have suggested that mem- tia, since patients with dementia have a higher ory problems are frequently associated with prevalence of depression than nondemented pop- menopause, although otherwise healthy post- ulations, and sometimes depression could be a menopausal women do not have signi fi cant prodromal sign of dementia [5 ] . A recent meta- memory problems as measured by standard psy- analysis of observational studies showed that chological testing [ 166, 167 ] . Blood levels of depression doubles the risk of developing demen- estrogenic hormones are not consistently associ- tia in later life. Findings of increased risk were ated with differential cognitive performance robust to sensitivity analyses. Interval between [168 ] . Another explanation of the excess of AD diagnoses of depression and AD was positively cases in women seen in observational designs has related to increased risk of developing AD, sug- been the longer survival of women compared to gesting that rather than a prodrome, depression men [ 169 ] . may be a risk factor for AD [160 ] . Even if the Several clinical trials and longitudinal studies overall evidence quality is low, [2 ] patients with have tried to disentangle this puzzle. Researchers cognitive complaints should be screened for observing a longitudinal cohort reported that hor- depression and treated when indicated. mone replacement therapy (HTR) was associated with better performance on psychological testing [170 ] although another group with a different Pharmacological Strategies cohort failed to reproduce this claim [ 171 ] . Two recent meta-analyses found a 29Ð34% risk reduc- Hormones tion for women using HRT vs. nonusers [ 168, 172 ] . The Women’s Health Initiative Memory Hippocampal atrophy is a major pathological Study (WHIMS) used a sample from a large, change in patients with MCI or AD. Shrinkage of population-based prospective cohort to enroll in the hippocampus can start in early adulthood and an RCT to test the hypothesis that HRT with accelerate with age; losses of 0.3Ð2.1% per year estrogen with progestin could reduce the risk of are reported, with slower rate of progression MCI or dementia. They enrolled 4,532 patients reported in women compared with men [ 161, who were randomized to active and control arms 162 ] . The apparent slower degeneration in women and followed up during approximately 13 months. in early adulthood reverses in the postmenopausal They failed to show that estrogen in combination stage, with greater odds of dementia for women with progesterone offers a protective effect when compared with men [163 ] . This has led to against cognitive decline in the form of MCI or multiple studies evaluating the role of estrogens probable dementia. On the contrary, they found and other gonadal hormones as neuroprotectors. an elevated risk of developing either MCI or Estrogens are known to in fl uence verbal dementia in patients using the HRT that almost fl uency, verbal memory, performance on spatial double the risk for those not using it [4 ] . This is tasks, and fi ne motor skills [ 164 ] . Estrogens can by far the largest and best-structured RCT to test mediate neuroprotection due to their ability to the hypothesis that hormonal supplement could mediate the oxidative processes in the brain, provide cognitive bene fi ts. The possibility of hor- besides altering the potassium conductance, monal replacement at earlier stages of gonadal apoptosis, and transcriptional factors regulation hormone withdrawal in perimenopausal women [163 ] . The aging process is associated with has not been explored, and some believe that decreased memory abilities, focusing attention larger periods of estrogen deprivation can lead to 12 Prevention of Cognitive Decline 181 irreversible damage to some brain structures toward the mind”) [179 ] . The mechanisms of [169, 173, 174] . This remains to be settled with action of these medications are related to their future RCT specifi cally designed to test this effects as GABA-mimetic, antioxidants, modula- hypothesis. At this point, there is no scienti fi c tors of intracellular calcium, as well as facilita- evidence to recommend hormonal supplementa- tors of cholinergic transmission in the tion in postmenopausal women to prevent or treat hippocampal area [ 180 ] . Some members of this cognitive decline. Anecdotally, many experts agree family are known as cognitive enhancers due to that when initiated after onset of menopause- the facilitation of cognitive processes. related cognitive symptoms, hormonal supple- Piracetam is the most studied compound as a mentation may be bene fi cial, yet there is no cognitive enhancer. It has been used to evaluate established scientifi c evidence to support this protection against cognitive decline in various observation. clinical settings like traumatic brain injury, cere- The role of dehydroepiandrosterone (DHEA) brovascular insuffi ciency, cardiac bypass cogni- has also been explored in the context of cognitive tive defi cit, and MCI with promising results decline. They are the most abundant circulating [180 ] . Part of its ef fi cacy can be attributed to the hormones in young adults, and they are major offset of depressive symptoms. Confl icting evi- precursors of androgens and estrogens in the cen- dence has been produced by meta-analysis [181, tral nervous system, [175 ] especially in the post- 182] , and no large-scale trial has been imple- menopausal stage in aged individuals where the mented so far to demonstrate the effects of this gonadal production of sex hormones drops [176 ] . compound in patients with MCI and dementia Some observational studies have suggested that [181, 182] . Less studied nootropic compounds the drop of DHEA with aging can account for are oxiracetam, aniracetam, and pramiracetam. some of the cognitive diffi culties associated with Phase I and II trials are promising, but the level of age, partially due to the unopposed deleterious evidence available at this point is not enough to effect of cortisol on the oxidative stress balance systematically recommend piracetam or any noo- [10, 177 ] . Although the supplementation with tropic drugs for the prevention or treatment of DHEA is appealing as a way to prevent cognitive cognitive decline. decline, human results have failed to prove any signi fi cant improvement in chronic supplementation of the hormones, and a few have shown neg- Acetylcholinesterase Inhibitors ative effects. As theorized with HRT, it is thought the timing of supplementation is important and Among the widespread neurodegeneration in AD that future trial should explore early supplemen- and MCI, the basal forebrain is affected. This area tation after the drop of “youthful” levels of the of the brain secretes acetylcholine that is part of hormones [178 ] . Other explanations for this lack an important neuronal pathway including mem- of results have been the age-associated decrement ory. It is believed that in part, the acetylcholine in enzymatic activity necessary to convert the defi ciency is responsible for memory dysfunction hormones into their active metabolites as well as in AD and MCI. Acetylcholinesterase (AChE) individuals with advanced disease. There is no inhibitors are drugs that block or inhibit the evidence at this point to recommend the supple- enzyme in charge of degrading acetylcholine, thus mentation of DHEA for the prevention or treat- favoring larger amount of acetylcholine present at ment of cognitive decline. the synaptic level [183 ] . It has also been suggested that AChE itself can somehow decrease the amyloid deposition making it also a good candidate as Piracetam and Piracetam-Like Drugs disease-modifying drugs [184 ] . In the USA, four AChE inhibitors have been Piracetam is a nootropic compound (“nootrope” approved: tacrine, donepezil, galantamine, and comes from ancient Greek meaning “for or rivastigmine, although the last three have 182 J. Gutierrez and R.S. Isaacson largely supplanted tacrine, the fi rst AChE tors in AD, vascular dementia, and MCI. approved [185 ] . Donepezil (Aricept¨ ) is an Donepezil and galantamine were found to offer AChE inhibitor with an N -benzylpiperidine and benefi t in cognition when compared to placebo in an indanone moiety that shows longer and more AD and vascular dementia patients, but donepe- selective action. It is currently FDA-approved zil failed to prove a signifi cant effect in MCI for the treatment of mild, moderate, and severe patients. The authors also evaluated a summary Alzheimer’s dementia. It is highly selective of relative risk for improvement or stabilization with AChE, and it has been shown to strongly input for providers and caregivers. In this analy- inhibit AChE as well as to increase the levels of sis, the effects remained signifi cant in all groups AChE in animal and humans models [ 186 ] . and for all drugs except for donepezil in vascular Galantamine (Razadyne¨ ) is a selective, revers- dementia treatment and rivastigmine for improve- ible competitive AChE inhibitor that has been ment/stabilization for all types of dementia [ 189 ] . approved for the symptomatic treatment of Two recent systematic reviews determined that Alzheimer’s disease. Galantamine is a natural there was no signi fi cant effect of AChE inhibitors product belonging to the Amaryllidaceae family in improvement or stabilization of cognitive of alkaloids [ 187 ] . Galantamine was the fi rst decline in aged adults based on moderate quality drugs of this class to have an extended release evidence [2, 3 ] . form and also the fi rst to come off patent and go The administration of AChE inhibitors is rec- generic. Rivastigmine (Exelon ¨) is a pseudo- ommended for patients with AD or vascular irreversible inhibitor of both AChE and butyryl- dementia upon proper medical evaluation and cholinesterase and has been shown in a number when there are no contraindications to their of clinical trials to be effi cacious in AD. Unlike administration. The drug of choice should be other cholinesterase inhibitors that are only individualized based on tolerability, indications, available in oral formulations, a novel transdermal as well as practical issues like insurance status, rivastigmine patch has been developed and route of administration, and familiarity of the approved for the treatment of mild-to-moderate physician with the drugs. There is no enough evi- AD [ 188] . Several clinical trials have shown dence at this point to support the use of AChE mild to modest improvement on various cognitive inhibitors in patients at risk for cognitive decline tests; however, more uncertainty exists in the or with MCI; better powered studies are needed behavioral outcome associated with these drugs. to discern this question. There have been multiple reviews and meta- analysis on whether AChE inhibitors are useful. The con fl icting results are mainly due to the cri- Memantine teria to evaluate the evidence and the trial results. Hansen et al. included 26 RCT of all AChE Memantine (Namenda¨ ) is an uncompetitive inhibitors and evaluated four outcomes: cogni- N-methyl- d -aspartate (NMDA) receptor antago- tion, function, behavior, and global score. The nist with moderate affi nity. In general, NMDA evidence was also rated according to its method- receptor antagonists are considered good neuro- ological strengths. Only four studies had good protectors due to their ability to counterweight evidence, the majority had fair qualifi cation, and excessive glutamate stimulation that is associated a few did not provided enough information to rate with increased intracellular calcium, mitochon- them. In cognition, function, and behavior, the drial dysfunction, and eventually apoptosis [ 190 ] . pooled means for all drugs were statistically The pharmacokinetic properties of memantine signi fi cant. In the global domain, galantamine make it a theoretical good drug for exitotoxicity- was borderline nonsignifi cant. No head-to-head related pathologies. comparison among AChE inhibitors was Memantine is approved for moderate to signi fi cant due to poor quality of the data avail- severe dementia and can be used in combination able for review [ 185 ] . Another meta-analysis with AChE inhibitors when indicated. The trials approach investigated the effects of AChE inhibi- that lead to the approval of memantine followed 12 Prevention of Cognitive Decline 183 the patient over no more than 28 weeks. The were found. Only 19% developed a serum outcome evaluation varied among them, and the response with positive antibodies against Ab results showed improvement in some but not all found in plaques and vascular amyloid but not to cognitive domains evaluated; the behavior soluble Ab . It was found also that respondents domain was certainly the least affected [ 191Ð had slower rate of cognitive decline, and in 193 ] . Subsequently, Wilcock et al. found autopsies done subsequently, it was found that signifi cant improvement in agitation/aggression respondents had less plaque deposition that non- markers in a 6-month follow-up trial [ 194 ] . In a respondents. Of interest, the presence of menin- recent meta-analysis, memantine was not better goencephalitis was independent of the antibody than placebo to improve ADAS-cog scores in response [ 195, 198 ] . Based on these encouraging patients with mild-to-moderate AD; however, it results, a new epitope is being investigated that did show benefi t in patients with vascular would be designed to target mainly B cells aim- dementia and better scores in a scale used to ing at avoiding or decreasing the risk of menin- evaluate the caregiver impression of stabiliza- goencephalitis shown in the previous trial. The tion or improvement of the disease (CIBIC-plus) results from animal models have so far been [189 ] . There is presently not enough data to promising, although no human phase I study is evaluate if memantine can provide protective currently going on [199 ] . effects in patients with MCI [ 2, 3 ] . Bapineuzumab is a humanized monoclonal antibody use for passive transfer of antibodies against soluble Ab . Preclinical trials have showed Novel Therapies a nonsignifi cant trend for improvement in cognition when compared to placebo in patient with Immune Therapy AD. Post hoc analysis found signi fi cant effects on cognition for APOE e 4 noncarriers compared The deposition of Ab is considered to be a major to no effects in carriers. A phase III trial is cur- pathway in the neurodegeneration seen in AD. rently underway [200 ] . Researchers have used either active or passive vaccination with antibodies against Ab to reduce deposition and/or increase clearance of Ab in the Gamma Secretase Inhibitors brain [ 195 ] . Intravenous immunoglobulins (IVIG) have been used in trials to treat Alzheimer’s Amyloid precursor protein is cleaved by beta dementia. The proposed mechanism of action and gamma secretases to produce multiple-sized includes catalization of Ab oligomers, conforma- A b fi brils. Gamma secretases can produce Ab 40 tional changes of A b fi brils making them less and Ab 42, the fi rst one being the most abundant prone to aggregation, and complement activa- and the second one the most prone to aggregation, among others [196 ] . In an open-label, small- tion and deposition [ 201 ] . Gamma secretase sample, dose- fi nding study, Relkin et al. found inhibition could potentially reduce A b produc- benefi t of administering IVIG on cognitive scores tion and decrease the aggregation and plaque in patient with Alzheimer’s dementia [ 197 ] . burden in AD. A phase I trial of a gamma Based on these and other preliminary results, a secretase compound called LY450139 has dem- phase III trial is currently underway to determine onstrated that it can reduce A b concentrations in the ef fi cacy of IVIG in the treatment of AD. The the brain, cerebrospinal fl uid, and serum [ 202 ] . fi rst vaccination attempt was stopped prema- A phase II trial of the same compound showed turely due to a major adverse event associated to signi fi cant reduction in the serum levels of Ab 40 the vaccine (6% of the patient enrolled developed and Ab 42 in serum nut not in CFS. No cognitive meningoencephalitis). It was hypothesized that effects were seen in either active group com- the patients developed a strong T-cell reaction pared to placebo, although the follow-up was that induced an autoimmune disease to the short (14 weeks). A phase III trial is currently affected areas of the brain where Ab deposits underway to evaluate effi cacy [ 203 ] . 184 J. Gutierrez and R.S. Isaacson

erals, and other components have failed to demon- Conclusions strate a reliable association does not mean that the intake of these is not bene fi cial. There is a possi- Effective strategies to prevent cognitive decline bility that the combination of multiple components in the context of normal aging, mild cognitive is what makes the difference. Additionally, trying impairment, and dementia are imperative to face to adhere to healthy lifestyle recommendations the oncoming epidemic of dementia and cogni- including a diet rich in essential nutrients, smok- tive disease in our society. Evidence-based ing abstinence, regular exercise, as well as ade- recommendations are imperative to avoid unnec- quate cardiovascular profi le is by all means a goal essary expenses and the creation of false expecta- in any patient. Challenging the brain with new tion in patients and their families. Methodological information and new experiences seems to be dif fi culties and biases assault several good- advisable, especially in those who already have intentioned trials. Existing studies have provided early cognitive complains. There is no evidence at some clues into the puzzle of prevention of cog- this point that pharmacological agents can slow nitive decline, yet it is rare that the evidence is down the progression of MCI to dementia. The unquestionable. The issue of studying a complex administration of AChE inhibitors in combination process like cognition represents challenges that with memantine should be prescribed when appli- researchers must be aware of. The presence of cable to demented patients to stabilize the disease multiple factors and covariates that can bias the and probably slow down the progression. Promising results presents a major hurdle in the design stage novel therapies include active and passive immu- as well as in the statistical analysis, especially in nization against Ab peptides and gamma secretase small-sample studies. inhibitors to reduce A b production. Table 12.1 When evaluating diet components, the major summarizes the literature on prevention of cogni- dif fi culty is in isolating the effect that a nutrient or tive decline. A summary of prevention strategies diet component has on cognition or the evolution for patients and their families is presented in of dementia. The fact that isolated vitamins, min- Table 12.2 .

Table 12.1 Summary of the literature on prevention of cognitive decline State of evidence in the prevention Strategy studied Presumptive mechanism of action of cognitive decline/dementia Vitamin 1 (thiamine)a Ð Normal functioning of the brainÐblood barrier Ð Not suf fi cient to recommend it Ð Adequate cellular functioning Vitamin B2 Ð Important cofactor in energy production Ð Not suf fi cient to recommend it (ribo fl avin) a Pyridoxine Ð Important cofactor for neurotransmitter production Ð Not suf fi cient to recommend it (vitamin B6) a Ð Involved in homocysteine metabolism Cobalamin Ð Important in cell reproduction and DNA synthesis Ð Not suf fi cient to recommend it (vitamin B12)a Ð Involved in homocysteine metabolism Ð Cobalamin levels are part of the Ð Cofactor is fatty acid synthesis initial dementia workup Folate a Ð Important in cell reproduction and DNA synthesis Ð Not suf fi cient to recommend it Ð Involved in homocysteine metabolism Ð Folate levels are part of the initial Ð Antioxidant properties dementia workup Vitamins C and Ea Ð Powerful antioxidants Ð Not suf fi cient to recommend it Ð Adequate cellular reproduction and functioning Ð Important for a healthy immune system Chromium Ð Improves insulin resistance Ð Not suf fi cient to recommend it Berries Ð Powerful antioxidants Ð Not suf fi cient to recommend it Ð Neuroprotectors (continued) Table 12.1 (continued) State of evidence in the prevention Strategy studied Presumptive mechanism of action of cognitive decline/dementia Curcumin Ð Antioxidant Ð Not suffi cient to recommend, weigh Ð Anti-in fl ammatory risk:bene fi t ratio individually Ð A b aggregation inhibitor Ð Anti-apoptotic Docosahexaenoic acid Ð Neuroprotector, specially for synaptic activity Ð Probably effective (DHA) Ð Anti-in fl ammatory Ð More ef fi cacious in APOE Ð Antioxidant e 4-negative patients Mediterranean diet Ð Supply of a synergistic combination of essential Ð Advised as part of a healthy lifestyle nutrient and vitamins for normal metabolic but not enough evidence to claim a functioning consistent bene fi t in cognition Garlic Ð Antioxidant Ð Not suf fi cient to recommend it Ð Hypolipemic Ginkgo biloba Ð Anti-in fl ammatory Ð Not suf fi cient to recommend it Ð Antioxidant Ð Improves blood circulation Low alcohol Ð Favors lipid pro fi le Ð Not suf fi cient to recommend it consumption Ð Flavonoids in some types of wines could serve as antioxidants Caffeine Ð Increases arousal, especially in aged individuals Ð Can provide a boost in some Ð Neuroprotective cognitive processes Ð Cognitive normalizer (see text) Ð More evidence needed to recommend it systematically Treatment of Ð Decreases oxidative processes in the brain Ð Essential component of all patients hypertension, Ð Improves cerebral circulation with cognitive complains diabetes, and Ð Decreases incidence of stroke Ð The negative results of trials treating dyslipidemia Ð Decreases incidence of vascular dementia these factors have to be taken in consideration for future strategies Smoking abstinence Ð Decreases oxidative process Ð Al patient should be strongly Ð Decreases incidence of stroke advice to quit smoking Physical exercise Ð Stimulates neurotrophic factors production Ð It should be recommended in all Ð Improves oxygenation capacity patients according to their Ð Improves lipid pro fi le capacities and needs Social cognitive Ð Improves cognitive reserve Ð Likely bene fi cial as part of a engagement Ð Could offset depressive symptoms and isolation multimodal therapeutic approach Cognitive training Ð Improves cognitive reserve Ð Recommended when possible as part of a multimodal therapeutic approach Treatment of Ð Improves overall neurological functioning Ð Recommended when indicated depression Ð Can impaired adequate oral intake, compliance Ð Depression screening is part of the with medications, social engagement, etc. initial dementia workup Hormonal replace- Ð Can prolonged the neuroprotective effects of Ð Not recommended ment estrogens in postmenopausal women Ð More studies needed to evaluate therapy Ð Improve cardiovascular pro fi le earlier interventions Ð Neurotrophic effects in the brain Dehydroepi- Ð Endogenous precursor of sexual hormones Ð Not suf fi cient to recommend it androsterone (DHEA) Ð Opposes the deleterious effects of increased cortisol in the brain Nootropic compounds Ð Cognitive facilitators Ð Not suf fi cient to recommend it (piracetam) Ð Antioxidants Ð Weak antidepressant Acetylcholinesterase Ð Increase cholinergic activity in the brain Ð Recommended for the treatment inhibitors facilitating cognitive processes of dementia if applicable Ð Weak Ab aggregation inhibitors Ð No suf fi cient evidence to recommended it for the treatment or prevention of MCI (continued) 186 J. Gutierrez and R.S. Isaacson

Table 12.1 (continued) State of evidence in the prevention Strategy studied Presumptive mechanism of action of cognitive decline/dementia Memantine Ð Neuroprotection by offsetting excessive Ð Recommended in patient with glutaminergic activity moderate to severe dementia when feasible Active and passive Ð Inhibits aggregation and deposition of Ab Ð Used only under research immunization against peptides in the brain protocols Ab Ð Decreases neurodegeneration associated to Ab plaques Gamma secretase Ð Decreased the production of Ab oligomers that Ð Used only under research inhibitors are prone to aggregation protocols MCI mild cognitive impairment, A b amyloid beta a In the context of proven de ﬁ ciencies, it should be treated accordingly

Table 12.2 Top ten strategies for Alzheimer’s disease prevention 1. Increase physical activity as tolerated and as approved by your primary care physician 2. Have a healthy diet (e.g., incorporating a Mediterranean-style diet, including fruits and vegetables, lean protein ( ﬁ sh, chicken, turkey), low-fat items, nuts, and seeds 3. Increase socialization, including activity programs, adult education classes, and social groups 4. De-stress! Think positive and see your primary care physician for general guidance 5. Increase mental activity 6. Listen to music (especially classical) and consider music therapy programs 7. Ongoing follow-up with your primary care doctor for routine health maintenance (i.e., control vascular risk factors such as high blood pressure, cholesterol, diabetes/high sugars) to decrease rate of progression of memory decline 8. Assure adequate dietary intake of essential vitamins. Consider a multivitamin each day, folic acid 1 mg (total) each day, and vitamin D 1,000Ð2,000 I.U. each day 9. Curcumin (turmeric root) one tablet twice per day. Buy in a health food store 10. Fish oil capsules, slowly increasing to at least three capsules each day Ð must have DHA in it, the more the better A more detailed review of treatment and prevention strategies for Alzheimer’s disease can be found at www.TheADplan. com . For a resource for patients and families, see Isaacson, Richard S. Alzheimer’s Treatment Alzheimer’s Prevention: A Patient and Family Guide. Florida: Alzheimer’s Disease Education Consultants, 2012

used under physician supervision. This is due Clinical Pearls to wide availability, lack of FDA oversight, cost, and possible contraindications/adverse ¥ When it comes to vitamins and minerals, if effects. de ﬁ cient, treat. There is no evidence that more ¥ A diet rich in vegetables, fruits, nuts, and ﬁ sh of something you already have is useful. is advisable to everybody, with particular ¥ What is good for the heart is good for the brain; emphasis in patients at risk of developing paying attention to CV risk factors is important. cognitive decline or Alzheimer’s or vascular ¥ There is no evidence that hormonal supple- dementia. mentation can decrease the incidence of ¥ Patients should remain active physically and dementia. If there is an indication for hor- mentally. Physical exercise is among the best of monal supplementation, the cognitive status all potential interventions against Alzheimer’s should not be a factor in the decision-making disease. process. ¥ Patients with diagnosis of Alzheimer’s demen- ¥ Some agents that are touted as having tia should be considered for medical therapy cognitive protective effects should only be unless contraindicated. 12 Prevention of Cognitive Decline 187

20. Kado DM, et al. Homocysteine versus the vitamins References folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. Am J Med. 1. Brown LA, Riby LM, Reay JL. Supplementing cog- 2005;118:161Ð7. nitive aging: a selective review of the effects of 21. Tucker KL, Qiao N, Scott T, Rosenberg I, Spiro 3rd ginkgo biloba and a number of everyday nutritional A. High homocysteine and low B vitamins predict substances. Exp Aging Res. 2010;36:105Ð22. cognitive decline in aging men: the Veterans Affairs 2. Plassman BL, Williams Jr JW, Burke JR, Holsinger T, Normative Aging Study. Am J Clin Nutr. 2005;82: Benjamin S. Systematic review: factors associated with 627Ð35. risk for and possible prevention of cognitive decline in 22. Terasawa M, Nakahara T, Tsukada N, Sugawara A, later life. Ann Intern Med. 2010;153: 182Ð93. Itokawa Y. The relationship between thiamine 3. Daviglus ML, et al. National Institutes of Health de fi ciency and performance of a learning task in rats. State-of-the-Science Conference statement: prevent- Metab Brain Dis. 1999;14:137Ð48. ing alzheimer disease and cognitive decline. Ann 23. Jolicoeur FB, Rondeau DB, Barbeau A, Wayner MJ. Intern Med. 2010;153:176Ð81. Comparison of neurobehavioral effects induced by 4. Shumaker SA, et al. Estrogen plus progestin and the various experimental models of ataxia in the rat. incidence of dementia and mild cognitive impair- Neurobehav Toxicol. 1979;1 Suppl 1:175Ð8. ment in postmenopausal women: the Women’s 24. Ciccia RM, Langlais PJ. An examination of the syn- Health Initiative Memory Study: a randomized con- ergistic interaction of ethanol and thiamine de fi ciency trolled trial. JAMA. 2003;289:2651Ð62. in the development of neurological signs and long- 5. Middleton LE, Yaffe K. Promising strategies for the pre- term cognitive and memory impairments. Alcohol vention of dementia. Arch Neurol. 2009;66:1210Ð5. Clin Exp Res. 2000;24:622Ð34. 6. Brookmeyer R, Damiano A. Statistical methods for 25. Meador K, et al. Preliminary fi ndings of high-dose short-term projections of AIDS incidence. Stat Med. thiamine in dementia of Alzheimer’s type. J Geriatr 1989;8:23Ð34. Psychiatry Neurol. 1993;6:222Ð9. 7. Frautschy SA, Cole GM. Why pleiotropic interven- 26. Mimori Y, Katsuoka H, Nakamura S. Thiamine ther- tions are needed for Alzheimer’s disease. Mol apy in Alzheimer’s disease. Metab Brain Dis. Neurobiol. 2010;41:392Ð409. 1996;11:89Ð94. 8. Nehlig A. Is caffeine a cognitive enhancer? J 27. Jia X, McNeill G, Avenell A. Does taking vitamin, Alzheimers Dis. 2010;20 Suppl 1:S85Ð94. mineral and fatty acid supplements prevent cognitive 9. Prasain JK, Carlson SH, Wyss JM. Flavonoids and decline? A systematic review of randomized con- age-related disease: risk, benefi ts and critical win- trolled trials J Hum Nutr Diet. 2008;21:317Ð36. dows. Maturitas. 2010;66:163Ð71. 28. Goodwin JS, Goodwin JM, Garry PJ. Association 10. Miller DB, O’Callaghan JP. Aging, stress and the between nutritional status and cognitive functioning hippocampus. Ageing Res Rev. 2005;4:123Ð40. in a healthy elderly population. JAMA. 1983;249: 11. Glade MJ. Oxidative stress and cognitive longevity. 2917Ð21. Nutrition. 2010;26:595Ð603. 29. Lee H, Kim HJ, Kim JM, Chang N. Effects of dietary 12. Akiyama H, et al. In fl ammation and Alzheimer’s folic acid supplementation on cerebrovascular disease. Neurobiol Aging. 2000;21:383Ð421. endothelial dysfunction in rats with induced hyper- 13. Tapsell LC, et al. Health benefi ts of herbs and spices: homocysteinemia. Brain Res. 2004;996:139Ð47. the past, the present, the future. Med J Aust. 30. Scileppi KP, Blass JP, Baker HG. Circulating vita- 2006;185:S4Ð24. mins in Alzheimer’s dementia as compared with 14. Balk E, et al. B vitamins and berries and age-related other dementias. J Am Geriatr Soc. 1984;32:709Ð11. neurodegenerative disorders. Evid Rep Technol 31. Mizrahi EH, et al. Plasma total homocysteine levels, Assess (Full Rep). 2006;164:1Ð161. dietary vitamin B6 and folate intake in AD and 15. Riggs KM, Spiro 3rd A, Tucker K, Rush D. Relations healthy aging. J Nutr Health Aging. 2003;7:160Ð5. of vitamin B-12, vitamin B-6, folate, and homo- 32. Dangour AD, et al. B-vitamins and fatty acids in the cysteine to cognitive performance in the Normative prevention and treatment of Alzheimer’s disease and Aging Study. Am J Clin Nutr. 1996;63:306Ð14. dementia: a systematic review. J Alzheimers Dis. 16. Wang HX, et al. Vitamin B(12) and folate in relation 2010;22:205Ð24. to the development of Alzheimer’s disease. 33. Masuda Y, Kokubu T, Yamashita M, Ikeda H, Inoue Neurology. 2001;56:1188Ð94. S. EGG phosphatidylcholine combined with vitamin 17. Seshadri S, et al. Plasma homocysteine as a risk fac- B12 improved memory impairment following lesion- tor for dementia and Alzheimer’s disease. N Engl J ing of nucleus basalis in rats. Life Sci. 1998;62: Med. 2002;346:476Ð83. 813Ð22. 18. Garcia A, Zanibbi K. Homocysteine and cognitive 34. Tangney CC, Tang Y, Evans DA, Morris MC. Biochemical function in elderly people. CMAJ. 2004;171:897Ð904. indicators of vitamin B12 and folate insuffi ciency and 19. Ravaglia G, et al. Homocysteine and folate as risk cognitive decline. Neurology. 2009;72:361Ð7. factors for dementia and Alzheimer disease. Am J 35. Kwok T, et al. Randomized trial of the effect of sup- Clin Nutr. 2005;82:636Ð43. plementation on the cognitive function of older 188 J. Gutierrez and R.S. Isaacson

people with subnormal cobalamin levels. Int J muscle Glut-4 translocation in obese, hyperinsu- Geriatr Psychiatry. 1998;13:611Ð6. linemic (JCR-LA corpulent) rats. J Nutr. 2002;132: 36. Hvas AM, Juul S, Lauritzen L, Nexo E, Ellegaard J. 1107Ð14. No effect of vitamin B-12 treatment on cognitive 51. Anderson RA, et al. Elevated intakes of supplemen- function and depression: a randomized placebo con- tal chromium improve glucose and insulin variables trolled study. J Affect Disord. 2004;81:269Ð73. in individuals with type 2 diabetes. Diabetes. 37. Kruman II, et al. Folic acid de fi ciency and homo- 1997;46:1786Ð91. cysteine impair DNA repair in hippocampal neurons 52. Hamaguchi T, Ono K, Murase A, Yamada M. and sensitize them to amyloid toxicity in experimen- Phenolic compounds prevent Alzheimer’s pathol- tal models of Alzheimer’s disease. J Neurosci. ogy through different effects on the amyloid-beta 2002;22:1752Ð62. aggregation pathway. Am J Pathol. 2009;175: 38. Mattson MP, Chan SL, Duan W. Modi fi cation of 2557Ð65. brain aging and neurodegenerative disorders by 53. Crozier A, Del Rio D, Clifford MN. Bioavailability genes, diet, and behavior. Physiol Rev. 2002;82: of dietary fl avonoids and phenolic compounds. Mol 637Ð72. Aspects Med. 2010;31(6):446Ð67. 39. Morris MC, et al. Dietary folate and vitamin B12 54. Moyer RA, Hummer KE, Finn CE, Frei B, Wrolstad intake and cognitive decline among community- RE. Anthocyanins, phenolics, and antioxidant capac- dwelling older persons. Arch Neurol. 2005;62: ity in diverse small fruits: vaccinium, rubus, and 641Ð5. ribes. J Agric Food Chem. 2002;50:519Ð25. 40. Fioravanti M, et al. Low folate levels in the cognitive 55. Halvorsen BL, et al. A systematic screening of total anti- decline of elderly patients and the effi cacy of folate oxidants in dietary plants. J Nutr. 2002;132: 461Ð71. as a treatment for improving memory defi cits. Arch 56. Saija A, Princi P, D’Amico N, De Pasquale R, Costa Gerontol Geriatr. 1998;26:1Ð13. G. Effect of Vaccinium myrtillus anthocyanins on 41. Bryan J, Calvaresi E, Hughes D. Short-term folate, triiodothyronine transport into brain in the rat. vitamin B-12 or vitamin B-6 supplementation Pharmacol Res. 1990;22 Suppl 3:59Ð60. slightly affects memory performance but not mood 57. Casadesus G, et al. Modulation of hippocampal plas- in women of various ages. J Nutr. 2002;132: ticity and cognitive behavior by short-term blueberry 1345Ð56. supplementation in aged rats. Nutr Neurosci. 2004;7: 42. Sommer BR, Hoff AL, Costa M. Folic acid supple- 309Ð16. mentation in dementia: a preliminary report. J Geriatr 58. Joseph JA, Fisher DR, Carey AN. Fruit extracts Psychiatry Neurol. 2003;16:156Ð9. antagonize Abeta- or DA-induced de fi cits in Ca2+ 43. Wald DS, Kasturiratne A, Simmonds M. Effect of fl ux in M1-transfected COS-7 cells. J Alzheimers folic acid, with or without other B vitamins, on cog- Dis. 2004;6:403Ð11. discussion 443Ð409. nitive decline: meta-analysis of randomized trials. 59. Yang F, et al. Curcumin inhibits formation of amy- Am J Med. 2010;123:522Ð7. e522. loid beta oligomers and fi brils, binds plaques, and 44. Perrig WJ, Perrig P, Stahelin HB. The relation reduces amyloid in vivo. J Biol Chem. 2005;280: between antioxidants and memory performance in 5892Ð901. the old and very old. J Am Geriatr Soc. 60. Rinwa P, Kaur B, Jaggi AS, Singh N. Involvement of 1997;45:718Ð24. PPAR-gamma in curcumin-mediated bene fi cial 45. Morris MC, Evans DA, Bienias JL, Tangney CC, effects in experimental dementia. Naunyn Wilson RS. Vitamin E and cognitive decline in older Schmiedebergs Arch Pharmacol. 2010;381:529Ð39. persons. Arch Neurol. 2002;59:1125Ð32. 61. Lao CD, et al. Dose escalation of a curcuminoid for- 46. Wengreen HJ, et al. Antioxidant intake and cognitive mulation. BMC Complement Altern Med. 2006;6:10. function of elderly men and women: the Cache 62. Baum L, et al. Six-month randomized, placebo-con- County Study. J Nutr Health Aging. 2007;11: trolled, double-blind, pilot clinical trial of curcumin 230Ð7. in patients with Alzheimer disease. J Clin Psycho- 47. Dangour AD, Sibson VL, Fletcher AE. Micronutrient pharmacol. 2008;28:110Ð3. supplementation in later life: limited evidence for 63. Hamaguchi T, Ono K, Yamada M. REVIEW: benefi t. J Gerontol A Biol Sci Med Sci. 2004;59: Curcumin and Alzheimer’s disease. CNS Neurosci 659Ð73. Ther. 2010;16:285Ð97. 48. Wallum BJ, et al. Cerebrospinal fl uid insulin levels 64. Oster T, Pillot T. Docosahexaenoic acid and synaptic increase during intravenous insulin infusions in man. protection in Alzheimer’s disease mice. Biochim J Clin Endocrinol Metab. 1987;64:190Ð4. Biophys Acta. 2010;1801:791Ð8. 49. Krikorian R, Eliassen JC, Boesp fl ug EL, Nash TA, 65. Greiner RS, Moriguchi T, Hutton A, Slotnick BM, Shidler MD. Improved cognitive-cerebral function Salem Jr N. Rats with low levels of brain docosa- in older adults with chromium supplementation. hexaenoic acid show impaired performance in olfac- Nutr Neurosci. 2010;13:116Ð22. tory-based and spatial learning tasks. Lipids. 1999; 50. Cefalu WT, Wang ZQ, Zhang XH, Baldor LC, 34(Suppl):S239Ð243. Russell JC. Oral chromium picolinate improves car- 66. Chiu CC, et al. The effects of omega-3 fatty acids bohydrate and lipid metabolism and enhances skeletal monotherapy in Alzheimer’s disease and mild cognitive 12 Prevention of Cognitive Decline 189

impairment: a preliminary randomized double-blind systematic review and meta-analysis. BMC Geriatr. placebo-controlled study. Prog Neuropsychopharmacol 2010;10:14. Biol Psychiatry. 2008;32:1538Ð44. 85. Peters R, Peters J, Warner J, Beckett N, Bulpitt C. 67. Freund-Levi Y, et al. Omega-3 fatty acid treatment in Alcohol, dementia and cognitive decline in the 174 patients with mild to moderate Alzheimer elderly: a systematic review. Age Ageing. 2008;37: disease: OmegAD study: a randomized double-blind 505Ð12. trial. Arch Neurol. 2006;63:1402Ð8. 86. Orgogozo JM, et al. Wine consumption and dementia in 68. Scheltens P, et al. Ef fi cacy of a medical food in mild the elderly: a prospective community study in the Bordeaux Alzheimer’s disease: A randomized, controlled trial. area. Rev Neurol (Paris). 1997;153:185Ð92. Alzheimers Dement. 2010;6:1Ð10. e11. 87. Koppelstaetter F, et al. Caffeine and cognition in 69. Quinn JF, et al. Docosahexaenoic acid supplementa- functional magnetic resonance imaging. J Alzheimers tion and cognitive decline in Alzheimer disease: a Dis. 2010;20 Suppl 1:S71Ð84. randomized trial. JAMA. 2010;304:1903Ð11. 88. Fredholm BB, Battig K, Holmen J, Nehlig A, Zvartau 70. Whalley LJ, et al. n-3 Fatty acid erythrocyte mem- EE. Actions of caffeine in the brain with special ref- brane content, APOE varepsilon4, and cognitive erence to factors that contribute to its widespread variation: an observational follow-up study in late use. Pharmacol Rev. 1999;51:83Ð133. adulthood. Am J Clin Nutr. 2008;87:449Ð54. 89. Dall’Igna OP, Porciuncula LO, Souza DO, Cunha 71. Feart C, Samieri C, Barberger-Gateau P. Mediterranean RA, Lara DR. Neuroprotection by caffeine and ade- diet and cognitive function in older adults. Curr Opin nosine A2A receptor blockade of beta-amyloid neu- Clin Nutr Metab Care. 2010;13:14Ð8. rotoxicity. Br J Pharmacol. 2003;138:1207Ð9. 72. Willett WC, et al. Mediterranean diet pyramid: a cul- 90. Arendash GW, et al. Caffeine protects Alzheimer’s tural model for healthy eating. Am J Clin Nutr. mice against cognitive impairment and reduces brain 1995;61:1402SÐ6S. beta-amyloid production. Neuroscience. 2006;142: 73. Kourlaba G, Polychronopoulos E, Zampelas A, 941Ð52. Lionis C, Panagiotakos DB. Development of a diet 91. Cunha RA, Agostinho PM. Chronic caffeine con- index for older adults and its relation to cardiovascu- sumption prevents memory disturbance in different lar disease risk factors: the Elderly Dietary Index. J animal models of memory decline. J Alzheimers Am Diet Assoc. 2009;109:1022Ð30. Dis. 2010;20 Suppl 1:S95Ð116. 74. Scarmeas N, Stern Y, Tang MX, Mayeux R, 92. Huang CC, Liang YC, Hsu KS. A role for extracel- Luchsinger JA. Mediterranean diet and risk for lular adenosine in time-dependent reversal of long- Alzheimer’s disease. Ann Neurol. 2006;59:912Ð21. term potentiation by low-frequency stimulation at 75. Scarmeas N, et al. Mediterranean diet and mild cog- hippocampal CA1 synapses. J Neurosci. 1999;19: nitive impairment. Arch Neurol. 2009;66:216Ð25. 9728Ð38. 76. Feart C, et al. Adherence to a Mediterranean diet, 93. d’Alcantara P, Ledent C, Swillens S, Schiffmann cognitive decline, and risk of dementia. JAMA. SN. Inactivation of adenosine A2A receptor impairs 2009;302:638Ð48. long term potentiation in the accumbens nucleus 77. Gu Y, Nieves JW, Stern Y, Luchsinger JA, Scarmeas without altering basal synaptic transmission. N. Food combination and Alzheimer disease risk: a Neuroscience. 2001;107:455Ð64. protective diet. Arch Neurol. 2010;67:699Ð706. 94. Lieberman HR, Tharion WJ, Shukitt-Hale B, 78. Borek C. Garlic reduces dementia and heart-disease Speckman KL, Tulley R. Effects of caffeine, sleep risk. J Nutr. 2006;136:810SÐ2S. loss, and stress on cognitive performance and mood 79. Peng Q, Buz’Zard AR, Lau BH. Neuroprotective during U.S. Navy SEAL training. Sea-Air-Land. effect of garlic compounds in amyloid-beta peptide- Psychopharmacology (Berl). 2002;164:250Ð61. induced apoptosis in vitro. Med Sci Monit. 95. Smith AP. Caffeine, cognitive failures and health in 2002;8:BR328Ð337. a non-working community sample. Hum Psycho- 80. Budoff MJ, et al. Inhibiting progression of coronary pharmacol. 2009;24:29Ð34. calcifi cation using Aged Garlic Extract in patients 96. Rees K, Allen D, Lader M. The infl uences of age and receiving statin therapy: a preliminary study. Prev caffeine on psychomotor and cognitive function. Med. 2004;39:985Ð91. Psychopharmacology (Berl). 1999;145:181Ð8. 81. Gold PE, Cahill L, Wenk GL. The lowdown on 97. Jarvis MJ. Does caffeine intake enhance absolute lev- Ginkgo biloba. Sci Am. 2003;288:86Ð91. els of cognitive performance? Psychopharmacology 82. Oken BS, Storzbach DM, Kaye JA. The ef fi cacy of (Berl). 1993;110:45Ð52. Ginkgo biloba on cognitive function in Alzheimer 98. Lorist MM, Snel J, Mulder G, Kok A. Aging, caf- disease. Arch Neurol. 1998;55:1409Ð15. feine, and information processing: an event-related 83. Dodge HH, Zitzelberger T, Oken BS, Howieson D, potential analysis. Electroencephalogr Clin Kaye J. A randomized placebo-controlled trial of Neurophysiol. 1995;96:453Ð67. Ginkgo biloba for the prevention of cognitive 99. Eskelinen MH, Ngandu T, Tuomilehto J, Soininen decline. Neurology. 2008;70:1809Ð17. H, Kivipelto M. Midlife coffee and tea drinking and 84. Weinmann S, Roll S, Schwarzbach C, Vauth C, the risk of late-life dementia: a population-based Willich SN. Effects of Ginkgo biloba in dementia: CAIDE study. J Alzheimers Dis. 2009;16:85Ð91. 190 J. Gutierrez and R.S. Isaacson

100. Ritchie K, et al. The neuroprotective effects of caf- 118. McGuinness B, Todd S, Passmore P, Bullock R. feine: a prospective population study (the Three City Blood pressure lowering in patients without prior Study). Neurology. 2007;69:536Ð45. cerebrovascular disease for prevention of cognitive 101. van Gelder BM, et al. Coffee consumption is impairment and dementia. Cochrane Database Syst inversely associated with cognitive decline in elderly Rev. 2009;2:CD004034. European men: the FINE Study. Eur J Clin Nutr. 119. McGuinness B, Craig D, Bullock R,. Passmore P. 2007;61:226Ð32. Statins for the prevention of dementia. Cochrane 102. Corley J, et al. Caffeine consumption and cognitive Database Syst Rev.2009;4:CD003160. function at age 70: the Lothian Birth Cohort 1936 120. Zhou B, Teramukai S, Fukushima M. Prevention and study. Psychosom Med. 2010;72:206Ð14. treatment of dementia or Alzheimer’s disease by sta- 103. van Boxtel MP, Schmitt JA, Bosma H, Jolles J. The tins: a meta-analysis. Dement Geriatr Cogn Disord. effects of habitual caffeine use on cognitive change: 2007;23:194Ð201. a longitudinal perspective. Pharmacol Biochem 121. Agostini JV, et al. Effects of statin use on muscle Behav. 2003;75:921Ð7. strength, cognition, and depressive symptoms in 104. de la Torre JC. Alzheimer disease as a vascular older adults. J Am Geriatr Soc. 2007;55:420Ð5. disorder: nosological evidence. Stroke. 2002;33: 122. Cook DG, et al. Reduced hippocampal insulin-de- 1152Ð62. grading enzyme in late-onset Alzheimer’s disease is 105. Snowdon DA, et al. Brain infarction and the clinical associated with the apolipoprotein E-epsilon4 allele. expression of Alzheimer disease. The Nun Study. Am J Pathol. 2003;162:313Ð9. JAMA. 1997;277:813Ð7. 123. Bruehl H, et al. Modi fi ers of cognitive function and 106. Stephan BC, Brayne C. Vascular factors and preven- brain structure in middle-aged and elderly individu- tion of dementia. Int Rev Psychiatry. 2008;20: als with type 2 diabetes mellitus. Brain Res. 2009; 344Ð56. 1280:186Ð94. 107. Kalaria RN. Comparison between Alzheimer’s dis- 124. Censori B, et al. Dementia after fi rst stroke. Stroke. ease and vascular dementia: implications for treat- 1996;27:1205Ð10. ment. Neurol Res. 2003;25:661Ð4. 125. Bourdel-Marchasson I, et al. Characteristics of undi- 108. Fernando MS, Ince PG. Vascular pathologies and agnosed diabetes in community-dwelling French cognition in a population-based cohort of elderly elderly: the 3 C study. Diabetes Res Clin Pract. 2007; people. J Neurol Sci. 2004;226:13Ð7. 76:257Ð64. 109. Luchsinger JA, et al. Aggregation of vascular risk 126. Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, factors and risk of incident Alzheimer disease. Bennett DA. Diabetes mellitus and risk of Alzheimer Neurology. 2005;65:545Ð51. disease and decline in cognitive function. Arch 110. Dartigues JF, Fabrigoule C, Barberger-Gateau P, Neurol. 2004;61:661Ð6. Orgogozo JM. Memory, aging and risk factors. 127. Allen KV, Frier BM, Strachan MW. The relationship Lessons from clinical trials and epidemiologic stud- between type 2 diabetes and cognitive dysfunction: ies. Therapie. 2000;55:503Ð5. longitudinal studies and their methodological limita- 111. Launer LJ. Regional differences in rates of demen- tions. Eur J Pharmacol. 2004;490:169Ð75. tia: MRC-CFAS. Lancet Neurol. 2005;4:694Ð5. 128. Yaffe K, et al. Diabetes, impaired fasting glucose, 112. Skoog I, et al. 15-year longitudinal study of blood and development of cognitive impairment in older pressure and dementia. Lancet. 1996;347:1141Ð5. women. Neurology. 2004;63:658Ð63. 113. Mielke MM, Zandi PP. Hematologic risk factors of 129. Areosa SA, Grimley EV. Effect of the treatment of vascular disease and their relation to dementia. Type II diabetes mellitus on the development of cog- Dement Geriatr Cogn Disord. 2006;21:335Ð52. nitive impairment and dementia. Cochrane Database 114. Forette F, et al. Prevention of dementia in randomised Syst Rev. 2002;4:D003804. double-blind placebo-controlled Systolic Hyper tension 130. Aggarwal NT, et al. The relation of cigarette smoking in Europe (Syst-Eur) trial. Lancet. 1998;352: 1347Ð51. to incident Alzheimer’s disease in a biracial urban 115. Lithell H, et al. The Study on Cognition and community population. Neuroepidemiology. Prognosis in the Elderly (SCOPE): principal results 2006;26:140Ð6. of a randomized double-blind intervention trial. 131. Ott A, et al. Smoking and risk of dementia and J Hypertens. 2003;21:875Ð86. Alzheimer’s disease in a population-based cohort study: 116. Curb JD, et al. Effect of diuretic-based antihypertensive the Rotterdam Study. Lancet. 1998;351:1840Ð3. treatment on cardiovascular disease risk in older diabetic 132. Merchant C, et al. The in fl uence of smoking on the risk patients with isolated systolic hypertension. Systolic of Alzheimer’s disease. Neurology. 1999;52:1408Ð12. Hypertension in the Elderly Program Cooperative 133. Juan D, et al. A 2-year follow-up study of cigarette Research Group. JAMA. 1996;276:1886Ð92. smoking and risk of dementia. Eur J Neurol. 2004; 117. McGuinness B, Todd S, Passmore P, Bullock R. The 11:277Ð82. effects of blood pressure lowering on development 134. Meyer J, Xu G, Thornby J, Chowdhury M, Quach of cognitive impairment and dementia in patients M. Longitudinal analysis of abnormal domains com- without apparent prior cerebrovascular disease. prising mild cognitive impairment (MCI) during Cochrane Database Syst Rev. 2006;19:CD004034. aging. J Neurol Sci. 2002;201:19Ð25. 12 Prevention of Cognitive Decline 191

135. Fratiglioni L, Wang HX. Smoking and Parkinson’s 153. Ball K, et al. Effects of cognitive training interven- and Alzheimer’s disease: review of the epidemio- tions with older adults: a randomized controlled trial. logical studies. Behav Brain Res. 2000;113:117Ð20. JAMA. 2002;288:2271Ð81. 136. Anstey KJ, von Sanden C, Salim A, O’Kearney R. 154. Willis SL, et al. Long-term effects of cognitive Smoking as a risk factor for dementia and cognitive training on everyday functional outcomes in older decline: a meta-analysis of prospective studies. Am J adults. JAMA. 2006;296:2805Ð14. Epidemiol. 2007;166:367Ð78. 155. Mahncke HW, et al. Memory enhancement in healthy 137. Dishman RK, et al. Neurobiology of exercise. older adults using a brain plasticity-based training Obesity (Silver Spring). 2006;14:345Ð56. program: a randomized, controlled study. Proc Natl 138. Rockwood K, Middleton L. Physical activity and the Acad Sci USA. 2006;103:12523Ð8. maintenance of cognitive function. Alzheimers 156. Gates N, Valenzuela M. Cognitive exercise and its Dement. 2007;3:S38Ð44. role in cognitive function in older adults. Curr 139. Ravaglia G, et al. Physical activity and dementia risk Psychiatry Rep. 2010;12:20Ð7. in the elderly: fi ndings from a prospective Italian 157. Troyer AK, Murphy KJ, Anderson ND, Moscovitch M, study. Neurology. 2008;70:1786Ð94. Craik FI. Changing everyday memory behaviour in 140. Lautenschlager NT, et al. Effect of physical activity amnestic mild cognitive impairment: a randomised con- on cognitive function in older adults at risk for trolled trial. Neuropsychol Rehabil. 2008;18:65Ð88. Alzheimer disease: a randomized trial. JAMA. 158. Rozzini L, et al. Ef fi cacy of cognitive rehabilitation 2008;300:1027Ð37. in patients with mild cognitive impairment treated 141. Angevaren M, Aufdemkampe G, Verhaar HJ, with cholinesterase inhibitors. Int J Geriatr Psychiatry. Aleman A, Vanhees L. Physical activity and 2007;22:356Ð60. enhanced fi tness to improve cognitive function in 159. Saczynski JS, et al. The effect of social engagement older people without known cognitive impairment. on incident dementia: the Honolulu-Asia Aging Cochrane Database Syst Rev. 2008;3:CD005381. Study. Am J Epidemiol. 2006;163:433Ð40. 142. Matthews FE, Stephan BC, McKeith IG, Bond J, 160. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein Brayne C. Two-year progression from mild cogni- D. Depression and risk for Alzheimer disease: system- tive impairment to dementia: to what extent do atic review, meta-analysis, and metaregression analysis. different defi nitions agree? J Am Geriatr Soc. Arch Gen Psychiatry. 2006;63:530Ð8. 2008;56:1424Ð33. 161. Tisserand DJ, Visser PJ, van Boxtel MP, Jolles J. The 143. Kirshner HS. Vascular dementia: a review of recent relation between global and limbic brain volumes on evidence for prevention and treatment. Curr Neurol MRI and cognitive performance in healthy individu- Neurosci Rep. 2009;9:437Ð42. als across the age range. Neurobiol Aging. 2000;21: 144. Pohjasvaara T, et al. How complex interactions of 569Ð76. ischemic brain infarcts, white matter lesions, and 162. Wolf H, et al. Structural correlates of mild cognitive atrophy relate to poststroke dementia. Arch Neurol. impairment. Neurobiol Aging. 2004;25:913Ð24. 2000;57:1295Ð300. 163. Markou A, Duka T, Prelevic GM. Estrogens and 145. Tatemichi TK, et al. Risk of dementia after stroke in brain function. Hormones (Athens). 2005;4:9Ð17. a hospitalized cohort: results of a longitudinal study. 164. Sherwin BB. Estrogenic effects on memory in Neurology. 1994;44:1885Ð91. women. Ann N Y Acad Sci. 1994;743:213Ð30. dis- 146. Moroney JT, et al. Risk factors for incident dementia cussion 230Ð211. after stroke. Role of hypoxic and ischemic disorders. 165. Murphy DG, et al. Sex differences in human brain Stroke. 1996;27:1283Ð9. morphometry and metabolism: an in vivo quantitative 147. Valenzuela MJ. Brain reserve and the prevention of magnetic resonance imaging and positron emission dementia. Curr Opin Psychiatry. 2008;21:296Ð302. tomography study on the effect of aging. Arch Gen 148. Stern Y. What is cognitive reserve? Theory and Psychiatry. 1996;53:585Ð94. research application of the reserve concept. J Int 166. Caldwell BM, Watson RI. An evaluation of psycho- Neuropsychol Soc. 2002;8:448Ð60. logic effects of sex hormone administration in aged 149. Verghese J, et al. Leisure activities and the risk of women. I. Results of therapy after six months. dementia in the elderly. N Engl J Med. 2003;348: J Gerontol. 1952;7:228Ð44. 2508Ð16. 167. Portin R, et al. Serum estrogen level, attention, mem- 150. Fratiglioni L, Wang HX, Ericsson K, Maytan M, ory and other cognitive functions in middle-aged Winblad B. In fl uence of social network on occur- women. Climacteric. 1999;2:115Ð23. rence of dementia: a community-based longitudinal 168. Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen study. Lancet. 2000;355:1315Ð9. therapy in postmenopausal women: effects on 151. Valenzuela MJ, Sachdev P. Brain reserve and demen- cognitive function and dementia. JAMA. 1998;279: tia: a systematic review. Psychol Med. 2006;36: 688Ð95. 441Ð54. 169. Barrett-Connor E, Laughlin GA. Endogenous and 152. Oswald WD, Rupprecht R, Gunzelmann T, Tritt K. exogenous estrogen, cognitive function, and demen- The SIMA-project: effects of 1 year cognitive and tia in postmenopausal women: evidence from epide- psychomotor training on cognitive abilities of the miologic studies and clinical trials. Semin Reprod elderly. Behav Brain Res. 1996;78:67Ð72. Med. 2009;27:275Ð82. 192 J. Gutierrez and R.S. Isaacson

170. Maki PM, Zonderman AB, Resnick SM. Enhanced a new type of acetylcholinesterase inhibitor. Jpn J verbal memory in nondemented elderly women Pharmacol. 2002;89:7Ð20. receiving hormone-replacement therapy. Am J 187. Marco L, do Carmo Carreiras M. Galanthamine, a Psychiatry. 2001;158:227Ð33. natural product for the treatment of Alzheimer’s dis- 171. Lokkegaard E, et al. The in fl uence of hormone ease. Recent Pat CNS Drug Discov. 2006;1:105Ð11. replacement therapy on the aging-related change in 188. Kurz A, Farlow M, Lefevre G. Pharmacokinetics of cognitive performance. Analysis based on a Danish a novel transdermal rivastigmine patch for the treat- cohort study. Maturitas. 2002;42:209Ð18. ment of Alzheimer’s disease: a review. Int J Clin 172. LeBlanc ES, Janowsky J, Chan BK, Nelson HD. Pract. 2009;63:799Ð805. Hormone replacement therapy and cognition: sys- 189. Raina P, et al. Effectiveness of cholinesterase inhibi- tematic review and meta-analysis. JAMA. 2001;285: tors and memantine for treating dementia: evidence 1489Ð99. review for a clinical practice guideline. Ann Intern 173. Matthews K, Cauley J, Yaffe K, Zmuda JM. Estrogen Med. 2008;148:379Ð97. replacement therapy and cognitive decline in older 190. Thomas SJ, Grossberg GT. Memantine: a review of community women. J Am Geriatr Soc. 1999;47: studies into its safety and ef fi cacy in treating 518Ð23. Alzheimer’s disease and other dementias. Clin Interv 174. Zandi PP, et al. Hormone replacement therapy and Aging. 2009;4:367Ð77. incidence of Alzheimer disease in older women: the 191. Winblad B, Poritis N. Memantine in severe demen- Cache County Study. JAMA. 2002;288:2123Ð9. tia: results of the 9 M-Best Study (Bene fi t and 175. Sorwell KG, Urbanski HF. Dehydroepiandrosterone effi cacy in severely demented patients during treat- and age-related cognitive decline. Age (Dordr). ment with memantine). Int J Geriatr Psychiatry. 2010;32:61Ð7. 1999;14:135Ð46. 176. Labrie F, et al. DHEA and the intracrine formation 192. Reisberg B, et al. Memantine in moderate-to-severe of androgens and estrogens in peripheral target Alzheimer’s disease. N Engl J Med. 2003;348:1333Ð41. tissues: its role during aging. Steroids. 1998;63: 193. Tariot PN, et al. Memantine treatment in patients 322Ð8. with moderate to severe Alzheimer disease already 177. Karishma KK, Herbert J. Dehydroepiandrosterone receiving donepezil: a randomized controlled trial. (DHEA) stimulates neurogenesis in the hippocam- JAMA. 2004;291:317Ð24. pus of the rat, promotes survival of newly formed 194. Wilcock G, Mobius HJ, Stof fl er A. A double-blind, neurons and prevents corticosterone-induced sup- placebo-controlled multicentre study of memantine pression. Eur J Neurosci. 2002;16:445Ð53. in mild to moderate vascular dementia (MMM500). 178. Wolf OT, Kudielka BM, Hellhammer DH, Hellhammer Int Clin Psychopharmacol. 2002;17:297Ð305. J, Kirschbaum C. Opposing effects of DHEA replace- 195. Lemere CA. Developing novel immunogens for a ment in elderly subjects on declarative memory and safe and effective Alzheimer’s disease vaccine. attention after exposure to a laboratory stressor. Prog Brain Res. 2009;175:83Ð93. Psychoneuroendocrinology. 1998;23:617Ð29. 196. Dodel R, et al. Intravenous immunoglobulins as a 179. Giurgea C. The “nootropic” approach to the pharma- treatment for Alzheimer’s disease: rationale and cology of the integrative activity of the brain. Cond current evidence. Drugs. 2010;70:513Ð28. Re fl ex. 1973;8:108Ð15. 197. Relkin NR, et al. 18-Month study of intravenous 180. Malykh AG, Sadaie MR. Piracetam and piracetam- immunoglobulin for treatment of mild Alzheimer like drugs: from basic science to novel clinical appli- disease. Neurobiol Aging. 2009;30:1728Ð36. cations to CNS disorders. Drugs. 2010;70:287Ð312. 198. Schenk D. Amyloid-beta immunotherapy for 181. Waegemans T, et al. Clinical ef fi cacy of piracetam in Alzheimer’s disease: the end of the beginning. Nat cognitive impairment: a meta-analysis. Dement Rev Neurosci. 2002;3:824Ð8. Geriatr Cogn Disord. 2002;13:217Ð24. 199. Fu HJ, Liu B, Frost JL, Lemere CA. Amyloid-beta 182. Flicker L, Grimley Evans J. Piracetam for dementia immunotherapy for Alzheimer’s disease. CNS or cognitive impairment. Cochrane Database Syst Neurol Disord Drug Targets. 2010;9:197Ð206. Rev. 2000;2:CD001011. 200. Salloway S, et al. A phase 2 multiple ascending 183. Palmer AM. Cholinergic therapies for Alzheimer’s dose trial of bapineuzumab in mild to moderate disease: progress and prospects. Curr Opin Investig Alzheimer disease. Neurology. 2009;73:2061Ð70. Drugs. 2003;4:820Ð5. 201. Portelius E, et al. A novel Abeta isoform pattern in 184. Rees TM, Brimijoin S. The role of acetylcholinest- CSF re fl ects gamma-secretase inhibition in erase in the pathogenesis of Alzheimer’s disease. Alzheimer disease. Alzheimers Res Ther. 2010;2:7. Drugs Today (Barc). 2003;39:75Ð83. 202. Siemers ER, et al. Safety, tolerability, and effects on 185. Hansen RA, et al. Ef fi cacy and safety of donepezil, plasma and cerebrospinal fl uid amyloid-beta after galantamine, and rivastigmine for the treatment of inhibition of gamma-secretase. Clin Neuropharmacol. Alzheimer’s disease: a systematic review and meta- 2007;30:317Ð25. analysis. Clin Interv Aging. 2008;3:211Ð25. 203. Fleisher AS, et al. Phase 2 safety trial targeting amy- 186. Sugimoto H, Ogura H, Arai Y, Limura Y, Yamanishi Y. loid beta production with a gamma-secretase inhibitor Research and development of donepezil hydrochloride, in Alzheimer disease. Arch Neurol. 2008;65:1031Ð8. Clinical Neuropsychology Practice and the Medicare Patient 1 3

Edward A. Peck III , Lucien W. Roberts III , and Joy M. O’Grady

Abstract Neuropsychology practices continue to see increasing constraints on utilization and reimbursement by Medicare and other payors. In this chapter, the authors share insights regarding the business aspects of providing clinical neuropsychological care to Medicare patients. They discuss the internal revenue and cost drivers of today’s neuropsychology practice and emphasize a proactive approach—whether in the private or institutional setting—to business planning and management. This chapter will help neuropsychologists maintain both ﬁ scal viability and a high level of professional quality in patient care. This chapter is divided into three sections. First, the authors delve into cost drivers and frequent inef ﬁ ciencies of the practice. Next, the authors address common Medicare scenarios, sharing both examples and helpful forms. Finally, the authors share several insights on the future of neuropsychology and their recommendations for thriving amidst the changes that will come.

Keywords Medicare ¥ Business issues ¥ Managed care ¥ Of ﬁ ce overhead costs ¥ Practice expenses ¥ Cost of practice ¥ Medicare opt-out issues

In 1965, President Johnson signed H.R. 6675 to establish Medicare for the elderly in Missouri. President Truman was the ﬁ rst to enroll in Medicare [1 ] . E. A. Peck III , Ph.D., ABPP-CN. (*) L. W. Roberts III , MHA, FACMPE Fast-forward a few years. The President of the J. M. O’Grady , Ph.D. United States, in his annual message to Congress, Neuropsychological Services of Virginia, Inc , complained about the rising cost of health-care 2010 Bremo Road, Suite 127 , Richmond , costs, the variations in access to health care, and VA 23226 , USA e-mail: [email protected] ; [email protected] ; the variation in the quality of health care across [email protected] social and income groups. He recommended a

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 193 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_13, © Springer Science+Business Media, LLC 2013 194 E.A. Peck III et al. more “level playing fi eld” approach to national putting more of the responsibility for care on the health-care reform that would rely on current patient. Plans such as health savings accounts, market forces to bring change to the US health- fl exible spending accounts, high deductible health care system. Congress voted deny the President plans, and tiered-pricing formularies are all what he wanted. A familiar story? The President examples of this effort to control health-care was Richard Nixon, and the date of the annual costs by involving the patient in the responsibil- speech to Congress was 1972. The concern was ity for their care. how much the then current federal programs con- The federal and state governments have contributed to “this growing investment in health” as tinued to attempt to control Medicare and a portion of national expenditures [2 ] . Medicaid expenditures. None of these attempts at Fast-forward to the early 1980s. At that time managing health-care costs have been particu- there were relatively few nationally identi fi ed fed- larly effective in tempering the rising costs of eral health-care sponsors besides Champus and health care signifi cantly. Nonetheless, we expect Medicare or multistate private insurance carriers that there will continue to be a migration toward such as Blue Cross/Blue Shield (aka Anthem/aka some form of managed care alternative to tradi- Wellpoint). However, the mid to late 1980s saw tional Part B Medicare, combined with reduced the fi rst sparks leading to the now recognized payments, in Medicare. The clinical neuropsy- baby boomer explosion of aging in the US popu- chologist cannot ignore Medicare HMOs and lation. Suddenly, mental health services were con- other limitations on Medicare, and simply hope fronted with the expansion of the Managed Care that they will go away. Many Medicare managed system and the resulting attempts by employers to care plans generally pay close to standard limit the costs of medical care, while simultane- Medicare, but may present the patient and the ously trying to continue to offer a comprehensive provider with additional constraints (e.g., ardu- insurance plan to their employees. For a much ous preauthorization processes or fewer testing more detailed review of this period of health-care units permitted). It is incumbent upon each change, the reader is directed to The Managed Medicare provider and/or professional practice Care Museum website [3 ] . group to understand the cost and hassle factor of Health maintenance organizations (HMOs), doing business with each plan, so that they can the predominant managed care “cost control” make informed fi nancial decisions with regard to strategy of the 1980s, offered an all-or-nothing participation in such plans. option: typically, only care provided by providers in a network HMOs was covered. Through much of this period and even today, mental health has Purpose of the Current Chapter been something of an afterthought for insurance payors. HMOs evolved and Preferred Provider This chapter is designed to provide practical Organizations (PPOs) were established to coun- information concerning the business aspects of ter the “all-or-nothing” nature of restrictive HMO providing clinical neuropsychological care to networks. These plans still had gatekeepers to Medicare patients under current (and projected) access, but they also offered patients various access and funding parameters. The speci fi c fi nancial and/or easier access to specifi ed provid- focus is on Medicare reimbursement as it relates ers. In turn, these providers had to agree to work to practice management issues in clinical within the limitations in practice and the fees neuropsychology. ordained by the PPO. Eventually, more costly Medicare is not going away. It already com- Point of Service (POS) plans were developed to prises about 15% of the population of our nation. offer patients an opportunity to circumvent the Medicare enrollment grew nearly 19% between more negative aspects of the gatekeeper provi- 2000 and 2010, from 39.6 million enrollees to sions to their plans. In recent years, we have seen 47.1 million enrollees. The fi rst baby boomers other efforts to control health-care costs by (those born between 1946 and 1964) became 13 Clinical Neuropsychology Practice and the Medicare Patient 195

Medicare eligible on January 1, 2011, and will contribute to an expected doubling of Medicare Understanding Your Cost enrollment by 2030. The existing health-care of Practice and Living Within Your infrastructure and Medicare reserves are not pre- Means pared. As a side note, Medicaid enrollment grew nearly 60% between 2000 and 2010, further Let us start with a basic point for the private prac- stressing federal and state funding [4 ] . titioner or institutional practitioner. For the pri- There will be increasing pressure on providers vate practitioner, the point is how much your to do more with less and to cope with increasing practice brings in per month is not as important constraints on utilization and reimbursement. In as how much you actually spend per month to response, it is incumbent upon every neuropsy- pay all the bills. You need to know the extent of chological practice to understand its internal rev- your fi nancial overhead in order to meet your enue and cost drivers and to be as effi cient—with responsibilities. For the institutional provider, the time and resources—as practically possible. point is to understand and appreciate what your Good business is good business, and many of administrator is setting as your minimum RVU or the matters we discuss in this chapter are appli- cost recovery value per time unit for a specifi c cable to your entire clinical practice and not just time period (quarterly, yearly, and so forth). You to your Medicare patient services. At the end of need to know to understand what you (or the the work day, the difference between the dollars institution) have to spend to keep your practice which your practice collects and what your prac- open. tice pays out in expenses is critical. A practice Our goal is to help you calculate what it actu- cannot thrive—much less survive—if it focuses ally costs your practice to operate. Knowing this on revenues while ignoring expenses, or vice cost is essential to managing your expenses and versa. The successful neuropsychology practice improving your operating margins. The fi rst thing must keep an eye on both revenues and expenses. you should do is to have your accountant or of fi ce In this chapter, we emphasize a proactive manager develop a fi nancial spreadsheet which response to the management of your professional lists all of the expense categories paid during practice, whether it is in a private or institutional each month and each year. Table 13.1 is an exam- setting. We believe that by being proactive in ple of a practice income statement; it lists many your business planning and management, you of the cost categories which should be included can avoid many patient- and insurance-related in such a spreadsheet [5 ] . problems. This is far more reasonable than trying The sum of your expenses is your total cost of to resolve a situation which has already gotten practice. To make a pro fi t, you must recoup more out of control. than this amount. Once you have calculated the This chapter is comprised of three sections: total expense for your of fi ce, you can calculate 1. Understanding your Cost of Practice and “what if” scenarios relating to profi t and loss. It is Living Within Your Means also helpful to look at a 3-year period when pos- 2. Addressing Common Medicare Scenarios: sible to trend/forecast changes. You should plan Examples and Forms to calculate cost escalations for each of these line 3. Medicare and Neuropsychology: A Look items, e.g., salaries and fringe benefi ts, as part of Forward to the Abyss or to Eden? What will projecting expenses for the coming 3 years. our business management practices look like Once you have an annual total cost of opera- in the future? tion, you can calculate your average total cost per The fi rst section offers insight into the busi- hour of practice. For example, an offi ce which is ness management of your practice. We urge our open 8 h a day, 5 days a week, has 2,080 operating readers to use this section as a building block hours per year, less holidays, vacations, bad upon which to improve the fi nancial operation of weather closings, and the like. Dividing your their practices. annual total cost by your total operating hours will 196 E.A. Peck III et al.

Table 13.1 A sample fi nancial report Sample fi nancial report Revenues Current month October Current year to date 10 months Prior year to date 10 months Fees received 46484.87 350875.00 320897.50 Other income 2490.00 30115.00 18737.00 Interest earned 30.39 429.00 190.00 Total revenue 49005.26 381419.00 339824.50 Cost of practice Accounting 300.00 3000.00 2800.00 Advertising 50.00 500.00 425.00 Bank charges 17.81 581.79 500.00 Co. car loan 350.00 3500.00 0.00 Co. car expenses 65.00 650.00 639.00 Charity contributions 100.00 225.00 200.00 Continuing education 120.00 250.00 250.00 Dues and subscriptions 400.00 2805.00 3000.00 Employee bene fi ts 660.00 6660.00 5000.00 Equipment—capital 0.00 2000.00 1000.00 Equipment—other 125.00 300.00 500.00 Insurance—malpractice 100.00 900.00 900.00 Insurance—Co. car 90.00 900.00 860.00 Insurance—other 140.00 1140.00 1000.00 Interest—loans 43.49 825.74 0.00 Legal fees 125.00 350.00 675.00 Licenses 100.00 450.00 450.00 Maintenance—equipment 475.00 2900.00 2500.00 Miscellaneous 50.00 2400.00 700.00 Of fi ce expense 239.00 3100.00 3000.00 Postage 135.00 1650.00 250.00 Refunds 50.50 1117.00 1750.00 Registrations—meeting 180.00 450.00 400.00 Rent—of fi ce 2000.00 20000.00 17000.00 Repairs 0.00 1000.00 800.00 Supplies—of fi ce 54.00 1334.75 1000.00 Supplies—test 125.25 375.00 350.00 Taxes—payroll 4800.00 48000.00 39000.00 Taxes—other 0.00 375.00 375.00 Telephone 210.24 2848.90 2500.00 Telephone ans. service 90.00 900.00 800.00 Travel 616.00 3300.00 1000.00 Meals and entertainment 75.00 590.00 200.00 Wages 8711.52 77810.64 74508.97 Total expenses 20597.81 193188.82 164332.97 Net income/loss 28407.45 188230.18 175491.53 Co. is company, ans . is answering calculate your practice’s average cost per hour of It is possible to take a more detailed look at operation. Simply stated, if your practice is not how much it costs you to provide an hour of test- bringing in at least this much per hour of operation ing or an hour of therapy. For example, you can (e.g., per week or per month), it is losing money. set up a spreadsheet which incorporates cost 13 Clinical Neuropsychology Practice and the Medicare Patient 197 items such as (1) technician salary and fringe readers a good checklist of areas where the cost benefi ts, (2) cost of test equipment, (3) cost of of your practice operations might be improved. room space rent, (4) cost of front offi ce (schedul- In this regard, while it is possible for your prac- ing to billing), and (5) your salary and benefi ts. tice to take a more detailed look at how much it However, this is secondary to getting a solid han- costs you to provide an hour of testing or an hour dle on your overall average cost per hour of oper- of therapy is only part of getting a solid handle on ation. Once you have a good feel for such data, your total average cost per hour of business you can dig deeper and look at individual fi nancial operation. facets of your practice. Having gotten a grasp on your expenses, you This juncture is a good time to review your should develop a spreadsheet that lists the actual expenses at a “line item” basis. Be critical. We reimbursement amount paid by each insurance urge you to focus on expenses because a dollar carrier, for each service you provide. Table 13.3 saved is a dollar earned, whereas a dollar charged presents such a spreadsheet, and it lists (for the often results in receipts of less than half that. purposes of this chapter) allowed payment rates Some axioms for consideration: A mere for CPT codes 96118 and 90806, Medicare 30 min of overtime a day for a technician earning Region 3, and for several other (unidentifi ed) $20 an hour will cost your practice $3,900 per plans. For the record, the other insurance plans year ($20/h times 0.50 h/day times 5 days/week are not named due to confi dentiality require- times 52 weeks/year times, at time-and-a-half). ments. Many insurance plans have subplans or Add in matching tax obligations of 7.65%, and carve outs to their plan, which may pay at differ- your cost exceeds $4,000 per year. ent rates. This includes Medicare HMO and PPO If you have a 5-year lease for 2,500 square feet plans. The spreadsheet that you develop should at $20 per square foot, a 4% escalation clause have the information organized so that each insur- will cost you $5,359 more than a 3% escalation ance plan can be viewed and compared for the clause over the term of the lease ($20/square foot CPT codes actually used in your of fi ce. Such a times 2,500 square feet is $50,000 in rent in year spreadsheet will serve several purposes, includ- 1; in year 5, you will be paying $58,493 with a ing allowing you to evaluate which insurance 4% escalation clause or $56,275 with a 3% esca- plans pay a better fee for a particular CPT code lation clause). unit of service. Table 13.4 provides a comparison By avoiding the overtime and higher rent of CPT allowed payments from different insurer escalation in these two examples, you would save sources. more than $26,000 over 5 years. Savings equals The following instances warrant consideration income . of contract termination or negotiation with the Review annual service agreements for copi- insurance company: ers, faxes, credit card processing, and postage ¥ If a payor pays relatively less than others or meters. Ask your vendors for better deals if you less than what it costs your practice to provide will renew for 24 months instead of 12 months. a service. Talk with other medical practices to ensure that ¥ If you and your of fi ce staff consistently spend your staff wages and annual increases are not too so much time getting testing units or evalua- far above or below the average range for your tions preapproved, or after providing the ser- geographic area. Ask the practices next door and vice, having to fi le and refi le the claim for across the hall if they would like to bid out janito- payment, that the cost of doing business with rial or some other service together to get a better that company is not worth the payment price. received. Remember, this is an overhead The checklist provided as Table 13.2 offers a expense. It may not be worth it to spend that roadmap for managing your practice better. time re fi ling the claim. It may be better that Clearly, Table 13.2 goes into more detail than you terminate that contract. we can discuss in the space of this chapter. While fee negotiation with Medicare is not However, we felt its inclusion would provide possible, it is possible to negotiate with Medicare 198 E.A. Peck III et al.

Table 13.2 Practice operations checklist 2011 2012 2013 2014 2015 Budgets Operating budget used to track performance? Operating budget includes prior year (PY) comparison? Capital budget established? Expenses compared to PY, budget, benchmarks? Retirement plans Service agreements (basis points) renegotiated? Expenses allocated to participants vs. borne by practice? Former employees removed if costing practice $$? Contributions balanced with operating cash? Timing/cost of plan valuations reviewed? Housekeeping Cost per square foot compared to other practices? Bid out or renegotiated alone or with other practices? Right sized frequency of service for satellite/nonclinical areas? Backed out square footage for space that will not be cleaned (e.g., samples closet, electrical/server closet, extra rooms)? Shredding Quarterly check of bins for nonpatient content? Bid out or renegotiated? Eliminated junk faxes? Checked for duplicate of fi ce notes, etc. , and rooted out causes? Overtime / wage management Given wage increases only when warranted? Compared wages/bene fi ts to those of other practices? Tracked overtime hours as a percent of worked hours? Reviewed schedules for smart scheduling? Tracked provider start time vs. scheduled start time? Avoided scheduling of “same sex” at end of day? Avoided scheduling of procedures at end of day? Ensured staff has exam rooms ready at start of day? Kept unwarranted overtime at a minimum? Employee retention Trended turnover rate vs. PY? By of fi ce/dept? Maintained undesired turnover at <5%? Engaged employees per the Gallup Q 12 Survey? Employees know what is expected of them? Employees have what they need to do their jobs? Employees have a chance to do their best everyday? Employees recognized/thanked every week? Employee development encouraged? Employee input requested and used? Equipment purchases and leases Obtained multiple bids? Bid out with other practices if buying common/same items? Asked fi nalists for better pricing/terms? Shopped for best interest rates? (continued) 13 Clinical Neuropsychology Practice and the Medicare Patient 199

Table 13.2 (continued) 2011 2012 2013 2014 2015 Negotiated caps or free years on equipment maintenance? For operating leases, de fi ned “fair market value” before signing? Locked in pricing on future purchases before signing? Looked for leases/loans with no personal guarantees? Negotiated supplies purchasing with future caps ? Evaluated re fi nancing of existing leases? Credit card processing Obtained multiple bids? Compared ALL costs/rates? Considered Internet-based processing services? Considered dual purpose “swipe” readers? Copiers / printers / scanners / faxes Inventoried existing units/leases/maintenance agreements? Determined cost per copy of existing units? Bid out with other practices? Asked for free consolidation audits/bids from vendors? Reviewed ways to reduce unnecessary/duplicate copies? Eliminated high cost and duplicative units? Reviewed processes for document retention (scan vs. print)? Copiers / printers / scanners / faxes Compared current pricing discounted plans? Compared current pricing to other professional organization vendors? Solicited others in local community or same specialty to join in group purchasing? When purchasing the following, look at volume buying with others: Copiers/faxes Housekeeping Shredding Supplies/equipment Payroll/accounting Legal advice *Contract review Electronic medical records and practice management systems Employee bene fi ts/insurance options Of fi ce supplies Kitchen/coffee service and supplies If you buy it, bid it… Revisit provider schedules Provider Time Off policies reviewed for impact on schedule? Provider Time Off policies reviewed for carryover limits? Provider Time Off truly and fairly tracked? Reviewed schedules to make sure schedulers are optimizing? Looked for possible scheduling inequities? Determine Relative Value Unit (RVU)/hour worked for each doctor/of fi ce? (continued) 200 E.A. Peck III et al.

Table 13.2 (continued) 2011 2012 2013 2014 2015 Provider compensation agreements Reviewed compensation relative to collections and overhead? Incentives and formulas understood by providers? Buy-in from providers on incentives and formulas? At least 50% of compensation to production incentives? Communications Evaluated elimination of pagers via cell phone use? Considered foregoing insurance on units if pagers are retained? Reviewed monthly answering service invoices? Negotiated better rates and eliminated extraneous charges? Considered group bidding? Reviewed existing cell phone agreements? Considered foregoing maintenance insurance? Bid out agreement? Evaluated “family” vs. “corporate” plans? Looked at size of bucket of minutes vs. usage? Looked at cost of data messaging options? Completion of patient forms Asked patients to fi ll in nonclinical parts before appt.? Had providers/support staff fi ll out remainder during appt.? Reviewed charge(s) for form completion? Increased charge for time-consuming forms? Ensured form collection fees are collected up front? Patient registration forms Posted online or e-mailing to reduce copying/postage expenses? If making copies, farmed out to minimize cost per copy? The rent Negotiated cap on Common Area Maintenance increases? Negotiated annual rent increase limits? Obtained guaranteed construction timeline in writing? Analyzed fi nancing options and rates? Locked in renewal terms, including $$$ for refurbishment? Included “No Trade” provisions in lease to protect against involuntary relocation? Asked landlord to pay for all construction, architectural, and space planning drawings? Re fi nanced existing loans? Insurance bene fi ts Medical malpractice Right sized limits to state caps? Bid out to ensure rates are competitive? Secured “tail” coverage for retiring docs at no cost? Ensured provider employment agreements are clear on tail coverage? Health/dental/disability/Section 125 Bid out to ensure rates are competitive? Ensured all alternatives considered have the key providers in network that your staff, your docs, and their families use? (continued) 13 Clinical Neuropsychology Practice and the Medicare Patient 201

Table 13.2 (continued) 2011 2012 2013 2014 2015 Considered alternatives along a continuum of co-pays, deductibles, and drug plans? Offered multiple options (PPO, HMO, HAS)? Set practice’s contribution to employee premiums as a fi xed dollar amount rather than a percentage? Evaluated a Section 125 plan for employee premiums? Asked for group billing discounts for individual long term disability (LTD) policies? Looked to American Psychological Association (APA) and others for discounts? Updated asset schedules for tax and business insurance calculations? Deleted unused assets? Used good descriptions/serial numbers for new assets? Most costs are fi xed , so … Evaluated adding one patient/provider/day or/half-day? Evaluated scheduling for ef fi cient fi lling of schedules? Evaluated scheduling for potential creation of overtime? Ensured electronic remittance is in place and working? Looked to limit your nonrevenue-producing task producers? Credentialing? Mail review (and other distractions)? Patient/family phone calls? Exam room turnover? Ensured exam/testing rooms are stocked and ready? Shared “best kept” secrets with referrers to help them? Evaluated/reduced avoidable “no shows”? Looked at space utilization/ef fi ciency/alternative uses? Subleasing? Shared satellite of fi ces? Optimized coding and documentation? Most costs are fi xed , so … Bell curve analyses vs. national norms and PY? Audited coding and documentation for problems/opportunities? Reviewed denial rates and trends by payor? Payor contracts Calculated operating expense and total expense per RVU? Compared payments for top 15Ð20 high dollar and high volume codes by payor to operating and total expense for same? Eliminated or renegotiated money-losing and marginal agreements? Actively managed “% of Medicare” contracts to ensure proper payment? Established base Medicare year for contracts to protect against cuts? Asked for annual fee schedule increases? Asked for relevant fee schedules (not sample fee schedule)? Completed a Strengths, Weaknesses/Limitations, Opportunities, and Threats (SWOT) analysis to assess negotiating strategy? Asked your providers and staff to complete Payor Report Cards? Asked for carve-outs for certain services or codes? (continued) 202 E.A. Peck III et al.

Table 13.2 (continued) 2011 2012 2013 2014 2015 Loaded updated fee schedules in practice management system? Audited payments on signed contracts? If giving notice, considered 45 + 45 strategy? Co-pays, deductibles Ensured patients know what they owe before visit? Offered multiple payment options? Tracked collection of co-pays, deducts by site, by employee? Reminded staff what it costs to collect a co-pay after the fact? Ensured eligibility and deductible status are being checked previsit? Reminded providers that downcoding for friends only helps the payor? No shows Tracked “no show” excuses for patterns, noncompliance? Established “no show” fees not to anger but to deter? Empowered your front of ﬁ ce to make decisions on excuse validity? After the fact collections Using Lockbox Services? Wasting $$ by sending pre-explanation of beneﬁ t (EOB) patient statements? Considering collections placement after two statements? After the fact collections Looked at service charges for second/third statements? Looked at service charges for statements for co-pays? Accounts payable Verifying ALL nonrecurring invoices? Reviewed renewing contracts for onerous “evergreen” clauses? Tracking and managing inventory? Considered online bill pay? Used a “rewards” credit card for paying bills where possible?

Table 13.3 Tracking of Medicare allowed payments This is also a time to review your commercial 2007 to 2011 for CPT codes 96118 and 90806 payor contracts and ensure you are being paid Year CPT code what you are due. Surprise, surprise, some pay- 96118 90806 ors have been known to pay less than what they 2007 $111.79 $87.71 have told you they will pay you! Medicare claims 2008 $106.45 $85.26 are generally paid accurately in terms of the num- 2009 $103.96 $91.77 ber of units allowed and billed. However, you 2010 $97.01 $85.11 must stay current with what are the published 2011 $95.74 $87.97 approved/allowed payment rates. If your current approved/allowed fee schedules have not been loaded into your practice man- managed plans offered by regional and national agement software system, make this a priority. payors. This is particularly true when they need This should be carried out for each insurance your specialty services due to local service sup- company and plan you bill. Updated and current ply shortages. It is better to walk away from an fee schedules in your practice management sys- agreement that costs you more to provide the ser- tem are the best way of tracking whether your vice than to provide the service for that plan. 13 Clinical Neuropsychology Practice and the Medicare Patient 203 Commercial Region 3 Commercial 1 Commercial 2 Ins 1 HMO Ins 2 PPO Ins 3 Medicaid Commercial Commercial Ins 4 Medicare Medicare Ins 5 Medicaid Commercial Ins 6 Medicare Ins 7 Ins 8 Ins 9 Ins 10 Comparison of CPT allowed payments from different insurer sources insurer sources payments from different Comparison of CPT allowed Table 13.4 90801 90806 DI Int 96101 Therapy 96102 Psy 97.85 81.37 test 96103 PT 81.37 102.88 96118 PT 81.35 96119 Np 85.00 test 81.45 70.00 81.37 96120 NT 81.37 30.90 NT 70.00 81.45 72.00 81.37 81.45 30.90 72.00 70.00 30.90 70.00 30.00 72.00 81.45 72.00 30.90 72.00 70.00 72.00 30.00 80.00 67.10 72.00 112.98 45.00 67.10 62.61 85.00 20.00 67.10 60.87 151.55 87.97 50.00 48.83 20.00 95.74 107.63 71.35 41.35 67.49 69.10 51.74 85.00 95.74 44.00 60.31 58.65 75.00 69.10 37.48 75.00 65.00 168.00 71.14 35.19 75.00 90.00 47.94 75.00 75.00 90.00 51.52 75.00 49.00 75.00 103.00 44.00 69.00 65.00 204 E.A. Peck III et al. practice is being paid the correct amount per unit for determining annual updates to physician of each plan contract. Make sure your billing staff reimbursements for services. The SGR was is cognizant of what you should be paid when intended to be a budgetary restraint on Medicare’s they are posting payments. We cannot overem- total expenditures to maintain budget neutrality. phasize this point. Your billing staff should know Absent Congressional intervention, the SGR will how much is paid per unit and when there is a dramatically cut provider reimbursement rates, deviation from the expected payment amount. while practice costs continue to rise. The SGR They need to know that you want to know when effectively caps total Medicare expenditures on problems in reimbursement arise. provider services [6 ] . Other spreadsheets can be prepared which cal- So, why should you be concerned with the culate various ratios of actual payment versus the SGR and Medicare payment cuts? All you want average length of time it takes to receive payment is to keep a full practice and pay your bills, and once your claim is submitted; number of fi rst earn your salary? Well, how are you going to submissions (called “clean claims”) leading to know if your practice is going to (a) make a profi t, payment versus multiple submission/resubmis- (b) break even, or (c) operate at a loss on Medicare sions of claims; and frequency of other problems services such as psychotherapy or testing if you leading to delay in payment and/or refusal of do not know what the amount of fee reimburse- payment by the insurance company. Many of ment is going to be a month, 3 months, or a year these spreadsheets are premade as part of com- from today. You HAVE to think about the basic mercial software billing programs. cost of delivering your professional service to the Over time, you will determine that some insur- public from a business management point of ance companies pay a lower fee per unit of ser- view. vice but that they actually cost less in terms of the Table 13.3 presents the hard reality of the actual cost to your practice. This is because they decline in Medicare allowed payment (the actual have a very high rate of clean claims, thereby amount you are paid) over the past 5 years. As lowering your claims processing costs. In turn, you can see, the actual CPT 96118 fee in Region others may promise a high rate of payment but 3 has declined from a 2007 level of 111.79 to a cost more to service the claim (or, as noted ear- 2011 level of 95.74 (14%). In contrast, the CPT lier, cost you so much more in staff and doctor 90806 fee has increased by 26 cents. Without a time getting preauthorizations than your actual doubt, your overhead has continued to increase reimbursement per hour or per unit due to having during this time period. Can you afford to see to resubmit claims and so forth). Medicare patients for these rates? Where can you Most of the above applies to Medicare as well make up the difference in lost revenue? as other federal, private, and commercial insur- At the institutional level, the same situation ance plans. With respect to Medicare, let us look regarding Medicare reimbursement is going to at the hard reality of what is going on at the time direct how the institution will allocate resources we wrote this chapter (January to May 2011). for patient care and professional salaries. Most of The United States has reached its national debt us have heard the real stories from our peers who limit, and Congress has only just agreed to have been told bluntly by their hospital adminis- increase the debt limit and thereby increase the trator to balance their department budget (includ- debt burden in the future. This may lead to fur- ing their continued salary and other overhead) by ther signi fi cant spending cuts in federally funded increasing actual cash receipts (not just billable insurance plans. Medicare and Medicaid spend- hours to indigent patients) to a level which covers ing accounted for 5.7% of Gross Domestic salary and other expenses, or their position would Product in fi scal year 2008 and is expected to be canceled. more than double in the next 30 years [4 ] . Here is a basic example using CPT 96118. If The Sustainable Growth Rate, or SGR, is a your offi ce cost of service is $150.00 per hour major component of Medicare’s current formula and you currently receive $150.00 per unit of 13 Clinical Neuropsychology Practice and the Medicare Patient 205

96118, then you are breaking even, with no pro fi t 2. Patients must be informed in advance of the or loss. Now, if the amount you receive is $95.74 “no show” charge (we recommend that you for each unit of 96118 provided to a Medicare inform patients at the time appointments are patient, that is a loss of 54.26 per unit. Thus, an made, at the time appointments are con fi rmed, 8-h service with 96118 leads to a loss of $434.08. and in your patient registration material). Where will you make up this loss? Have you cal- 3. The charge must be reasonable (there is no culated the total number of Medicare-based CPT guideline for “reasonable,” though we are units of service billed by your practice in the past aware of $25–50 being common for “no show” 12 months? Please take a minute or two and cal- charges per hour in our community). A simple culate this amount versus your actual overhead. method to fi nd out what is the common charge Consider what an additional projected 21% SGR in your community is to call YOUR personal cut would do to your offi ce fi nancial picture. This physician’s of fi ce and ask what they charge is only one of the many reasons why large num- for a “no show.” Just remember, most PCP vis- bers of physicians and psychologists are consid- its are much shorter that the typically 1-h min- ering whether they can afford to continue to imal unit of time you set aside for a patient. provide services to Medicare patients. 4. “No show” charges are billed directly to How you spend your professional time is a patients as a “noncovered” service; they can- decision based upon multiple issues. Having an not be billed to Medicare or other insurance accurate picture of your offi ce’s fi nancial status companies. and how it can be affected by seeing patients who lead to fi nancial pro fi t or loss for your practice is critical to your business decision making. Once Medicare Participation Options you actually analyze your costs for carrying out a neuropsychological evaluation to a patient with a Neuropsychologists and other providers are specifi c insurance plan, is continued service to not required to see Medicare patients. Three patients with that plan justi fi ed from a business options exist for contracting with Medicare: perspective? (1) participating (PAR), (2) nonparticipating Another concern that drives up of fi ce costs is (NON-PAR), and (3) opting out/private con- the matter of patient “no shows.” These are the tracting (OPT-OUT) [ 8 ] . instances in which patients do not show for their As a general rule, Medicare contractors send scheduled appointments. “No shows” cost your letters to providers in mid-November of each practice money since they represent unproductive year, informing them of the upcoming calendar “no income” time in which you still have the cost year’s payment rates and offering them an oppor- associated with running a practice. Virtually all tunity to change their participation status. insurance companies (Medicaid is a notable Providers then have until December 31 of that exception in most states) permit neuropsycholo- year to make their participation decisions. Unless gists and other providers to charge patients who CMS reopens this “open enrollment period,” fail to show for their appointments. While “no participation is binding for the entire calendar show” charges do not offset all the lost revenue year. from a “no show,” they can provide an incentive 1. PAR: When a neuropsychologist agrees to to patients to keep their appointments. “participate” in Medicare, they agree to accept As of October 1, 2007, Medicare allows the Medicare’s reimbursement rates as payment clinical neuropsychologist to charge patients a in full for the calendar year in question. “no show” fee, provided the following conditions Medicare reimburses participating providers are met [7 ] : at 100% of the approved payment rate and 1. The “no show” charge must be applied consis- pays them more rapidly than nonparticipating tently to all patient insurance groups (Medicaid providers. Generally speaking, 80% of the being an allowed exception) and not just to payment comes from Medicare, with the bal- Medicare patients. ance coming from the patient. 206 E.A. Peck III et al.

2. NON-PAR: If a neuropsychologist elects not The af fi davit of participation status must be to participate in Medicare, they have the option completed at least 30 days before the fi rst day of whether or not to “accept assignment.” If the the next calendar quarter; there is a 90-day window NON-PAR provider accepts assignment, for rescinding the affi davit. The opted-out neu- Medicare pays claims at 95% of the participat- ropsychologist and Medicare patient must sign a ing provider amount, with 80% of that amount written contract before any service is rendered. coming from the contractor and 20% from the The contract must clearly state that, by signing patient. If the NON-PAR provider decides not the contract, the patient (1) declines all Medicare to accept assignment, they must fi ll out a payments for services rendered by the neuropsy- Medicare benefi ciary’s claim form and submit chologist, (2) is liable for all charges without the claim directly to Medicare. Medicare then Medicare balance billing limitations or assistance pays the patient directly, leaving the physician from Medigap or other supplemental insurance, to bill the patient for services rendered. and (3) acknowledges that the patient has the right Physicians cannot charge Medicare patients to receive services from other medical providers. for fi ling their claims, but by refusing assign- Where a neuropsychologist opts out and is a ment, NON-PAR providers can balance bill member of a group practice or otherwise reas- patients up to the “limiting charge” (federal signs his or her rights to Medicare payment to an law restricts Medicare nonparticipating pro- organization, the organization may no longer bill viders from balance billing more than 115% Medicare or be paid by Medicare for services of the Medicare nonparticipating reimburse- that the neuropsychologist furnishes to Medicare ment rate. This is called the “limiting charge.” bene fi ciaries. However, if the neuropsychologist The potential reimbursement rate for NON- continues to grant the organization the right to PAR providers is 115% of the Medicare NON- bill and be paid for the services he furnishes to PAR reimbursement rate, which is 109.25% of patients, the organization may bill and be paid the participating provider reimbursement by the Medicare patient for the services that are rate). Of course, as a NON-PAR provider, the provided under the private contract. The deci- onus is on your practice to bill and collect sion of an individual provider to opt out of from your patients. For many practices, the Medicare does not affect the ability of the group cost of billing Medicare on behalf of their practice or organization to bill Medicare for the patients, then billing the patients to collect services of those and practitioners who continue what Medicare paid directly to them, and then in a participating or nonparticipating status with attempting to collect from these patients is not Medicare. worth it. 3. OPT-OUT: Neuropsychologists also may elect to opt out of the Medicare system entirely. To Other Critical Medicare Issues do so, one agrees to not participate in the Medicare program for 2 years and privately We would be remiss if we did not discuss two contracts with Medicare bene fi ciaries for ser- enormous claims-related issues facing practices vices rendered. Neuropsychologists can then before 2014: the transition to the 5010 claims bill patients directly for their services at rates transaction standard and the transition to ICD-10. agreed to between the patient and neuropsy- Both have the potential to bring cash fl ow from chologist. To meet the legal requirements for most insurance payors to an absolute standstill . the opt-out option, one must sign and fi le an The fi rst deadline of January 1, 2012, is for af fi davit in which they agree not to bill or the adoption of a new standard—the 5010 receive payment from Medicare for at least standard—for electronic claims transactions. 2 years. This change must be done to accommodate core 13 Clinical Neuropsychology Practice and the Medicare Patient 207 processes such as claims submission and remis- From a business perspective, ICD-10 matters, sion and additional processes such as claim too…a great deal. Why? Because ICD-10 codes status inquiry, eligibility inquiry, and transaction consist of between 3 and 7 alphanumeric charac- acknowledgment. ters; ICD-9 codes consist of 3Ð5 digital charac- The second deadline is the long-awaited dead- ters. This expansion from a maximum of fi ve line for moving from ICD-9 to ICD-10. This characters to seven characters and the change deadline is slated for October 1, 2013. In addition from a numeric fi eld to an alphanumeric fi eld will to changes neuropsychologists will have to make require numerous behind-the-scene changes to in recording diagnoses and procedures, the move the “business” of neuropsychology. to ICD-10 will require extensive programming The following list of questions for your prac- and testing of practice management systems, tice management system vendor should guide revision of encounter and testing forms, and your practice in its preparations [9 ] . numerous other changes. [Note: Many neuropsychologists use DMS-IV/TR for billing. Many of Practice Management System Vendor the same issues will occur when the revised Questions: 5010 DSM-V is published.] ¥ When will your product be upgraded to sup- It is critical that practices be ready for these port the 5010 standard? two deadlines. Failure to prepare for either ¥ When will we be able to run test claims using could bring a practice to its operational—and the 5010 standard? [If the date they provide fi nancial—knees. you is later than October 1, 2011, push for an earlier date]. ¥ In addition to claims submission, what trans- Moving from X12 4010A1 to 5010 actions will we be able to test? ¥ What preparation is needed on our end to test HIPAA law requires the Department of Health and the 5010 standard? Human Services (HHS) to adopt standards that ¥ Is the upgrade to 5010 included in my ongoing “covered entities” (i.e., all practices, health plans, maintenance expense? electronic billing clearinghouses) must use when ¥ Will your product support both the 4010A1 electronically conducting core administrative trans- and the 5010 standard during a transition actions. The current version of this standard is the phase? Accredited Standards Committee’s X12 Version ¥ Will we be permitted to migrate to the 5010 4010/4010A1. Beginning January 1, 2012, the standard prior to January 1, 2012? required standard will be Version 5010, which will There are several questions you should ask of allow for additional functionality. The new standard your clearinghouse and payors along these same holds the promise of more ef fi cient claims transac- lines: tions for your staff and, if your practice is ready, will ¥ When will you be ready to support the 5010 have no impact on your clinical routine. standard for all of our electronic transactions? ¥ Will your software be upgraded to support all Moving from ICD-9 to ICD-10 features of the 5010 standard? ¥ What changes must be made on our end to From a clinical perspective, ICD-10 will require support the 5010 standard? Are additional reg- much more specifi city. The number of diagnoses istrations/noti fi cations required? increases from about 13,000 to more than 68,000, ¥ Will there be additional fees associated with while the number of procedures will go from this migration? This is a question for your 4,000 to 72,589. The more you understand the clearinghouse. ICD-10 nomenclature, the better off you will be ¥ When can we test the 5010 standard process in on October 1, 2013. total with our practice management software, 208 E.A. Peck III et al.

our clearinghouse, and payors all testing the Some Common Medicare Patient same data set(s)? Request Situations: What Is the ¥ What are your plans to support both the Appropriate Response? 4010A1 and 5010 standards concurrently?

Practice Management System Vendor These responses are based upon a review of the Questions: ICD-10 current APA ethics code as well as our years of clinical and business-related experience. Our ¥ When will your product be upgraded to sup- responses should be viewed as guidelines to be port ICD-10? considered by the reader. You may develop other ¥ When will we be able to run test claims using responses to these situations that are also appro- ICD-10? [If the date they provide you is later than priate or, perhaps, even more appropriate than June 1, 2013, push for an earlier date. This transi- what is noted below. The main thrust of each tion is going to be a huge one for all of us.] response deals with (a) making a priori service ¥ What preparation is needed on our end to test delivery decisions about the contractual arrange- ICD-10? ments you set up with the patient and (b) using ¥ Is the upgrade to ICD-10 included in my ongo- your understanding of how the patient’s insuring maintenance expense? ance approval and reimbursement system works. ¥ Will our practice management (and/or electronic health record) software include a search- Situation A . The patient who wants you to carry able ICD-10 database? out a comprehensive, attorney-requested or court- ¥ Will your product support both ICD-9 and ordered, forensic examination, which is to be ICD-10 during a transition phase? Do you billed in its entirety to Medicare. The purpose of have projected dates for the transition phase? this evaluation is for a forensic opinion(s) to be ¥ Will we be permitted to migrate to ICD-10 developed and used in a legal matter. prior to October 1, 2013? Response. Do not accept the referral with the proviso of billing Medicare for a forensic (admin- Questions for Clearinghouses and Payors istrative) service. This is not a medically neces- ¥ When will you be ready to accept ICD-10 sary service. You may be in violation of several codes on claims? ethical rules as well as run the risk of committing ¥ What changes must be made on our end to fraud in terms of your contractual relationship support ICD-10? Are additional registrations/ with the insurance payor. Ask yourself the ques- noti fi cations required? tion, “Is the referral question and the resultant ¥ Will there be additional fees associated with testing medically necessary as they relate to the ICD-10? making of a diagnosis or alleviating a medical or ¥ What “claim scrubbing” edit changes will be mental problem? Would the testing be necessary made to your software to process ICD-10 if there was no active litigation?” claims? When will you be able to provide us with an explanation of how these new edits Medicare speci fi cally states . The services of CPs will impact operations? are not covered if the service is otherwise ¥ When can we test ICD-10 submissions in total excluded from Medicare coverage even though a with our practice management software, our clinical psychologist is authorized by State law to clearinghouse, and payors all testing the same perform them. For example, the Social Security data set(s) using ICD-10 codes in 5010 Act (Section 1862(a)(1)(A)) excludes from cov- transactions? erage services that are not “reasonable and neces- ¥ What are your plans to support both ICD-9 sary for the diagnosis or treatment of an illness or and ICD-10 concurrently? injury or to improve the functioning of a mal- ¥ Will you be ready for migration to ICD-10 formed body member.” Therefore, even though prior to October 1, 2013? the services are authorized by State law, the 13 Clinical Neuropsychology Practice and the Medicare Patient 209 services of a CP that are determined to be not Please note the following caveats. Many of the reasonable and necessary are not covered [10 ] . forms have been reviewed by our company attor- Situation B. The patient has always wondered if ney for acceptable legal standards according to the they could have a learning disability, and now laws of the Commonwealth of Virginia. You will they want to be tested under Medicare for that need to determine whether the wording in these service. They want educational testing to identify forms is legally valid in your jurisdiction. Also, we a diagnosis of a learning disability, and the patient feel that these forms refl ect an appropriate profes- wants you to bill the services to Medicare. They sional standard of practice according to current are not complaining of any other form of medi- APA ethics standards. Please do not try to interpret cal, neurological illness or injury or mental health these documents out of context. Our offi ce will problem that may be causally associated with change these forms whenever it is deemed neces- such an educational condition. sary so as to maintain acceptable legal and ethical Response. It is our understanding that Medicare standards. Finally, each of these forms is designed does not cover testing for educational purposes, to be completed on an a priori service delivery such as to identify a learning disability, as it does basis. This issue is critical in many of the circum- not meet the criteria for medical necessity/cov- stances relevant to these forms. ered service. (a) Referral form (Fig. 13.1 ): This intake form is Situation C . The patient asks or demands that you typically completed as part of a telephone waive either their co-pay, their deductible, or both. call from either the referral source or the Response . Do not waive the co-pay or deductible. patient/patient’s family. Please note that it Not only are you providing a service well below also prompts for secondary and tertiary insur- your cost basis but you may fi nd that you have ance information. Some patients have violated the law! The Centers for Medicare & Medicare plans that may require a preautho- Medicaid Services (CMS) has mandated that rization for services. You do not want to have physicians and other providers of health care to try to get a preauthorization while the MUST collect co-pays and deductibles [11 ] . patient is waiting at the registration window The reasoning behind this is as follows: If you and waiting for their appointment. (the neuropsychologist) waive the co-pay or (b) Registration form (Fig. 13.2 ): Page 1 asks for deductible, you are, in effect, giving the patient a the typical information. Page 2 addresses a discount. Therefore, if you are willing to “sell” number of specifi c issues. Without going into your service to the patient at a discount, you a line by line annotation, please note several should also give a discount to the insurer. A sec- items of particular interest: fi rst, that the time ond (and lesser) reason for requiring co-pays and for testing includes administration, scoring, deductibles is to cause the patient to have a share and report preparation as well as report dis- in the cost of their health care, thereby reducing cussion and, second, that the cost of respond- unnecessary consumption of covered services. ing to medical legal matters requires time and that fees will be charged for these services; page 3 deals with documenting the Medicare A Review of Some Sample Forms No Show policy and other general insurance for a Private Practice in Clinical matters. Neuropsychology (c) Waiver of insurance (Fig. 13.3 ): This form is a copy of the standard Medicare “Advance The items that follow are examples of the types Notice for Medically Unnecessary Services— of forms that we have developed to address com- Waiver of Medical Necessity” form [ 12 ] . mon situations which occur in management of This form should be used in those situations our practice. Please feel free to adapt them to where you have a Medicare enrollee who is your practice as needed. Versions of some of requesting services which, in their speci fi c these forms have been presented elsewhere [5 ] . situation, are not likely to be deemed medically 210 E.A. Peck III et al.

Fig. 13.1 Referral form 13 Clinical Neuropsychology Practice and the Medicare Patient 211

Fig. 13.2 Patient registration form 212 E.A. Peck III et al.

Fig. 13.2 (continued) 13 Clinical Neuropsychology Practice and the Medicare Patient 213

Fig. 13.2 (continued) 214 E.A. Peck III et al.

Fig. 13.3 Medicare noncovered service form 13 Clinical Neuropsychology Practice and the Medicare Patient 215

necessary by Medicare. In many situations, the PCP’s offi ce and be interviewed and then federal rules still require the provider to sub- accessed via Internet-based video connection mit the claim, even though they have good (e.g., Skype-type service). reason to believe in advance that the service, (f) As Medicare moves toward its uncertain e.g., forensic issues, is not going to meet the future, Congress will explore other mecha- accepted standard of medical necessity . This nisms to rein in the costs of caring for a signed waiver allows the provider to bill the growing Medicare population. We, as a pro- enrollee for the service instead of having to fession, must work together to create a qual- write off the claim. For further information itative and quantitative value proposition. regarding this complex issue, please refer to Neuropsychology can and should play a key the website of your state’s Medicare Part B role in caring for Medicare patients. If they carrier. are unable to make a strong case for such, we run the risk of neuropsychology being pushed to the sidelines of patient care . Medicare and Neuropsychology: A (g) As electronic medical records become more Look Forward to the Abyss or to Eden? widespread, private practice neuropsycholo- What Will Our Business Management gists will adopt such technology in greater Practices Look Like in the Future? numbers. There will be many reasons, but simply being able to maintain record access from (a) We expect to see per unit reimbursement referral sources, and to provide quick transmis- levels continue to decline over the next sion and access of our reports to other sources 10 years. We also expect to see the upper will become more critical. If we do not stay on limit of allowable testing units decline as an EMR technology par with our MD referral Medicare increases the demand for comput- sources, then the MD will see the cost of their erized testing. of fi ce having to copy or fax records to us as a (b) These changes will result in an even greater fi nancial disincentive for a referral. reliance on forensic and other professional It is therefore incumbent to focus on the services where fee structures are less regu- “value” of the services we offer. Even as many of lated. This will also “make up” some of the our tests become computerized, we must continue lost revenue for those who continue to see to demonstrate the value of the personal interac- Medicare patients. tion between neuropsychologist and patient. We (c) We also envision more neuropsychologists must be able to demonstrate how the information choosing to “opt out” of Medicare and work we provide is better and more accurate than solely on a private contract arrangement with “shortcut” software-based neuropsychological patients. testing being sold to (and used by) other medical (d) Many of the “a la carte” options typically professions who do not have our training and offered to patients for free or little cost will expertise. We must be able to show how our care need to become full fee expenses. These creates better patient outcomes. To the extent we items include (1) forms that the patient wants can do this, our future is much brighter. completed and (2) letters to document some element of care or diagnosis. Other services, which may not be billed to Medicare. Clinical Pearls (e) Once Medicare and other insurance companies allow for services where the professional ¥ Know what constitutes a medically necessary is not actually physically present on-site with service and agree to bill Medicare for such the patient, the entire question of in-of fi ce service and the patient for services that are not testing will become moot. The patient will medically necessary according to Medicare. not have to come to the neuropsychologist’s ¥ Do not hesitate to educate the patient as to what of fi ce if they can go to another site such as is a medically necessary service and what is not 216 E.A. Peck III et al.

medically necessary. The patient should have a References say in their health-care delivery choices. This includes accepting fi nancial responsibility for 1 . http://www.kff.org/medicare/timeline/pf_intro.htm . nonmedically necessary services. Accessed 29 May 2011. ¥ Document time and service provided to the 2. President Richard M. Nixon. Health care: requests for patient properly the fi rst time, according to action on three programs (1972, March 2), message to documentation standards, and you will reduce Congress on Health Care, Congressional Quarterly Almanac 1972. Washington, DC: Congressional the risk of audit problems in the future. Quarterly Books; 1972. p. 43A. ¥ Know what your cost of practice is and use 3 . http://www.managedcaremuseum.com . Accessed 25 that information properly in your clinical care May 2011. decisions. 4. Medicare and Medicaid statistical supplement (2010 Edition). Centers for Medicare and Medicaid Services; ¥ Do not forget the rules you knew yesterday 2010. may have changed overnight. Keep up to date 5. Peck EA. Business aspects of private practice in clini- at sites such as http://www.cms.gov/mlnmat- cal neuropsychology. In: Lamberty GJ, Courtney JC, tersarticles/downloads/SE0816.pdf and other Heilbronner RL, editors. The practice of clinical neuropsychology: a survey of practices and settings. Medicare websites [13, 14 ]. Lisse: Swets & Zeitlinger; 2003. ¥ Be clear and consistent with patients about 6. The long-term outlook for Medicare, Medicaid, and collecting co-pays and deductibles. total health care spending. In: Chapter 2, The long-term ¥ One cannot provide “Luxury car quality care budget outlook. Congressional Budget Of fi ce; 2010. 7. Transmittal 1279. Change request 5613, Pub 100-04 at used car rates of reimbursement.” for Medicare claims processing. Department of Health ¥ We enjoy helping people or we would not & Human Services, Centers for Medicare & Medicaid work in this fi eld. We feel that our professional Services.http://www.cms.go v//transmittals/downloads time has value and that the business arrange- /R1279CP.pdf . 29 Jun 2007. 8. Medicare participation options for physicians. The ments that we make are reasonable and appro- American Medical Association; 2010. priate to providing care to our patients. We 9. Lucien W Roberts III. Preparing Your Practice for cannot provide quality services if we cannot 5010. In: Physicians practice pearls (weekly meet our fi nancial obligations. e-publication of Physicians Practice); 2010. 10. http://www.ssa.gov/OP_Home/ssact/title18/1862. ¥ The next time you visit your doctor, read the htm . Accessed 25 May 2011. sign next to the receptionist’s window. Typically, 11. http://oig.hhs.gov/fraud/docs/alertsandbulletins/ it will state that “Co-pays are expected at time 121994.html . Accessed 25 May 2011. of service” and that “the doctor cannot see you 12. https://www.cms.gov/bni/ . Accessed 25 May 2011. 13. http://www.cms.gov/mlnmattersarticles/downloads/ without your HMO authorization number.” SE0816.pdf . Accessed 25 May 2011. Treat your patients appropriately and in the 14. Medicare Learning Network Centers for Medicare same manner you are treated when you are the and Medicaid Services. 2011. http://www.cms.gov/ patient at the receptionist window. mlnmattersarticles . Accessed 25 May 2011. Professional Competence as the Foundation for Ethical 1 4 Neuropsychological Practice with Older Adults

Arthur C. Russo , Shane S. Bush , and Donna Rasin-Waters

Abstract This chapter provides practical guidelines for the neuropsychologist contemplating a transition into the professional and ethical practice of geriatric neuropsychology. The focus is pragmatic, with an emphasis on advanced preparation. The chapter uses a top-down structure, with each section identifying the relevant core biomedical ethical principles, followed by an elaboration of the relevant ethical requirements as deﬁ ned by the American Psychological Association’s Code of Ethics. Each section then ends with pragmatic suggestions for translating the core ethical principles and relevant ethical requirements into action so that the ethical standards are met at the highest standard. Topics covered include (a) acquiring professional competence, (b) guidelines and resources, (c) what aspiring geriatric neuropsychologists need to know, and (d) recommendations for promoting professional competence in geriatric neuropsychology.

Keywords Ethics • Geriatrics • Older adults • Neuropsychological • Assessment • Evaluation

We do not act rightly because we have virtue or excellence, but rather we have those because we have acted rightly. We are what we repeatedly do. Excellence, then, is not an act but a habit. A. C. Russo , Ph.D. (*) Durant paraphrasing Aristotle (1926) Psychology Department , VA New York Harbor Healthcare System , 800 Poly Place, Room 16-209H , Geriatric neuropsychology is facing a dilemma Brooklyn , NY 11209 , USA with ethical implications that are fueled by two Fordham University , New York , NY , USA divergent trends—the increasingly large number e-mail: [email protected] of older adults, and the relatively small number S. S. Bush , Ph.D., ABPP (CN, RP)., ABN. of professionals trained to assess them. The pro- D. Rasin-Waters , Ph.D. portion of older adults has steadily increased VA New York Harbor Healthcare System , New York , NY , USA since the turn of the last century, with projections e-mail: [email protected] ; [email protected] that it will continue to increase. According to the

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 217 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_14, © Springer Science+Business Media, LLC 2013 218 A.C. Russo et al.

US Census Bureau [ 1 ] , Americans 65 years of for translating the core ethical principles and age or older made up 12% of the population in relevant ethical requirements into action so that 2000. That number is projected to increase to professional practice is conducted at the highest 16% in 2020 and increase again to 20% in 2040. ethical level. Among older adults, the fastest growing segment is expected to be in the oldest age group, those 85 years of age or older, with a US Census Bureau Preparing to Transition into Geriatric projected increase of 233% in the same 40-year Neuropsychology: Acquiring period. By 2050, persons 85 years of age and Professional Competence older are expected to number 19 million [2 ] . At the same time that the population is aging, Developing and maintaining pro fi ciency in clini- neuropsychology is experiencing a current and cal specialties are fundamental to ethical practice. projected shortage of professionals trained to ser- Well before clinical contact with older patients, vice the older adult [3, 4] . A 2002 survey of prac- neuropsychologists transitioning into the fi eld of ticing psychologists found that fewer than 30% geriatric neuropsychology should insure that they had any graduate coursework in geropsychology are competent to provide the service. A core com- and fewer than 20% had any supervised practi- petence in clinical neuropsychology is a prerequi- cum or internship experience with older adults; site to the practice of geriatric neuropsychology over half of the respondents reported that they and in some clinical contexts suf fi ces. As the APA needed further training [5 ] . Packard [6 ] noted [ 13 ] noted in its Guidelines for Psychological that although 70% of psychologists have older Practice with Older Adults, some problems of adults as patients, only 3% have formal geropsy- older adults are essentially the same as those of chology training. This disparity poses an ethical other ages, and clinicians working with older dilemma due to the increasing likelihood that adult patients can generally respond with the same psychologists will be servicing a population for skill set for which all professional psychologists whom they have had little training. have generic training. However, for many prob- The purpose of this chapter is to examine the lems facing older adults, a generic competence in ethical issues and challenges for neuropsycholo- neuropsychology is simply not enough. gists contemplating a career in, or transition into, The core biomedical ethical principles rele- the practice of geriatric neuropsychology. The vant for professional competence are (a) promo- focus is pragmatic with an emphasis on preparation of patient welfare (benefi cence) and (b) tion, consistent with a proactive approach to eth- avoidance of harm (nonmale fi cence); together ics [7– 9] . A proactive approach assumes that these constitute the fi rst general principle of the mandated professional standards represent only a APA Ethics Code (see also [ 11 ] ). The APA [12 ] minimum requirement that the ethical profes- Ethics Code further details these core ethical sional uses as a starting point in the pursuit of principles in several standards. Ethical Standard practicing at the highest ethical level possible 2.01 (Boundaries of Competence) states that psy- [ 10] . A proactive ethical approach recognizes chologists only provide services with populations that preparing in advance for anticipated ethical and in areas “within the boundaries of their com- challenges is always a better course than remedi- petence, based on education, training, supervised ating the ethical impact of poor preparation. We experience, consultation, study or professional will use a top-down structure, describing the rel- experience.” Ethical Standard 2.03 (Maintaining evant core biomedical ethical principles [ 11 ] , fol- Competence) requires psychologists to develop lowed by an elaboration of the relevant ethical and maintain competence through ongoing requirements as defi ned by the American efforts. Ethical Standard 3.04 (Avoiding Harm) Psychological Association [12 ] Ethical Principles echoes the bioethical principle of nonmalefi cence of Psychologists and Code of Conduct . In the in stating that psychologists “take reasonable conclusion, we will offer pragmatic suggestions steps to avoid harming their clients… and to 14 Ethical Practice 219

minimize harm where it is foreseeable and available at the national, state, and local levels and unavoidable.” Standard 9.07 (Assessment by include national professional associations, state Unquali fi ed Persons) speci fi es that “psycholo- licensing and ethics boards, liability insurance car- gists do not promote the use of psychological riers, institutional ethical guidelines and ethics assessment techniques by unquali fi ed persons,” committees, and an increasingly large number of except for training purposes. scholarly books and articles. The study of sentinel To maximize the probability of promoting or paradigm cases helps prepare a foundation for patient welfare while minimizing the potential sound ethical judgment. for patients to be harmed by the service, geriatric The integration of core competencies in clini- neuropsychologists must possess the required cal neuropsychology combined with the knowl- specialized knowledge base and skill set to per- edge and skills in geropsychology advocated by form assessments with this population. This spe- the above resources provides the foundation for cialized knowledge and skill set goes beyond a competent practice of geriatric neuropsychology generic competence in neuropsychology. [8 ] . At all times, geriatric neuropsychologists are well served by developing familiarity with these guidelines and resources before they are needed, Guidelines and Resources preparation being one of the hallmarks of a proactive ethical approach. Fortunately, excellent resources are now readily available to promote ethical practice and facilitate ethical decision making. APA’s [ 13 ] A Nonexhaustive List of What Guidelines for Psychological Practice with Older Aspiring Geriatric Neuropsychologists Adults provides a resource for self-assessment of Need to Know current knowledge and skills; it is a good starting point for neuropsychologists who want to transi- Knowledge of gerontology complements neurop- tion to clinical assessment of older persons. In sychological competence in multiple ways. It is addition, the American Bar Association particularly valuable for clinicians to consider (1) Commission on Law and Aging—American late adulthood as a distinct developmental stage, Psychological Association [14 ] Assessment of (2) medical aspects of aging, (3) psychopathol- Older Adults with Diminished Capacity: A ogy and neuropathology in older adults, (4) fam- Handbook for Psychologists provides general ily and social systems, (5) cohort effects, (6) approaches to assessment of the frail elderly with cultural issues, and (7) unique ethical and legal speci fi c recommendations for assessment of vari- requirements. ous capacities related to cognitive and functional ability within the legal system. The most recent and comprehensive guidelines Late Adulthood as a Distinct are derived from the Pikes Peak model for training Developmental Stage in clinical geropsychology that evolved out of the 2006 National Conference on Training in The professional and ethical practice of geriatric Professional Geropsychology [15 ] . These compre- neuropsychology requires a knowledge base con- hensive competencies emphasize self-evaluation sisting of the theory and research in aging, with an and supervisee rating in core knowledge and skill in-depth understanding of expected life span areas, including clinical assessment, intervention, development. Competent geriatric neuropsychol- consultation, and other professional services for ogists have a developmental perspective and an older persons. Experience with older adults across understanding of successful aging, as well as the a wide range of care settings and demographic and common changes in cognition over time. Cognitive sociocultural diversity are emphasized. In addi- abilities change at different rates, with some abili- tion, resources relating to ethical practice are also ties more vulnerable to aging than others [16, 17 ] . 220 A.C. Russo et al.

Without this knowledge, clinicians may be more practical adaptations for each potential defi cit, at risk of misinterpreting normative age-related including tests available in large print or orally decline as pathological deterioration. Not only presented versions with norms, and shortened does cognition change over time, but that change batteries to prevent fatigue. is differentially impacted by life experience. For example, although research has found that short- term memory often declines with age, short-term Psychopathology and Neuropathology memory related to one’s expertise, which Horn described as expertise-wide span memory, is more Competent geriatric neuropsychologists under- robust and may increase with age [17, 18 ] . stand pathological changes in personality and cognition, and how such changes manifest in the older patient. For example, late-life depres- Medical Status sion may coexist with cognitive impairment and may manifest without an obvious display of An understanding of biological and health-related sadness. Other problems, such as dementia due aspects of aging contributes to patient care. to degenerative brain disease and stroke, are Therefore, geriatric neuropsychologists pay par- rarely seen among the young but fi nd an increas- ticular attention to gathering a thorough medical ing rate of incidence among an older population history, including determining the older person’s [ 13] . Without a competent grounding in geriat- functional status. Over 80% of older adults have ric neuropsychological pathology, clinicians at least one chronic health condition, with may fail to accurately differentiate normal from 75-year-olds averaging three chronic conditions abnormal changes or fail to accurately differen- and fi ve prescriptions [ 19, 20 ] . The aging process tiate among disease categories such as demen- affects how the body metabolizes medication, tias due to stroke, frontal-temporal conditions, with older adults at risk for being given medica- or Alzheimer’s disease, leading to compromised tion or dosages that are inappropriate [ 19 ] . This treatment recommendations [ 24, 25 ] . interplay of chronic medical condition and medications poses a particular challenge to geriatric neuropsychology because of its potential impact Family and Social Systems on cognition and the possibility of confusing a permanent with a medically based reversible cog- The impact of family and social systems on nitive impairment. patient functioning and independence has age- Sensory abilities must be taken into account related aspects. As questions of independent because sensory defi cits disproportionately functioning arise, the reliance on family and non- impact older adults. Surveys fi nd that 37% of family support systems comes to the fore. In those 65 years of age and older have hearing addition, issues surrounding loss increasingly impairment and 30% have impaired vision [ 21 ] . surface. Not only are older adults more likely to Peripheral sensory defi cits can impact perfor- have experienced loss, but they may fi nd them- mance on neurocognitive tests and may be con- selves the only surviving member of their family fused with cortical impairments [22 ] . For or peer group [ 26 ] . Often the issues of loss example, the older adult may be mistakenly become intertwined with the challenge of recre- diagnosed with memory impairment due to an ating a meaningful identity and social world. apparent inability to learn new information when With issues such as dementia, the patient and the real problem is sensory loss that interferes caregivers can benefi t from the support and with the reception of new information. Potter knowledge of local and national resources. The and Attix [ 23] suggested additional consider- aspiring geriatric neuropsychologist should ations for issues of motor function, fatigue, lit- develop working knowledge of these resources eracy, rapport, and motivation. They recommend prior to serving the older person. 14 Ethical Practice 221

Cohort Effects informal ways, but we need something that’s more systematic” (p. 34). Because each generation is in part the product of From a proactive ethical approach, the best unique historic circumstances, the practitioner pathway toward competence is one that is struc- needs to understand cohort or generational tured, comprehensive, and supervised. Competent effects. For example, disruption of education was professional and ethical practice does not happen common among older adults coming of age dur- by chance [ 9] , nor is it best left to the subjective ing the Depression Era and WWII. Differences in judgment of the person seeking competence. attitudes toward test taking and familiarity with Some obvious limitations to self-assessment and computers and multiple choice items may vary. self-study are that they lack informative feedback, And fi nally, the stigma of seeing a psychologist/ and that they are unable to identify and correct neuropsychologist who handles “mental health”- those blind spots which by de fi nition are outside related issues can often carry a stigma for many the person’s awareness. The development of older persons. Sensitivity to such issues is impor- expertise requires deliberative, repetitive practice tant in the development of rapport and interpreta- presented at an appropriate level of dif fi culty, for tion of behavior during the assessment. which the person receives informative and cor- rective feedback [28, 29 ] . Some clinicians achieve the needed additional education and training from Cultural Considerations a postdoctoral or respecialization program. For those unable to pursue a formal specialization Cultural issues must be taken into account. An training program, guided study and supervised understanding of variables such as ethnicity, accul- clinical experience under the direction of an turation, quality of education, and racial socializa- expert mentor may suf fi ce. tion is important in the interpretation of assessment results [27 ] (See Chap. 3 in this volume). Recommendations for Promoting Professional Competence in Geriatric Ethical and Legal Requirements Neuropsychology

Aspiring geriatric neuropsychologists must develop Preparation is the hallmark of a proactive ethical knowledge of the ethical and legal issues related approach to geriatric neuropsychology. For neu- to geriatric neuropsychology, such as decision- ropsychologists aspiring to serve older adults, making capacity, competence, confi dentiality, preparation starts with acquiring the specialized informed consent, and managing the potential knowledge and skill set of geriatric neuropsy- confl icts of interests inherent in dealing with chology with appropriate consultation of guide- family and nonfamily caretakers, health care sys- lines, best practices, and supervision prior to tems, and other entities. serving this population. A proactive ethical approach recognizes that preparing in advance for ethical challenges is always a better choice Developing Professional Competence than remediating the ethical impact of poor preparation. Clinicians who invest the time and effort Despite the availability of numerous resources to establish and maintain competence in neuro- for establishing professional competence, we psychological practice with older adults will fi nd believe, like Packard [6 ] , that these resources are themselves well positioned to provide valuable at best a partial and piecemeal solution. Qualls services to others while increasing the likelihood (as cited in [ 6 ] ) presented a similar argument, of having a personally and professionally reward- stating “I think people are getting this training in ing career. 222 A.C. Russo et al.

with older adults: current patterns, sources of training, Clinical Pearls and need for continuing education. Prof Psychol Res Pract. 2002;33:435–42. 6. Packard E. Polishing those golden years. APA • Enlist the aid of a competent geriatric neuro- Monitor. 2007;38:34. psychologist to serve as a mentor to guide 7. Bush SS. Ethical decision making in clinical neurop- your skill development. sychology. New York: Oxford University Press; 2007. • Do a self-assessment using the APA’s [13 ] 8. Bush SS. Geriatric mental health ethics: a casebook. Guidelines for Psychological Practice with New York: Springer; 2009. Older Adults and Knight et al.’s [ 15 ] Pikes Peak 9. Martin T, Bush S. Ethical considerations in geriatric neu- model for training in professional geropsychol- ropsychology. NeuroRehabilitation. 2008;23: 447–54. 10. Knapp SJ, Vandecreek LD. Practical ethics for psy- ogy to identify the areas of competence you chologists: a positive approach. Washington, DC: need to develop. Review this with your mentor American Psychological Association; 2006. for accuracy to identify blind spots. 11. Beauchamp TL, Childress JF. Principles of biomedi- • Consider utilizing resources from the Council cal ethics. 5th ed. New York: Oxford University Press; 2001. of Professional Geropsychology Training 12. American Psychological Association. Ethical princi- Programs (CoPGTP; available at http://www. ples of psychologists and code of conduct. Washington, uccs.edu/~cpgtp/ ). The CoPGTP was an unex- DC: American Psychological Association; 2002. pected outgrowth from the Pikes Peak confer- 13. American Psychological Association. Guidelines for psychological practice with older adults. Am Psychol. ence and offers multiple resources for 2004;59:236–60. programs as well as individuals for all levels 14. American Bar Association Commission on Law and of training in clinical geropsychology [30 ] . Aging, American Psychological Association. • With your mentor, create a course of study which Assessment of older adults with diminished capacity: a handbook for psychologists. 2008. www.apa.org/pi/ addresses any weaknesses discovered during the aging/programs/assessment/capacity-psychologist- self-assessment. Include supervised practice in handbook.pdf . Retrieved 1 Feb 2011. geriatric neuropsychology as needed. 15. Knight B, Karel M, Hinrichsen G, Qualls S, Duffy M. Pikes Peak model for training in professional geropsychology. Am Psychol. 2009;64(3):205–14. 16. Horn JL, Noll J. Human cognitive abilities: Gf-Gc theory. References In: Flanagan DP, Genshaft JL, Harrison PL, editors. Contemporary intellectual assessment: theories, tests, and 1. US Census Bureau. Projections of the population by issues. New York: Guilford Press; 1997. p. 53–91. selected age groups and sex for the United States: 17. Horn JL, Blankson N. Foundations for better under- 2010 to 2050 (NP2008-T12). 2008. www.census.gov/ standing of cognitive abilities. In: Flanagan D, population/www/projections/summarytables.html . Harrison P, editors. Contemporary intellectual assess- Retrieved 24 Jul 2010. ment. New York: Guilford Press; 2005. p. 41–60. 2. Vincent GK, Velkoff VA. The next four decades. The 18. Horn JL, Masunaga H. On the emergence of wisdom: older population in the United States: 2010 to 2050. expertise development. In: Brown W, editor. In: Current population reports. Washington, DC: U.S. Understanding wisdom: source, science and society. 2010 Census Bureau; 2010. p. 25–1138. www.census. Philadelphia, PA: Templeton Foundation Press; 2000. gov/prod/2010pubs/p25-1138.pdf. Retrieved 24 Jul p. 245–76. 2010. 19. Merck Institute of Aging and Health. The state of 3. Clay R. Geropsychology grants in peril: seven gerop- aging and health in America. Washington, DC: Merck sychology training efforts have lost funding they Institute of Aging and Health; 2004. receive through the Federal Graduate Psychology 20. National Academy on an Aging Society. Chronic con- Education (GPE) Program. Monitor Psychol. ditions: a challenge for the 21st century, Challenges 2006;37:46. for the 21st century: chronic and disabling conditions, 4. Rosen AL. Testimony to the Policy Committee of the vol. 1. Washington, DC: National Academy on an White House Conference on Aging. The shortage of Aging Society; 1999. an adequately trained geriatric mental health work- 21. Desai M, Pratt LA, Lentzner H, Robinson KN. Trends force. 2005. www.whcoa.gov/about/policy/meetings/ in vision and hearing among older Americans. Aging Jan_24/Rosen%20WHCOA%20testimony.pdf . trends, No. 2.. Hyattsville, MD: National Center for Retrieved 26 May 2010. Health Statistics; 2001. 5. Qualls S, Qualls SH, Segal DL, Norman S, Niederehe 22. Baltes PB, Lindenberger U. Emergence of a pow- G, Gallagher-Thompson D. Psychologists in practice erful connection between sensory and cognitive 14 Ethical Practice 223

functions across the adult life span: a new window term care: a comprehensive guide. New York: to the study of cognitive aging? Psychol Aging. Hatherleigh Press; 2000. p. 201–26. 1997;12:12–21. 27. Manly JJ. Cultural issues. In: Attix DK, Welsh- 23. Potter G, Attix D. An integrated model for geriatric Bohmer KA, editors. Geriatric neuropsychology: neuropsychological assessment. In: Attix DK, Welsh- assessment and intervention. New York: Guilford Bohmer KA, editors. Geriatric neuropsychology: Press; 2006. p. 198–222. assessment and intervention. New York: The Guilford 28. Ericsson K. The road to excellence: the acquisition of Press; 2006. p. 5–26. expert performance in the arts and sciences, sports, 24. American Psychiatric Association. Practice guide- and games. Mahwah, NJ: Erlbaum; 1996. lines for the treatment of patients with Alzheimer’ 29. Sternberg RJ, Grigorenko EL, editors. The psychol- disease and other dementias of late life. Am ogy of abilities, competencies, and expertise. New J Psychiatry. 1997;154(5 Suppl):1–39. York: Cambridge University Press; 2003. 25. American Psychological Association. Guidelines for 30. Karel MJ, Emery EE, Molinari V, the CoPGTP Task the evaluation of dementia and age related cognitive Force on the Assessment of Geropsychology decline. Am Psychol. 1998;53:1298–303. Competencies. Development of a tool to evaluate 26. Kastenbaum R. Counseling the dying patient. In: geropsychology knowledge and skill competencies. Molinari V, editor. Professional psychology in long Int Psychogeriatr. 2010;22:886–96. Ethical Considerations in the Neuropsychological Assessment 1 5 of Older Adults

Arthur C. Russo , Shane S. Bush , and Donna Rasin-Waters

Abstract Translating core ethical principles and relevant ethical requirements into pragmatic action often presents its own set of challenges for geriatric neuropsychologists aspiring to practice at the highest ethical level. The purpose of this chapter is to provide pragmatic suggestions with an emphasis on preparation. Topics include (a) preparing the older adult and concerned others for what to expect from the assessment, (b) preparing all for potentially distressing results, (c) technical test preparation as seen in the thoughtful selection of instruments that are sufﬁ ciently comprehensive, adequately normed, and well grounded in current theory and research, and (d) ethically preparing the feedback session.

Keywords Ethics • Geriatrics • Older adults • Neuropsychological • Assessment • Evaluation

In theory there is no difference between theory and practice. In practice there is. Jan van de Snepscheut/Yogi Bera

A. C. Russo , Ph.D. () Translating core ethical principles and relevant Psychology Department , VA New York Harbor ethical requirements into pragmatic action often Healthcare System , 800 Poly Place, Room 16-209H , presents its own set of challenges for geriatric Brooklyn , NY 11209 , USA neuropsychologists aspiring to practice at the Fordham University , New York , NY , USA highest ethical level. The purpose of this chapter e-mail: [email protected] is to provide pragmatic suggestions with an S. S. Bush , Ph.D. • D. Rasin-Waters , Ph.D. emphasis on preparation, consistent with the VA New York Harbor Healthcare System , New York , NY , USA proactive approach to ethics espoused earlier e-mail: [email protected] ; [email protected] (see chap. 14, also [1– 3 ] ).

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 225 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_15, © Springer Science+Business Media, LLC 2013 226 A.C. Russo et al.

Assessments), 4.04 (Minimizing Intrusions on Preparing the Patient and Concerned Privacy), 3.07 (Third-Party Requests for Services), Others Prior to Performing the and 6.04 (Fees and Financial Arrangements) [ 6 ] . Neuropsychological Assessment The basic idea is that the person contemplating a professional service has a right to (a) certain Prior to conducting the neuropsychological information before consenting to the service, (b) assessment, the geriatric neuropsychologist have this information provided in language he or ensures that the examinee, and any concerned she can understand, and (c) ask questions and third-party participants, thoroughly understands receive answers to these questions prior to giving the parameters of the evaluation, including who consent. Although there may be adverse conse- the client is, what the service entails, who has quences in some contexts for doing so, the person access to the report, and how it will be used, as also has the right to decline the service. well as other considerations detailed in this chap- In terms of specifi c content, the person has a ter. Many of the ethical pitfalls facing aspiring right to know (a) the nature and purpose of the geriatric neuropsychologists stem from a failure service, (b) who will receive a report, (c) who to properly prepare the older adult and any con- will have access to the information obtained, (d) cerned third-party individuals and institutions for how the information may be used, (e) the possible the assessment. Often this failure in preparation impact the service may have on his or her life, (f) is due to the clinician’s lack of clarity regarding the limits of con fi dentiality, (g) the involvement the relevant ethical requirements and guidelines of third parties, and (h) the fee. The person also and a lack of experience in translating the rele- has the right to refuse the service even after it is vant requirements into pragmatic actions. underway. In addition, the person consenting to a At the core of principle-based ethics are four professional service maintains the right to pri- general bioethical principles: respect for patient vacy, so the patient decides how much informa- autonomy, bene fi cence, nonmale fi cence, and jus- tion may be communicated to others; the tice [4 ] . Although all four principles are important neuropsychologist is obligated to share only as to geriatric neuropsychology, respect for auton- much information as is needed to ful fi ll the terms omy assumes a primary role in the preparation of of the service. There are some exceptions. When patients and other involved parties for the neuro- the service is court mandated, prior consent is psychological assessment. The principle of respect usually not required. But even here the person for autonomy is often used to emphasize the free- has a right to know that the service is court man- dom to make choices, with freedom understood as dated and what the service will entail, and the being free from interference. This aspect of auton- person may refuse the service if the consequence omy recognizes the basic right of competent for doing so is preferable to the person. Rather adults not to be interfered with against their wishes than “informed consent,” the examinee in such and supports the fundamental human rights of pri- instances is provided “notifi cation of purpose.” In vacy, dignity, and freedom of self-determination addition, if elder abuse is discovered, or the older [5 ] . When it comes to seeking professional ser- person poses a danger to self or others, the neu- vices, freedom of self-determination implies the ropsychologist may be required to report that freedom to make knowledgeable choices and information to help promote safety. underlies the importance of informed consent. In addition to these common ethical practices, In many instances, the same considerations geriatric neuropsychologists often confront less regarding privacy and informed consent that hold common ethical concerns regarding privacy and for the general practice of neuropsychology also confi dentiality due to the nature of the population hold for the more specialized practice of geriatric served and the specialized preparation required neuropsychology. The American Psychological for informed consent. These aspects of prepara- Association Ethics Code addresses these consid- tion include (a) preparing the competent older erations in several standards, such as 3.10 person who has compromised functioning; (b) (Informed Consent), 9.03 (Informed Consent in preparing the incompetent older person and the 15 Ethical Considerations in Assessment 227 legal surrogate or guardian; (c) preparing family The older adult with compromised hearing might members, caretakers, and third-party systems; have material presented at a higher volume at the and (d) preparing the older person and relevant same time it is presented visually. Oftentimes, the caretakers for potentially distressing and unwel- way the person is approached and spoken to has a comed results. direct bearing on the older person’s decision- making capacity, with infantilizing “elder speak” undermining the process [7 ] . Preparing the Competent Older Adult Additionally, a diagnosis of dementia does not with Assumed Compromised mean the person lacks all capacity or is incompe- Functioning tent. Until the disease advances, the older adult with a diagnosis of dementia often remains com- Capacity and competence are sometimes confused. petent and can provide consent if remedial steps Capacity is the clinical term that refers to the are fi rst taken. Even with the progression of ability to make rational and informed decisions. dementia, many who cannot give consent can still Competence is the legal term that refers to the abil- assent to the service (Ethical Standard 3.10, ity to make rational and informed decisions. Only a Informed Consent). court can make a determination of incompetence; If the older person has fl uctuating levels of until then, adults are considered competent. capacity, the clinician defers discussing informed Although geriatric neuropsychologists assume consent until the older person is more likely to older adults are legally competent, unless a court have suffi cient capacity to consider it. Some older rules otherwise, they should not necessarily persons do better with select others present, so assume older adults have full capacity for informed the clinician may wait until the person can dis- consent. Cognitive abilities differentially decline cuss consent in the company of a trusted, sup- with age. For example, an older person with oth- portive family member or caretaker whose erwise sound mind may show compromised cog- presence brings out the best in the person. But nitive ef fi ciency as processing speed and working regardless of the particulars, ethical geriatric neu- memory decline with age. Sensory impairment ropsychologists strive to ensure that patients are may compromise the person’s ability to under- at their cognitive best when discussing consent. stand. Medical, psychological, or pharmacologi- See Chap. 31 in this volume for more information cal factors may impact capacity temporarily or in about evaluating capacity in older adults. a fl uctuating manner, with the older adult having better and worse days. Simple factors such as fatigue and rest may impact capacity. A person Preparing the Incompetent Older may lack suf fi cient capacity to make a decision in Adult and the Legal Surrogate the evening when tired but show quite adequate or Guardian capacity to make the same decision the following morning when rested [7 ] . When working with incompetent older adults, geri- Consistent with a positive, proactive ethical atric neuropsychologists have specifi c regulatory approach [8 ] , geriatric neuropsychologists exer- ethical requirements to both the older adults and to cise care to ensure that older adult patients are the legal surrogates or guardians. With incompe- well prepared to understand all information nec- tent older adults, clinicians inform the patients to essary to provide informed consent. This process the extent possible of the nature and purpose of the may require the clinician to speak slower and service, using language that is reasonably under- present fewer items for consideration at a time, standable. Clinicians answer any questions and thus giving the older adult the necessary extra concerns, seek assent, and protect patient rights time to process the information without being and welfare ([ 6 ] ; Ethical Standards 3.10, Informed overwhelmed. Sensory impairment may require Consent, and 9.03, Informed Consent in compensatory sensory aids, as well as presenting Assessments). For clients with a legal surrogate or information via more intact sensory channels. guardian, the responsible person must also be fully 228 A.C. Russo et al. informed of all the issues in order to provide in any care decision. When compromised older consent for the assessment of the older adult. adults lack the capacity to make major decisions, From a proactive ethical approach, geriatric they may nonetheless have suf fi cient capacity to neuropsychologists are well served by carefully make other decisions or at least indicate some considering the concept of autonomy. Tradi- preference [7 ] . The experienced geriatric neurop- tionally, autonomy is given an individualistic sychologist realizes that regardless of the older emphasis with the value placed on freedom from adult’s competence, it is unproductive to attempt interference. However, the concept of autonomy as an evaluation without the person’s cooperation. “no interference” can be too limiting, especially when applied to the incapacitated older adult. This traditional concept of autonomy fails to take into Preparing Family Members, account that people are inherently relational and Caretakers, and Third-Party Systems fi nd their autonomy and dignity enhanced and supported by caring relationships. This position was Family members, caretakers, and third-party enti- taken by the Nuf fi eld Council on Bioethics [7 ] : ties (e.g., residential homes and inpatient set- (“…most adults simply do not make autonomous tings) often pose ethical dilemmas for aspiring decision in isolation: rather they come to those geriatric neuropsychologists because of the decisions supported by those close to them and in confl icting agendas and pressure they may bring light of those relationships” (p. 8). Mackenzie and to bear to obtain confi dential information or sway Stoljar [9 ] used the phrase “relational autonomy” clinical opinions. In some cases, the problem is to re fl ect this enhanced de fi nition. due to confl icts between individualistic and rela- From a proactive ethical approach, geriatric tional concepts of autonomy. In such cases, care- neuropsychologists embrace the values of both takers want to help the aging family members individualistic and relational concepts of auton- retain as much autonomous functioning and dig- omy. With the former, ethical clinicians are obli- nity as possible, despite cognitive decline and gated to protect cognitively compromised older evidence of increasing functional impairment. adult patients from harmful interference. With Oftentimes, they anxiously seek information to the latter, ethical clinicians recognize that as older make sense of the deterioration they suspect and adults become more dependent on others due to fear. Caretakers want information regarding dementia or other cognitive impairment, they which capacities are impaired and which remain, also become more dependent on others for help and they want to know what to expect over time, in retaining their autonomy and sense of self [10 ] . say that they can plan care options. So, clinicians strive to identify and enlist those Sometimes family members and caretakers caring relationships the older adult fi nds neces- believe they are entitled to information because sary to support and enhance autonomy and dig- of the investment in time, labor, and money made nity. Patients typically benefi t when clinicians toward the older adult. Many caretakers are inti- encourage joint decision-making, to the extent mately involved in maintaining the older family possible, regarding assessment and treatment. member at home. Almost 80% of people needing Molinari et al. [11 ] noted that joint decision- long-term care live at home or in a community making may help older adults during that inter- setting [12 ] . In some instances, family members vening period between the time they possess full pay for the neuropsychological service, often- capacity and the time they are deemed incom- times with the expectation that they will or should petent. We extend this emphasis on shared have access to the obtained information. decision-making and suggest that even after older Occasionally, family members, caretakers, and adults are declared incompetent, geriatric neu- third-party systems have agendas that are not in ropsychologists make every effort to uncover the the best interest of the older adult. capacity that remains and the ways the person Geriatric neuropsychologists prepare involved might still be encouraged to actively participate third-party members and institutions in advance. 15 Ethical Considerations in Assessment 229

When services are provided at the request of third APA Ethical Standard 3.04 (Avoiding Harm), parties, geriatric neuropsychologists are ethically which obligates clinicians to minimize harm, obligated to clarify beforehand the role of the including emotional harm caused by distressing clinician, who the client is or clients are, how the test results, where it is foreseeable and obtained information is likely to be used, and unavoidable. possible limits of confi dentiality (Standards 3.07, Experience suggests that the assessment Third-Party Requests for Services, and 4.01, results with the greatest potential to provoke Maintaining Confi dentiality). When the demands marked distress concern those pertaining to loss of an organization con fl ict with the APA Ethics of functioning, autonomy, and personhood. Code, the clinician clarifi es the confl ict in advance Geriatric neuropsychological evaluations are and, when possible, resolves it to the satisfaction often de fi cit-focused, with referral sources seek- of all parties (Standard 1.03, Confl icts between ing to know if, and to what extent, older adults Ethics and Organizational Demands; see the 2010 have lost cognitive functioning and if previously amendments to the APA Ethics Code, [13 ] ). held capacities remain. The older adult may no Pragmatically, geriatric neuropsychologists longer be able to manage a household unassisted, and their older adult patients both benefi t from manage complex fi nances, or safely drive, and, as the information and support that family mem- the impairment progresses, may lose the right to bers, caregivers, and other third-party members make legal decisions such as making or altering a provide. Oftentimes, families provide details will or providing informed consent. about the older adult’s previous levels of func- A diagnosis of dementia can be particularly tioning, current capacities, and the onset of cog- devastating. Historically, dementia has been a nitive decline. Caretakers can provide information taboo subject, with many families unwilling to on whether the impairment is transient, acknowledge that a loved one had been diagnosed fl uctuating, or chronic. These contributions by with the disorder or even unwilling to discuss the family members become increasingly important topic in general [ 14 ] . Survey data suggests that as memory impairment becomes part of the clin- older adults are more concerned with a diagnosis ical presentation. Institutional staff can help of dementia than they are about cancer, heart dis- ensure that neuropsychological assessments are ease, or stroke [15 ] . conducted in appropriate private settings free Faced with a potential loss of functioning, from interruptions that could undermine the autonomy, or personhood, it is not unusual for assessment process and results (see also Ethical older adults to react with depression or despair, Standard 3.09, Cooperation with Other interpreting the results as evidence of personal Professionals). dishonor or disgrace [7 ] . Some may react by feeling stigmatized. Thompsell [ 16 ] poignantly related how one woman saw her diagnosis of Preparing Older Adult Patients and dementia as being “certifi ed as a nonperson.” Relevant Others for Potentially Unfortunately, the diagnosis of dementia or deter- Distressing and Unwelcome Results mination of declining capacity may lead some older adults to keep this information secret, thus Ethical geriatric neuropsychologists begin to pre- losing out on the opportunity for social support pare older adult patients and relevant others for when it is most needed. potentially distressing results well in advance of Discussing the bene fi ts of an early diagnosis the actual feedback session. From the proactive is helpful, especially if dementia is suspected. approach advocated here, the possibility of For example, knowing the diagnosis may reduce unwelcome results is addressed during the the fear of the unknown, allow for a better under- informed consent process because such informa- standing of the changes in cognition and function relates to the anticipated risks of the assess- tioning over time, and provide time to make ment process. This preparation is consistent with plans and to form supportive relationships with 230 A.C. Russo et al. professionals and other support groups before both sessions reduces the potential confusion the condition is advanced. due to differing accounts of the person’s past Ideally, all parties will reach an agreement or current functioning [17 ] . Encourage all about who will attend the feedback session, what involved family members and caretakers to information will be disclosed, what information attend the feedback session to avoid later may have to be disclosed, and the possible conse- problems with disclosure. quences of disclosing the obtained information. 5. Assess the degree to which the older adult and However, if the competent older adult refuses to family are involved in social systems that offer have anyone attend the feedback session or support, education, and referral information. refuses to have information disclosed, this prefer- This information provides the clinician an ence must be honored, except where permitted or estimate of the additional information and mandated by law (APA Ethical Standard 4.05, resources that may be needed at the time of the Disclosures). feedback session. 6. Carefully document the above process and information, including all agreements and Recommendations for Preparing disagreements. the Patient and Concerned Others Prior to Performing the Assessment Preparing the Assessment 1. Inform patients and their families or other caregivers during the informed consent pro- Geriatric neuropsychological evaluations include cess of the nature and purpose of the feedback a clinical interview of the older adult, a review of session. Inform them that the information pro- the available biographical and medical informa- vided will include a discussion of the older tion, behavioral observations, and neuropsycho- adult’s strengths and weaknesses, an explana- logical testing. Relevant family members and tion for any changes in cognitive functioning caretakers are often interviewed. This section of to the extent possible, and a probable diagno- the chapter is limited to the ethical issues sur- sis or the reasons why a diagnosis is not rounding the testing of the older adult. possible. The informing bioethical principles [ 4 ] 2. Encourage older adult patients and their fam- include nonmalefi cence and benefi cence. Ethical ily members to discuss any feared results, geriatric neuropsychologists use assessment including possible limitations to autonomy techniques and instruments that are psychomet- and freedom. Manage the discussion so that it rically sound, supported by research, and appro- is done in a sensitive and measured manner priate for use with older adults (Ethical Standard that signals an openness to discuss distressing 9.02, Use of Assessments), to the extent that material. such measures exist for a given patient or patient 3. Tactfully elicit how the older adult and family population. members typically react to distressing infor- The selection of appropriate tests follows cur- mation. Identify the coping strategies and rent theory and research. When selecting tests social supports the patient and family employ normed during different decades, knowledgeable to manage diffi cult information, and enlist clinicians consider differences in sample compo- these strategies and supports in the event of sition and take into account Flynn or cohort adverse neuropsychological fi ndings. effects. Newer tests or revisions of tests may not 4. Encourage the older adult to attend the feed- provide the best assessment of a given construct back session with a trusted and supportive for certain patient populations [ 18 ] . Ethical geri- family member, preferable the same member atric neuropsychologists consider the current or members who attended the pre-assessment research on best practices in cross battery test session. Having the same family members at selection [19 ] . 15 Ethical Considerations in Assessment 231

Ethical geriatric neuropsychologists choose norms for older adults. Norms for the frail elderly assessment measures to address several purposes who are often seen at bedside are scarce. Some typically encountered in the assessment of the normative studies lack adequate inclusion and older adult. The primary focus invariably con- exclusion criteria. In the selection of appropriate cerns the purpose of the assessment. For older norms, the quality of the patient’s education, as adults, referral questions are often a mix of opposed to years of education, may be the most descriptive and diagnostic concerns [ 20 ] . important consideration [ 22 ] . When an instru- Descriptive referral questions seek information ment’s validity or reliability is in question, clini- about level of cognitive capacity relative to the cians need to account for such limitations when patient’s peers. Often older adults or their family interpreting and reporting the results. members notice a decline in cognition and want The test measures or batteries chosen for eval- to know to what extent such decline is an age- uations should be comprehensive enough to both expected decline or something more ominous. adequately assess the referral question and rule With diagnostic referral questions, clinicians are out possible con fl icting hypotheses. To address tasked with determining whether there is a dis- the referral question, an adequate sampling of the ease process and deriving a differential diagnosis. relevant constructs is important. Popular screen- Often the question is whether the person has ing measures by themselves are typically inade- dementia and, if so, what kind. quate [23 ] and may lead to over diagnosis of The basis upon which to make these judg- dementia among some ethnic minority groups. ments differs. Descriptive interpretations are Screening measures can also be insensitive to based on normative data and depend on where subtle cognitive changes in high-functioning patients rank compared to age-related peers. patients. Because memory complaints are often Diagnostic interpretations are based on some cri- the presenting problems, a thorough assessment teria of ability and pathology. Ethical problems of various forms of memory is commonly may result from confusing the two types of refer- required. ral questions. For example, if the average 75-year- Capacity evaluations pose a unique problem old has three chronic health problems, a particular because they require both a professional compe- 75-year-old with two is fairing relatively better. tence in geriatric neuropsychology as well as This is a descriptive statistic based on the norma- specialized competencies in four areas: (a) know- tive average of three. However, it would be erro- ing the relevant and state-speci fi c legal standards neous to use this norm to say that the 75-year-old pertaining to capacity, (b) performing risk analy- is therefore enjoying above-average health. sis to determine the older person’s risk of harm Unfortunately, more serious examples are some- and need for supervision, (c) assessing decision- times seen in the reports of diagnosed dementia making capacity, and (d) assessing executional based solely on a standard score cutoff score, capacity or the ability to implement or carry out without any reference to previous premorbid plans once decided upon [24 ] . functioning (see also [21 ] ). In addition, the concept of capacity is still Geriatric neuropsychologists determine which evolving. Earlier conceptualizations focused assessment instruments are appropriate to answer almost solely on the presence of a disabling con- specifi c referral questions for each older adult dition with the assumption that impaired capacity patient. The selected instruments must assess the was monolithic, and either present or not [ 25 ] . relevant abilities and have acceptable levels of More current conceptualizations are more likely validity and reliability for the person’s age range. to emphasize functional impairment, with the This selection process requires discernment. For understanding that a lack of capacity in one area example, some instruments provide both a global does not imply a lack of capacity in another score and several subscores, but only the global [25, 26] . Elderly persons unable to drive may still score has reliability adequate for interpretation. be able to manage a household or consent to Many instruments have inadequate or missing medical care. 232 A.C. Russo et al.

Ethical geriatric neuropsychologists use a that the clinician will be assessing best perfor- multidimensional assessment approach that mance. Multiple sessions control for changes includes weighing evidence and information over time and allow for the discovery of fl uctuating from multiple sources in order to determine the cognitive performance. It is also wise for clini- extent to which elderly persons are able to (1) cians to note the medications the person took understand relevant information, (2) make a prior to the exam, as well as whether the current decision or convey a preference, (3) understand medications are a recent change in type or dos- the implications and likely consequences of age, which may account for variable performance their decisions, and (4) skillfully carry out the across testing sessions. actions needed to implement their decision [27 ] . This assessment approach also includes the assessment of basic activities of daily living Recommendations for Preparing (ADLs), such as eating, dressing, and mobility, the Assessment as well as the assessment of more complex instrumental activities of daily living (IADLs), 1. Use assessment techniques and instruments such as management of money, home, and trans- that are psychometrically sound, supported by portation [28 ] . Given the need to balance legal, research, and appropriate for use with the par- medical, familial, and psychological consider- ticular older adult being evaluated. Be mindful ations, geriatric neuropsychologists aspiring to of inadequate or missing norms. provide ethical capacity evaluations prepare in 2. Tailor the assessment to answer the referral advance by seeking training, supervision, and question while at least briefl y covering all knowledge of the literature (see [ 24 ] for a useful neuropsychological domains. When the framework). answer sought is more descriptive, adequacy Finally, ethical geriatric neuropsychologists of the normative data is imperative. When the anticipate and prepare for the possible confound- answer sought is more diagnostic, criteria of ing impact of non-neurological variables on cog- ability and an understanding of pathology nitive functioning, including cultural factors, become more crucial. sensory and motor defi cits, fatigue, emotional 3. Choose combinations of tests or batteries that state, motivation, physical pain and other acute are suf fi ciently comprehensive to assess the medical conditions, medications, hunger, and cognitive functions in question and to rule out environmental conditions. Older adults with little con fl icting hypotheses. Consider the best exposure to standardized testing may need more practices in cross battery selection. preparation and considerable encouragement to 4. Acquire the additional specialized competen- feel at ease with the test demands. This exposure cies if aspiring to perform capacity evaluations. factor becomes more apparent when computer 5. Anticipate and prepare for possible confound- applications are part of the assessment procedure, ing non-neurological factors. and the patient has had little experience using a mouse or keyboard [29, 30 ] . Sensory and motor limitations may force the Preparing the Feedback Session clinician to employ a nonstandardized administration [31– 33] . Arthritis may impact the use of The neuropsychological feedback session can be manipulables, decreasing performance on motor- a unique opportunity to provide older adults and dependent tasks such as block design and other their family members with much needed infor- construction tasks. The older adults may need mation, guidance, and support. Often neuropsy- additional rest breaks or an assessment spaced chological feedback sessions are the fi rst time over several shorter sessions rather than fewer that older adult patients and their families are longer ones. Morning sessions may fi nd the per- presented with a detailed understanding of the son better rested, with the increased likelihood patient’s condition, leaving clinicians the role of 15 Ethical Considerations in Assessment 233 introducing patients and family members to the Occasionally, caretakers may attempt to limit available resources, supports, and care systems. the discussion due to the belief that a diagnosis of When this opportunity is missed, older adult dementia will so distress the older adult that there patients and their family members may be left is no benefi t receiving it. However, research confused, anxious, and frightened. The Nuffi eld shows that the vast majority of older adults with Council on Bioethics [7 ] stated: mild dementia want to be informed about their “There is ample evidence that, in many condition and that fears to the contrary are cases, people are presented with a diagnosis of unfounded [34, 35 ] . dementia and simply told to come back in a The content of the feedback session will be year’s time. It was argued forcefully in one of infl uenced by the extent to which older adult our fact-fi nding meetings with people in front- patients and their family members are already line dementia care that such a lack of informa- embedded in a system of care. For example, tion and support in the immediate aftermath of those under the care of a multidisciplinary team diagnosis is simply morally wrong. We agree. of geriatric specialists often need less informa- (p. 46).” tion, guidance, and support from the geriatric The aspiring geriatric neuropsychologist can neuropsychologist. Those not involved in a prevent such failure to educate patients and system of supportive care will typically need families by maintaining adequate preparation more guidance on how to access information and a sensitive approach to the feedback ses- and support; the ethical geriatric neuropsy- sion. The stance taken by clinicians during chologist comes prepared to the feedback ses- feedback supports the older adult’s autonomy sion with handouts of useful information and and dignity and recognizes that autonomy and contact information for local, state, and national dignity are often best preserved within a caring resources. interpersonal matrix. The informing bioethical Finally, the way information is conveyed is at principles include respect for patient autonomy, least as important as what is conveyed. Respect nonmale fi cence, and bene fi cence. The APA for the autonomy and dignity of patients is Ethics Code (3.04, Avoiding Harm) obligates refl ected in an emphasis on strengths, and ways to psychologists to take reasonable steps to avoid support the person’s capacities and opportunities harming their clients and “to minimize harm to act, and to fi nd continued enjoyment and where it is foreseeable and unavoidable.” meaning. Neuropsychologists typically explain the assessment results to the patients or their desig- nated representatives, although there are some Recommendations for Preparing exceptions (Ethical Standard 9.10, Explaining the Feedback Session Assessment Results). Consistent with a proactive ethical approach, geriatric neuropsychologists 1. Establish a warm, supportive environment. will have prepared the older adult and family in When the feedback session is conducted in an advance and will have previously obtained con- institutional facility, prepare in advance to sent to disclose the information to those present. ensure that the session will be conducted in an Results should be presented at the level of detail uninterrupted, private setting. the older adult and family can receive. Some fam- 2. Offer a diagnostic formulation and prognosis ily members want and can understand precise that takes into account the degree of confi dence details about their loved one’s strengths and that can be placed in the diagnosis. For some weaknesses and the predicted course of the con- assessments, clinicians have considerable dition. Other patients or family members may, information, such as history, test results, and due to anxiety or other factors, benefi t from less radiological reports that converge on a single detailed information or need time to digest basic diagnosis. However, for many assessments, information. the diagnosis is uncertain, and the results serve 234 A.C. Russo et al.

as a baseline against which to compare later 6. American Psychological Association. Ethical princi- evaluations. It can also be informative to ples of psychologists and code of conduct. Washington, DC: American Psychological Association; 2002. describe alternative diagnoses that have been 7. Nuf fi eld Council on Bioethics. Dementia: ethical ruled out. issues. London: Author; 2009. 3. Anticipate the need to provide resources for 8. Knapp SJ, Vandecreek LD. Practical ethics for psy- local, state, and national information and support chologists: a positive approach. Washington, DC: American Psychological Association; 2006. services, and have written handouts available. 9. Mackenzie C, Stoljar N. Relational autonomy: femi- 4. Maintain focus on the importance of patient nist essays on autonomy, agency and the social self. autonomy and dignity and take steps to pro- New York: Oxford University; 2000. mote both, such as describing ways to modify 10. Agich G. Dependence and autonomy in old age: an ethical framework for long-term care. Cambridge, the patient’s environment to maximize inde- England: Cambridge University; 2003. pendence and quality of life. 11. Molinari V, McCullough LB, Coverdale JH, Workman R. Principles and practice of geriatric assent. Aging Ment Health. 2006;10:48–54. 12. Merck Institute of Aging and Health. The state of Conclusions aging and health in America. Washington, DC: Author; 2004. Preparation remains the hallmark of a proactive 13. American Psychological Association. Ethical princi- ethical approach as geriatric neuropsychologists ples of psychologists and code of conduct: 2010 amendments. Retrieved 2/17/11 from www.apa.org/ move from consideration of ethical principles to ethics/code/index.aspx (2010). pragmatic assessment application. Ethical assess- 14. Corner L, Bond J. Being at risk of dementia: Fears ment preparation starts and ends with preparing and anxieties of older adults. J Aging Stud. older adults and concerned others for what to 2004;18:143–55. 15. Foundation MetLife. Alzheimer’s survey: what expect from the assessment and for potentially America thinks. New York: Author; 2006. distressing results, and includes the information 16. Thompsell A. Life worth living. J Dementia Care. and support they might need to manage poten- 2008;16:5. tially troubling diagnoses. This preparation takes 17. Green J. Neuropsychological evaluation of the older adult. New York: Academic; 2000. into account the non-neuropsychological vari- 18. Bush SS. Determining whether or when to adopt new ables that may impact older adults. Technical versions of psychological and neuropsychological assessment preparation then logically follows in tests. Clin Neuropsychol. 2010;24:7–16. the thoughtful selection of instruments that are 19. Flanagan DP, Ortiz SO. Essentials of cross-battery assessment. 2nd ed. New York: John Wiley & Sons; suffi ciently comprehensive, adequately normed, 2007. and well grounded in current theory and research. 20. Jamora C, Ruff RM, Connor BB. Geriatric neuropsy- The patients and their loved ones bene fi t from the chology: implications for front line clinicians. preparation. NeuroRehabilitation. 2008;23:381–94. 21. American Psychological Association. Guidelines for the evaluation of dementia and age related cognitive decline. Am Psychol. 1998;53:1298–303. 22. Manly JJ. Cultural issues. In: Attix DK, Welsh- References Bohmer KA, editors. Geriatric neuropsychology: assessment and intervention. New York, NY: Guilford; 1. Bush SS. Ethical decision making in clinical neurop- 2006. p. 198–222. sychology. New York: Oxford University; 2007. 23. Spann PE, Raaijmakers JG, Jonker C. Early assess- 2. Bush SS. Geriatric mental health ethics: a casebook. ments of dementia: the contribution of different mem- New York: Springer; 2009. ory components. Neuropsychology. 2005;19:629–40. 3. Martin T, Bush S. Ethical considerations in geriatric 24. American Bar Association and American neuropsychology. NeuroRehabilitation. 2008;23: Psychological Association. Assessment of older 447–54. adults with diminished capacity: a handbook for psy- 4. Beauchamp TL, Childress JF. Principles of biomedical chologists. Washington, DC: American Bar ethics. 5th ed. New York: Oxford University; 2001. Association Commission on Law and Aging – 5. Koocher GP, Keith-Spiegel PC. Ethics in psychology: American Psychological Association; 2008. Professional standards and cases. 2nd ed. New York: 25. Smyer M. Aging and decision-making capacity: an Oxford University; 1998. overview. In: Qualis S, Smyer M, editors. 15 Ethical Considerations in Assessment 235

Decision-making capacity in older adults: assessment 31. Caplan B, Schecter JA. Test accommodations in and intervention. New York: John Wiley & Sons; 2007. geriatric neuropsychology. In: Bush SS, Martin TA, p. 3–24. editors. Geriatric neuropsychology: practice essen- 26. Zarit S, Zarit J. Mental disorders in older adults: fun- tials. New York: Psychology; 2005. p. 97–114. damentals of assessment and treatment. 2nd ed. New 32. Morgan J. Ethical issues in the practice of geriatric York: Guilford; 2007. neuropsychology. In: Bush SS, Drexler ML, edi- 27. Moye J. Assessment of competency and decision tors. Ethical issues in clinical neuropsychology. making capacity. In: Lichtenberg P, editor. Handbook Lisse, NL: Swets & Zeitlinger Publishers; 2002. of assessment in clinical gerontology. New York: John p. 87–101. Wiley & Sons; 1999. p. 488–528. 33. Morgan JE (2005). Ethical challenges in geriatric neu- 28. Grisso T. Evaluating competencies. New York: John ropsychology, part II. In: Bush SS, editor. A casebook Wiley & Sons Plenum; 1986. of ethical challenges in neuropsychology. New York. 29. Byrd DA, Manly JJ. Cultural considerations in neu- pp. 153–158. ropsychological assessment of older adults. In: Bush 34. Carpenter BD, Xiong C, Poresnky EK, Lee MM, SS, Martin TA, editors. Geriatric neuropsychology: Brown PJ, Coats M, et al. Reaction to a dementia practice essentials. New York: Psychology; 2005. diagnosis in individuals with Alzheimer’s disease and p. 115–40. mild cognitive impairment. J Am Geriatr Soc. 30. Schatz P. Applications of technology to assessment 2008;56:405–12. and intervention with older adults. In: Bush SS, Martin 35. Pinner G, Bouman WP. Attitudes of patients with TA, editors. Geriatric neuropsychology: practice mild dementia and their carers towards disclosure of essentials. New York: Psychology; 2005. p. 85–96. the diagnosis. Int Psychogeriatr. 2003;15:279–88. Part II

Late Life Cognitive Disorders Mild Cognitive Impairment and Normal Aging 1 6

Lauren A. Rog and Joseph W. Fink

Abstract Mild cognitive impairment (MCI) represents an intermediate zone of neurocognitive functioning that falls between normal age-appropriate functioning and dementia. During the past decade, research and clinical interest in MCI has burgeoned. Delineating the cusp between normal aging and MCI is of critical importance not only for accurate diagnosis but also for determining the earliest appropriate time-point to implement early interventions. This chapter will focus on a pragmatic approach to differentiating MCI from normal aging.

Keywords Mild cognitive impairment • Normal cognitive aging • Neuropsychological assessment/evaluation • Older adults • Cognitive aging theories

structure and function of the aging brain. In the Background United States, the current life expectancy at birth is 76 years for men and 81 years for women, and Normal Cognitive Aging approximately 13% of US citizens are 65 years and older [ 1, 2 ] . The US Census Bureau’s projec- As people live longer, scientists are given greater tions estimate that about one in fi ve citizens will be opportunity to improve their knowledge of the seniors by the year 2030 and the oldest old (85 years and older) is the fastest growing segment of the population. Given these statistics, there is a L. A. Rog , Ph.D. (*) great need for clinical services and research focus- Illinois Institute of Technology , Chicago , IL , USA ing on normal and pathological cognitive aging. e-mail: [email protected] It is generally accepted that some degree of J. W. Fink , Ph.D. cognitive decline associated with aging is inevi- Department of Psychiatry and Behavioral Neuroscience , table, with a great deal of variability as to when Neuropsychology Service, University of Chicago , these changes begin [3 ] . Interindividual variation MC-3077, 5841 S. Maryland Ave , Chicago , IL 60637 , USA in cognitive performance in areas such as e-mail: fi [email protected] memory and fl uid intelligence increases with age.

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 239 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_16, © Springer Science+Business Media, LLC 2013 240 L.A. Rog and J.W. Fink

Thus, with advancing age, there becomes an account for age-related de fi cits in various aspects increase in the proportion of elderly persons who of executive performance, including shifting cog- show normative age-associated cognitive decline nitive set, suppressing responses, and response [4– 7 ] . It can become dif fi cult to parse out “normal” competition [8 ] . Cognitive aging is also associ- cognitive aging versus pathological cognitive ated with poorer effortful or controlled process- decline in the absence of neuropsychological ing, while automatic processing remains relatively testing with normative comparison data. intact [20 ] . Older adults retain relatively good Some aspects of cognition remain relatively memory for “gist” or familiar stimuli, while intact with normal aging, including implicit source memory and recollection of contextual memory, vocabulary, and storage of general details decline [11 ] . knowledge [4, 7, 8] . The cognitive decline that Normal age-related changes in language func- typically accompanies normal cognitive aging tion include increased inef fi ciency in phonologi- involves decreased effi ciency in information pro- cal retrieval, resulting in word-fi nding diffi culties cessing in several areas, including speed of pro- that are often referred to as the “tip of the tongue” cessing, reaction time, working memory capacity, phenomenon [ 21] . The literature shows that con- short-term memory, executive control (e.g., frontation naming performance declines with inhibitory functions), and verbal fl uency [ 4, 9– 11 ] . age, with the rate of decline accelerating in older Visuoperception, visuoconstruction, and spatial age groups [22– 24 ] . Semantic fl uency or the abil- orientation also decline with age [12, 13 ] . ity to retrieve words associated with a particular Slowed processing speed is a key cognitive category also declines with age, as does lexical change in the aging brain. It has been widely fl uency (i.e., the ability to retrieve words from found, for example, that visual-motor tracking, declarative memory that begin with a particular sequencing, and set shifting slow with age [ 14– 16 ] . letter or sound) [ 25] . However, it is suspected that Reduced processing speed is suspected to medi- the age-related decline in verbal fl uency is at least ate cognitive ef fi ciency by restricting the speed at partly due to the substantial contributions of audi- which cognitive processes can be executed [ 8, 10, tory attention and verbal memory abilities to the 17, 18 ] . Reduced processing can also affect the tasks, rather than simply a primary degradation quality and accuracy of performance due to the of semantic or lexical networks [26 ] . decreased quantity of information processed that is necessary for completion of the task [ 18 ] . Structural Brain Changes Further, products of earlier processing may be Numerous changes in brain structure accompany lost by the time later processing occurs, render- normal aging, including volumetric shrinkage, ing integration of relevant information diffi cult or decreased white matter density, loss of dopamin- impossible. The consequences of reduced pro- ergic receptors, and the emergence of cessing include decreased working memory neuro fi brillary plaques and tangles. The greatest capacity because less information can be pro- degree of cortical thinning and volumetric brain cessed within a given time, as well as impaired shrinkage across the lifespan occurs in the hip- higher-order cognitive functions such as abstrac- pocampus, caudate, cerebellum, and calcarine tion or elaboration, because the relevant informa- (i.e., occipital) and prefrontal areas [27, 28 ] . tion is no longer available in working memory or Ventricular volume also increases in old age storage [18 ] . [ 29] . Decreases in white matter density and other Age-related changes in working memory are white matter abnormalities are particularly evi- likely due to reduced inhibitory mechanisms of dent in the frontal and occipital regions of the selective attention [ 19 ] . That is, older adults show brain [ 30, 31 ] . White matter changes may be the decreased ability to effectively suppress the pro- primary culprit for age-related cognitive slow- cessing of irrelevant, or marginally relevant, ing, as their main function is to transport signals stimuli and thoughts. This leads to a generalized to and from different areas of the brain via myeli- attentional dysregulation that is also thought to nated axons. As myelin integrity degrades with 16 Mild Cognitive Impairment and Normal Aging 241 age, so does the speed of cognitive processing. two of nine participants who were nondemented Together with fi ndings on cortical volume and in the few months prior to death met pathological thinning, studies on age-associated white matter criteria for Alzheimer’s disease, suggesting indi- changes point to signi fi cant alterations in frontal vidual variability in the relationship between networks [ 30, 31 ] . brain pathology and cognitive presentation. One Loss of dopaminergic receptors occurs with explanation for this variability is the notion of age and is thought to contribute to the attentional cognitive reserve, a hypothesized degree of pro- dysregulation, executive dysfunction, and tection against disease or injury whereby one is diffi culty with contextual processing that accom- behaviorally unaffected by pathology suf fi cient panies normal cognitive aging [32– 34 ] . It has to cause dementia in someone with less cognitive been proposed that context processing involves reserve. The construct of cognitive reserve is using internally represented task-relevant infor- discussed more fully elsewhere in this volume mation in a way that infl uences processing in the (see Chap. 2 ). pathways responsible for task performance [35 ] . Functional imaging techniques such as posi- For example, performance on the Stroop task is tron emission tomography (PET) and functional dependent upon the ability to use the context of magnetic resonance imaging (fMRI) allow for task instructions (i.e., inhibit reading color-named the examination of blood fl ow and oxygenation words while saying the printed ink color) in order to particular brain structures, in participants as to maintain attention toward ink color rather than they engage in cognitive tasks. Comparisons of the printed word. Braver and Barch (2002) postu- older and younger adults reveal an increase in lated that contextual representations are housed bilateral activation with age, whereby tasks asso- within the dorsolateral prefrontal cortex and are ciated with focal, unilateral activation in younger regulated by dopamine projections to this area. adults (e.g., verbal memory) become associated The mechanism of context processing subserves with bilateral activation in older adults [37, 38 ] . cognitive functions such as attention, working Further, bilateral activation in older adults is memory, and inhibition by affecting the selec- associated with better performance on cognitive tion, maintenance, and suppression of informa- tasks, including working memory, semantic tion relevant (or irrelevant) to the task, accounting learning, and perception [ 39– 42 ] . This suggests for the decline in these abilities with age [35 ]. that the older brain engages in more widely dis- An autopsy study on clinically nondemented tributed compensatory processing by activating oldest old (age ³ 85 at death; n = 9) found the contralateral hemisphere to achieve greater neuro fi brillary tangles (NFTs) in one or more cognitive bene fi ts [8 ] . limbic regions in all study participants [36 ] . The most affected regions included the entorhinal Theories of Aging cortex, amygdala, subiculum, CA1 fi eld of the In a process termed “dedifferentiation,” sensory hippocampus, and inferior temporal regions. function (i.e., visual acuity and audition) has been Midfrontal, orbitofrontal, and parietal regions shown to predict performance on a wide range of were less affected, and occipital regions were cognitive tasks in older, but not younger, adults minimally affected in clinically nondemented [43, 44] . It has been proposed that abilities that persons. Senile plaque (SP) formation also was are relatively independent earlier in life, such as observed in this group and was found to affect all sensory ability and cognition, become more inter- brain regions equally, with the exception of rela- related with old age. Functionally, this can be tive sparing of the occipital cortex. Participants thought of as a decrease in neural speci fi city, who were clinically nondemented at death whereby regions that respond selectively in showed signi fi cantly less NFTs and SPs than par- younger adults change to respond to a wider array ticipants with mild cognitive impairment (MCI) of inputs in older adults. Similarly, in older adults, and dementia. Pathological lesion density was increased prefrontal activation is associated signi fi cantly related to cognitive status. However, with decreased parahippocampal activation and 242 L.A. Rog and J.W. Fink

hippocampal volume shrinkage [ 45, 46 ] . Whereas remain available for compensatory processing activation in the parahippocampal regions is asso- [ 45 ] . In the aging brain, scaffolding is thought to ciated with learning new material in younger and maintain healthy cognitive function in the face of middle-aged adults, increased prefrontal activa- neural degradation. These circuits can provide tion is instead observed in older adults, suggesting supplementary, complementary, or alternative greater frontal activity may be a compensatory ways to complete a cognitive task and are thought mechanism for decreased mesiotemporal activa- to reside largely within the prefrontal cortex, con- tion [ 8, 45 ] . sistent with fi ndings on overactivation of frontal Salthouse proposed the processing-speed the- networks with age [8 ] . Scaffolded networks, ory of cognitive aging, which assumes that a however, are less effi cient and more prone to wide range of cognitive task performances are error than honed circuits, which are highly func- limited by the imposed constraints on the speed tionally interconnected. According to scaffolding of processing [18 ] . Slow processing speed damp- theory, this results in the observable and measur- ens cognition in two ways: (1) cognitive opera- able cognitive decline seen in older adults. The tions are executed too slowly to be successfully need for compensatory scaffolding exceeds the completed in the available time and (2) the available networks, resulting in a more profound amount of simultaneously available information, decline in functioning in the oldest old. necessary for higher-level processing, is reduced, as early processing is no longer available when Individual Factors in Cognitive Aging new processing occurs. Complex operations are Given the considerable variation in cognitive per- most affected by slow processing speed since formance in older persons, particularly in the old- they are dependent on the products of simpler est old, examination of individual difference (and earlier) operations, and often, the accuracy factors related to the cognitive aging process is of performance is dependent on the number of warranted [4, 5 ] . Factors shown to contribute to operations that can be carried out in a given time cognitive reserve or to be related to cognitive period (e.g., associations, rehearsals). The decline in clinical studies include education, amount of simultaneously available information occupational complexity, physical health, and may also be reduced due to disruptions in the diet [ 47 ] . It is suspected that cognitive reserve is synchronization of neural signals and activation represented biologically by a number of pro- patterns [18 ] . cesses, including (1) richer interconnectivity and The scaffolding theory of aging and cognition organization of neural circuits; (2) alterations in proposes that structural brain changes associated synaptic effi ciency, marked by changes in neu- with aging are accompanied by effort on the part rotransmitter release, receptor density, and recep- of neural networks to maintain homeostatic cog- tor affi nity; (3) and changes in intracellular nitive functioning in the face of these changes signaling pathways [47 ] . [8 ] . This leads to changes in brain function Physical health status is arguably one of the through “strengthening of existing connections, more important factors to consider when predict- formation of new connections, and disuse of con- ing performances on cognitive assessment in nections that have become weak or faulty” (p. noncognitively impaired elderly. Clinical and 175). Scaffolding is described as the brain’s “nor- subclinical medical disorders have been found to mal response to challenge” (p. 183), and the the- be better predictors of neuropsychological perfor- ory can be used to explain the process of acquiring mance than chronological age, and these disorders a novel skill. The initially engaged neural net- include hypertension, hypercholesterolemia, obe- works shift from broad and dispersed to a specifi c sity, and white matter lesions [ 48 ] . Cardiac and honed circuit of neural regions. While the arrhythmias [49 ] , sensory loss [ 50 ] , pulmonary more speci fi c regions assume dominant control function [ 51] , and other measures of biological over functions, the initial broad networks con- age [ 52 ] have also been associated with poorer tinue to be minimally active, suggesting that they cognitive functioning. 16 Mild Cognitive Impairment and Normal Aging 243

Higher education has been associated with normal aging process. Incidence and prevalence preserved cognitive performance over time (i.e., rates vary as a consequence of study details, less decline) in aging adults [53, 54 ] , though not including diagnostic criteria, assessment proce- all research has supported this outcome [ 55 ] . dures, and sample characteristics (e.g., commu- Occupational complexity is shown to be related nity versus clinic, age, education, gender, race, to relatively better cognitive functioning with health comorbidities). Within the general popula- age, above and beyond the benefi ts afforded by tion, prevalence rates have been found to range higher levels of education [ 56 ] . More speci fi cally, from 1 to 19% [59 ] . cognitive ability in older adults was found to be The original criteria for MCI proposed by related to the degree of complexity of one’s work Petersen et al. [57 ] are as follows: with people but not to occupational complexity 1. Presence of a memory complaint with data or things [56 ] . In particular, participants 2. Normal activities of daily living who held jobs with high complexity of work with 3. Normal general cognitive function people demonstrated better cognitive perfor- 4. Abnormal memory for age mance on measures of verbal skills, spatial skills, 5. Not demented and processing speed than participants with low These criteria are particularly useful for occupational complexity with people. No differ- patients who have impairment in the memory ences in memory performances were found. The domain but intact cognitive performance and cognitive benefi t received from high occupational functioning in all other domains. Such patients complexity ceased following retirement, suggest- would be labeled as having amnesic MCI ing that once these occupational skills are no lon- (a-MCI). Revised criteria were proposed by a ger being practiced, they fail to retain their multidisciplinary, international group of experts, effectiveness in bolstering cognitive ability. in light of the heterogeneity of MCI clinical presentations re fl ected in the literature [60 ] . For example, some patients have a primary impair- Mild Cognitive Impairment ment in the memory domain only, whereas others have memory impairment in addition to other De fi ning Mild Cognitive Impairment domain impairment(s). Still others have impairments in single or multiple nonmemory cognitive Neuropsychological referrals are often made on domains. These heterogenous clinical presenta- the basis of a patient’s or their family’s perceived tions may have multiple etiologies, including (i.e., subjective) report of a decline in cognitive degenerative, vascular, metabolic, traumatic, ability. An integral part of the neuropsycholo- psychiatric, etc. [58, 60 ] . gist’s role is to determine whether a patient’s The most updated clinical diagnostic criteria complaints or their family’s observations of cog- for MCI are recommended by the National nitive decline are due to the normal cognitive Institute on Aging and Alzheimer’s Association aging process or if they instead represent an workgroup [61 ] . The diagnostic criteria for MCI objective impairment in cognitive functioning in a clinical setting are as follows: relative to the patient’s same-age peers. The con- 1. Concern regarding change in cognition: There struct of MCI represents a decline in cognitive is evidence of concern for change in the performance greater than would be expected for patient’s cognitive status as compared to his/ the person’s age but not suf fi cient to meet criteria her previous level. This concern may be on the for a diagnosis of dementia. [ 57 ] Petersen part of the patient, an informant who knows described MCI as interposed between normal the patient well, or from a skilled clinician cognitive changes associated with aging and the who has observed the patient. very early stages of a dementing process [ 58 ] . It 2. Impairment in one or more cognitive domains: is therefore conceptualized as a pathological There is evidence of lower performance in one condition and not merely a manifestation of the or more cognitive domains that is greater than 244 L.A. Rog and J.W. Fink

what would be expected for the patient’s age domain MCI. More specifi cally, in the event that and educational background. Impairment may a defi cit in memory is present, a patient is given a be in a variety of domains, including memory, diagnosis of multiple-domain MCI with amnesia attention, language, executive function, and (md-MCI + a); if memory impairment is not evi- visuospatial skills. dent, then a diagnosis of multiple-domain MCI 3. Preservation of independence in functional without amnesia (md-MCI-a) is appropriate. abilities: The patient generally maintains his/ her independence of function in daily life without considerable aids or assistance. Etiology and Prognosis However, patients may have mild problems performing complex functional tasks (e.g., In addition to different subtypes, there also are paying bills, preparing meals, shopping), multiple etiologies for MCI. Petersen suggested whereby they may be less effi cient, take more four main etiologies: (1) degenerative (e.g., time, and make more errors than in the past. Alzheimer’s disease), (2) vascular (e.g., cerebro- 4. Not demented: These cognitive changes are vascular disease), (3) psychiatric (e.g., depres- suf fi ciently mild so that there is no evidence of sion), and/or (4) traumatic (e.g., head injury) signifi cant impairment in social or occupa- [58 ] . Of course, a host of other potential etiolo- tional functioning. A diagnosis of MCI gies should always be considered in the differen- requires evidence of intraindividual change. If tial diagnosis, including medication side effects the patient has been evaluated only once, and other toxic factors, metabolic factors (e.g., change will be inferred from the history and/ thyroid dysfunction, vitamin B12 de fi ciency), or or evidence that cognitive performance is infection. Particular subtypes of MCI are reported impaired beyond what is expected for that to be more commonly associated with certain eti- patient. Practical application of these criteria ologies. For example, patients with a-MCI are will be considered below in the Assessment more likely to convert to Alzheimer’s disease section. than patients with na-MCI [ 57, 62– 64 ] . An impairment in episodic memory, i.e., the ability to learn and retain new information, is most com- Subtypes monly seen in MCI patients who later convert to Alzheimer’s disease [61 ] . Additionally, a longitu- We have already mentioned single-domain dinal decline in cognition provides additional amnesic MCI (a-MCI) , which is a useful category evidence for a likely etiology of Alzheimer’s dis- for patients who have impairment in memory but ease [61 ] . Those with impairments in nonmem- intact cognitive performance in all other domains ory domains such as executive function and and in daily functioning. As research on MCI has visuospatial skills may be more likely to convert advanced to include cognitive impairment in to dementia with Lewy bodies [ 58 ] . Persons with domains other than memory, several other sub- na-MCI in one study were least likely to convert types of MCI have been proposed. [58 ] Some to any form of dementia [61 ] . patients display impairment in a single nonmem- Follow-up data from the initial Petersen et al. ory cognitive domain (e.g., executive function) study on MCI using patients (N = 220) from the but perform normally in other domains, includ- Mayo Alzheimer’s Disease Center/Alzheimer’s ing memory. These patients would be given labels Disease Patient Registry (ADC/ADPR) demon- of single-domain non-amnesic MCI (na-MCI). strated a rate of progression from MCI to demen- Still other patients present with impairments in tia of 12% per year [ 57, 58] . At a 6-year follow-up, multiple domains while continuing to display approximately 80% of MCI patients in the same relatively intact activities of daily living (ADLs) study were reported to have progressed to demen- and general cognitive functioning; these patients tia. Other studies have found conversion rates of would be classi fi ed generally as having multiple- 10–19% per year from MCI to Alzheimer’s 16 Mild Cognitive Impairment and Normal Aging 245

disease [63, 65] . In comparison, 1–2% of the MCI patients who remained stable during fol- general population develop Alzheimer’s disease low-up periods. Magnetic resonance imaging per year, providing evidence that MCI places one (MRI) has been used to examine trajectories of at increased risk for future dementia above the volumetric brain loss in a healthy aging sample rate that is expected for a person’s age [ 57 ] . over a 15-year period [ 29] . Ventricular expan- Persons diagnosed with a-MCI were found in one sion was found to be faster in persons developing study to have a fourfold greater risk than MCI years prior to the emergence of clinical noncognitively impaired individuals to develop symptoms. An increasingly rapid expansion Alzheimer’s disease over a 2-year follow-up occurred approximately 2 years prior to the clin- period [66 ] . When considering a general diagno- ical diagnosis of MCI. sis of MCI (i.e., not taking into account subtype), Neuroimaging studies show that subjects who patients are found to have a three times greater progressed to AD within an 18-month follow-up risk of developing Alzheimer’s disease (average period had greater volume loss than a stable MCI follow-up of 4.5 years) [67 ] . group and a control group in areas consistent At the same time, however, many persons with with volume loss in AD (i.e., medial and inferior MCI remain stable with this diagnosis or revert to temporal lobes, temporoparietal neocortex, pos- normal. For example, in a clinical sample, 41% terior and anterior cingulate, precuneus, and remained stable over an average 3.5-year follow- frontal lobes). [ 70 ] Autopsy studies reveal that up and 17% returned to normal cognitive status subjects who died with a classi fi cation of a-MCI [68 ] . These data suggest that for some patients, showed the early pathologic changes seen in MCI represents an intermediate point on the con- subjects diagnosed with AD prior to death [ 71, tinuum from normal cognition to dementia, while 72 ] . Annual increase in ventricular volume as for others, MCI is a transient period of cognitive assessed by serial MRI has revealed the greatest decline that resolves with time. The latter may be volume increase in AD subjects, followed by an seen in patients with reversible causes of cogni- intermediate increase in a-MCI subjects, and the tive dysfunction, such as metabolic abnormalities smallest change in cognitive normals. Further, or substance use. Those with na-MCI are most a-MCI and AD subjects with APOE-e 4 genotype likely to revert to normal or improve their cogni- show the greatest increase in ventricular volume. tive status over time [62 ] . These fi ndings also correlate clinically with concurrent change in cognitive and functional status [ 73] . Specifi c and distinguishing MRI abnormal- Pathophysiology and Neurodiagnostic ities also have been identifi ed in MCI subjects Findings who ultimately convert to AD, vascular dementia, and Lewy body dementia, lending support Neuroimaging data lends further support for for MCI as a prodrome to multiple dementing MCI as a unique diagnostic entity, separate from processes [ 74 ] . both normal cognitive functioning and dementia states. Retention of Pittsburgh compound B (PIB), used to image beta-amyloid plaques in Assessment neuronal tissue, has been examined using positron emission tomography (PET) in persons with Referrals normal cognition, MCI, and Alzheimer’s disease (AD) [ 69] . In their study, Forsberg et al. found Referrals for neuropsychological evaluation that PIB retention in MCI patients is higher than when MCI is a diagnostic consideration may that of normal controls but lower than in AD come from a variety of sources. Neurologists are patients. Additionally, the MCI patients who likely to be one of the most common referral converted to AD within the 2–16-month follow-up sources, along with primary care physicians, period had higher mean PIB retention than the psychiatrists, and self-referral (initiated either by 246 L.A. Rog and J.W. Fink

Table 16.1 MCI differential diagnosis an opinion as to whether the patient may require Common differential diagnoses associated with MCI a formal driving evaluation. Assessment of driv- Normal cognitive aging ing abilities is detailed elsewhere in this volume Dementia (e.g., Alzheimer’s, vascular, frontotemporal (see Chap. 10 ). dementia, Parkinson’s plus syndromes) Depression/“pseudodementia” Delirium Clinical Interview Other reversible causes for cognitive dysfunction (e.g., metabolic abnormalities, substance use, obstructive sleep apnea) An important component of the clinical interview when assessing patients with MCI involves obtaining an accurate picture of the emergence of the patient or a family member). One study of cognitive symptoms and any functional male patients with MCI receiving care at a dif fi culties. For this reason, it is ideal to have a Veterans Affairs hospital found that generally, collateral informant present at the interview to either patients or their families prompted the con- provide his or her insight into the patient’s behav- sultation for memory loss [75 ] . In many cases, iors and functional status. The informant is typi- patients may be seen fi rst by neurologists who cally a spouse, child, sibling, or other close family then provide a neuropsychological referral for a member or friend who is knowledgeable about more comprehensive cognitive evaluation. Most the patient’s history and can provide information typical referral questions from other medical pro- about changes in cognitive and functional status. fessionals in the context of an evaluation for MCI One of the diagnostic criteria of MCI is the will pertain to differential diagnosis and etiology. presence of a subjective cognitive complaint. Typical differentials will include normal cogni- Patient complaints may be corroborated by the tive aging versus MCI versus dementia, as well as collateral informant, whereas in some cases, the depression or “pseudodementia” versus MCI or friend or family member’s report is the only evi- dementia. Etiology of cognitive impairment also dence for subjective cognitive change. This may is a common referring question and usually occur in cases where the patient has little to no involves a question of Alzheimer’s disease pathol- insight into their cognitive changes. It is impor- ogy versus other causes such as vascular cogni- tant to obtain a thorough history of the emer- tive impairment, frontotemporal dementia, a gence of cognitive symptoms, including Parkinson’s plus syndrome (e.g., Lewy body examples of cognitive problems the patient is dementia, multiple system atrophy, progressive experiencing in everyday life. For example, the supranuclear palsy, corticobasal degeneration), early and prominent emergence of language or metabolic causes. Table 16.1 shows a list of symptoms may be indicative of a primarily apha- common differential diagnoses for MCI. There sic dementing process, whereas early memory are other associated issues that may be relevant to diffi culties may signal mesial temporal lobe referring physicians, such as beginning an appro- involvement, the area initially and primarily priate cognitive enhancing medication or psycho- affected in Alzheimer’s disease. Evaluating tropic drugs for treatment of mood disorders. The functional abilities also is essential when consid- neuropsychological evaluation is often requested ering a diagnosis of MCI. Functional indepen- to serve as a baseline for subsequent serial evalu- dence is the key factor in the differential diagnosis ations in order to track the trajectory of cognitive of MCI or early dementia. Patients with MCI are decline or improvement following treatment. considered to have intact basic activities of daily Assessment of functional independence may be living (ADLs), with predominantly intact instru- requested based on cognitive testing, such as mental ADLs. An assessment of functioning whether the patient is completely independent or should include questions about the patient’s abil- requires in-home assistance as part of their daily ity to care for his or her basic needs, such as functioning. Cognitive testing may also help form hygiene, dressing, and feeding oneself, as well 16 Mild Cognitive Impairment and Normal Aging 247 as his or her more instrumental needs, such as diagnosed with sleep apnea, which has known making and keeping appointments, fi nancial effects on executive cognitive functioning [ 83 ] . management, driving abilities, and medication A review of the patient’s current and recent medi- management. cations is also critical in order to consider medi- The patient and his or her informant should cation-induced cognitive changes. It is important also be questioned about changes in behavior to obtain not only a list of the patient’s medica- or personality, which are often early indicators tions but also a careful chronology of when each of a primarily behavioral dementing process, potentially psychoactive medication was intro- such as frontotemporal dementia. Behaviors to duced in relation to the chronology of cognitive consider include those indicative of apathy, dis- symptom emergence. A review of the patient’s inhibition, perseveration, or behaviors that are use of recreational substances is necessary to rule out of the ordinary for the person. In addition, out preventable causes for cognitive changes. irritability often accompanies symptoms of cog- Finally, family history of dementia should be nitive decline. Patients should be questioned assessed, including approximate age of onset of about emotional symptoms and psychiatric his- cognitive dif fi culties in family members. tory to assess for the presence or increase in symptoms of depression, anxiety, or other salient psychological problems. This is particularly Functional Impairment important because approximately 35–75% of patients with MCI endorse at least one neuropsy- In assessing whether ability to carry out activi- chiatric symptom at a prevalence rate that is ties of daily living (ADLs) is essentially normal higher than same-age non-MCI peers [ 76– 79 ] . (a diagnostic criterion for MCI), a thorough his- The most commonly endorsed symptoms include tory from the patient (and ideally an informant) depression/dysphoria, apathy, anxiety, and agita- should be obtained. Self-report or clinician- tion [ 80, 81] . Commonly reported symptoms of administered ADL scales can also be employed depression in MCI include poor concentration, but do not replace a careful detailed interview, inner tension, pessimistic thoughts, lassitude, since many of the ADL scales do not pick up on reduced sleep, thoughts of death, inability to subtle changes in functioning. Petersen noted feel, and reduced appetite [ 82 ] . There is some that minor inconveniences in a patient’s daily evidence for higher rates of depression in a-MCI functioning may be present, but they are not versus na-MCI and in multiple-domain MCI ver- suf fi cient in severity to constitute a major dis- sus single-domain MCI patients [ 76, 80] . Given ability in functioning [ 58 ] . Patients with MCI evidence for elevated rates of mood symptoms in tend to report some degree of decline in their persons with MCI, it is imperative that patients ability to handle daily tasks, whereby they feel are screened for clinical and subclinical symp- they are more forgetful, are less able to multi- toms of depression, anxiety, apathy, and task, and have dif fi culties with planning and irritability. organization [ 84 ] . These inef fi ciencies can man- The clinician should obtain a thorough medi- ifest in a variety of ways, such as problems cal history and assessment of the patient’s current remembering where one has placed objects, for- health status. Results should be obtained from getting new names, diffi culty completing two any completed neurodiagnostic studies (e.g., tasks at once, and trouble remembering shopping MRI, CT, EEG) for consideration in the differen- items, recalling conversations, or prioritizing tial diagnosis. Evaluating the presence of vascu- tasks by importance. It is often the ability to lar risk factors such as hypertension, learn, retain new information and perform hypercholesterolemia, and diabetes is essential higher-order executive skills that is dampened in when considering etiology of cognitive decline. persons with MCI, resulting in somewhat less An assessment of the patient’s sleep quality is ef fi cient daily functioning [84– 86] . Persons with important, including whether he or she has been MCI tend to make errors in performing tasks 248 L.A. Rog and J.W. Fink accurately and effi ciently while still remaining matched controls. However, Petersen emphasizes able to complete tasks [ 87 ] . This is in contrast to that this was not intended to serve as a cutoff dementia patients, who tend to also make these score and that it is ultimately left up to clinician errors in addition to omitting major portions of judgment whether or not a patient displays objec- tasks. tive memory impairment relative to his or her Poorer memory performance on cognitive baseline [58 ] . The most recent consensus criteria testing has been found to predict future notes that scores on cognitive tests for patients dif fi culties in fi nancial management in patients with MCI are typically 1–1.5 SD below the mean with MCI, and impaired memory and psycho- for age and education matched peers on cultur- motor speed are the cognitive domains most ally appropriate normative data [ 61 ] . It is empha- strongly related to functional abilities [ 88 ] . sized that these ranges are to be used as guidelines Other research suggests that attention and exec- and not cutoff scores. utive functioning, but not memory, are associ- Selecting neuropsychological instruments for ated with diffi culties managing multiple-step evaluating MCI should include an evaluation of fi nancial tasks, such as bill payment and prepa- the patient’s performance in all major cognitive ration and management of bank statements [89 ] . domains (i.e., memory, attention, processing Persons with MCI tend to show subtle functional speed, language, executive functioning, visu- declines in driving abilities when compared to ospatial skills, motor functioning) in order to noncognitively impaired persons, though their ensure a comprehensive assessment. Typically, a overall performances are not at the level of frank dementia screening measure is also administered driving impairments [ 90] . Instead, they are less and ideally an estimate of premorbid functioning likely than their cognitively normal peers to per- (e.g., word reading). A comprehensive assess- form certain driving routines seamlessly (e.g., ment approach that employs detailed neuropsy- left-hand turns, maintaining lane control), and chological assessment is advocated to improve their performances are more often rated as “less the reliability and stability of the MCI diagnosis than optimal.” Although some dampening in [91 ] . Although all major neurocognitive domains functioning is observed in MCI patients, it is should be validly sampled, it is of particular much less severe than the functional decline importance to obtain multiple measures of mem- seen in patients with dementia. MCI patients ory, as this domain is typically the presenting tend to perform functionally on a level interme- subjective complaint and is essential for differen- diate between persons with normal cognition tial diagnosis. Because there are multiple possi- and dementia patients [ 87 ] . MCI patients are ble etiologies of MCI, it would be inappropriate still able to function independently, albeit per- to focus only on memory testing and a global haps less ef fi ciently and with the use of com- screening measure. Assessment of other areas, pensatory strategies. including executive, attentional, and motor abilities in assessing for a vascular etiology, as well as visuospatial functioning in assessing for Lewy Cognitive Impairment body pathology, allows for the most comprehensive approach to determining etiology, a common Criteria for diagnosing MCI include not only referral question. Careful examination of mem- self- or family report of cognitive decline but also ory pro fi le patterns is also helpful in this regard. objective measurements of de fi cits in cognitive Given that a signifi cant proportion of MCI functioning. An exact cutoff for what constitutes patients present with neuropsychiatric symptoms, “mild” impairment has not been set in stone, but it is important to also include self-report mea- traditionally, a cutoff score of 1.5 SD below age sures of mood functioning, such as assessments norms has been used based on Petersen et al.’s of depression and anxiety symptoms. Table 16.2 original study [ 57 ] . In that study, the MCI group provides a sample test battery for a comprehensive performed, on average, 1.5 SD below age- neuropsychological evaluation when MCI is con- 16 Mild Cognitive Impairment and Normal Aging 249

Table 16.2 Sample core neuropsychological battery for display reduced learning, rapid forgetting, poor assessment in MCI recognition discrimination, and elevated intru- Mini-Mental State Exam [106 ] sion errors [92, 94 ] . Repeatable Battery for the Assessment of In terms of overall cognitive pro fi les, MCI Neuropsychological Status [107 ] patients have been found to show clearly defi ned Wechsler Adult Intelligence Scale IV [108 ] or Wechsler memory impairments with only mild impair- Abbreviated Scale of Intelligence [109 ] ments in other domains, such as executive func- Wide Range Achievement Test 4 (Reading subtest) [110 ] Trail Making Test A & B [111 ] tioning [95, 96] . While a-MCI patients may Stroop Color Word Test [112 ] show some dif fi culty in planning and problem California Verbal Learning Test II [113 ] or Hopkins solving, md-MCI patients show the most severe Verbal Learning Test—Revised [114 ] impairments [97 ] . It is unclear whether md- Rey Complex Figure Test [115, 116 ] or Brief MCI patients’ cognitive pro fi les are more Visuospatial Memory Test—Revised [117 ] impaired due to different disease etiology (e.g., Wechsler Memory Scale III (Logical Memory) [118 ] vascular) or whether differences are due to md- Boston Naming Test [119 ] MCI patients being further along in the disease Controlled Oral Word Association [120 ] and Semantic process. Fluency (i.e., Animal Fluency) [121 ] Wisconsin Card Sorting Test [122 ] Although visual confrontation naming impair- Clock Drawing and Copy [123 ] ment is a hallmark symptom of AD, patients with Finger Tapping Test [ 124 ] a-MCI have not been found to differ from con- Grooved Pegboard [125 ] trols on such tasks, suggesting that the breakdown Geriatric Depression Scale [126 ] or Beck Depression in semantic knowledge does not typically occur Inventory, Second Edition [127 ] at the MCI stage [98 ] . At the same time, however, State-Trait Anxiety Inventory [128 ] MCI patients have been shown to have poorer performance than controls on tasks of semantic memory, receive less bene fi t than controls when sidered in the differential diagnosis. Other mea- semantically cued on memory tasks, and use less sures and test batteries may be chosen, but the semantic clustering strategies on verbal learning guiding principles of test selection should be tasks [ 67, 99, 100 ] . It may be the case that these comprehensive sampling of cognitive domains, defi cits in semantically related learning are due at appropriate norms for age and other patient least in part to dampened executive functioning demographic factors, and wide range of measure- processes that affect categorization or semantic ment between the fl oor and ceiling captured by organization [101 ] . the measures, and whenever possible, measures In the attention domain, MCI patients who with alternate forms for retesting over time should ultimately convert to AD demonstrate poorer be used. immediate serial recall and divided attention than their MCI counterparts who remain cognitively stable [102 ] . This subgroup demonstrates the Common Neurocognitive Defi cits early stages of attentional impairment seen in AD, suggesting that such attentional impairments The most common neuropsychological impair- slowly decline over the course of the disease. ment seen in MCI patients who ultimately con- Vascular MCI has been less extensively stud- vert to Alzheimer’s disease is a decline in episodic ied in the research literature, though data suggest learning and memory early in the disease process that patients with vascular disease or signifi cant [92, 93] . This is thought to be consistent with vascular risk factors demonstrate poorer atten- early involvement of structures in the medial tion, executive function, visuospatial perfor- temporal lobes (e.g., hippocampus, entorhinal mance, and slower processing speed than patients cortex) in the progression to Alzheimer’s disease without vascular risk factors [103, 104 ] . (AD). Memory pro fi le patterns in a-MCI tend to 250 L.A. Rog and J.W. Fink

Diagnosing MCI Subtypes a-MCI is diagnosed, given its heightened association with a progression to Alzheimer’s demen- Once a diagnosis of MCI is established based on tia, retesting may be recommended in 1 year. For diagnostic criteria, selecting an MCI subtype is other types of MCI, it may be more appropriate to based on the results of the neurocognitive profi le. recommend retesting as clinically warranted, if In amnesic MCI (a-MCI), there is a single defi cit further cognitive changes are suspected by the in the learning and memory domain with pre- patient, family, or referring clinician. served cognitive functioning in all other domains. Useful information for clinicians disclosing Other patients have impaired learning and mem- an MCI diagnosis, including the meaning and ory in addition to impairment in another domain impact for the patient, can be gleaned from a (oftentimes, executive functioning, but any other unique analysis of qualitative interview data from domain is possible), and these patients would a small clinical sample of MCI patients (N = 12, receive a diagnosis of multiple-domain amnesic- diagnosed 3 to 6 months prior) [ 105 ] . The authors MCI (md-MCI + a). Patients who have a single examined patient’s experiences of living with and nonmemory domain impairment (again, often making sense of an MCI diagnosis. Interestingly, executive dysfunction or attention/processing over 40% (n = 5) of their sample used positively speed) are given the diagnosis of non-amnesic valenced words to depict their emotional reac- MCI (na-MCI). A subset of patients demonstrates tions to the diagnosis. Narrative accounts typi- impairment in two or more nonmemory domains cally revealed satisfaction in fi nding professional and would be diagnosed with multiple-domain validation for their subjective symptoms, as well non-amnesic MCI (md-MCI-a). as relief associated with a negative dementia diagnosis. Given evidence that MCI often is a precursor for dementia, this raises the issue of Feedback and Recommendations whether patients with MCI are adequately explained their increased risk of developing When reporting a diagnosis of MCI to a patient dementia in the future. Only 2 of 12 participants and possibly his or her family members, it is expressed a negative reaction to their diagnosis, important that the clinician clearly explain the and this occurred in the context of a perceived nature of the MCI diagnosis. Important informa- looming dementia diagnosis. Several participants tion to highlight includes the degree of cognitive did mention awareness of the possibility of fur- impairment associated with the diagnosis (i.e., ther decline in cognitive status, often in the con- greater than normal for the patient’s age but not text of being unsure whether a decline would severe enough to warrant a diagnosis of demen- occur. Oftentimes, a current state of relief tia). Equally important to convey sensitively is occurred simultaneously with tension surround- the patient’s increased risk for converting to ing an uncertain dementia prognosis. Around half dementia in the future, particularly for patients of the participants related MCI as part of the nor- given an amnesic MCI diagnosis (single or mul- mal aging process. Taken together, these fi ndings tiple domain), which has the greatest association suggest that there are varying interpretations of with future conversion to dementia, typically an MCI diagnosis, which the investigators pointed Alzheimer’s disease [62, 66 ] . Patients should be out have the potential to impact health behaviors, made aware of their particular areas of dif fi culty including returning for follow-up cognitive test- (e.g., memory, executive functioning) and the ing or planning for future states of decisional real-world implications for these defi cits. At the incapacity. same time, cognitive and other personal strengths Recommendations for patients diagnosed with should be highlighted in the context of develop- MCI may include follow-up with the patient’s ing compensatory strategies for dealing with neurologist or psychiatrist to discuss potentially objective cognitive defi cits and the functional beginning a trial of anti-dementia medication, diffi culties that often accompany such defi cits. If such as an acetylcholinesterase inhibitor. If the 16 Mild Cognitive Impairment and Normal Aging 251 patient does not already have established medical with some patients remaining in the MCI cate- care within these specialties, an appropriate refer- gory for years after initial evaluation and others ral should be made, particularly if baseline neu- converting to dementia rather rapidly. Patients rodiagnostic studies (e.g., MRI, EEG) have not present for their initial neuropsychological evalu- yet been completed. Management of risk factors ation at various points on the continuum, further associated with cognitive decline, such as medi- complicating an estimate for possible dementia cal comorbidities (e.g., vascular risk factors such conversion. Two points of reference can be help- as hypertension, diabetes, hyperlipidemia, sleep ful in determining a follow-up evaluation: (1) the apnea, metabolic levels) should be recommended. severity and number of domains impaired and (2) Similarly, patients should be encouraged to par- the patient’s functional status. It is likely that ticipate in a physician-approved exercise regimen patients with relatively more severe cognitive and maintain a healthful diet. Given that mood impairments are further along in their disease factors can exacerbate symptoms of cognitive progression and patients with multiple impaired impairment, appropriate monitoring of depres- domains may reach a dementia diagnosis sooner. sion, anxiety, or other psychological factors is Similarly, patients who show relatively greater necessary. In some cases, a psychiatric or psy- impairment in daily functioning may be closer to chotherapy referral is warranted to assist in man- a dementia diagnosis. Perhaps the safest bench- aging symptoms pharmacologically or mark for retesting is a 1-year follow-up period, in cognitively/behaviorally. Patients should be conjunction with the recommendation that the encouraged to remain cognitively and socially patient return for testing earlier should he or she active and to continue to complete daily tasks as (or family members) notice a signi fi cant decline independently as possible. in cognitive ability or functional status prior to In terms of functional abilities, it is important the 1-year mark. for patients and their families to continuously In conclusion, accurate clinical discrimination monitor functional status, particularly with regard between normal cognitive aging and MCI is an to potentially dangerous tasks such as driving. A important diagnostic challenge. This discrimina- change in functional status may be the simplest tion will become increasingly critical as new way for families of patients with MCI to recog- interventions are developed to target the very ear- nize advancing cognitive decline, and they should liest manifestations of incipient brain disease. be encouraged to assist the patient in monitoring instrumental activities of daily living (IADLs) such as fi nancial management, driving, medica- Clinical Pearls tion management, and higher-level organizational abilities. A decline in the ability to manage and • A signi fi cant proportion of MCI patients will perform IADLs is likely to represent a concor- ultimately convert to dementia, although many dant decline in cognitive status and may alert the will remain stable or will revert to normal, patient and family that neuropsychological depending on the etiology of the cognitive reevaluation is warranted to assess for progres- disturbance. sion to a dementia syndrome. • The most recent consensus criteria indicate With regard to neuropsychological retesting, it MCI is associated with cognitive test scores is diffi cult to establish a universally appropriate that are typically 1–1.5 SD below the mean for time for follow-up evaluation. Whereas a age and education matched peers; it is empha- signifi cant proportion of MCI patients will ulti- sized that these ranges are to be used as guide- mately convert to dementia, many will also lines, not cutoff scores . remain stable with the diagnosis or will revert to • Although memory complaints of some kind normal, depending on etiology. In those patients are typically the most common presenting rea- who ultimately receive a dementia diagnosis, the son for evaluation, it is important to carefully course of cognitive decline may be quite variable, assess the nature of the complaint since other 252 L.A. Rog and J.W. Fink

aspects of cognition may actually underlie the 5. Der G, Allerhand M, Starr JM, Hofer SM, Deary IJ. perceived de fi cit. Age-related changes in memory and fl uid reasoning in a sample of healthy old people. Aging, • Memory complains such as forgetting what Neuropsychol Cognition. 2009;17:55–70. you went into a room for or diffi culty recalling 6. Lindenberger U, Baltes PB. Intellectual functioning names are common in older adults and may not in old and very old age: Cross-sectional results from be clinically signifi cant. However, collateral the Berlin Aging Study. Psychol Aging. 1997;12:410–32. reports suggesting repetitive speech/question- 7. Rabbit PMA, McInnes L, Diggle P, Holland F, Bent ing or trouble navigating a familiar environ- N, Abson V, Horan M. The University of Manchester ment are more likely to be clinically relevant. longitudinal study of cognition in normal healthy old • Assessment of mood/personality functioning age, 1983 through 2003. Aging NeuropsycholCognition. 2004;11:245–79. is critical since subjective memory complaints 8. Park DC, Reuter-Lorenz P. The adaptive brain: tend to be more strongly correlated with nega- Aging and neurocognitive scaffolding. Annu Rev tive affect than with objective memory Psychol. 2009;60:173–96. performance. 9. Gunstad J, Paul RH, Brickman AM, Cohen RA, Arns M, Roe D, Gordon E. Patterns of cognitive per- • The examiner should get the patient’s consent formance in middle-aged and older adults: A cluster to obtain collateral information from a well- analytic examination. J Geriatr Psychiatry Neurol. known source. The congruence, or lack 2006;19:59–64. thereof, between patient self-report and collat- 10. Park DC, Lautenschlager G, Hedden T, Davidson NS, Smith AD, Smith PK. Models of visuospatial eral report is clinically informative in terms of and verbal memory across the adult life span. Psychol lack of insight/awareness of defi cits or a ten- Aging. 2002;17:299–320. dency to amplify complaints. 11. Rush BK, Barch DM, Braver TS. Accounting for • Assessing impact on activities of daily living cognitive aging: Context processing, inhibition, or processing speed? Aging, Neuropsychol Cognition. (ADLs) requires careful clinical judgment. Be 2006;13:588–610. certain to clarify how ADLs are impaired by 12. Howieson D, Holm L, Kaye J, Oken B. Neurologic cognitive factors as opposed to physical or function in the optimally healthy oldest old: emotional factors. Ask the collateral source if Neuropsychological evaluation. Neurology. 1993;43:1882–6. the patient would still be capable of perform- 13. Woodard J, Benedict R, Roberts V, Goldstein F. ing activities (e.g., driving, managing fi nances) Short-form alternatives to the Judgment of Line that other family members are conducting. Orientation Test. J Clin Exp Neuropsychol. • In addition to taking a general medical history, 1996;18:898–904. 14. Giovagnoli AR, Del Pesce M, Mascheroni S, be sure to inquire about pain, sleep, and sub- Simoncelli M, Laiacona M, Capitani E. Trail Making stance use in the context of the cognitive Test: Normative values from 287 normal adult con- complaints. trols. Ital J Neurol Sci. 1996;17:305–9. 15. Goul WR, Brown M. Effects of age and intelligence on Trail Making Test performance and validity. Percept Mot Skills. 1970;30:319–26. References 16. Kennedy KJ. Age effects on Trail Making Test performance. Percept Mot Skills. 1981;52:671–5. 1. World Health Organization. World health statistics 17. Clay OJ, Edwards JD, Ross LA, Okonkwo O, 2010. Geneva, Switzerland: WHO Press; 2010. Wadley VG, Roth DL, Ball KK. Visual function and 2. US Census Bureau. Annual estimates of the resident cognitive speed of processing mediate age-related population by sex and fi ve-year age groups for the decline in memory span and fl uid intelligence. United States: April 1, 2000 to July 1, 2009. Retrieved J Aging Health. 2009;21:547–66. October 15, 2010 from http://www.census.gov/ 18. Salthouse TA. The processing speed theory of adult popest/national/asrh/NC-EST2009-sa.htmlv . age differences in cognition. Psychol Rev. 3. Christensen H. What cognitive changes can be 1996;103:403–28. expected with normal aging? Aust N Z J Psychiatry. 19. Kane MJ, Hasher L, Stoltzfus ER, Zacks RT, 2001;35:768–75. Connelly SL. Inhibitory attention mechanisms and 4. Christensen H, Mackinnon A, Jorm AF, Henderson aging. Psychol Aging. 1994;9:103–12. AS, Scott LR, Korten AE. Age differences and inter- 20. Jennings JM, Jacoby LL. Automatic versus inten- individual variation in cognition in community- tional uses of memory: Aging, attention, and control. dwelling elderly. Psychol Aging. 1994;9:381–90. Psychol Aging. 1993;8:283–93. 16 Mild Cognitive Impairment and Normal Aging 253

21. Shafto MA, Burker DM, Stamatakis EA, Tam PP, 36. Green MS, Kaye JA, Ball MJ. The Oregon Brain Tyler LK. On the tip-of-the-tongue: Neural corre- Aging Study: Neuropathology accompanying lates of increased word-fi nding failures in normal healthy aging in the oldest old. Neurology. aging. J Cogn Neurosci. 2007;19:2060–70. 2000;54:105–13. 22. Au R, Joung P, Nicholas M, Obler L. Naming ability 37. Cabeza R, Grady CL, Nyberg L, McIntosh AR, across the adult life span. Aging Cognition. Tulving E, Kapur S, Craik FIM. Age-related 1995;2:300–11. differences in neural activity during memory encod- 23. Randolph C, Lansing AE, Ivnik RJ, Cullum CM, ing and retrieval: A positron emission tomography Hermann BP. Determinants of confrontation naming study. J Neurosci. 1997;17:391–400. performance. Arch Clin Neuropsychol. 38. Grady CL, McIntosh AR, Rajah MN, Beig S, Craik 1999;6:489–96. FI. The effects of age on the neural correlates of epi- 24. Ross TP, Lichtenberg PA. Effects of age and educa- sodic encoding. Cereb Cortex. 1999;9:805–14. tion on neuropsychological test performance: A 39. Cherry BJ, Adamson M, Duclos A, Hellige JB. comparison of normal versus cognitively impaired Aging and individual variation in interhemispheric geriatric medical patients. Aging, Neuropsychol collaboration and hemispheric asymmetry. Aging, Cognition. 1997;4:74–80. Neuropsychol Cognition. 2005;12:316–39. 25. Kempler D, Tang E, Dick M, Taussig I, Davis D. The 40. Fera F, Weickert TW, Goldberg TE, Tessitore A, effects of age, education, and ethnicity on verbal Hariri A, Das S, Mattay VS. Neural mechanisms fl uency. J Int Neuropsychol Soc. 1998;4:531–8. underlying probabilistic category learning in normal 26. Ruff RM, Light RH, Parker SB, Levin HS. The psy- aging. J Neurosci. 2005;25:11340–8. chological construct of word fl uency. Brain Lang. 41. Reuter-Lorenz PA, Marshuetz C, Jonides J, Smith 1997;57:394–405. EE, Hartley A, Koeppe R. Neurocognitive ageing of 27. Raz N, Lindenberger U, Rodrigue KM, Kennedy storage and executive processes. Eur J Cognit KM, Head D, Williamson A, Acker JD. Regional Psychol. 2001;13:257–78. brain changes in aging healthy adults: General 42. Rypma B, D’Esposito M. Age-related changes in trends, individual differences, and modifi ers. Cereb brain-behaviour relationships: Evidence from event- Cortex. 2005;15:1676–89. related functional MRI studies. Eur J Cognit Psychol. 28. Salat DH, Buckner RL, Snyder AZ, Greve DN, 2001;13:235–56. Desikan RSR, Busa E, Fischl B. Thinning of the 43. Baltes PB, Lindenberger U. Emergence of a power- cerebral cortex in aging. Cereb Cortex. 2004;14: ful connection between sensory and cognitive func- 721–30. tions across the adult life span: A new window to the 29. Carlson NE, Moore MM, Dame A, Howieson D, study of cognitive aging? Psychol Aging. Silbert LC, Quinn JF, Kaye JA. Trajectories of brain 1997;12:12–21. loss in aging and the development of cognitive 44. Lindenberger U, Baltes PB. Sensory functioning and impairment. Neurology. 2008;70:828–33. intelligence in old age: A strong connection. Psychol 30. Head D, Buckner RL, Shimony JS, Williams LE, Aging. 1994;9:339–55. Akbudak E, Conturo TE, Snyder AZ. Differential 45. Gutchess AH, Welsch RC, Hedden T, Bangert A, vulnerability of anterior white matter in nonde- Minear M, Liu LL, Park DC. Aging and the neural mented aging with minimal acceleration in dementia correlates of successful picture encoding: Frontal of the Alzheimer type: Evidence from diffusion ten- activations compensate for decreased medial- sor imaging. Cereb Cortex. 2004;14:410–23. temporal activity. J Cogn Neurosci. 2005;17:84–96. 31. Wen W, Sachdev P. The topography of white matter 46. Persson J, Nyberg L, Lind J, Larsson A, Nilsson L, hyperintensities on brain MRI in healthy 60- to Ingvar M, Buckner RL. Structure-function correlates of 64-year-old individuals. Neuroimage. cognitive decline in aging. Cereb Cortex. 2004;22:144–54. 2006;16:907–15. 32. Backman L, Ginovart N, Dixon RA, Robins Wahlin 47. Whalley LJ, Deary IJ, Appleton CL, Starr JM. TB, Wahlin A, Halldin C, Farde L. Age-related cog- Cognitive reserve and the neurobiology of cognitive nitive de fi cits mediated by changes in the striatal aging. Ageing Res Rev. 2004;3:369–82. dopamine system. Am J Psychiatry. 2000;157: 48. Bergman I, Blomberg M, Almkvist O. The important 635–7. of impaired physical health and age in normal cogni- 33. Backman L, Nyberg L, Lindenberger U, Li S, Farde tive aging. Scandanavian J Psychol. L. The correlative triad among aging, dopamine, and 2007;48:115–25. cognition: Current status and future prospects. 49. Kilander L, Andren B, Nyman H, Lind L, Boberg M, Neurosci Biobehav Rev. 2006;30:791–807. Lithell H. Atrial fi brillation is an independent deter- 34. Li S, Lindenberger U, Sikstrom S. Aging cognition: minant of low cognitive function: A cross-sectional From neuromodulation to representation. Trends study in older men. Stroke. 1998;29:1816–20. Cogn Sci. 2001;5:479–86. 50. Anstey KJ, Smith GA. Interrelationships among bio- 35. Braver TS, Barch DM. A theory of cognitive control, logical markers of aging, health, activity, accultura- aging cognition, and neuromodulation. Neurosci tion, and cognitive performance in late adulthood. Biobehav Rev. 2002;26:809–17. Psychol Aging. 1999;14:605–18. 254 L.A. Rog and J.W. Fink

51. Moss M, Franks M, Briggs P, Kennedy D, Scholey 64. Taber MH, Manly JJ, Liu X, Pelton GH, Rosenblum A. Compromised arterial oxygen saturation in S, Jacobs M, Devanand DP, et al. Neuropsychological elderly asthma sufferers results in selective cognitive prediction of conversion to Alzheimer disease in impairment. J Clin Exp Neuropsychol. patients with mild cognitive impairment. Arch Gen 2005;27:139–50. Psychiatry. 2006;63:916–24. 52. Wahlin A, MacDonald SWS, deFrias CM, Nilsson 65. Fleisher AS, Sowell BB, Taylor C, Gamst AC, L, Dixon RA. How do health and biological age Petersen RC, Thal LJ. Clinical predictors of progres- infl uence chronological age and sex differences in sion to Alzheimer’s disease in amnestic mild cogni- cognitive aging: Moderating, mediating, or both? tive impairment. Neurology. 2007;68:1588–95. Psychol Aging. 2006;21:318–32. 66. Ganguli M, Dodge HH, Shen C, DeKosky ST. Mild 53. Johnson W, Deary IJ, McGue M, Christensen K. cognitive impairment, amnestic type: an epidemio- Genetic and environmental transactions linking cog- logic study. Neurology. 2004;63:115–21. nitive ability, physical fi tness, and education in late 67. Bennett DA, Wilson RS, Schneider JA, Evans DA, life. Psychol Aging. 2009;24:48–62. Beckett LA, Aggarwal NT, Bach J. Natural History 54. Yaffe K, Fiocco AJ, Lindquist K, Vittinghoff E, of mild cognitive impairment in older persons. Simonsick EM, Newman AB, Harris TB. Predictors Neurology. 2002;59:198–205. of maintaining cognitive function in older adults: 68. Alexopolous P, Grimmer T, Perneczky R, Domes G, The Health ABC Study. Neurology. 2009;72: Kurz A. Do all patients with mild cognitive impair- 2029–35. ment progress to dementia? J Am Geriatr Soc. 55. Van Dijk KRA, Van Gerven PWM, Van Boxtel MPJ, 2006;54:1008–10. Van der Elst W, Jolles J. No protective effects of edu- 69. Forsberg A, Engler H, Almkvist O, Blomquist G, cation during normal cognitive aging: Results from Hagman H, Wall A, Nordberg A. PET imaging of the 6-year follow-up of the Maastricht Aging Study. amyloid deposition in patients with mild cognitive Psychol Aging. 2008;23:119–30. impairment. 2007. 56. Finkel D, Andel R, Gatz M, Pedersen NL. The role 70. Whitwell JL, Shiung MM, Przybelski SA, Weigand of occupational complexity in trajectories of cogni- SD, Knopman DS, Boeve BF, Jack CR. MRI pat- tive aging before and after retirement. Psychol terns of atrophy associated with progression to AD Aging. 2009;24:563–73. in amnestic mild cognitive impairment. Neurology. 57. Petersen RC, Smith GE, Waring SC, Ivnik RJ, 2008;70:512–20. Tangalos EG, Kokmen E. Mild cognitive impair- 71. Makesbery WR, Schmitt FA, Kryscio RJ, Davis DG, ment: Clinical characterization and outcome. Arch Smith CD, Wekstein DR. Neuropathologic substrate Neurol. 1999;56:303–8. of mild cognitive impairment. Arch Neurol. 58. Petersen RC. Mild cognitive impairment as a diag- 2006;63:38–46. nostic entity. J Intern Med. 2004;256:193–4. 72. Petersen RC, Parisi JE, Dickson DW, Johnson KA, 59. Panza F, D’Introno A, Colacicco AM, Capurso C, Knopman DS, Boeve BF, Kokmen E, et al. Del Parigi A, Caselli RJ, Solfrizzi V. Current epide- Neuropathologic features of amnestic mild cogni- miology of mild cognitive impairment and other pretive impairment. Arch Neurol. 2006;63:665–72. dementia syndromes. Am J Geriatr Psychiatry. 73. Vemuri P, Wiste HJ, Weigand SD, Knopman DS, 2005;13:633–44. Trojanowski JQ, Shaw LM, Jack CR. Serial MRI 60. Winblad B, Palmer K, Kivipelto M, Jelic V, and CSF biomarkers in normal aging, MCI, and AD. Fratiglioni L, Wahlund L-O, Petersen RC. Mild cog- Neurology. 2010;75:143–51. nitive impairment - beyond controversies, towards a 74. Meyer JS, Huang J, Chowdhury MH. MRI con fi rms consensus: Report of the International Working mild cognitive impairments prodromal for Group on Mild Cognitive Impairment. J Intern Med. Alzheimer’s, vascular, and Parkinson-Lewy body 2004;56:240–6. dementias. J Neurol Sci. 2007;257:97–104. 61. Albert MS, DeKosky ST, Dickson D, Dubois B, 75. Prodan CI, Monnot M, Brumback RA, Ross ED. Feldman HH, Fox NC, Phelps CH (2011). The diag- Initiating referral in mild cognitive impairment: Who nosis of mild cognitive impairment due to rings the bell? J Am Geriatr Soc. 2007;55:1147–9. Alzheimer’s disease: Recommendations from the 76. Apostolova LG, Cummings JL. Neuropsychiatric National Institute on Aging and Alzheimer’s manifestations in mild cognitive impairment: A sys- Association workgroup. Alzheimer’s & Dementia, tematic review of the literature. Dement Geriatr 7: in press. Cogn Disord. 2008;25:115–26. 62. Busse A, Hensel A, Guhne U, Angermeyer MC, 77. Chan D, Kasper JD, Black BS, Rabins PV. Prevalence Riedel-Heller SG. Mild cognitive impairment: long- and correlates of behavioral and psychiatric symp- term course of four clinical subtypes. Neurology. toms in community-dwelling elders with dementia or 2006;67:2176–85. mild cognitive impairment: The Memory and Medical 63. Fischer P, Jungwirth S, Zehetmayer S, Weissgram S, Care Study. Int J Geriatr Psychiatry. Hoeningschnabl S, Gelpi E, Tragl KH. Conversion 2003;18:174–82. from subtypes of mild cognitive impairment to 78. Geda YE, Roberts RO, Knopman DS, Petersen RC, Alzheimer dementia. Neurology. 2007;68:288–91. Christianson TJH, Pankratz VS, Rocca WA. 16 Mild Cognitive Impairment and Normal Aging 255

Prevalence of neuropsychiatric symptoms in mild contributions to the early identifi cation of Alzheimer’s cognitive impairment and normal cognitive aging: disease. Neuropsychol Rev. 2008;18:73–90. Population-based study. Arch Gen Psychiatry. 92. Bondi MW, Salmon DP, Galasko D, Thomas RG, 2008;65:1193–8. Thal LJ. Neuropsychological function and apolipo- 79. Lyketsos CG, Sheppard JE, Steinberg M, Tschanz protein E genotype in the preclinical detection of JT, Norton MC, Steffens DC, et al. Neuropsychiatric Alzheimer’s disease. Psychol Aging. 1999;14: disturbance in Alzheimer’s disease clusters into 295–303. three groups: The Cache County study. Int J Geriatr 93. Collie A, Maruff P. The neuropsychology of preclin- Psychiatry. 2001;16:1043–53. ical Alzheimer’s disease and mild cognitive impair- 80. Ellison JM, Harper DG, Berlow Y, Zeranski L. ment. Neurosci Biobehav Rev. 2000;24:365–74. Beyond the “C” in MCI: Noncognitive symptoms in 94. Greenaway MC, Lacritz LH, Binegar D, Weiner MF, amnestic and non-amnestic mild cognitive impair- Lipton A, Cullum CM. Patterns of verbal memory ment. CNS Spectr. 2008;13:66–72. performance in mild cognitive impairment, 81. Hwang TJ, Masterman DL, Ortiz F, Fairbanks LA, Alzheimer disease, and normal aging. Cogn Behav Cummings JL. Mild cognitive impairment is associ- Neurol. 2006;19:79–84. ated with characteristic neuropsychiatric symptoms. 95. Crowell TA, Luis CA, Vanderploeg RD, Schinka JA, Alzheimer Dis Assoc Disord. 2004;18:17–21. Mullan M. Memory patterns and executive function- 82. Gabryelewicz T, Styczynska M, Pfeffer A, Wasiak ing in mild cognitive impairment and Alzheimer’s B, Barczak A, Luczywek E, et al. Prevalence of disease. Aging Neuropsychol Cognition. major and minor depression in elderly persons with 2002;9:288–97. mild cognitive impairment: MADRS factor analysis. 96. Grundman M, Petersen RC, Ferris SH, Thomas RG, Int J Geriatr Psychiatry. 2004;19:1168–72. Aisen PS, Bennett DA, Thal LJ. Mild cognitive 83. Beebe DW, Gozal D. Obstructive sleep apnea and impairment can be distinguished from Alzheimer’s the prefrontal cortex: Towards a comprehensive disease and normal aging for clinical trials. Arch model linking noctural upper airway obstruction to Neurol. 2004;61:59–66. daytime cognitive and behavioral de fi cits. J Sleep 97. Brandt J, Aretouli E, Neijstrom E, Samek J, Manning Res. 2002;11:1–16. K, Albert MS, Bandeen-Roche K. Selectivity of 84. Farias ST, Mungas D, Reed BR, Harvey D, Cahn- executive function defi cits in mild cognitive impair- Weiner D, DeCarli C. MCI is associated with defi cits ment. Neuropsychology. 2009;23:607–18. in everyday functioning. Alzheimer Dis Assoc 98. Balthazar MLF, Cendes F, Damasceno BP. Semantic Disord. 2006;20:217–33. error patterns on the Boston Naming Test in normal 85. Royall DR, Palmer R, Chiodo LK, Polk MJ. aging, amnestic mild cognitive impairment, and mild Executive control mediates memory’s association Alzheimer’s disease: Is there semantic disruption? with change in instrumental activities of daily living: Neuropsychology. 2008;22:703–9. The Freedom House Study. J Am Geriatr Soc. 99. Ribeiro F, Guerreiro M, De Mendonca A. Verbal 2005;53:11–7. learning and memory de fi cits in mild cognitive impair- 86. Schmitter-Edgecombe M, Woo E, Greeley DR. ment. J Clin Exp Neuropsychol. 2007;29:187–97. Characterizing multiple memory defi cits and their 100. Spaan PEJ, Raaijmakers JGW, Jonker C. Early relation to everyday functioning in individuals with assessment of dementia: the contribution of different mild cognitive impairment. Neuropsychology. memory components. Neuropsychology. 2005;19: 2009;23:168–77. 629–40. 87. Giovannetti T, Bettcher BM, Brennan L, Libon DJ, 101. Taler V, Phillips NA. Language performance in Burke M, Duey K, Wambach D. Characterization of Alzheimer’s disease and mild cognitive impairment: everyday functioning in mild cognitive impairment: a comparative review. J Clin Exp Neuropsychol. A direct assessment approach. Dement Geriatr Cogn 2008;30:501–56. Disord. 2008;25:359–65. 102. Belleville S, Chertkow H, Gauthier S. Working 88. Tuokko H, Morris C, Ebert P. Mild cognitive impair- memory and control of attention in persons with ment and every day functioning in older adults. Alzheimer’s disease and mild cognitive impairment. Neurocase. 2005;11:40–7. Neuropsychology. 2007;21:458–69. 89. Okonkwo OC, Wadley VG, Grif fi th HR, Ball K, 103. Gainotti G, Ferraccioli M, Vita M, Marra C. Patterns Marson DC. Cognitive correlates of fi nancial abili- of neuropsychological impairment in MCI patients ties in mild cognitive impairment. J Am Geriatr Soc. with small subcortical infarcts or hippocampal atro- 2006;54:1745–50. phy. J Int Neuropsychol Soc. 2008;14:611–9. 90. Wadley VG, Okonkwo O, Crowe M, Vance DE, 104. Norlund A, Rolstad S, Klang O, Lind K, Hansen S, Elgin JM, Ball KK, Owsley C. Mild cognitive Wallin A. Cognitive profi les of mild cognitive impairment and every day function: an investigation impairment with and without vascular disease. of driving performance. J Geriatr Psychiatry Neurol. Neuropsychology. 2007;21:706–12. 2009;22:87–94. 105. Lingler JH, Nightingale MC, Erlen JA, Kane AL, 91. Bondi MW, Jak AJ, Delano-Wood L, Jacobson Reynolds CF, Schulz R, DeKosky ST. Making MW, Delis DC, Salmon DP. Neuropsychological sense of mild cognitive impairment: a qualitative 256 L.A. Rog and J.W. Fink

exploration of the patient’s experience. 118. Wechsler D. WAIS-III/WMS-III technical manual. Gerontologist. 2006;46:791–800. San Antonio: The Psychological Corporation; 106. Folstein MF, Folstein SE, McHugh PR. Mini-mental 1997. state. A practical method for grading the cognitive 119. Kaplan E, Goodglass H, Weintraub S. The Boston state of patients for the clinician. J Psychiatr Res. Naming Test. Philadelphia, PA: Lea and Febiger; 1975;12:189–98. 1983. 107. Randolph C, Tierney MC, Mohr E, Chase TN. The 120. Benton AL, Hamsher K, Sivan AB. Multilingual Repeatable Battery for the Assessment of Aphasia Examination. 3rd ed. Iowa City, IA: AJA Neuropsychological Status (RBANS): Preliminary clini- Associates; 1994. cal validity. J Clin Exp Neuropsychol. 1998;20:310–9. 121. Tombaugh T, Kazak J, Rees L. Normative data 108. Wechsler D. Wechsler Adult Intelligence Scale, strati fi ed by age and education for two measures of Fourth Edition administration and scoring manual. verbal fl uency: FAS and animal naming. Arch Clin San Antonio, TX: Pearson; 2008. Neuropsychol. 1999;14:167–77. 109. Wechsler D. Wechsler Abbreviated Scale of Intelligence 122. Heaton RK, Chelune GJ, Talley JL, Kay GG, Curtis (WASI) manual. San Antonio, TX: Pearson; 1999. G. Wisconsin Card Sorting Test (WCST) manual, 110. Wilkinson GS, Robertson GJ. Wide Range revised and expanded. Odessa, TX: Psychological Achievement Test-4 professional manual. Lutz, FL: Assessment Resources, Inc.; 1993. Psychological Assessment Resources; 2006. 123. Goodglass H, Kaplan E. The assessment of aphasia 111. Reitan RM. Validity of the Trail Making Test as an and related disorders. 2nd ed. Philadelphia, PA: Lea indicator of organic brain damage. Percept Mot & Febiger; 1982. Skills. 1958;8:271–6. 124. Halstead WC. Brain and intelligence. A quantitative 112. Golden CJ. Stroop Color and Word Test: a manual study of the frontal lobes. Chicago: University of for clinical and experimental uses. Chicago, IL: Chicago; 1947. Skoelting; 1978. 125. Heaton RK, Grant I, Matthews CG. Comprehensive 113. Delis DC, Kramer JH, Kaplan E, Ober BA. California norms for an expanded Halstead-Reitan battery. Verbal Learning Test. 2nd ed. San Antonio, TX: Odessa, FL: Psychological Assessment Resources; Psychological Corporation; 2000. 1992. 114. Brandt J, Benedict RHB. Hopkins Verbal Learning 126. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Test-Revised. Lutz, FL: Psychological Assessment Adey M, Leirer VO. Development and validation of Resources; 2001. a geriatric depression screening scale: A preliminary 115. Rey A. L’examen psychologique dans les cas report. J Psychiatr Res. 1983;17:37–49. d’encéphalopathie traumatic. Arch Psychol. 127. Beck AT, Steer RA, Brown GK. Manual for Beck 1941;28:286–340. Depression Inventory II (BDI-II). San Antonio, TX: 116. Osterrieth PA. Le test de copie d’une fi gure com- Psychology Corporation; 1996. plexe. Arch Psychol. 1944;30:206–356. 128. Spielberger CD, Gorsuch RL, Lushene PR, Vagg 117. Benedict RH. Brief Visuospatial Memory Test— PR, Jacobs AG. Manual for the State-Trait Anxiety Revised. Odessa, FL: Psychological Assessment Inventory (form Y). Palo Alto, CA: Consulting Resources, Inc.; 1997. Psychologists Press, Inc.; 1983. Differential Diagnosis of Depression and Dementia 1 7

Linas A. Bieliauskas and Lauren L. Drag

Abstract Cognitive complaints and depressive symptoms are common in older adults. While depressive symptoms may represent a primary mood disorder, they may also reﬂ ect the early signs of a dementia. Depression and dementia often differ in terms of their cognitive proﬁ le as well as the phenomenology of the depressive symptoms. Neuropsychologists can play an important role in making diagnostic decisions by providing objective assessment of both cognitive and psychological functioning. This chapter reviews considerations for differential diagnosis and provides practical tips for the clinician.

Keywords Depression ¥ Aging ¥ Dementia ¥ Pseudodementia ¥ Diagnosis

Depression in older adults has prevalence rates depression has been associated with negative estimated to be between 3 and 14% in the com- outcomes such as functional impairment and dis- munity-dwelling population [ 1Ð 3 ] . Approxi- ability, increased medical symptoms, negative mately 1 in 15 older adults may experience major rehabilitation outcomes, and increased utilization depression over the course of 1 year [2 ]. Late-life of health care services [ 4Ð 6 ] . Depression can also have signiﬁ cant economic costs. Due to unexplained somatic complaints and functional L. A. Bieliauskas, Ph.D. () impairments, older adults with depression tend to Mental Health Service, Ann Arbor VA Healthcare System, use more medical services. Katon et al. [7 ] found Neuropsychology Section, Department of Psychiatry , that depressed older adults incurred approxi- University of Michigan Healthcare System, 2101 Commonwealth Blvd, Suite C , Ann Arbor , mately 50% higher medical costs than their non- MI 48105 , USA depressed counterparts, even when taking chronic e-mail: [email protected] medical illness into account. Only a small part of L. L. Drag, Ph.D. these costs went to mental health care; the major- Neuropsychology Section, Department of Psychiatry , ity of costs were associated with primary care University of Michigan Healthcare System , visits, diagnostic visits, emergency room visits, Ann Arbor , MI , USA e-mail: [email protected] and pharmacy costs. Thus, late-life depression

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 257 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_17, © Springer Science+Business Media, LLC 2013 258 L.A. Bieliauskas and L.L. Drag can place a signifi cant burden on patients, their whereas depressed individuals did not make caregivers, and the health-care system, illustrating attempts to compensate for their diffi culties. the importance of adequately assessing, managing, Despite the initial popularity of “pseudode- and treating this disorder. mentia” amongst clinicians, there has been debate about the use of this term and it has generally fallen out of favor in current practice. The term Depression-Related Cognitive has been of historical importance in that it encour- Impairment or “Pseudodementia” aged clinicians to evaluate every patient carefully and look for alternate causes of cognitive decline In addition to negative clinical outcomes, late-life other than dementia. However, as Reifl er [ 9 ] has depression can be accompanied by signifi cant pointed out, there were some drawbacks to using cognitive impairments. These depression-related this term. Pseudodementia implies a mutually changes are often similar to those associated with exclusive process, which can lead a clinician to dementia. Historically, a psychiatric illness that focus on whether a patient is depressed or mimicked dementia symptoms was referred to as demented at the exclusion of the possibility that “pseudodementia.” The cognitive symptoms of both conditions could be present. The term also pseudodementia were assumed to be related to implies complete reversibility and a lack of transient mood symptoms and therefore revers- organic pathology without taking into account ible with adequate psychiatric treatment. that there may be both reversible and irreversible Therefore, the term “reversible dementia” was components to the illness. Several more recent also used to describe depression-induced cogni- studies have con fi rmed that the cognitive de fi cits tive impairments. One of the early clinicians to associated with “reversible dementias” may not popularize this term, Wells [ 8 ] , provided a detailed actually be truly reversible. For example, Fretter characterization of pseudodementia based on his and colleagues [10 ] examined individuals with own clinical observations. He noted that individu- dementia and found that of the 45 individuals with als with pseudodementia typically had complaints potentially reversible causes (e.g., depression, of memory loss that were not apparent to the alcohol abuse, vitamin defi ciencies), only seven examiner. They tended to highlight their failures individuals (16%) showed improvement of their and emphasize their disability; however, their cognitive symptoms following successful treat- functional de fi cits were often incongruent with ment. Similarly, Butters and colleagues [11 ] found the typically mild nature of their cognitive defi cits. that in some older adults with depression and cog- This was in stark contrast to patients with demen- nitive impairment, executive functioning did tia, who often lacked insight into the extent and improve following successful antidepressant treat- severity of their dysfunction and therefore tended ment but failed to reach normal levels of perfor- to minimize their symptoms. Wells also reported mance. Finally, Alexopoulos and colleagues [ 12 ] that patients with pseudodementia often provided followed older adults with depression who showed “don’t know” responses to close-ended questions a pattern of “reversible dementia” as demonstrated despite being able to provide coherent and by cognitive impairment at baseline followed by detailed responses to open-ended questions. In improvement in cognitive symptoms subsequent addition, patients with depression-related de fi cits to treatment for their depression. However, at fol- typically had equally severe recent and remote low-up 1 year later, individuals with reversible memory de fi cits (compared to the temporally dementia were fi ve times more likely than graded memory defi cits typically seen in degen- depressed individuals without cognitive impair- erative dementia), a clear onset of cognitive ment to develop a true dementia syndrome. symptoms, and limited symptoms of sundown- Although the treatment of depression may initially ing. According to Wells, demented individuals lead to improvements in dementia-related symp- also often tried to rely on notes and calendars, toms, follow-up over time suggests that true 17 Differential Diagnosis of Depression and Dementia 259 reversibility of such dementia is an uncommon dementia, longitudinal research has demonstrated occurrence [13 ] . The term “pseudodementia” is that depressive symptoms may actually be an discussed in the Diagnostic and Statistical Manual early sign or risk factor for subsequent cognitive of Mental Disorders (DSM) III, [14 ] but is no lon- impairment and dementia [ 26 ] . Modrego and ger used in more current revisions of the DSM. Ferrández [27 ] followed individuals with amnesic mild cognitive impairment over 3 years and found that those individuals with baseline depres- Depression as a Symptom sion were more than twice as likely to develop of Dementia dementia compared to their nondepressed counterparts and also more likely to develop dementia Although late-life depression can sometimes earlier. Similarly, Rosenberg and colleagues [ 28 ] refl ect a primary psychiatric disorder, it is often followed a large sample of 436 older women over the case that depressive symptoms are in fact early a 9-year period and found that baseline depres- manifestations of an underlying progressive sive symptoms were associated with increased dementing illness. High rates of depression and rates of incident impairments on cognitive tests psychiatric symptoms in general are found across across multiple domains. Although it may be that various neurodegenerative disorders, including depression is a risk factor for dementia (possibly Alzheimer’s disease (AD), vascular dementia, through neuronal loss via dysregulation of gluco- Lewy body dementia, multiple system atrophy, corticoids), it is just as likely that depression is a and Parkinson’s disease [ 15Ð 20] . Okura and col- behavioral manifestation of the dementia process leagues [ 21 ] found that approximately half of all itself [ 29] . Further research is needed to better individuals with cognitive impairment or diag- elucidate the possible causal relationships nosed with dementia exhibited at least one psychi- between depressive symptoms and subsequent atric symptom. Depression was the most common cognitive impairment. psychiatric symptom in individuals with cognitive impairment or mild dementia. In a study of nursing home residents, Verkaik and colleagues [ 22 ] Clinical Assessment demonstrated a depression prevalence rate of 19% amongst residents with dementia, with depressed Neuropsychologists play an important role in mood, irritability, and fatigue being the most fre- the assessment and treatment of both depression quently endorsed symptoms. Similarly, Starkstein and dementia. Various clinicians such as pri- and colleagues [ 23 ] examined 670 patients with mary care practitioners, psychologists, psychia- probable AD and found that approximately half of trists, or neurologists often refer older adults these individuals had signi fi cant symptoms of for neuropsychological evaluation to better depression. Thus, depressive symptoms appear to clarify a patient’s cognitive and psychiatric be highly prevalent in individuals with dementia. complaints. Neuropsychological evaluation can It is not likely that depression can be attributed have signi fi cant contributions to diagnosis, man- solely to a reaction to the disease itself as aware- agement, and treatment of these symptoms ness of defi cits has not clearly been linked to the through an objective characterization of cogni- development of depressive symptoms [ 24] . There tive and psychiatric profi les, identifi cation of has also not been strong support for an association areas of weakness that can lead to functional between severity of dementia and depression; impairments or be addressed through interven- depressive symptoms have been shown to be tions, and follow-up assessments that can track equally prevalent across disease stages [ 22, 25 ] . the extent to which symptoms improve, worsen, While this cross-sectional research illustrates or remain stable in response to interventions the high comorbidity between depression and or time [ 30 ] . 260 L.A. Bieliauskas and L.L. Drag

Table 17.1 Instruments commonly used to assess Assessment of Geriatric Depression depression in older adults For use in both adults and older adults An important part of a neuropsychological Beck Depression Inventory-II [35 ] evaluation of a patient with depressive symptoms Center for Epidemiological Studies Depression Scale is to gain both a qualitative and quantitative (CES-D) [94 ] understanding of these symptoms. However, Zung Depression Rating Scale [95 ] depression is often diffi cult to assess in older DSM-IV Depression Checklist [96 ] adults for a number of reasons. Symptoms of Hamilton Depression Rating Scale [36 ] depression are easily confounded by the effects For use in older adults of age and medical disorders. Changes in weight, Geriatric Depression Scale [37 ] appetite, and libido; psychomotor retardation or Geriatric Depression Scale (short form) [97 ] agitation; and a loss of interest in activities are For use in patients with dementia common to medical illnesses, physical effects of Cornell Scale for Depression in Dementia [98 ] aging, and age-related lifestyle changes, as well Dementia Mood Assessment Scale [99 ] as depression. For instance, a patient may endorse Depression Sign Scale [100 ] Neuropsychiatric Inventory [101 ] a decline in social activities, but upon further CERAD Behavior Rating Scale [102 ] prompting, clarify that he or she can no longer drive and do not have many friends or family members who live nearby. Similarly, it may be recovery from medical or surgical procedures, that a preference to stay home refl ects fatigue and refusal of treatment [33 ] . related to medical conditions rather than a symp- Patients may be referred for a neuropsycho- tom such as anhedonia. logical assessment for subjective cognitive com- Older adults may also be more likely to under- plaints, and only after detailed questioning will estimate their depressive symptoms. They may evidence of possible depression emerge. Older have lower functional expectations for them- adults with depression are more likely to initially selves due to their increasing age (e.g., they may present to their primary care physician rather believe that their fatigue is a normal part of the than to a specialist such as a psychiatrist [ 34 ] and aging process) and therefore dismiss their depres- may report only vague physical symptoms. sive symptoms as a common response to life Therefore, depression may go undetected in some stressors or normal aging. This is a common mis- patients unless a careful evaluation is performed. conception; depression is not a normal part of aging This suggests that all older adults complaining of (Table 17.1). While older adults may be prone to cognitive problems should be screened for depressive symptoms due to declining health and depression, regardless of the referral question. functioning, the aging process itself does not con- Several psychometric instruments have been fer an increased risk for depression [31 ] . developed to screen for depression (Table 17.1 ) . Further complicating matters, older adults are Popular instruments include the Beck Depression less likely to report dysphoric mood than their Inventory-II (BDI-II) [ 35 ] and the Hamilton younger counterparts. Rather, they tend to pre- Depression Rating Scale (HDRS) [36 ] . The sent with vague symptoms such as sleep distur- Geriatric Depression Scale (GDS) [ 37 ] bances or fatigue [ 32 ] . Given that older adults speci fi cally targets symptoms common to depres- may not endorse prominent dysphoria, clinicians sion in older adults. Several rating scales have need to be aware of the more subtle indicators of also been developed specifi cally for use in depression. These can include frequent offi ce vis- patients with dementia. Table 17.1 provides a list its or use of medical services, persistent reports of psychometric instruments that are commonly of pain, fatigue, insomnia, headaches, changes in used to assess depression in older adults. These sleep or appetite, unexplained GI symptoms, inventories can be useful to quantify and monitor social isolation, increased dependency, delayed depressive symptoms over time, yet they should 17 Differential Diagnosis of Depression and Dementia 261 be used as a supplement to a clinical interview. been associated with both cognitive and psychiatric Individuals with cognitive impairment may symptoms in older adults. Primary psychiatric endorse depressive symptoms, but further prompt- disorders such as depression, anxiety, and bipolar ing may be required to tease apart primary depres- disorder should be considered, although an initial sion from possible secondary effects of cognitive onset of psychiatric symptoms in late adulthood symptoms. Cognitive impairment can limit a per- is unusual. Psychiatric symptoms such as depres- son’s ability (but not necessarily desire) to be sion, irritability, and apathy are also common involved and engaged with activities. For exam- across many of the dementia subtypes, including ple, individuals with cognitive impairment may AD, Lewy body dementia, frontotemporal be unable to drive or have diffi culty keeping up dementia, and vascular dementia. Whether symp- with social activities (e.g., playing complex card toms primarily represent depression or a dement- games) like they used to. On questionnaires such ing condition is typically considered a major as the GDS, which probes for symptoms such as consideration, and a more detailed discussion of a decrease in activities or boredom, further dis- the differential diagnosis between primary cussion is warranted to determine whether these depression and dementia is provided below. symptoms re fl ect a true underlying depression Changes in mood and cognition can also be asso- rather than situational factors. ciated with strokes, particularly those affecting frontal regions or frontostriatal circuits. In addition, many medications commonly used to Considerations for Differential treat medical illness in older adults can cause Diagnosis depression-like symptoms [ 38 ] . For example, calcium channel blockers, beta-blockers, When a patient presents with reported changes in levodopa, corticosteroids, and even certain anti- both mood and cognitive functioning, there are biotics can affect both mood and cognitive func- several potential rule-out diagnoses to consider. tioning. While depression can be the direct Table 17.2 provides a list of disorders that have physiological sequelae of some medical conditions such as hypothyroidism or vitamin Table 17.2 Common differential diagnoses to consider de fi ciencies, clinicians should also consider that for older adults with psychiatric symptoms and cognitive depression may be a secondary reaction to a complaints chronic medical illness. Digestive disorders, respi- Dementias ratory ailments, and heart disease in particular Alzheimer’s disease have been associated with an increased rate of Frontotemporal dementia depressive symptoms, most likely due to functional Lewy body dementia limitations associated with the disorder and a lack Vascular dementia/stroke of perceived control over medical symptoms [ 39 ] . Dementia associated with Parkinson’s disease Psychiatric disorders Depression Differences Between Depression Bipolar disorder and Dementia Anxiety Other potential causes Cognitive and psychiatric symptoms associated Medications (e.g., beta-blockers, calcium channel with a primary depression can differ from those blockers) Vitamin de fi ciencies (e.g., vitamin D, vitamin B12, associated with a dementia process. Depression thiamine) is typically associated with a more acute onset of Hormonal conditions (e.g., hypothyroidism, symptoms (e.g., days to weeks), whereas the menopause) impairments associated with dementia can prog- Substance abuse ress over the course of years. Therefore, a gradual Brain tumor onset and progression of cognitive and mood Normal pressure hydrocephalus symptoms is more likely to re fl ect an underlying 262 L.A. Bieliauskas and L.L. Drag dementing process, whereas a more acute onset is early marker of preclinical AD, whereas dysphoric typically associated with depression. In addition, mood may be more indicative of a primary depression is often accompanied by signifi cant depressive disorder [50, 51 ] . subjective cognitive complaints [ 40, 41 ] . Older When assessing apathy in patients with cogni- adults with depression are more likely to com- tive impairments, it is important that clinicians plain more about their cognitive dif fi culties than focus on the behaviors for which a patient is still individuals with dementia [42 ] , and these cogni- capable of performing, as cognitive impairments tive complaints may be out of proportion to an can limit a person’s ability to engage with their individual’s actual level of functioning. For environment independent of motivational factors. example, a patient may complain of severe mem- Structured measures have been designed to ory de fi cits yet continue to independently man- speci fi cally measure symptoms of apathy, includ- age his or her medications and fi nances. In ing the Neuropsychiatric Inventory [ 52 ] and the contrast, a lack of insight into symptoms is com- Apathy Evaluation Scale [ 53 ] . The Irritability/ mon in dementia, particularly AD, making these Apathy Scale has been used to measure apathy in individuals more likely to minimize their cogni- patients with dementia [54 ] . tive dif fi culties. In addition to apathy, depressive symptoms The presence of apathetic symptoms can also associated with dementia may be characterized have clinical indications when differentiating by fewer and less prominent symptoms compared between depression and dementia. Apathy is to a primary depression, with salient features of typically de fi ned as a loss of motivation and can social withdrawal and irritability [55 ] . Because manifest as diminished initiation, lack of inter- depressive profi les can differ between primary est, low social engagement, and a blunted emo- depression and dementia, a new set of diagnostic tional response. While apathy can be a principal criteria has been proposed speci fi cally for depres- symptom of depression, it can also refl ect an sion in the context of AD [ 56 ] . These new criteria independent syndrome, distinct from the dys- require the presence of three symptoms (com- phoria typically associated with depression. pared to the fi ve required for a diagnosis of major Apathy is often characterized by indifference, depressive disorder). Symptoms are similar to and dysphoric symptoms are better character- those in major depressive disorder with the addi- ized by sadness, guilt, self-criticism, hopeless- tion of social isolation and irritability. A depressed ness, and helplessness. Bieliauskas [ 43 ] suggests mood or decreased positive affect or pleasure in that true primary depression signi fi cantly response to social contacts or usual activities is includes a loss of self-esteem and that, in the required. Given that depressive symptoms in AD absence of this loss, depressive symptoms likely are less prominent compared to those associated refl ect neurological change. Apathy is a promi- with a primary depression, symptoms are not nent feature in various neurodegenerative disor- required to be present nearly every day. ders, including AD, frontotemporal dementia, The age of onset of depressive symptoms and Parkinson’s disease [44, 45 ] . In AD in par- should also be taken into consideration. There are ticular, apathy symptoms are more prevalent signi fi cant differences both phenomenologically than dysphoric symptoms [ 46, 47 ] and older and etiologically between early-onset and late- adults who present with apathetic symptoms are onset depression, suggesting that these may be more likely to develop AD than those with either distinct psychiatric entities. The median age of no depression or depression without apathy onset in depression is 32 years of age with 50% [ 48, 49] . This affi rms that mood symptoms in of individuals reporting onset between ages 19 the early stages of dementia are better character- and 44 [ 57 ] . Late-onset depression is typically ized by an apathetic syndrome rather than dys- de fi ned as depression with a fi rst onset between phoric mood. Therefore, apathy, particularly in 45 and 60 years of age. It is likely that there are the context of cognitive changes, may be an stronger pathogenetic contributions from brain 17 Differential Diagnosis of Depression and Dementia 263 degenerative changes in late-onset depression in distinguishing depression from dementia compared to early-onset depression [ 58, 59 ] . (which is associated with reduced REM); how- Bieliauskas [43 ] suggested that when older ever, this type of detailed sleep data is typically patients present cognitive diffi culties associated not available to clinicians without requesting a with an initial onset of depression, these are most formal sleep study [67 ] . likely based on neurological disease. Lamberty In sum, the phenomenology of a depressive and Bieliauskas [ 60 ] reviewed a number of stud- syndrome can differ between primary depression ies showing high correlations between cognitive and dementia. Depression is associated with an changes with depression and positive fi ndings on earlier age of onset of symptoms; subjective neuroimaging. In a later review of neuroimaging reporting of signi fi cant cognitive symptoms; an fi ndings, Kumar, Bilker Jin, and Udupa [61 ] sug- acute onset of cognitive de fi cits; the presence of gest that atrophy and high-intensity lesions may dysphoria, including loss of self-esteem, rather represent relatively independent pathways to late- than apathy; and early morning awakenings. This life major depression. The underlying neurologi- is in contrast to dementia-related symptoms that cal basis for depressive symptoms has been are associated with a later age of onset of symp- recently explored by Langenecker et al. [ 62 ] , not toms, a lack of insight into cognitive symptoms, a only for depression with onset in late life, but for gradual onset of cognitive defi cits, the presence a neuroanatomical network impacted in the of apathy rather than dysphoria, and dif fi culty majority of individuals with mood disorders. waking in the morning. Although these patterns Loss of interest is also greater in late-onset can be useful as a heuristic in combination with depression [61, 63] , which is consistent with the other observations and objective testing, caution fi ndings that apathy may be an indicator of a pro- needs to be taken when applying fi ndings using gressive dementing process. Similarly, in patients group differences to a single individual given the with both depression and dementia, age of onset signi fi cant variability across individuals. was later than in patients with depression alone [64 ] . Again, depression with a late age of onset is more likely to be associated with underlying neu- Neuropsychological Profi les ropathology or the early stages of dementia [65 ] . of Depression and Dementia Depression and dementia can also differ with regard to sleep , although the clinical utility sleep Differences in symptom presentation between patterns in differential diagnosis is uncertain. AD depression and dementia can be informative; is typically associated with poor sleep effi ciency however, a neuropsychologist’s unique contribu- with frequent night awakenings. Phase delays are tion to differential diagnosis is the ability to pro- prominent, meaning that the onset of sleep is later vide an objective assessment of cognitive and accompanied by dif fi culty awakening in the functioning. As discussed previously, older adults morning [66 ] . While older adults with depression with depression are more likely to report subjec- also have frequent night awakenings, impaired tive cognitive diffi culties than patients with sleep continuity, and diffi culty falling asleep, dementia. However, as these complaints are not early morning awakenings are a prominent fea- always indicative of true impairments [69, 70 ] ; ture of depression [ 67 ] . Individuals with depres- the importance of objective neuropsychological sion have dif fi culty staying asleep in the morning, testing is highlighted. whereas those with dementia are more likely to In general, the cognitive changes associated have diffi culty waking up. In addition, when with dementia tend to be more severe than those directly compared to individuals with AD, indi- associated with depression [71Ð 73 ] . Aside from viduals with depression had a higher number of differences in severity, research also suggests that night awakenings [ 68 ] . Increased REM sleep there are qualitative differences between the two may also be a speci fi c to depression and helpful disorders with regard to neuropsychological 264 L.A. Bieliauskas and L.L. Drag profi les. Cognitive symptoms associated with signifi cantly when given cues. This is because in neurodegenerative disorders are progressive, depression, memory diffi culties are associated whereas cognitive defi cits related to depression with defi cits in executive functioning and strate- should generally stabilize or even improve with gic processing. When there is a reduced demand adequate management of psychiatric symptoms. on strategic processing, as is the case when cues Thus, repeat neuropsychological evaluations can or organization are already provided, memory be helpful to monitor cognitive changes over abilities are better. For example, Elderkin- time. In addition, the cognitive changes that Thompson and colleagues [79 ] demonstrated that accompany depression are also generally thought older adults with depression performed poorly on to re fl ect de fi cits in effortful processing , leading list learning tasks, but when given semantic cues, to diffi culty on tasks that require a high degree of memory signi fi cantly improved to normal levels. cognitive resources. According to this hypothe- Thus, it appears that depressed patients derive more sis, performance is generally adequate on tasks benefi t from cuing than AD patients. This is con- that are more automatic and require less effort to sistent with multiple studies comparing individu- complete [74 ] . In contrast, the de fi cits found in als with AD and depression that have found an dementia are associated with decrements in abil- AD-specifi c defi cit in cued recall tasks [ 80Ð 83 ] . ity rather than effort, and therefore, impairments This suggests that this cued recall tasks may be are apparent independent of the degree of effortful effective in distinguishing AD from depression. processing required. While this effortful-automatic Suggestions for cued recall tasks that can be hypothesis can be a useful heuristic, it may be included in a neuropsychological battery include overly generalized and has not consistently been Verbal Paired Associates from the Wechsler supported by research. Memory Scale-IV [ 84 ] , Paired Associates Late-life depression is typically associated Learning from the CANTAB [ 85 ] , and Cued with cognitive defi cits primarily in the domains Recall from the California Verbal Learning of memory, executive functioning, and attention Test-II [86 ] . [ 75Ð 78 ] . In general, executive functioning Recognition performance is another way to diffi culties are most prominent in depression and differentiate between memory diffi culties associ- can mediate the cognitive dif fi culties found in ated with dementia versus depression. Given that other domains, such as memory [ 79 ] . In contrast, recognition tasks minimize the need for effortful AD is typi fi ed by prominent memory de fi cits . and strategic retrieval, depressed individuals With regard to memory, although depression and typically show adequate performance on these dementia can both impact performance on imme- tasks. In contrast, patients with AD tend to show diate and delayed memory tasks, delayed retrieval impairments given that information is often not tasks can be useful for differentiating between encoded or retained in memory and therefore the groups [73 ] . AD is associated with rapid for- even recognition of this information is defi cient. getting of information, which results in poor In addition, there are also differences in how indi- delayed recall and recognition performance. viduals with depression and dementia approach Therefore, patients with AD do not benefi t recognition tasks. Whereas depressed individuals signi fi cantly when given mnemonic support such tend to take a more conservative approach, lead- as cues at retrieval, as information has not ade- ing to “I don’t know” answers and false-negative quately been retained in memory. This diffi culty errors, individuals with AD tend to adopt a more with the retention of information in memory is liberal response bias, leading to a high number of not surprising given that AD pathology affects false-positive errors [87 ] . Suggestions for mem- the hippocampus and surrounding regions and ory tasks with a recognition component include areas critical to memory encoding and storage. In Logical Memory, Visual Reproduction, and contrast, depressed individuals may struggle with Verbal Paired Associates from the Wechsler delayed recall, but performance can improve Memory Scale-IV, the Hopkins Verbal Learning 17 Differential Diagnosis of Depression and Dementia 265

Test-Revised [88 ] , the California Verbal Learning left orientation), and ideomotor and ideational Test, the Brief Visuospatial Memory Test-Revised praxis [71, 72, 81 ] . [89 ] , the Rey Auditory Verbal Learning Test [90 ] , Overall, depression and dementia can differ in and the Recognition Memory Test [91 ] . both the quantity and quality of cognitive defi cits. Analysis of serial position effects can also be The cognitive profi le associated with AD is most informative. Foldi [92 ] found that patients with refl ective of a cortical dementia, typifi ed by a AD showed poorer overall recall of a word list prominent memory disturbance and additional compared to depressed individuals. Moreover, defi cits in language and praxis. In contrast, AD was associated with an advantage of recency depression is better represented by a frontally over primacy (i.e., individuals recalled words mediated (or subcortical) pattern leading to exec- from the end of the list better than those at the utive functioning defi cits that can affect other beginning), which is consistent with dif fi culty cognitive domains due to the lack of initiation of retaining information in memory over time. In strategic or effortful processing. contrast, individuals with depression showed both a strong primacy and recency effect with poorer recall of words in the middle of the list. Conclusions This poor middle-list performance distinguished depressed patients from healthy controls. Depressive symptoms and cognitive complaints Therefore, recall abilities in individuals with AD are common in older adults. While depressive across a word list can re fl ect an upward-sloping symptoms may refl ect a primary depressive dis- line (with better performance at the end of the order, they may also represent the early signs of a word list), whereas the performance of individu- dementing process. Depression and dementia can als with depression may be better characterized differ in terms of their cognitive profi le as well as by a U-shaped function (with better performance the phenomenology of the depressive symptoms. at the beginning and end of the word list). Table 17.3 presents differential features of depres- Patients with depression and AD can also dif- sion and AD that can be used as a general guide- fer on other nonmemory tasks. For example, line in clinical practice. Accurate differential Kaschel and colleagues [ 93 ] found that even diagnosis has signifi cant clinical implications as when memory performance was equated, AD treatment approaches and prognosis vary patients had more diffi culty compared to signifi cantly depending on etiology. Neuro- depressed patients on tasks requiring dual-tasking . psychologists can play an important role in dif- In addition, compared to depression, dementia is ferential diagnosis by providing an objective more associated with impairments on tasks of assessment of an individual’s cognitive and naming, visuoperceptual processing (e.g., right- psychological functioning.

Table 17.3 Differential features of depression and AD Depression AD Onset of depressive symptoms Early Late Prior psychiatric history Present Absent Family psychiatric history Present Absent Sleep Frequent night and morning Delayed sleep onset, dif ﬁ culty awakenings; increased REM waking in morning Onset of cognitive symptoms Acute Gradual Severity of cognitive symptoms Less impaired More impaired Severity of mood symptoms More severe Less severe Prominent mood symptom Dysphoria Apathy (continued) 266 L.A. Bieliauskas and L.L. Drag

Table 17.3 Continued Depression AD Temporal relationship between Mood symptoms precede or Mood symptoms precede, equal cognitive and mood symptoms concurrent with cognitive symptoms to, or follow cognitive symptoms Insight into cognitive de ﬁ cits Exaggerated complaints Poor insight Memory Serial position curve Intact primacy and recency, reduced Impaired primacy, intact recency middle Cued recall Intact Impaired Immediate recall Impaired Impaired Delayed recall Impaired Substantially impaired Recognition Generally intact Impaired Language (naming) Intact Impaired Response biases “I don’t know” answers Prone to guessing False negatives False positives Praxis Intact Impaired Retention Adequate Rapid forgetting Orientation Adequate Can be impaired Copying Intact Impaired Dual-tasking Intact Impaired Effortful processing Impaired Depends on task Automatic processing Intact Depends on task Primary area of cognitive impairment Executive functioning Memory Pattern of cognitive de ﬁ cits Subcortical Cortical

Clinical Pearls neurologic, the patient may feel better after pharmacological intervention, but cognitive ¥ Depressive symptoms of apathy tend to be ef fi ciency will not improve. associated with neurologic disorders as compared to the dysphoria (especially with a loss of self-esteem) that is more often associated References with primary depressive disorders. ¥ Signi fi cant subjective complaints, in particular 1. Beekman AT, Copeland JR, Prince MJ. Review of community prevalence of depression in later life. Br those that are disproportionate to objective J Psychiatry. 1999;174:307Ð11. fi ndings, are more often associated with primary 2. Mojtabai R, Olfson M. Major depression in commu- depression rather than a neurologic etiology. nity-dwelling middle-aged and older adults: preva- ¥ Symptoms of sadness, misery, and a feeling of lence and 2- and 4-year follow-up symptoms. Psychol Med. 2004;34(4):623Ð34. being abandoned by others are not uncommon 3. Steffens DC, Fisher GG, Langa KM, Potter GG, with older age, failing health, and loss of close Plassman BL. Prevalence of depression among older friends and older relatives. They represent Americans: the Aging, Demographics and Memory losses that lead more to expressions of grief Study. Int Psychogeriatr. 2009;21(5):879Ð88. 4. Alexopoulos G. Depression in the elderly. Lancet. and are not equivalent to depression. 2005;365(9475):1961Ð70. ¥ If the onset is gradual, there is more likely an 5. Baldwin RC, Gallagley A, Gourlay M, Jackson A, underlying neurological basis than an affec- Burns A. Prognosis of late life depression: a three- tive one. year cohort study of outcome and potential predictors. Int J Geriatr Psychiatry. 2006;21(1):57Ð63. ¥ Pharm acological intervention will often be 6. Katz IR, Streim J, Parmelee P. Prevention of depres- associated with some improvements in cogni- sion, recurrences, and complications in late life. Prev tive weaknesses. If the underlying cause is Med. 1994;23(5):743Ð50. 17 Differential Diagnosis of Depression and Dementia 267

7. Katon WJ, Lin E, Russo J, Unutzer J. Increased 22. Verkaik R, Francke AL, van Meijel B, Ribbe MW, medical costs of a population-based sample of Bensing JM. Comorbid depression in dementia on depressed elderly patients. Arch Gen Psychiatry. psychogeriatric nursing home wards: which symp- 2003;60(9):897Ð903. toms are prominent? Am J Geriatr Psychiatry. 8. Wells CE. Pseudodementia. Am J Psychiatry. 2009;17(7):565Ð73. 1979;136(7):895Ð900. 23. Starkstein SE, Jorge R, Mizrahi R, Robinson RG. 9. Rei fl er BV. Arguments for abandoning the term The construct of minor and major depression in pseudodementia. J Am Geriatr Soc. 1982;30(10): Alzheimer’s disease. Am J Psychiatry. 2005;162(11): 665Ð8. 2086Ð93. 10. Fretter S, Bergman H, Gold S, Chertkow H, Clarfi eld 24. Verhey FRJ, Rozendaal N, Ponds RWHM, Jolles J. aM. Prevalence of potentially reversible dementias Dementia, awareness and depression. Int J Geriatr and actual reversibility in a memory clinic cohort. Psychiatry. 1993;8(10):851Ð6. Can Med Assoc J. 1998;159(6):657Ð62. 25. Verkaik R, Nuyen J, Francke A. The relationship 11. Butters MA, Becker JT, Nebes RD, Zmuda MD, between severity of Alzheimer’s Disease and preva- Mulsant BH, Pollock BG, et al. Changes in cogni- lence of comorbid depressive symptoms and depres- tive functioning following treatment of late-life sion: a systematic review. Int J Geriatr Psychiatry. depression. Am J Psychiatry. 2000;157(12): 2007;22(11):1063Ð86. 1949Ð54. 26. Modrego PJ, Ferrández J. Depression in patients 12. Alexopoulos GS, Meyers BS, Young RC, Mattis S, with mild cognitive impairment increases the risk Kakuma T. The course of geriatric depression with of developing dementia of Alzheimer type: a pro- “reversible dementia”: a controlled study. Am J spective cohort study. Arch Neurol. 2004;61(8): Psychiatry. 1993;150(11):1693Ð9. 1290Ð3. 13. Clar fi eld AM. The decreasing prevalence of revers- 27. Jorm AF. Is depression a risk factor for dementia or ible dementias: an updated meta-analysis. Arch cognitive decline? A review. Gerontology. Intern Med. 2003;163(18):2219Ð29. 2000;46(4):219Ð27. 14. American Psychiatric Association. Diagnostic and sta- 28. Rosenberg PB, Mielke MM, Xue Q-L, Carlson MC. tistical manual of mental disorders. 3rd ed. Washington, Depressive symptoms predict incident cognitive DC: American Psychiatric Association; 1980. impairment in cognitive healthy older women. Am 15. Becker C, Brobert GP, Johansson S, Jick SS, Meier J Geriatr Psychiatry. 2010;18(3):204Ð11. CR. Risk of incident depression in patients with 29. Pfennig A, Littmann E, Bauer M. Neurocognitive Parkinson disease in the UK. Eur J Neurol. 2010; impairment and dementia in mood disorders. J (17):1Ð6. Neuropsychiatry Clin Neurosci. 2007;19(4):373Ð82. 16. Josephs KA, Whitwell JL. Parkinson disease and 30. Steffens DC, Potter GG. Geriatric depression and down in the dumps: pumped or stumped? Neurology. cognitive impairment. Psychol Med. 2008;38(2): 2010;75(10):846Ð7. 163Ð75. 17. Kao AW, Racine CA, Quitania LC, Kramer JH, 31. Roberts RE, Kaplan GA, Shema SJ, Strawbridge Christine CW, Miller BL. Cognitive and neuropsy- WJ. Does growing old increase the risk for chiatric pro fi le of the synucleinopathies: Parkinson depression? Am J Psychiatry. 1997;154(10): disease, dementia with Lewy bodies, and multiple 1384Ð90. system atrophy. Alzheimer Dis Assoc Disord. 32. Gallo JJ, Anthony JC, Muthén BO. Age differences 2009;23(4):365Ð70. in the symptoms of depression: a latent trait analy- 18. Newman SC. The prevalence of depression in sis. J Gerontol. 1994;49(6):251Ð64. Alzheimer’s disease and vascular dementia in a popu- 33. Birrer RB, Vemuri SP. Depression in later life: a lation sample. J Affect Disord. 1999;52(1Ð3):169Ð76. diagnostic and therapeutic challenge. Am Fam 19. Payne JL, Lyketsos CG, Steele C, Baker L, Galik E, Physician. 2004;69(10):2375Ð82. Kopunek S, et al. Relationship of cognitive and func- 34. Boswell EB, Stoudemire A. Major depression in the tional impairment to depressive features in Alzheimer’s primary care setting. Am J Med. 1996;101(6A): disease and other dementias. J Neuropsychiatr. 3SÐ9S. 1998;10(4):440Ð7. 35. Beck AT, Steer RA, Brown GK. Manual for the beck 20. Spalletta G, Musicco M, Padovani A, Rozzini L, depression inventory-II. San Antonio, TX: Perri R, Fadda L, et al. Neuropsychiatric symptoms Psychological Corporation; 1996. and syndromes in a large cohort of newly diagnosed, 36. Hamilton M. A rating scale for depression. J Neurol untreated patients with Alzheimer disease. Am J Neurosurg Psychiatry. 1960;23:56Ð62. Geriatr Psychiatry. 2010;18(11):1026Ð35. 37. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, 21. Okura T, Plassman BL, Steffens DC, Llewellyn DJ, Adey M, et al. Development and validation of a geri- Potter GG, Langa KM. Prevalence of neuropsychiat- atric depression screening scale: A preliminary ric symptoms and their association with functional report. J Psychiatr Res. 1982;17(1):37Ð49. limitations in older adults in the United States: the 38. Kotlyar M, Dysken M, Adson DE. Update on drug- aging, demographics, and memory study. J Am induced depression in the elderly. Am J Geriatr Geriatr Soc. 2010;58(2):330Ð7. Pharmacother. 2005;3(4):288Ð300. 268 L.A. Bieliauskas and L.L. Drag

39. Mills TL. Comorbid depressive symptomatology: 53. Marin RS, Biedrzycki RC, Firinciogullari S. isolating the effects of chronic medical conditions on Reliability and validity of the apathy evaluation self-reported depressive symptoms among commu- scale. Psychiatry Res. 1991;38(2):143Ð62. nity-dwelling older adults. Soc Sci Med. 2001;53(5): 54. Burns A, Folstein S, Brandt J, Folstein M. Clinical 569Ð78. assessment of irritability, aggression, and apathy in 40. Ginó S, Mendes T, Maroco J, Ribeiro F, Schmand Huntington and Alzheimer disease. J Nerv Ment BA, de Mendonça A, et al. Memory complaints are Dis. 1990;178(1):20Ð6. frequent but qualitatively different in young and 55. Zubenko GS, Zubenko WN, McPherson S, Spoor E, elderly healthy people. Gerontology. 2010;56(3): Marin DB, Farlow MR, et al. A collaborative study 272Ð7. of the emergence and clinical features of the major 41. Jessen F, Wiese B, Cvetanovska G, Fuchs A, depressive syndrome of Alzheimer’s disease. Am J Kaduszkiewicz H, Kölsch H, et al. Patterns of sub- Psychiatry. 2003;160(5):857Ð66. jective memory impairment in the elderly: associa- 56. Olin JT, Katz IR, Meyers BS, Schneider LS, tion with memory performance. Psychol Med. Lebowitz BD. Provisional diagnostic criteria for 2007;37(12):1753Ð62. depression of Alzheimer disease: rationale and 42. Siu AL. Screening for dementia and investigating its background. Am J Geriatr Psychiatry. 2002;10(2): causes. Ann Intern Med. 1991;115(2):122Ð32. 129Ð41. 43. Bieliauskas LA. Depressed or not depressed? That is 57. Kessler RC, Angermeyer M, Anthony JC, de Graaf R, the question. J Clin Exp Neuropsychol. 1993;15: Demyttenaere K, Gasquet I, et al. Lifetime prevalence 119Ð34. and age-of-onset distributions of mental disorders 44. Chase, TN. Apathy in neuropsychiatric disease: in the World Health Organization’s World Mental diagnosis, pathophysiology, and treatment. Neurotox Health Survey Initiative. World Psychiatry. 2007; Res . 2010 , epub ahead of print. 6(3):168Ð76. 45. Zgaljardic DJ, Borod JC, Foldi NS, Rocco M, Mattis 58. Alexopoulos GS, Young RC, Meyers BS, Abrams PJ, Gordon MF, et al. Relationship between self- RC, Shamoian CA. Late-onset depression. Psychiatr reported apathy and executive dysfunction in nonde- Clin North Am. 1988;11(1):101Ð15. mented patients with Parkinson disease. Cogn Behav 59. Brodaty H, Luscombe G, Parker G, Wilhelm K, Neurol. 2007;20(3):184Ð92. Hickie I, Austin MP, et al. Early and late onset 46. Clarke DE, van Reekum R, Simard M, Streiner DL, depression in old age: different aetiologies, same Conn D, Cohen T, et al. Apathy in dementia: clinical phenomenology. J Affect Disord. 2001;66(2Ð3): and sociodemographic correlates. J Neuropsychiatry 225Ð36. Clin Neurosci. 2008;20(3):337Ð47. 60. Lamberty GJ, Bieliauskas LA. Distinguishing 47. Landes AM, DP, Sperry SD, Strauss ME. Prevalence between depression and dementia in the elderly: A of apathy, dysphoria, and depression in relation to review of neuropsychological ﬁ ndings. Arch Clin dementia severity in Alzheimer’s disease. J Neuropsychol. 1993;8:149Ð70. Neuropsychiatry & Clinical Neurosciences. 2005;17: 61. Kumar A, Bilker W, Jin Z, Udupa J. 342Ð9. Neuropsychopharmacology. 2000;22:264Ð74. 48. Berger AK, Fratiglioni L, Forsell Y, Winblad B, 62. Langenecker SA, Lee HJ, Bieliauskas LA. Bäckman L. The occurrence of depressive symptoms Neuropsychology of depression and related mood dis- in the preclinical phase of AD: a population-based orders. In: Grant I, Adams KM, editors. study. Neurology. 1999;53(9):1998Ð2002. Neuropsychological assessment of neuropsychiatric 49. Robert PH, Berr C, Volteau M, Bertogliati C, Benoit and neuromedical disorders, 3rd ed. New York: Oxford, M, Sarazin M, et al. Apathy in patients with mild 2009;523Ð59. cognitive impairment and the risk of developing 63. Krishnan KR, Hays JC, Tupler LA, George LK, dementia of Alzheimer’s disease: a one-year follow- Blazer DG. Clinical and phenomenological compar- up study. Clin Neurol Neurosurg. 2006;108(8): isons of late-onset and early-onset depression. Am J 733Ð6. Psychiatry. 1995;152(5):785Ð8. 50. Hattori H, Yoshiyama K, Miura R, Fujie S. Clinical 64. Alexopoulos GS, Young RC, Meyers BS. Geriatric psychological tests useful for differentiating depres- depression: age of onset and dementia. Biol sive state with Alzheimer’s disease from major Psychiatry. 1993;34(3):141Ð5. depression of the elderly. Psychogeriatrics. 65. van Reekum R, Simard M, Clarke D, Binns MA, 2010;10(1):29Ð33. Conn D. Late-life depression as a possible predictor 51. Landes AM, Sperry SD, Strauss ME, Geldmacher of dementia: cross-sectional and short-term follow-up DS. Apathy in Alzheimer’s disease. J Am Geriatr results. Am J Geriatr Psychiatry. 1999;7(2):151Ð9. Soc. 2001;49(12):1700Ð7. 66. Song Y, Dowling GA, Wallhagen MI, Lee KA, 52. Cummings JL, Mega M, Gray K, Rosenberg- Strawbridge WJ. Sleep in older adults with Alzheimer’s Thompson S, Carusi DA, Gornbein J. The disease. Neuroscience. 2010;42(4):190Ð8. Neuropsychiatric Inventory: comprehensive assess- 67. Buysse DJ. Insomnia, depression and aging. ment of psychopathology in dementia. Neurology. Assessing sleep and mood interactions in older 1994;44(12):2308Ð14. adults. Geriatrics. 2004;59(2):47Ð51. 17 Differential Diagnosis of Depression and Dementia 269

68. Dykierek P, Stadtmuller G, Schramma P, Bahro M, depression by means of cued recall. Psychol Med. Vancalker D, Braus D, et al. The value of REM sleep 2007;37(5):747Ð55. parameters in differentiating Alzheimer’s disease 83. Swainson R, Hodges JR, Galton CJ, Semple J, from old-age depression and normal aging. J Psychiatr Michael A, Dunn BD, et al. Early Detection and Res. 1998;32(1):1Ð9. Differential Diagnosis of Alzheimer’s Disease and 69. Gallassi R, Oppi F, Poda R, Scortichini S, Stanzani Depression with Neuropsychological Tasks. Dement Maserati M, Marano G, et al. Are subjective cogni- Geriatr Cogn Disord. 2001;12(4):265Ð80. tive complaints a risk factor for dementia? Neurol 84. Wecshler D. Wechsler memory scale: fourth edition Sci. 2010;31(3):327Ð36. technical and interpretive manual. San Antonio: 70. Reid LM, Maclullich AMJ. Subjective memory Pearson; 2009. p. 2009. complaints and cognitive impairment in older peo- 85. Sahakian BJ, Morris RG, Evenden JL, Heald A, ple. Dement Geriatr Cogn Disord. Levy R, Philpot M, et al. A comparative study of 2006;22(5Ð6):471Ð85. visuospatial memory and learning in Alzheimer-type 71. Crowe SF, Hoogenraad K. Differentiation of demen- dementia and Parkinson’s disease. Brain. 1988;111: tia of the Alzheimer’s type from depression with 695Ð718. cognitive impairment on the basis of a cortical versus 86. Delis DC, Kramer JH, Kaplan E, Ober BA. The subcortical pattern of cognitive de fi cit. Arch Clin California Verbal Learning Test. 2nd ed. San Neuropsychol. 2000;15(1):9Ð19. Antonio: The Psychological Corporation; 2000. 72. King DA, Caine ED, Conwell Y, Cox C. The neurop- 87. Gainotti G, Marra C. Some aspects of memory disor- sychology of depression in the elderly: a comparative ders clearly distinguish dementia of the Alzheimer’s study of normal aging and Alzheimer’s disease. type from depressive pseudo-dementia. J Clin Exp J Neuropsychiatry Clin Neurosci. 1991;3(2):163Ð8. Neuropsychol. 1994;16(1):65Ð78. 73. Lachner G, Engel RR. Differentiation of dementia 88. Shapiro AM, Benedict RH, Schretlen D, Brandt J. and depression by memory tests. A meta-analysis. J Construct and concurrent validity of the Hopkins Nerv Mental Dis. 1994;182(1):34Ð9. Verbal Learning Test-revised. Clin Neuropsychol. 74. Hartlage S, Alloy LB, Vázquez C, Dykman B. 1999;13(3):348Ð58. Automatic and effortful processing in depression. 89. Benedict RHB, Schretlen D, Groninger L, Dobraski M, Psychol Bull. 1993;113(2):247Ð78. Shpritz B. Revision of the Brief Visuospatial Memory 75. Butters MA, Whyte EM, Nebes RD, Begley AE, Test: Studies of normal performance, reliability, and Dew MA, Mulsant BH, et al. The nature and deter- validity. Psychol Assess. 1996;8(2):145Ð53. minants of neuropsychological functioning in late- 90. Rey A. L’examen clinique en psychologie. Paris: life depression. Arch Gen Psychiatry. 2004;61(6): Presses Universitaires de France; 1964. 587Ð95. 91. Warrington EK. Recognition Memory Test manual. 76. Hickie I, Naismith S, Ward PB, Turner K, Scott E, Windsor, England: NFER-Nelson; 1984. Mitchell P, et al. Reduced hippocampal volumes 92. Foldi N. Distinct serial position pro fi les and neurop- and memory loss in patients with early- and late- sychological measures differentiate late life depres- onset depression. Br J Psychiatry. 2005;186: sion from normal aging and Alzheimer’s disease. 197Ð202. Psychiatry Res. 2003;120(1):71Ð84. 77. Lockwood KA, Alexopoulos GS, Kakuma T, Van 93. Kaschel R, Logie RH, Kazén M, Della Sala S. Gorp WG. Subtypes of cognitive impairment in Alzheimer’s disease, but not ageing or depression, depressed older adults. Am J Geriatr Psychiatry. affects dual-tasking. J Neurol. 2009;256(11): 2000;8(3):201Ð8. 1860Ð8. 78. Salloway S, Malloy P, Kohn R, Gillard E, Duffy J, 94. Radloff LS. ‘The CES-D scale: A self report depres- Rogg J, et al. MRI and neuropsychological differ- sion scale for research in the general population’. ences in early- and late-life-onset geriatric depres- Applied Psychological Measurement. 1977; sion. Neurology. 1996;46(6):1567Ð74. 1:385Ð401. 79. Elderkin-Thompson V, Mintz J, Haroon E, Lavretsky 95. Zung WW. “A self-rating depression scale”. Archives H, Kumar A. Executive dysfunction and memory in of General Psychiatry. 1965;12:63Ð70. older patients with major and minor depression. 96. Kashani J, McKnew D, & Cytryn L. Symptom Arch Clin Neuropsychol. 2007;22(2):261Ð70. checklist for major depressive disorders (Adapted). 80. Blackwell AD, Sahakian BJ, Vesey R, Semple JM, Psychopharmacology Bulletin, 1985;21:957Ð958. Robbins TW, Hodges JR, Dementia & Geriatric 97. Sheikh JI, Yesavage JA. Geriatric Depression Scale Cognitive Disorders. 2004;17(1-2):42Ð8. (GDS): recent evidence and development of a shorter 81. Christensen H, Grif fi ths K, Mackinnon A. A quanti- version. Clin Gerontol. 1986;June;5(1/2):165Ð173. tative review of cognitive de fi cits in depression and 98. Alexopoulos GA, Abrams RC, Young RC & Alzheimer-type dementia Selection of Studies. J Int Shamoian CA: Cornell scale for depression in Neuropsychol Soc. 1997;3(6):631Ð51. dementia. Biol Psych, 1988;23:271Ð284. 82. Dierckx E, Engelborghs S, De Raedt R, De Deyn PP, 99. Trey Sunderland and Marcia Minichiello. Dementia Ponjaert-Kristoffersen I. Differentiation between Mood Assessment Scale. International Psycho- mild cognitive impairment, Alzheimer’s disease and geriatrics, 1997;8:329Ð331. 270 L.A. Bieliauskas and L.L. Drag

100. Hammond MF, O’Keeffe ST, Barer DH. Development ment of psychopathology in dementia. Neurology and validation of a brief observerrated screening 1994;44: 2308Ð2314. scale for depression in elderly medical patients. Age 102. Mack, J.L., & Patterson, M.B. (1993). CERAD Ageing. 2000;Nov;29(6):511Ð5 Behavioral Rating Scale for Dementia. CERAD. 101. Cummings JL, Mega M, Gray K, Rosenberg- [Unpublished; Center for Mental Health Services Thompson S, Carusi DA, Gornbein J. The Research, Washington University in St. Louis]. Neuropsychiatric Inventory: comprehensive assess- Assessment of Alzheimer’s Disease 1 8 David Loewenstein

Abstract Alzheimer’s disease (AD) is a devastating illness, affecting over 5.5 million adults in the United States and costing over 170 billion dollars annually. In addition, there is growing recognition that mild cognitive impairment (MCI) constitutes a risk factor for AD and other neurodegenerative disorders. In this chapter, we describe the clinical manifestations of early AD and other neurogenerative brain disorders and describe the appropriate neuropsychological measures that tap the important cognitive domains that should be assessed in these conditions. A summary of useful clinical tips as well as future directions in the ﬁ eld are addressed.

Keywords Cognitive assessment • Alzheimer’s • MCI diagnosis • Early Alzheimer’s disease

this disorder could reach epidemic proportions. The Diagnosis of Alzheimer’s Disease Alzheimer’s disease (AD) was fi rst discovered in 1906, but the causes of this devastating disorder Alzheimer’s disease (AD) is a devastating illness, were not known until recently. The characteristic affecting over 5.5 million adults in the United neuropathology of AD is the presence of senile States and costing over 170 billion dollars annu- plaques and neurofi brillary tangles upon autopsy. ally [ 1, 3 ] . With a growing aging population and It is thought that plaque formation in AD begins the fact that age is the greatest risk factor for AD, with the abnormal misfolding of a protein called beta amyloid (A-beta) that causes toxic amyloid fi brils as many as 20–30 years before any clinical D. Loewenstein , Ph.D. () symptoms of the disease are manifested. These Department of Psychiatry and Behavioral Sciences , abnormal proteins continue to aggregate, particu- Miller School of Medicine, University of Miami Miller larly in the frontal lobes, anterior cingulate, pos- School of Medicine , Mental Health Building, 1695 NW 9th Avenue, Suite 3208G , Miami , FL 33136 , USA terior cingulate, precuneas and striatum. e-mail: [email protected] Eventually, a cascade effect occurs in which there

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 271 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_18, © Springer Science+Business Media, LLC 2013 272 D. Loewenstein are dif fi culties with the phosphorylation of the affect cognitive impairment are generally microtubule-associated protein (MAP) tau which referred to as possible AD. While the accuracy results in neurofi brillary degeneration [ 4 ] and is of the clinical criteria for probable AD gener- seen as neurofi brillary tangles. These changes ally exceeds 85% in most specialized memory lead to synaptic disruption and neurodegenera- disorders centers, a fi nal diagnosis of the disorder tion of structures such as the hippocampus and can only be rendered upon examination of the the entorhinal cortex, and these changes can density of senile plaques and neurofi brillary eventually be visualized on structural magnetic tangles upon autopsy (see [ 7] ). Recently, the resonance imaging (MRI). National Institutes on Aging and the Alzheimer’s Because of early neurodegeneration in medial Association workgroup recommended a revision temporal lobe structures, the fi rst clinical mani- in the proposed guidelines for the clinical diag- festations of AD are typically seen as the disrup- nosis of AD [6 ] . They re fi ned the diagnosis of tion of short-term memories. As the disease probable AD to include nonamnesic presenta- progresses, there are typically more pronounced tions of the illness (i.e., language presentation, memory dif fi culties evidenced by misplacing visuospatial presentation, and executive presen- possessions, forgetting appointments, repetitive tation). Possible AD would represent a case conversations, and worsening ability to recall meeting all clinical core criteria for AD dementia recent events. The patient may begin to have but would present with an atypical course or dif fi culties with word fi nding, may get lost while insuf fi cient evidence of cognitive decline. An driving, and begin to exhibit problems with important feature of these new proposed criteria judgment. This refl ects the increasing involve- is the addition of biomarkers which strengthen ment of the cortical regions of the brain such the certainty of diagnoses, such as positive posi- as the frontal, temporal, and parietal lobes. Over tron emission tomography (PET), amyloid time, the patient becomes less able to manage imaging, low AB42 in the cerebrospinal fl uid, as their affairs and loses the ability to perform activ- well as downstream neuronal markers of injury ities of daily living. The progression of the illness including decreased fl uorodeoxyglucose (FDG) is quite variable from several years to as many as uptake on PET scan in the temporoparietal cortex; 20 years, but eventually leads to total disability disproportionate atrophy in the medial, basal, and eventual death [1 ] . and lateral temporal lobe and medial parietal The clinical diagnosis of probable AD by the cortex on structural MRI; or CSF elevation of National Institute of Neurologic, Communicative tau or p-tau proteins. These recommendations Disorders and Stroke–AD and Related Disorders usher in an era where the clinical diagnosis of Association (NINCDS–ADRDA) [ 5 ] criteria AD is no longer a diagnosis of exclusion and requires (a) memory impairment and impairment where clinical criteria for the diagnosis are in at least one other cognitive domain, (b) impair- strengthened by the presence of beta amyloid in ment in social and/or occupational function, the brain and specifi c patterns of neuronal degen- and (c) ruling out any other possible causes of eration on neuroimaging. the dementia syndrome. In short, a clinical diag- In diagnosing AD, there is nothing more nosis of probable AD is a diagnosis of exclusion, important than establishing the presence or which can only be rendered after all other absence of cognitive impairment, which is related causes for the dementia have been ruled out. to the integrity of specifi c brain systems. In cases Neuropsychological assessment is recommended where an individual is moderately or severely as a means of con fi rming the presence and quan- impaired, the clinician is provided with ample tifying the degree of different cognitive de fi cits. information to arrive at a clinical impression. Typical presentations of AD with gradual onset However, there are a signifi cant number of cases of memory decline and progressive course are where the cognitive defi cits can be quite mild typically referred to as probable AD, while atyp- and even dif fi cult to detect by experienced clini- ical presentations when other etiologies may cians. Persons with high cognitive reserve can 18 Assessment of Alzheimer’s Disease 273 employ other cognitive and brain resources to Implicit to this characterization was the notion mask any overt defi cits. It is not uncommon to that amnesic dif fi culties do not represent a static see family members completely unaware of the state of affairs, but refl ect a decline from premor- substantial cognitive defi cits that are only uncov- bid levels of function that heightens the probabil- ered with a comprehensive neuropsychological ity of progression to probable AD [ 9 ] . Indeed, a evaluation. number of studies have suggested that impair- At the present time, there is a reluctance by some ment of episodic memory may be the best cogni- to seek early evaluation given that current treat- tive marker of AD in its predementia state, ments for Alzheimer’s disease, such as the cholin- [10– 12 ] even among asymptomatic, community- esterase inhibitors, are merely palliative and do dwelling elders [ 13 ] . In clinical settings, the rate not treat the underlying pathology of AD. However, of progression from amnesic MCI to dementia a recent advance in knowledge suggests that emerg- was 10–15% per year [ 8, 9, 14 ] , while 100% of ing treatments will be most effective in the earliest subjects diagnosed with MCI progressed to stages of AD, before the advent of multisystem dementia over a 9.5-year period, and 84% degeneration [ 7 ] . Moreover, accurate diagnosis can received a neuropathological diagnosis of proba- ensure that the patient and family receive proper ble AD [ 15 ] . In contrast, the progression to counseling and advice to better help manage their dementia among subjects with MCI is consider- lives and to plan for the future. Conversely, neurop- ably less in community settings where the base sychological methods can help reassure persons rates of MCI is lower [7, 16 ] . with unimpaired cognitive function and can provide Subsequently, Petersen [17 ] proposed that a valuable baseline to compare future results for MCI did not have to be con fi ned to only an those at risk. Finally, there are a number of condi- amnesic impairment, but could also be de fi ned by tions that may mimic the symptoms of AD where nonmemory impairments. Different types of MCI neuropsychological assessment can be an important included amnesic MCI single domain, amnesic part of differential diagnosis. MCI multiple domains, nonamnesic MCI single domain, and nonamnesic MCI multiple domains. The degree of impairment on both amnesic as Mild Cognitive Impairment well as nonamnesic measures is associated with the likelihood that individuals with MCI will It has been increasingly recognized that the clini- progress to dementia versus reverting to a normal cal manifestations of Alzheimer’s disease (AD) state over time [ 18 ] . Alexopolous et al. [19 ] found occur well before the manifestation of a dementia that 25% of subjects with amnesic MCI, 38% of syndrome [48 ] and a clinical diagnosis of the dis- subjects with nonamnesic MCI, and 54% of indi- order. Petersen [8, 9 ] coined the term mild cogni- viduals with mixed amnesic and nonamnesic tive impairment (MCI) as an intermediary state impairment progressed to dementia over a 3.5- between a normal cognitive state and dementia. year follow-up period. Roundtree et al. [ 20 ] The criteria for MCI are as follows: found no differences in the rates of progression (a) Subjective memory complaint by the patient between those with amnesic MCI (56%) versus or preferably by a knowledgeable informant. those with nonamnesic MCI (52%) over a 4-year (b) Objective evidence of memory impairment follow-up. Manley and associates found that confi rmed by neuropsychological testing, impairment in more than one cognitive domain typically 1.5 SD below expected levels. was most predictive of progression to dementia (c) Intact intellectual function and global mental over a 4.5-year period. In a more recent study, status as defi ned by an MMSE score of 24 or Loewenstein and associates [ 18 ] showed that above. those with multiple memory impairments, multi- (d) Not suf fi cient cognitive impairment to cause ple nonmemory impairments, or a combination signifi cant impairment in social and/or occu- of nonmemory impairments have a much greater pational function. likelihood of stability or worsening of their 274 D. Loewenstein defi cits over a 2- to 3-year period. The greatest associated with memory or whether they also likelihood of progression to dementia was in the represent language, executive, attention, or visu- multiple memory impairment group followed by ospatial disturbance. Most individuals with early the mixed memory and nonmemory group. Alzheimer’s disease have recent memory defi cits Subsequent studies have also shown that indi- while still able to recall information from the viduals with multiple-domain MCI have a much recent past. This is related to medial temporal greater likelihood of progression to dementia upon lobe de fi cits, speci fi cally in the hippocampus and longitudinal follow-up [ 21, 22 ] . The National entorhinal cortex, which interfere with the stor- Institute on Aging and the Alzheimer’s Association age and consolidation of new information. recently published guidelines that guide research While memory impairment is a hallmark criteria for MCI related to AD, recognizing the feature of the disease, individuals may initially changes to the brain occur well before the mani- present with language defi cits, visuospatial dis- festation of dementia symptoms. These criteria turbance, or problems with executive function. allow for incorporation of biomarkers such as Sometimes, the cognitive symptoms of AD will amyloid imaging of the brain by PET or lower fi rst become apparent in the face of stressful life CSF levels AB42 as well as evidence of neuronal events which tax an individual’s cognitive reserve degeneration characteristic of AD by FDG PET, (e.g., the loss of a loved one, a taxing physical MRI, or elevated CSF tau. These criteria address illness, depression). These underlying symptoms the question of whether the individual with MCI may abate after time as the person marshals the has an AD or non-AD etiology. Further research cognitive resources to compensate for these is required to determine applicability to clinical defi cits or these stressors are no longer present. practice [47 ] . Unfortunately, the neurodegenerative process continues until the individual progresses to the point where successful compensation is no longer The Clinical Interview possible. Occasionally, the fi rst defi cits exhibited by An important part of a comprehensive neuropsy- patients with Alzheimer’s (particularly those who chological assessment is a detailed clinical inter- are 70 years or younger) will be characterized by a view with the patient and a collateral informant language disturbance such as the inability to who is very familiar with the patient’s activities retrieve words. Some patients present with primary of daily living. This is especially true when eval- defi cits with reasoning, judgment, and other uating older adults with cognitive impairment. It aspects of executive function. In younger patients, is generally most effective to interview the patient when the predominant symptoms are language and and the caregiver separately so that they feel free executive dysfunction (such as disinhibition), the to speak honestly about their concerns. Many clinician must consider the possibility of a fronto- informants, particularly spouses and children, are temporal dementia versus AD. On the other hand, reluctant to share sensitive information about diffuse Lewy body disease must be considered if cognitive and functional deterioration in front of there are predominant concerns with attention, their loved ones. The informant may be particu- cognitive slowing, executive and visuospatial dis- larly reluctant to disclose information in front of turbance particularly in the presence of Parkinsonian a patient who is in denial about their symptoms features, psychiatric disturbances such as visual or who tends to react negatively to any sugges- hallucinations, and rapid eye movement REM tion of memory loss. behavior sleep disorders. REM behavior sleep During the clinical interview, it is important to disorders are evidenced by diffi culties in sleeping initially gather information about the current and dream-enacting behaviors such as punching, cognitive dif fi culties experienced by the patient. kicking, or jumping from the bed. It is especially helpful to determine whether the It is important to determine whether there has primary symptoms reported are primarily those been a sudden onset of cognitive symptoms (often 18 Assessment of Alzheimer’s Disease 275 observed in vascular or other non-AD neurologi- cognition. The clinical interview also provides an cal disorders) or whether the cognitive disorder opportunity to determine the effects of premorbid has a slowly progressive course with a gradual factors such as learning disabilities, attention defi cit worsening of symptoms such as is typically seen disorder, a lack of formal education, and previous in AD. While the clinical interview often starts as as well as current diffi culties such as alcohol and open ended so that the clinician can obtain as drug abuse might have on cognitive performance. much information in the patient’s and caregiver’s The importance of the clinical interview is own words, there are often a follow-up series of that it provides a context in which to view and questions (see Table 18.1 ) that can be helpful in interpret neuropsychological fi ndings. elucidating the exact nature of cognitive symptoms. The clinical interview allows the examiner to Overview of Neuropsychological ascertain the premorbid function of the patient, to Assessment determine the nature and extent of cognitive decline, and to determine the extent to which The most sophisticated neuropsychological bat- observed defi cits interfere with social or occupa- teries assess different aspects of neuropsycho- tional function. It also provides an opportunity to logical function at baseline and ensure that their determine the effects of anxiety and depression on measurements have suf fi cient range to track function and to assess the effects of current medi- changes in different cognitive domains longitudi- cal conditions as well as current medications on nally. The optimal neuropsychological battery assesses (1) learning and retentive memory, (2) exec- Table 18.1 Questions that help elucidate cognitive utive function, (3) language, and (4) visuospatial symptoms skills. It is also bene fi cial to have measures of both attention and processing speed, as these are (1) Are there increasing dif fi culties with remembering recent events (i.e., conversations, activities)? frequently impaired by a variety of brain disor- (2) Are there problems with misplacing possessions? ders and may serve as a more general marker of (3) Are there issues with remembering the names of impairment. familiar persons or changes in the ability to remember persons one has just met? (4) Are there dif fi culties getting lost driving, losing Assessment of Memory one’s way in a public place, or getting lost in the neighborhood? (5) Is there repetitive questioning? There are a plethora of validated measures for the (6) Is there a decline in the ability to drive, to operate assessment of memory. In evaluating an individ- a computer, or to use household objects? ual for the presence of MCI or early dementia, (7) Are there dif fi culties with fi nding the correct word the most important memory measure is a list or words in free speech? learning task. The advantage of such an assess- (8) Is there a decline in the ability to understand what ment is that it provides an assessment of learning one has read in a newspaper, magazine, or book? (9) Are there dif fi culties remembering what one has over several trials that can evaluate the effects of seen on television or the movies? proactive and retroactive interference and pro- (10) Has the person withdrawn from activities such as vide measures of delayed recall. Recognition work, playing cards, or social clubs as a result of memory or cued recall can also be assessed. Each cognitive changes? of these components is important in the evalua- (11) Has there been any changes in the ability of the tion of AD. Diffi culties with delayed recall and person to manage fi nances (i.e., write a check, balancing a checkbook) rate of forgetting are seen as hallmark features of (12) Has the person shown increasingly poor judgment AD [ 23, 24] , but there is evidence that not all AD in work and social situations? patients exhibit these de fi cits [25 ] . Dif fi culties (13) Has there been a change in personality (disinhibi- with learning and a fl at learning curve may be tion, ability, apathy)? among the most prominent defi cits in AD patients 276 D. Loewenstein

Table 18.2 List learning and other memory tests for the signifi cant hearing defi cits are an issue, a modifi ed assessment of AD Three-Trial Fuld Object Memory Evaluation California Verbal Learning Test (CVLT-II: [27 ] ) [31, 32 ] can be quite useful. This requires the indi- Hopkins Verbal Learning Test—Revised (HVLT-R: [30 ] ) vidual to select ten common objects from a bag Rey Auditory Verbal Learning Test [28, 29 ] and to recall the objects after a verbal fl uency dis- Modi fi ed Fuld Object Memory Evaluation [31, 32 ] tracter task. The participant is then selectively Semantic Interference Test [26 ] reminded of those items not recalled and then Logical Memory for Passages (Wechsler Memory another distracter task is administered followed by Scale—4th Edition: [34 ] ) Visual Reproduction (Wechsler Memory Scale—4th the real objects for a total of three recall trials. Edition; 2008) Loewenstein et al. [26 ] modifi ed the Three-Trial Paired Associates (Wechsler Memory Scale—4th Fuld Object Memory Evaluation paradigm by Edition; 2008) having subjects recall a second list of items that Brief Visual Memory Test-Revised (BVMT-R) [35 ] are all semantically similar to the original to-be- remembered targets (i.e., ring versus bracelet). [26 ] . A list of commonly used list learning mea- Reduced recall for the second list compared to the sures is presented in Table 18.2 . fi rst list was thought to be due to competition from The choice of memory test depends on the cir- the previously presented targets on the fi rst list cumstances of the evaluation. The California (proactive interference), while reduced recall for Verbal Learning Test—Second Edition (CVLT-II: the fi rst list after recall of the second list was [ 27 ] ) is the most comprehensive test, presenting thought to be related to retroactive interference. the older adult with 16 items representing four The Semantic Interference Test (SIT: [26 ] ) evi- semantic categories. The patient has fi ve trials to denced high sensitivity and speci fi city in distin- learn the to-be-remembered targets, and a second guishing normal elderly subjects from subjects list of 16 items is then administered to assess the with MCI and early dementia. Moreover, vulner- potential effects of proactive interference (old ability to proactive interference was most associ- learning interfering with new learning), retroac- ated with those MCI subjects who progressed to tive interference (presentation of the new list inter- dementia over a 2- to 3-year period [ 33 ] . fering with learning from the old list), and the use There are also a number of memory tasks that of semantic cues to facilitate recall. There is a tap other aspects of memory function including delayed free and cued recall after a 20-min period measures such as logical memory for story pas- as well a recognition memory test. Even though sages, paired-associate learning, and immediate there is the availability of shorter CVLT-II lists for and delayed recall of simple and increasingly older adults, the standard edition is typically pref- complex geometric designs. Some of the memory erable for the evaluation of early patients. There tests that we have found useful in our clinical are numerous indices for learning and memory laboratory are listed in Table 18.2 . that can be very helpful in diagnostic determina- In our laboratory, we typically like to augment tion. An alternative to the CVLT-II is the Rey a list learning test with a nonverbal test of imme- Auditory Verbal Learning Test (AVLT: [ 28, 29 ] ) diate and delayed visual reproduction and imme- which is similar to the CVLT-II but does not make diate and delayed logical memory for two story use of semantic cues or different semantic catego- passages. Other memory measures can be admin- ries. For subjects that are depressed or anxious, a istered as the need arises. list learning task across fi ve learning trials can be sometimes experienced as overwhelming and are relatively lengthy to give. An excellent alternative Assessment of Nonmemory Functions is the Hopkins Verbal Learning Test—Revised (HVLT-R: [ 30 ] ), which requires the older partici- The assessment of language function includes pant to learn 12 words across only 3 learning tri- both an evaluation of expressive and receptive als. When issues such as very low education or language skills. Confrontation naming and word 18 Assessment of Alzheimer’s Disease 277 retrieval skills can be assessed by measures such Attention may be assessed by tests of digit as the Boston Naming Test [ 36 ] . Access from span or continuous performance tasks that require semantic lexicon can be evaluated using a cate- vigilance and a response when certain stimuli gory fl uency test for animals, fruits, and vegeta- fl ash across a computer screen. Psychomotor bles [37 ] . In contrast, letter fl uency is a more speed may be assessed by Trails A in which a orthographic memory task that requires retrieval patient connects numbers spread out across a from phonological stores and is sensitive to fron- page as quickly as possible, employing tests of tal lobe dysfunction (see [ 38 ] ). We also obtain a simple or choice reaction time on the computer or brief reading sample, a writing sample, as well as manual fi nger tapping. repetition of phrases. Receptive language can be assessed by having the subject perform simple and more complex commands or performing the When Should Neuropsychological Token Test [39 , 44 ] . Tests Be Administered Common elements of executive function tests are the ability to plan, solve problems, engage in Neuropsychological testing should be adminis- concept formation, and shift cognitive sets. One tered to any older adult in which it is important to of the most sensitive measures for executive dys- establish the presence, or absence of cognitive function is the Wisconsin Card Sorting Test [ 40 ] , de fi cits or where the clinician is unsure about the which provides an excellent measure of concept nature and the extent of cognitive defi cits. formation, perseverations, and the ability to shift Examining different patterns of neuropsycholog- cognitive sets. Unfortunately, since this is a test ical defi cits may also help the clinician in diag- of novel learning, this is not an optimal measure nostic formulation and provide an objective for repeated testing. The Trail-Making Test baseline in which to monitor progression and [41, 42] , a test of simple visual scanning abilities response to treatment. Finally, neuropsychologi- which requires alternation between numbers and cal test results can highlight patterns of strengths letters and shifting cognitive sets, is widely and weaknesses that can be helpful in patient thought to be an executive function task. Since management. there are so many cognitive processes required Consider the example of an 85-year-old for this test of complex visual scanning abilities, woman born in Lithuania with a fi fth grade edu- Trails B is very sensitive to cerebral dysfunction cation, presenting with signifi cant depression in in general, although observed de fi cits may not be an outpatient setting. On her mental status eval- specifi c to dysexecutive impairments and can uation, she gave the wrong day of the week and also be highly infl uenced by motor skills and recalled two of three objects. One of her sisters speed. Visuospatial disturbances and construc- insisted that she had cognitive decline, whereas tional praxis can be ascertained by constructional another sister insisted that there had been no tasks such as the Block Design Subtest of the change in cognitive function. In this case, the Wechsler Adult Intelligence Scale (WAIS-IV; clinician was unsure of the diagnosis and [43 ] ). When it is important to distinguish between ordered a neuropsychological evaluation. The a perceptual disturbance from the inability to neuropsychologist can test memory, language, construct fi gures based on that perception, tests executive function, attention, and language and such as Judgment of Line Orientation [ 44 ] or by using objective normative data appropriate Hooper Visual Organization Test [ 45 ] may be to the patient’s age, education, and background useful. Praxis is the ability to perform skilled as well as comparing test results in different motor movements. Simple tests of ideational domains. This data can greatly assist with deter- praxis may be to have the patient prepare a letter mining the presence or absence of cognitive for mailing while simple tests of ideomotor praxis impairment in patients such as the one described are to show how to use scissors, use a hammer, or above, and can contribute greatly to the diag- blow out a match. nostic determination. 278 D. Loewenstein

There are some cases that will remain equivocal deposition in the brain by PET imaging, CSF even with the most sensitive neuropsychological evidence of amyloid or tau levels suggestive of assessment. In these instances, the neuropsychol- AD, atrophy of the hippocampus, entorhinal ogist may conduct serial assessments in cortex and other medial temporal structures on 6–9 months to track progression. Sometimes, the MRI, or being homozygous for the APOE-e 4 neuropsychologist will use parallel forms when allele. Despite these advances in technology available to reduce the possibility of practice that will aid in early detection of AD, assess- effects. The CVLT-II, HVLT-Revised, and AVLT ment of memory and other cognitive defi cits are all examples of memory tests with alternate will always be essential in characterizing the forms. The neuropsychologist may also use reli- disease, monitoring progression over time, and able change indices to determine the extent to helping to evaluate the effectiveness of treat- which changes on certain other tests re fl ect true ment strategies. Finally, as new treatments are differences, rather than resulting from chance or developed, cognitive and functional measures practice effects. It should be noted that neuropsy- will be at the forefront as a means to measure chological test results provide a snapshot of a outcome. person’s performance at one point in time, but that longitudinal assessment may be required to more accurately de fi ne the parameters of a Clinical Pearls particular condition. • The hallmark features of Alzheimer’s disease (AD) are de fi cits in delayed recall and rate of Summary and Future Trends forgetting. However, some AD patients will in Neuropsychological Assessment evidence their greatest de fi cits in learning information across multiple trials. Neuropsychological assessment has an impor- • List learning tests are optimal for assessment tant role in distinguishing between the cognitive of AD in that they test the ability to learn new effects of normal aging versus defi cits related to information across multiple trials and also cerebral dysfunction. The objective nature of assess delayed recall and rate of forgetting. the tests, the ability to relate results to appropri- • It is desirable to assess memory for verbal as ate normative data, and the comparison of pat- well as nonverbal information (i.e., immediate terns of strengths and weaknesses all contribute and delayed visual reproduction). important information that can improve clinical • The AD patient may on occasion present with decision making. As efforts are made to detect primary impairments in executive dysfunction, AD in its earliest stages, it will become even language, or visuospatial function. Therefore, more important for the fi eld of neuropsychology it is important to assess these domains. to develop tests that are sensitive to specifi c • Amnesic mild cognitive impairment (aMCI) defi cits in utilizing semantic cues, the effects of is a risk factor for Alzheimer’s disease and semantic interference, and evidence of subtle memory disorders. In specialty memory disor- executive dysfunction. With the increased reli- ders clinics, the rate of progression to demen- ance on biomarkers for early detection of AD, tia and a diagnosis of probable AD is 12–15% there will also be a need to develop algorithms per year while the rate of progression in other that incorporate both cognitive variables and settings where the base rates may be lower are biomarkers. To this point, a recent investigation considerably less. has revealed that measures of episodic memory • The clinical diagnosis of probable AD requires and combined FDG-PET scans together pre- a dementia syndrome by DSM-IV criteria, and dicted progression from MCI to AD better than cognitive impairment must be suffi ciently either measure alone [ 46] . The diagnosis of severe to interfere with social and/or occupa- early AD is strengthened by evidence of amyloid tional function. 18 Assessment of Alzheimer’s Disease 279

• A new diagnosis of dementia cannot be made 3. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans in the presence of a delirium. DA. Alzheimer’s disease in the U.S. population: prevalence estimates using the 2000 census. Arch Neurol. • A clinical diagnosis of AD is greatly strength- 2003;60:1119–22. ened by evidence of medial temporal lobe atro- 4. Iqbal K, Liu F, Gong CX, Alonso Adel C, Grundke- phy on MRI (particularly in the hippocampus Iqbal I. Mechanisms of tau induced neurodegenera- and entorhinal cortex), CSF fi ndings of A b-42/ tion. Acta Neuropathol. 2009;118(1):53–69. 5. McKhann G, Drachman D, Folstein M, Katzman R, Ab -40 ratios or A b-42/tau40 ratio suggestive Price D, Stadlan E. Clinical diagnosis of Alzheimer’s of AD, blood tests showing two APOE-e 4 disease: report of the NINCDS-ADRDA work group alleles, positron emission tomography (PET) under the auspices of department of health and human scans showing abnormal beta amyloid imaging services task force on Alzheimer’s disease. Neurology. 1984;34:939–44. on PET imaging, or hypometabolism in tem- 6. McKhann G, Knopman D, Chertkow H, Hyman BT, poral and parietal cortices. Jack CR, Kawas KH, Klunk WE, Koroshetz WJ, • Parkinsonian signs and symptoms, REM sleep Manley JJ, Mayeux R, Mohs RC, Morris JC, et al. The behavioral disturbance, fl uctuating attention, diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institutes on memory, executive and visuospatial de fi cits Aging-Alzheimer’s Association workgroup on diag- should raise the possibility of diffuse Lewy nostic guidelines for Alzheimer’s disease. Alzheimers body disease. Dement. 2011;7(3):263–9. • Early language disturbances or predominant 7. Brooks LG, Loewenstein DA. Assessing the progression of mild cognitive impairment (MCI) to changes in personality (i.e., disinhibition) and Alzheimer’s disease: current trends and future direc- an earlier onset of symptoms should raise the tions. Alzheimers Res Ther. 2010;2:28. possibility of frontotemporal dementia (FTD). 8. Petersen RC, Smith GE, Waring SC, Ivnik RJ, These individuals typically have predominant Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. frontal temporal atrophy on structural MRI, 1999;56:303–8. high levels of executive dysfunction and char- 9. Petersen RC. Mild cognitive impairment: transition acteristic patterns of frontal and temporal lobe between aging and Alzheimer’s disease. Neurologia. decreased metabolism or blood fl ow, and func- 2000;15:93–101. 10. Grober E, Lipton RB, Hall C, et al. Memory impair- tional neuroimaging such as PET or SPECT. ment on free and cued selective reminding predicts • Serial testing is recommended in cases where dementia. Neurology. 2000;54:827–32. the presence or the extent of cognitive defi cits is 11. Howieson DB, Dame A, Camicioli R, et al. Cognitive unclear or when it is important to monitor poten- markers preceding Alzheimer’s dementia in the healthy oldest old. J Am Geriatr Soc. 1997;45:584–9. tial improvement or worsening over time. 12. Small BJ, Mobly JL, Laukka EJ, Jones S, Backman L. • Denial of symptoms is commonly observed in Cognitive de fi cits in preclinical Alzheimer’s disease. AD, yet some early AD patients are aware of Acta Neurol Scand Suppl. 2003;179:29–33. changes, which may lead to signifi cant levels 13. Assal F, Cummings JL. Neuropsychiatric symptoms in the dementias. Curr Opin Neurol. 2002;15:445–50. of depression and anxiety. Although pseudo- 14. Luis CA, Loewenstein DA, Acevedo A, Barker WW, dementia is relatively uncommon in outpatient Duara R. Mild cognitive impairment: directions for settings, the clinician should be aware of the future research. Neurology. 2003;61:438–44. effects of anxiety and depression in depress- 15. Morris JC, Storandt M, Miller JP, McKeel DW, Price JL, Rubin EH, Berg L. Mild cognitive impairment ing performance on neuropsychological tests. represents early-stage Alzheimer’s disease. Arch Neurol. 2001;58(3):397–405. 16. Larrieu S, Letenneur L, Orgogozo JM, Fabrigoule C, Amieva H, Le Carret N, Barberger-Gateau P, Dartigues References JF. Incidence and outcome of mild cognitive impairment in a population-based prospective cohort. 1. Alzheimer’s Association. Alzheimer’s disease facts Neurology. 2002;59:1594–9. and fi gures. Alzheimers Dement. 2010;6:158–94. 17. Petersen R. Mild cognitive impairment. J Intern Med. 2. Park D, Schwartz N. Cognitive aging: a primer. 2004;256:183–94. Philadelphia: Taylor and Francis (Psychology Press); 18. Loewenstein DA, Amarilis Acevedo A, Small BJ, 2000. Agron J, Crocco E, Duara R. Stability of different 280 D. Loewenstein

subtypes of mild cognitive impairment among the 33. Loewenstein DA, Acevedo A, Agron J, Duara R. elderly over a two to three year follow-up period. Vulnerability to proactive semantic interference and Dement Geriatr Cogn Disord. 2009;17(5):437–40. progression to dementia older adults with mild cogni- 19. Alexopoulos P, Grimmer T, Perneczky R, Domes G, tive impairment (MCI). Dement Geriatr Cogn Disord. Kurz A. Progression to dementia in clinical subtypes 2007;24(5):363–8. of mild cognitive impairment. Dement Geriatr Cogn 34. Wechsler D. The Wechsler Memory Scale. 4th ed. San Disord. 2006;22:27–34. Antonio: The Psychological Corporation; 2008. 20. Rountree SD, Waring SC, Chan WC, Lupo PJ, Darby 35. Benedict R. Brief Visual Memory Test. Odessa: EJ, Doody RS. Importance of subtle amnestic and Psychological Assessment Resources; 1996. nonamnestic defi cits in mild cognitive impairment: 36. Goodglass H, Kaplan E, Weintraub S. The Boston prognosis and conversion to dementia. Dement Geriatr Naming Test. Philadelphia: Lea and Febiger; 1983. Cogn Disord. 2007;24:476–82. 37. Monsch AY, Bondi MW, Butters N, Salmon DP, 21. Manly JJ, Tang MX, Schupf N, Stern Y, Vonsattel JP, Katzman R, Thal L. Comparison of verbal fl uency Mayeux R. Frequency and course of mild cognitive tasks in the detection of dementia of the Alzheimer’s impairment in a multiethnic community. Ann Neurol. type. Arch Neurol. 1992;49(12):1253–8. 2008;63:494–506. 38. Spreen O, Strauss E. A compendium of neuropsycho- 22. Ritchie LJ, Tuokko H. Patterns of cognitive decline, logical tests: administration, norms, and commentary. conversion rates, and predictive validity for 3 models 2nd ed. New York: Oxford University Press; 1998. of MCI. Am J Alzheimers Dis Other Demen. 39. Benton A, des Hamsher K, Sivan AB. Multilingual 2010;25(7):592–603. aphasia examination. Iowa City: AJA Associates; 1994. 23. Locasio JJ, Growdon JH, Corkin S. Cognitive test per- 40. Heaton RK, Chelune GJ, Talley JL, Kay GG, formance in detecting, staging, and tracking Curtiss G. Wisconsin Card Sorting Test manual: Alzheimer’sdisease. Arch Neurol. 1995;52:1087–99. revised and expanded. Odessa: Psychological 24. Tröster AI, Butters N, Salmon D, Cullum CM, Jacobs Assessment Resources; 1993. D, Brandt J, White RF. The diagnostic utility of sav- 41. War Department Adjutant General’s Of fi ce. Army ings scores: differentiating Alzheimer’s and Individual Test Battery. Manual of directions and Huntington’s disease with the logical memory and scoring. Washington, DC: War Department Adjutant visual reproduction tests. J Clin Exp Neuropsychol. General’s Of fi ce; 1944. 1993;5:773–88. 42. Reitan RM, Wolfson D. The Halstead-Reitan neurop- 25. Christensen H, Kopelman MD, Stanhope N, Lorentz sychological test battery: theory and clinical interpre- L, Owen P. Rates of forgetting in Alzheimer demen- tation. 2nd ed. Tucson: Neuropsychology Press; 1993. tia. Neuropsychologia. 1998;36:547–57. 43. Wechsler D. The Wechsler Adult Intelligence Scale. 26. Loewenstein DA, Acevedo A, Luis CA, Crum T, 4th ed. San Antonio: The Psychological Corporation; Barker WW, Duara R. Semantic interference de fi cits 2008. and the detection of mild Alzheimer’s disease and 44. Benton A, Sivan AG, des Hamsher K, Varney NR, mild cognitive impairment without dementia. J Int Spreen O. Contributions to neuropsychological assess- Neuropsychol Soc. 2004;1:91–100. ment: a clinical manual. 2nd ed. Oxford: London; 1994. 27. Delis DC, Kramer JH, Kaplan E, Ober BA. California 45. Hooper HE. Hooper Visual Organization Test (VOT). verbal learning test- second edition. San Antonio: The Los Angeles: Western Psychological Services; 1983. Psychological Corporation; 2000. 46. Landau SM, Harvey D, Madison CM, Reiman EM, 28. Rey A. L’examen Clinique en psychologie. Paris: Foster NL, Aisen PS, Petersen RC, Shaw LM, Presses Universitaries de France; 1964. Trojanowski JQ, Jack Jr CR, Weiner MW, Jagust WJ. 29. Lezak MD. Neuropsychological assessment. New Comparing predictors of conversion and decline in mild York: Oxford University Press; 1998. cognitive impairment. Neurology. 2010;75:230–8. 30. Benedict R, Schretlen D, Groninger L, et al. Hopkins 47. Albert MS, Dekosky ST, Dicksen D, Dubois B, Verbal Learning Test—Revised: normative data and Feldman HH, Fox N, Gamst A, Holtzman D, Jagust analysis of inter-form and test-retest reliability. Clin WJ, Petersen R. The diagnosis of mild cognitive Neuropsychol. 1998;12:43–55. impairment due to Alzheimer’s disease: 31. Fuld PA. Fuld object-memory evaluation. Chicago: Recommendations from the National Institute on Stoelting Co; 1981. Aging and Alzheimer’s Association workgroup. 32. Loewenstein DA, Arguelles T, Barker WW, et al. The Alzheimer’s & Dementia; 2011. p. 1–10. utility of a modi fi ed Object Memory Test in distin- 48. American Psychiatric Association. Task force on guishing between three different age groups of DSM-IV: diagnostic and statistical manual of mental Alzheimer’s disease patients and normal controls. disorders: DSM-IV. 4th ed. Washington, DC: J Mental Health Aging. 2001;7:317–24. American Psychiatric Association; 1994. Vascular Cognitive Impairment 1 9 Robert Paul , Elizabeth Lane , and Angela Jefferson

Abstract The risk of cerebrovascular disease increases with advanced age, with almost two thirds of individuals over 70 exhibiting vascular lesions on MRI. Cognitive presentations vary from little or no no cognitive impairment to clinical dementia, and the extent of cognitive impairment is not necessarily correlated with lesion size or burden. The term vascular cognitive impairment (VCI) describes all forms of cognitive impairment caused by cerebrovascular disease. Early identiﬁ cation of vascular disease is critical since many risk factors are modiﬁ able, and the neuropsychologist can play an important role in characterizing the extent of cognitive and behavioral change. This chapter provides an overview of the clinical guidelines to consider when evaluating older adults with possible VCI and includes an illustrative case example and useful recommendations for the clinician.

Keywords Vascular dementia • Dementia • Stroke • Neuropsychology

R. Paul , Ph.D. () • Elizabeth Lane, Ph.D. University of Missouri, St. Louis, MO, USA Department of Psychology, Division of Behavioral Neurosciences , 1 University Blvd, St. Louis , MO 63121 , USA e-mail: [email protected] ; [email protected] A. Jefferson , Ph.D. Vanderbilt Memory & Alzheimer’s Center, Department of Neurology, Vanderbilt University Medical Center, A0118 Medical Center North, Nashville, TN 37232 , USA e-mail: [email protected]

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 281 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_19, © Springer Science+Business Media, LLC 2013 282 R. Paul et al.

The risk of cerebrovascular disease increases as Table 19.1 Common stroke sites and corresponding individuals age, with as many as 70% of individ- clinical features uals over the age of 70 exhibiting evidence of Stroke site Clinical features vascular lesions on MRI [1 ] . Such lesions can Middle cerebral Hemiplegia, aphasia, homonymous, yield different clinical profi les, with some smaller artery hemianopia, hemianesthesia contralateral lesions resulting in little to no cognitive impair- Anterior cerebral Paraplegia, incontinence, abulia, ment and other lesions severe enough to result in artery executive dysfunction, personality clinical dementia. The term vascular cognitive changes impairment (VCI) was introduced to describe all Posterior cerebral Homonymous hemianopia, alexia forms of cognitive impairment caused by cere- artery with or without agraphia, visual agnosias, color anomia, Balint brovascular disease. The type of impairment syndrome, prosopagnosia associated with VCI can be variable depending on the location and amount of damaged tissue, which in turn infl uences the severity of cognitive, behavioral, and psychiatric features. Early identi- though this position is controversial in the fi cation of vascular disease is critical since many fi eld. Even though the diagnosis of VCI can be of the risk factors for VaD are modifi able, yet it is complicated by several factors, there appears to not known exactly how much damage is neces- be a general cognitive pattern associated with the sary to produce clinical impairment. type of de fi cits found in this disorder. At the mildest stage, VCI is referred to as vascular cognitive impairment no dementia (VCIND) and is often secondary to small vessel ischemic Clinical Presentation disease. At the more severe clinical end, VCI is referred to as vascular dementia (VaD) and is In the case of VCI, clinical preconceptions of dis- believed to represent one of the more common ease expression and progression are often not types of dementia among older adults after AD. realized, as heterogeneity is the rule. As dis- About one-third of individuals will develop cussed in greater detail below, patterns of abrupt dementia within 1 year after a stroke [1 ] . When a onset and stepwise decline in function are less stroke is strategically located (e.g., in Broca’s common than a slow and progressive disease area) or affects a very large vessel, the clinical course [ 3] . Further, while a pattern of executive result is likely consistent with the traditional con- dysfunction may predominate, the neuropsycho- cept of dementia due to stroke (i.e., a sudden loss logical presentation will be driven by the extent of cognitive function and a stepwise pattern of of focal and diffuse vascular injuries in the brain. cognitive deterioration). However, clinical symp- Below, clinical concepts on the VCI spectrum are toms associated with stroke are highly variable described in more detail. and depend upon the area impacted. Table 19.1 lists common stroke sites and corresponding defi cits, which can be viewed on structural brain Vascular Cognitive Impairment: imaging as cortical or lacunar infarcts. While No Dementia impairment due to strategic or large vessel stroke is most commonly tied to the concept of VaD, it VCIND refers to vascular lesions evident on MRI is not the most common expression of the disease. that cause impairment too mild to impact activi- As discussed in more detail below, VaD more ties of daily living. The most common types of often has an insidious onset with a slow and lesions associated with VCIND are visualized on gradual decline. Additionally, mixed dementia MRI as lacunes (i.e., small cerebrospinal fi lled between VCI and AD is common and argued by cavities in the white matter) and subcortical some to share neuropathogenic mechanisms [2 ] , hyperintensities (SH; i.e., areas of bright white 19 Vascular Cognitive Impairment 283 on neuroimaging that represent vascular-related cerebral arteries, or some combination of the two. damage). However, it is not uncommon for an Executive function, learning, and delayed mem- individual to have this type of vascular damage ory, with intact recognition memory are the most and exhibit normal neuropsychological abilities. consistently impaired domains of function in These “silent” infarcts may not be truly silent, as VaD [11 ] . De fi cits in executive function are most they represent vascular damage that may be a typically found on tests of verbal fl uency, mental core determinant of what is considered normal fl exibility, and response inhibition [ 10 ] . Episodic age-related cognitive decline. As such, not all memory defi cits are typically found on tests of patients with MRI lesions will exhibit neuropsy- list learning and recall, but recognition may chological impairment in part because the clini- remain intact particularly if the structures of the cal norms likely included older individuals with medial temporal lobe are spared of vascular damage-related infarcts as well. age. These patterns of impairment are useful in Most importantly, VCIND may be a prodromal distinguishing VaD from strategic stroke and AD. stage for VaD, and as such, modifi able risk fac- Physical symptoms of VaD include extrapyrami- tors may be important in reducing the progres- dal symptoms, bilateral pyramidal symptoms, sion of the disease. A longitudinal study by positive masseter re fl ex, imbalance, incontinence, Wentzel et al. [4 ] revealed that half of the VCIND dysarthria, and dysphagia [12 ] . cases progressed to dementia over a 5-year period Depression is the most common behavioral of time. Further, individuals with VCIND and feature associated with stroke. About 20% of indi- evidence of frontal white matter hyperintensities viduals with stroke also exhibit depression [ 13 ] . are less likely to revert back to normal cognitive The strongest predictor of depression is reduc- function after 1 year as compared to individuals tion in the ability to carry out activities of daily with VCIND who do not have frontal white mat- living [13 ] , which may be confounded by stroke ter hyperintensities [5 ] . Modi fi able risk factors, severity. Additionally, increased depression is such as hypertension, may play an important role associated with greater cognitive impairment in determining the progression of VCIND to and increased mortality. Of note, the cognitive VaD. Notably, current pharmacological treatment de fi cits found in patients with VaD cannot be options for VaD are comparable to AD treatment explained by the depression, as they persist even options (i.e., relatively ineffective at arresting when the depressive symptoms are statistically disease progression) [6 ] , emphasizing the need controlled [ 10 ] . for early identi fi cation and clinical intervention. Several diagnostic criteria have been pro- Though there does not appear to be a consis- posed for VaD. The three most commonly used tent neuropsychological pro fi le that is predictive diagnostic criteria include the Diagnostic and of advancement from VCIND to VaD [7 ] , indi- Statistical Manual, Fourth Edition [14 ] viduals with VCIND often display poor perfor- (DSM-IV; see Table 19.2 ), the State of mance on tests of cognitive fl exibility and verbal California Alzheimer’s Disease Diagnostic and retrieval [8 ] , learning [9 ] , and psychomotor speed Treatment Centers criteria [15 ] (ADDTC), and [9 ] . Additionally, VCIND may increase the the National Institute of Neurological Disorders incidence of depression, although it is unknown and Stroke-Association Internationale pour la if vascular damage is the cause of depression or a Recherche et L’Enseignement en Neurosciences result of perceived de fi cits [9 ] . [ 16] (NINDS-AIREN) criteria. The most commonly used criteria in the clinical setting are the DSM-IV given that third-party insurance Vascular Dementia reimbursement is tied to the DSM-IV (and ICD). The DSM-IV criteria are based on symp- VaD is the result of extensive white matter lesions toms similar to AD and require memory de fi cits and lacunar infarcts due to small vessel disease as a prominent feature. This requirement pres- [10 ] , the result of one or more strokes to the main ents a diagnostic conundrum since core aspects 284 R. Paul et al.

Table 19.2 DSM-IV criteria for VaD A. The development of multiple cognitive de fi cits manifested by both 1. Memory impairment (impaired ability to learn new information or to recall previously learned information) 2. One (or more) of the following cognitive disturbances: (a) Aphasia (language disturbance) (b) Apraxia (impaired ability to carry out motor activities despite intact motor function) (c) Agnosia (failure to recognize or identify objects despite intact sensory function) (d) Disturbance in executive functioning (i.e., planning, organizing, sequencing, abstracting) B. The cognitive de fi cits in criteria A1 and A2 each cause signi fi cant impairment in social or occupational functioning and represent a signi fi cant decline from a previous level of functioning C. Focal neurological signs and symptoms (e.g., exaggeration of deep tendon re fl exes, extensor plantar response, pseudobulbar palsy, gait abnormalities, weakness of an extremity) or laboratory evidence indicative of cerebrovascular disease (e.g., multiple infarctions involving cortex and underlying white matter) that are judged to be etiologically related to the disturbance D. The de fi cits do not occur exclusively during the course of a delirium

of episodic memory can remain intact in the in very young children, it is most common context of vascular disease, and memory impair- among older individuals. In fact, the greatest ment may not be the primary feature of the dis- risk factor associated with VCI is age. Additional ease. Additionally, the DSM-IV criteria do not unmodifi able risk factors for stroke include male require neuroimaging evidence of cerebrovas- sex, low birth weight, atrial fi brillation, race (i.e., cular disease, increasing the likelihood that an African American), and ethnicity (i.e., Latino) individual may be misdiagnosed. [ 18] . Additionally, there are several determinis- Both the ADDTC and NINDS-AIREN criteria tic and susceptibility genetic factors that increase are used most often in research settings. Both sets an individuals’ risk of vascular disease, includ- of criteria allow for the diagnosis of possible, ing cerebral autosomal dominant arteriopathy probable, and de fi nite VaD, and both require with subcortical infarcts leukoencephalopathy neuroimaging evidence of cerebrovascular (CADASIL) as a deterministic factor and angio- disease for a probable diagnosis. However, the tensinogen as susceptibility factor. NINDS-AIREN criteria are still modeled after CADASIL, a rare autosomal dominant dis- the diagnostic criteria for AD and require epi- ease, is associated with a Notch3 defect that sodic memory impairment for the diagnosis, causes infarcts in the deep white matter, basal yielding misdiagnosis issues consistent with the ganglia, and brain stem. The average age of onset DMS-IV criteria. The ADDTC criteria are the for stroke is age 45, although many individuals most fl exible with regard to the neuropsychologi- with CADASIL will experience migraine with cal pattern of impairment, allowing for diagnosis aura with an average onset at age 30 years. even when memory is not the prominent area of Individuals with CADASIL typically develop cognitive impairment. For a more detailed review dementia by the sixth decade of life with death in on VaD diagnostic criteria convergence and the seventh decade. Cognitive de fi cits associated divergence, the reader is referred to Cosentino with CADASIL typically follow a subcortical et al. [17 ] . pattern impacting executive function, organization abilities, and attention [19 ] . In contrast to the deterministic nature of CADASIL, one major VCI Risk Factors susceptibility gene for vascular disease that has been identi fi ed is angiotensinogen. Studies have There are a number of variables associated with shown that angiotensinogen may be involved in increased risk for stroke. Though stroke occurs abnormal vascular responsivity and the develop- in younger cohorts, such as sickle cell anemia ment of subcortical ischemic disease [20 ] . 19 Vascular Cognitive Impairment 285

Since cerebrovascular disease is the underly- many patients likely exhibit some degree of ing cause of VCI, the risk factors related to the shared disease presentation in vivo. It remains development of VCI overlap with those related to unclear, however, whether both conditions cardiovascular disease. Not surprisingly, improve- develop independently or whether the development in risk factors underlying overall cardiovas- ment of one condition precipitates the develop- cular health lowers the risk of stroke. Speciﬁ cally, ment or progression of the other. Regardless of studies have demonstrated that successful lower- the temporal association or causation of these two ing of hypertension and cessation of smoking pathologies, the clinician is challenged with sort- result in reduced stroke risk in advanced age [19 ] . ing through the possible diagnostic entities using Other modiﬁ able factors include control of dia- a combination of clinical interview data, neurop- betes mellitus, hypertension, and dyslipidemia. sychological outcomes, and neuroimaging results. More details regarding best strategies for clinically evaluating patients and interpreting relevant data VCI Differential Diagnosis are provided below.

Diagnostic considerations that will challenge the clinician when evaluating older adults for VCI Clinical Evaluation might include Lewy body dementia, AD, frontotemporal dementias, and normal pressure hydro- Perhaps more so than other neurodegenerative cephalus (NPH). NPH can clinically present very conditions, the model of vascular-mediated brain similarly to VCI as both conditions share frontal injury has evolved over the last few decades. symptoms [21 ] ; however, NPH more frequently Historical beliefs regarding the course of decline, includes urinary urgency (or urinary frequency/ the neuropsychological pattern, and the utility or incontinence) and gait disturbance [ 22 ] . The com- necessity of MRI-de fi ned vascular burden have bination of gait disturbance and urinary symptoms shifted the approach and accuracy of the neurop- greatly increases the likelihood of NPH as the sychological evaluation. To effectively navigate appropriate diagnosis even when executive dys- these challenges, the clinical evaluation of vascular- function is present. Of course, evidence of MRI mediated cognitive impairment should follow a abnormalities characteristic of either NPH traditional hypothesis-driven, patient-oriented (i.e., grossly enlarged lateral ventricles) or VCI approach. Further, the integration of personal, (e.g., lacunar infarcts, white matter hyperintensi- medical (including laboratory and MRI data), and ties) will provide more defi nitive information neuropsychological information is necessary to regarding the differential diagnosis. Frontotemporal reach a sound conceptualization and clinical dementia typically presents with more unique diagnosis. Below we describe clinical evaluation symptoms than VCI, such as signifi cant aphasia guidelines along with some of the common hur- or personality abnormalities. Furthermore, the dles that clinicians face in the process of integrat- age of onset for VCI is often, but not always, older ing this information (see Paul et al. [ 23 ] for a more than what is typical for frontotemporal dementia complete review of these clinical concerns). with behavioral disturbances present before age 65. Ruling out AD or diagnosing mixed dementia Clinical Interview and History (i.e., AD and VCI) is defi nitely more challenging for the clinician. Historically, the course of decline The clinical interview is an important area of and neuropsychological patterns seen in AD ver- neuropsychological assessment for vascular dis- sus VCI were believed to be disease specifi c, but ease. Patients may have very good insight into more recent research has challenged this position. the nature of their cognitive diffi culties, though it Autopsy evidence suggests that AD and vascular would be incorrect to presume that insight is fully neuropathology frequently coexist; therefore, intact for all patients. Attention is needed to 286 R. Paul et al. review signs and symptoms with patients and to vessel disease where the microvasculature ensure that descriptions of stroke-related terms degrades slowly over a period of time, especially and MRI fi ndings are communicated accurately. when isolated to the subcortical white matter. Oftentimes, patients will confuse concepts such Such small vessel infarcts are now recognized as as transient ischemic attack (or TIA) with stroke, the most common form of stroke associated with or they will misinterpret the MRI report regard- age (compared to large vessel strokes) [24 ] , and ing subcortical versus cortical vascular disease. functional status (associated with such small ves- Obviously, access to medical records will clarify sel infarcts) deteriorates along a slow and pro- these issues, but for some clinicians working in gressive course that is similar to AD. In short, independent practice, the records may arrive after clinicians cannot rely on the course of decline as the patient has been evaluated (as in the clinical a pathogenic sign of vascular disease, and detailed case provided below), or they may never arrive. review of both neuropsychological data and The interview can also provide an excellent neuroimaging results are critical to reach a solid opportunity to observe language skills and the and accurate case conceptualization. potential for various aphasic abnormalities. In some instances, family members may attri- Solicitation of responses during the interview bute the slow insidious changes in function process and probing of specifi c areas represents caused by small vessel disease as “normal aging.” an excellent opportunity to informally character- It is not until the patient suffers a sharp decline in ize the pattern of memory impairments as indi- function due to a strategic stroke or large vessel viduals recall personal and medical-related stroke that the family (or primary care physician) information. Patients may describe memory fail- initiates a clinical evaluation. In our studies of ures as “tip of the tongue” phenomena rather than VaD, all patients with large vessel infarcts also outright amnesic failure (e.g., “I cannot remem- exhibited signifi cant, concomitant microvascular ber the word”). Finally, mood and apathy are rel- disease in the subcortical white matter, empha- evant constructs to extract from the interview sizing that small vessel disease is more the norm process. While neither may be particularly than the exception. The combination of cortical affected in cases of small vessel ischemic involve- or strategic infarcts and small vessel ischemic ment, large vessel stroke is a predictor of depres- damage in the white matter signi fi cantly compli- sion and apathy [13 ] . cates the clinical picture owning to the presence One common hurdle that clinicians face dur- of mixed symptoms, and in turn, this clinical pre- ing the clinical interview and conceptualization sentation almost always complicates the descrip- of VCI is differentiating between a stepwise ver- tion of disease course by family members. sus progressive decline. Historically, the VCI literature has characterized the decline in cognitive and physical status associated with stroke as Neuropsychological Assessment “stepwise,” which contrasted the insidious and progressive decline characterizing AD. If the Neuropsychological evaluation of VCI requires patient or family described a repetitive pattern of suffi cient breadth and coverage. Screening mea- sharp decline followed by stabilization, the step- sures, such as the mini mental state exam, lack wise pattern was confi rmed and a diagnosis of sensitivity to vascular-related cognitive impair- vascular etiology would be considered more ment [25, 26 ] . More recently, the Montreal likely than a diagnosis of AD. Such a description Cognitive Assessment (MoCA) was introduced to of decline was, and still is, appropriate for large provide greater coverage of executive processes vessel infarcts (e.g., middle cerebral, anterior in the screening of dementia [ 27 ] . Studies indi- cerebral, or posterior cerebral arteries) or very cate that the MoCA has greater sensitivity to more strategic small vessel strokes (e.g., thalamic subtle cognitive impairment and early AD than infarct), but the pattern does not hold for small the MMSE [27 ] . However, the MoCA was not 19 Vascular Cognitive Impairment 287

Table 19.3 Neuropsychological protocol recommendations Domain Harmonization 30-min Harmonization 60-min Authors’ recommended protocola protocola protocol b Global MMSE MMSE MoCA Executive function/ Animal fl uency Animal fl uency Animal fl uency activation Letter fl uency Letter fl uency Letter fl uency Digit Symbol Coding Digit Symbol Coding Digit Symbol Coding Trail Making Trail Making Letter-Number Sequencing Stroop Test Psychomotor speed Grooved Pegboard Test Language Boston Naming Test Boston Naming Test Attention/reaction time Simple and Choice RT Digit Span Visuospatial skill Rey Complex Figure Test Rey Complex Figure Test Memory Hopkins Verbal Hopkins Verbal Learning Hopkins Verbal Learning Learning Test—Revised Test—Revised or California Test—Revised or California Verbal Learning Test-II Verbal Learning Test-II Brief Visual Memory Test—Revised Neuropsychiatric/ Mood questionnaire Neuropsychiatric Inventory Mood questionnaire depressive symptoms Mood questionnaire (BDI II, CES-D) MoCA Montreal Cognitive Assessment, BDI II Beck Depression Inventory II a Adapted from NINDS and Canadian Stroke Harmonization Network Protocol Recommendations (Hachinski et al.) b Recommended by Robert Paul, Liz Lane, and Angela Jefferson (Note, animal fl uency is recommended by the authors as a measure of language rather than executive function/activation) developed speci fi cally for VCI, and it is unclear measures that capture learning ef fi ciency across whether the limited task demands adequately cap- trials, delayed retention, and recognition. This ture mild to moderate cognitive impairments assessment strategy will help to differentiate the associated with cerebrovascular disease. Overall, amnesic pattern of AD from the inef fi cient learn- studies to date do not suggest that brief screening ing pattern common in, but not necessarily pathog- measures offer suffi cient neuropsychological nomonic of, vascular disease. Similarly, it is coverage for detecting milder forms of VCI. recommended that measures of both lexical (let- In 2006, the NINDS and Canadian Stroke ter) and semantic (category) fl uency are adminis- Harmonization Network [ 28 ] recommended a tered, as vascular pathology tends to result in brief 30-min and a more comprehensive 60-min poorer performance on lexical than semantic neuropsychological battery for VCI, which are tasks. The opposite pattern is more characteristic summarized in Table 19.3 . As evident from the of AD, though this differential pattern remains table, the 30-min battery is limited to verbal mem- only a heuristic and not an algorithm [29, 30 ] . ory, psychomotor speed, and verbal fl uency. By Finally, as evident from Table 19.3 , there is a contrast, the 60-min battery was designed to rep- heavy weighting on the heterogeneous aspects of resent all major cognitive systems, including executive dysfunction, including working mem- attention, processing speed, working memory, ory, response inhibition, cognitive fl exibility, multiple aspects of executive function, verbal and planning, and organization. Comprehensive cover- visual learning and memory, psychomotor speed, age of executive function skills is important, as language, visuospatial skill, and mood. In terms vascular disease purportedly interrupts frontal- of memory assessment, it is critical to include subcortical circuits that mediate executive 288 R. Paul et al. diffi culties commonly associated with VCI [ 31, 32 ] , pattern of executive dysfunction in the absence of and performance on executive function tasks is a amnesic episodic memory impairment and/or critical determinant of ADL completion, which is anomic aphasia can lead clinicians toward a vas- directly tied to diagnostic criteria for dementia. cular conceptualization. This conceptualization is While it is not recommended that one make even more likely when patients present with assumptions about ADL independence based on signifi cant vascular risk factors (e.g., high blood performance in this domain, there are times clini- pressure, high cholesterol, diabetes) in the absence cally when vascular patients report no diffi culties of other obvious rule outs, such as NPH or cortical in their abilities to perform ADLs, yet they exhibit dementias (e.g., frontotemporal dementia). striking impairments across multiple executive However, in the absence of a known “fi ngerprint” function measures. In these instances, it is impor- of neuropsychological impairment for VCI, it is tant to communicate to families that while the absolutely critical that neuroimaging results are patient may be independent today with instru- integrated into the case conceptualization to reach mental activities that facilitate independence a more complete diagnostic formulation. (e.g., cooking, driving, medication, and fi nancial Neuroimaging abnormalities associated with management), this independence is likely to stroke are most readily identifi ed on high- change. Such changes or decline cannot be pre- powered MRI (e.g., 3T) using fl uid-attenuated dicted, and an unfortunate accident may result inversion recovery (FLAIR) scans [ 33 ] . Imaging before some intervention is initiated. abnormalities are also evident at lower fi eld strengths (e.g., 1.5T), but recent data suggests that abnormalities on 3T may not be readily vis- Neuroimaging Corroboration ible at 1.5T [34, 35 ] . Most often, vascular disease on FLAIR images is characterized by It can be tempting to rely too heavily on neuropsy- lacunes in subcortical gray and white matter, chological data alone to determine the etiology of white matter hyperintensities, and/or periventric- cognitive impairment with any clinical referral, ular capping along the perimeter of the lateral and reliance on the cognitive data can be most ventricles (see Fig. 19.1 ). Neuropsychologists problematic to the clinician in the case of VCI. A are not routinely trained to review fi lms

Fig. 19.1 Evidence of vascular disease using 3T MRI. subcortical lesions in a mildly impaired older adult with (a ) Example of periventricular capping in a “healthy” ischemic vascular disease older adult. (b ) Evidence of periventricular capping and 19 Vascular Cognitive Impairment 289

independently, so the degree of vascular burden Clinical Case Example must be gleaned from the radiologist’s report. This situation is an unfortunate reality because A case example is included below that incorpo- the fi eld of radiology, unlike the fi eld of neurop- rates the necessary elements of a clinical evalua- sychology, does not utilize a standard metric tion for illustration purposes. The case involves a system for determining the level of pathologic baseline and 12-month follow-up neuropsycho- burden. That is, the semantic labels often logical evaluation that required the integration of included in radiology reports to describe the clinical history, neuropsychological data, and extent of vascular damage (e.g., “age-related,” neuroimaging fi ndings. As is often the case in “mild,” “severe”) re fl ect the training and per- general private practice settings, the MRI report sonal nuances of a particular radiologist rather was not available at the time of the initial evalua- than a standardized measure of variance from tion. Similarly, while corroboration of the clinical “normal” (e.g., evidence that 25% of the white history from family is always important, the matter is affected with hyperintensities [ 36 ] ). patient’s husband was in poor health and could Complicating the picture further is that cere- not participate in the clinical interview in person brovascular disease is common among the or by phone, which further limited the informa- general population after age 65 years [ 37, 38 ] . tion available for the clinical interview. The case Collectively, the key question is not whether or example was extracted from a clinical fi le and not the MRI report included any reference to modi fi ed to remove personal identi fi cation. vascular disease, but rather whether or not the amount of vascular burden is suffi cient to account for the cognitive dif fi culties. Background and History So, how does a neuropsychologist incorporate neuroimaging data into a clinical evaluation? Mrs. Smith ( fi ctional name) is a 71-year-old, First, if there is no MRI report available, then the right-handed, married woman who was referred diagnosis of VCI can only be described as a pos- for neuropsychological evaluation by her neurol- sibility pending a subsequent MRI. Second, if an ogist for concern regarding cognitive dif fi culties. MRI has been conducted and there is no mention During the interview, Mrs. Smith reported a history of vascular disease, it is unlikely that a person’s of TIAs, “stroke,” and memory loss that began cognitive impairment is driven largely (solely) by 5 years prior to the evaluation, but she exhibited vascular mechanisms. Third, if the radiology some dif fi culty describing the chronology of report describes some degree of vascular disease these events. Mrs. Smith experienced a TIA-like (e.g., “mild ischemic vascular disease is noted…” event in 2003 followed by an episode of electro- or “age-appropriate ischemic vascular disease”), lyte depletion and “stroke.” She was unable to then the possibility of a vascular etiology (at least provide any details regarding the “stroke.” in part) exists but is not necessarily con fi rmed However, she stopped driving in 2004 due to (i.e., necessary but not suf fi cient). Descriptors recurrent sensory episodes that involved tingling such as “extensive vascular disease” or strategic in her hands. lacunar infarcts are plausibly related to cognitive Since 2004, Mrs. Smith described problems status. Further, while debated across various with short-term memory, including frequently groups, we believe it is appropriate to conclude repeating herself and dif fi culty remembering the that descriptors, such as “extensive vascular dis- names of people she has recently met (though she ease,” are etiologically relevant regardless of has no dif fi culty remembering the names of peo- other comorbid conditions. That is, even if the ple well known to her). She remains independent fi nal diagnosis appears consistent with AD, the in terms of medication management and other vascular burden likely contributes to the overall aspects of activities of daily living. She denied clinical picture in some form. 290 R. Paul et al. hallucinations, fl uctuating symptoms, urinary across three learning trials on a verbal learning incontinence/urgency/frequency, signi fi cant visu- and measure (HVLT-R). After a brief delay, she ospatial abnormalities, or any changes in recalled 6 out of 12 target words (low average personality. performance). Her performance was less strong Mrs. Smith’s medical history includes high on a recognition trial, as she tended to endorse cholesterol, high blood pressure, TIAs as described semantically related foils. It is of interest that she above, and possible seizures secondary to vascu- appeared a bit more confused on this aspect of lar injury (insert relative time frame). Psychiatric the test compared to the free recall portions of the history is unremarkable. Mrs. Smith completed task. On a test of learning and memory of prose college with a degree in business education, and passages, Mrs. Smith exhibited generally intact she worked as a high school business teacher for learning and retention of information, and she many years. Mrs. Smith and her husband now live performed one standard deviation above average in an independent senior community where they on the delayed trial, suggesting no rapid loss of enjoy a very active lifestyle; as noted above, her information. Further, her recognition memory husband was unavailable for corroboration of the was adequate. Performance on a test of visual clinical history. She does not smoke cigarettes or learning and memory (BVMT-R) was signifi cantly drink alcohol. She reported no family history of impaired in terms of learning and retention, dementia. A brain MRI report dated 3 weeks prior though her recognition memory was intact. Mrs. to the neuropsychological evaluation was remark- Smith’s performance on the learning trial was able for “periventricular white matter low attenu- severely impaired, and while she retained what ation related to chronic small vessel ischemia” she learned on the delayed trial, her overall per- and “ fi ndings consistent with generalized age- formances were low on both trials. related cerebral volume loss.” No other abnormal- On a measure of semantic (animal) fl uency, ities were noted, and the original scans were not Mrs. Smith performed within expectations for her available for visual inspection. age with 17 animals named within 1 min. By con- No clear disturbances in gait, posture, physical trast, on the lexical (FAS) fl uency test, she pro- asymmetries, or evidence of tremor or rigidity duced only 20 words across all three-letter cues were noted. Mrs. Smith was oriented to person, (i.e., 3 min), resulting in a below-average perfor- time, and place. Her conversational speech was mance. Mrs. Smith also correctly named only fl uent and goal directed. She exhibited appropri- 47/60 items on the Boston Naming Test (below- ate prosody, and there was no evidence of para- average performance), and the incorrect items phasias. Mild word-fi nding diffi culties were noted included both high- and low-frequency test items. in conversational speech, and she exhibited some Her copy reconstruction of a Rey Complex Figure confusion in the chronology of her recent medical was very impaired. She did not appear to grasp the and cognitive histories as noted above. Receptive gestalt of the overall design, and her placement of speech was generally intact, and Mrs. Smith details was poorly planned and organized. exhibited no dif fi culty comprehending simple or Mrs. Smith’s ability to repeat a string of digits complex material. She was very friendly and forward was intact suggesting adequate simple cooperative. Her mood was euthymic, and she attention. Her performance on a test of visual remained engaged throughout the evaluation. scanning and psychomotor speed (Trail Making Test, Part A) was moderately impaired. Though she successfully completed the practice trial of Baseline Neuropsychological Test Trail Making Test, Part B, she became very con- Results fused on the test trial, which she was unable to complete, suggesting signi fi cant problems with Baseline neuropsychological data are presented cognitive fl exibility. Similarly, she exhibited in Table 19.4 . Mrs. Smith recalled 23 words signi fi cant impairment on the Stroop interference 19 Vascular Cognitive Impairment 291

Table 19.4 Baseline and 12-month follow-up neuropsychological data for case example Test Baseline (raw) 12-month evaluation (raw) Outcome Attention WAIS III Digit Span 14 10 Decline Executive function Trail Making B Timed outa Unable to complete due to confusionb Decline Clock Unable to draw accurately Concrete setting Stable WAIS III Digit Symbol 25 a 27a Stable Psychomotor speed Trail Making A 77a 141b Decline WAIS III Symbol Search 12a 11a Stable Pegs dominant 145 155b Decline Pegs nondominant 123 133a Decline Activation/language Semantic fl uency 17 17 Stable Letter fl uency 20a 16b Decline Boston Naming Test 47a 48a Stable Visuospatial Rey Copy 15.5a 18.5 (more disorganized)a Decline Memory HVLT-R learning 23 17a Decline HVLT-R delay 6 6 Stable HVLT-R recognition 6b 9 Improve BVMT-R learning 10b 16a Improve BVMT-R delay 3b 7 Improve BVMTR recognition 100% 100% Stable WMS III LM I 40 36 Stable WMS III LM II 26 24 Stable Beck Depression 4 3 Stable a Mild impairment b Moderate impairment test (i.e., a test of response inhibition). Mild to Inventory-II was not suggestive of current moderate diffi culties were noted on tests of depressive symptoms. psychomotor speed and visual scanning (i.e., Based on the comprehensive neuropsycholog- Digit Symbol and Symbol Search). When asked ical test results, clinical history, and neuroimag- to construct a clock and set the hands to a specifi ed ing data, the evaluation suggests that the etiology time, she drew a clock with the numbers in the of cognitive diffi culties is consistent with cere- reverse order on two separate efforts. When a brovascular disease. Based on this initial evalua- clock was drawn for her and she was then asked tion, diagnostically, it appeared that Mrs. Smith to set the hands of the clock to a specifi ed time, met criteria for mild cognitive impairment, sin- she was unable to complete the task. gle-domain (executive function). Psychomotor speed performance on the Grooved Pegboard Test was moderately impaired for the dominant (right) hand, but her perfor- Repeat Neuropsychological Evaluation mance on the nondominant (left) hand was stronger, with a score in the borderline normal range. One year later, Mrs. Smith returned for a follow- Mrs. Smith’s total score on the Beck Depression up examination, which yielded little change in her 292 R. Paul et al. neuropsychological pro fi le. As evident in the data Clinical Pearls provided in Table 19.4, the predominant change in function was isolated to domains of executive As a summary, there are a number of clinical function and processing speed. Performance on a guidelines to consider when evaluating older test of learning effi ciency mildly declined, but adults with cognitive diffi culties that have possi- performance on a test of visual learning improved, ble VCI. We outline a few of these take-home and there was no decline on either test of verbal messages below: retention. Overall, the lack of decline in retention • The course of decline associated with VCI can of newly learned information argues against a be abrupt with stepwise decline or slow, insid- change in diagnostic formulation for this patient, ious, and progressive, resembling the course suggesting that the original clinical diagnosis of a for age-related neurodegenerative diseases, vascular etiology was accurate. Her MRI report such as AD or frontotemporal dementia. The dated 11 months after the fi rst MRI revealed presence of an insidious course should not be “Mild to moderate diffuse punctuate T2 and used to differentiate between VCI and primary FLAIR hyperintensities within the left and right dementing disorders. frontal parietal periventricular subcortical white • The pattern of neuropsychological defi cits matter and more confl uent increased T2 and associated with vascular burden is heteroge- FLAIR signal within the left and right parietal neous and dependent on the location of the periventricular white matter are again identi fi ed cerebrovascular damage. Executive impair- without change suggesting mild to moderate ment may be dominant but not universal and small vessel ischemic changes. There may be not necessary for the diagnosis. mild diffuse cortical atrophy with prominent sulci • Integration of structural brain MRI results is bilateral cerebral hemispheres.” critical for the diagnosis of VCI. • The progression of VCI can be infl uenced by Case Summary healthy lifestyle interventions. Early diagnosis is critical. The case above exempli fi es several common issues in the evaluation of VCI. First, the patient’s age and medical history places VCI high in the References list of differential diagnoses. Second, the patient’s own description of her medical history and vas- 1. O’Brien JT, Erkinjuntti T, Reisberg B, et al. Vascular cular injuries was limited, and there was no avail- cognitive impairment. Lancet Neurol. 2003;2:89–98. able informant to corroborate the patient’s history. 2. Sadowski M, Pankiewicz J, Sholtzava H, et al. Links between the pathology of Alzheimer’s disease and vas- Third, the neuropsychological pattern was fairly cular dementia. Neurochem Res. 2004;29(6):1257–66. typical of a “subcortical” pattern with impair- 3. Hachinski VC, Lliff D, Zihlka E, et al. Cerebral blood ment in learning, executive function, and motor fl ow in dementia. Arch Neurol. 1975;32(9):632–7. skills; however, performances were also low in 4. Wentzel C, Rockwood K, MacKnight C, et al. Progression of impairment in patients with vascular other cognitive domains, such as language. Also, cognitive impairment without dementia. Neurology. this patient performed poorly on the recognition 2001;57(4):714–6. trial of a verbal serial list learning test, but it is 5. Williamson JB, Nyenhuis DL, Pedelty L, et al. unlikely that such poor performance was due to Baseline differences between vascular cognitive impairment reverters and nonreverters. J Neurol an amnesic form of memory impairment, since Neurosurg Psychiatry. 2008;79(11):1208–14. the patient’s score on the retention trial demon- 6. Williams M. Progress in Alzheimer’s disease drug strated no appreciable loss of information. Finally, discovery: an update. Curr Opin Investig Drugs. her brain MRIs were congruent with her history 2009;10(1):23–34. 7. Ingles JL, Wentzel C, Fisk JD, Rockwood K. and neuropsychological patterns. Neuropsychological predictors of incident dementia 19 Vascular Cognitive Impairment 293

in patients with vascular cognitive impairment, no hydrocephalus. Dement Geriatr Cogn Disord. dementia. Stroke. 2002;33:1999–2002. 2006;21(2):113–9. 8. Garrett KD, Browndyke JN, Whelihan W, Paul RH, 22. Factora R, Luciano M. When to consider normal pres- DiCarlo M, Moser DJ, et al. The neuropsychological sure hydrocephalus in the patient with gait distur- pro fi le of vascular cognitive impairment—no demen- bance. Geriatrics. 2008;63(2):32–7. tia: comparisons to patients at risk for cerebrovascular 23. Paul R, Garrett K, Cohen R. Vascular dementia: a disease and vascular dementia. Arch Clin Neuropsychol. diagnostic conundrum for the clinical neuropsycholo- 2004;19:745–57. gist. Appl Neuropsychol. 2003;10(3):129–36. 9. Nyenhuis DL, Gorelick PB, Geenen EJ, et al. The pat- 24. Chui H, Gontheir R. Natural history of vascular demen- tern of neuropsychological de fi cits in vascular cogni- tia. Alzheimer Dis Assoc Disord. 1999;13:S124–30. tive impairment—no dementia (Vascular CIND). Clin 25. O’Sullivan M, Morris RG, Markus HS. Brief cogni- Neuropsychol. 2004;18(1):41–9. tive assessment for patients with cerebral small vessel 10. Jokinen H, Kalska H, Mantyla R, et al. Cognitive disease. J Neurol Neurosurg Psychiatry. 2005;76(8): pro fi le of subcortical ischaemic vascular disease. 1140–5. J Neurol Neurosurg Psychiatry. 2006;77:28–33. 26. Pachet A, Astner K, Brown L. Clinical utility of the 11. Traykov L, Baudic S, Rauox N, et al. Patterns of mini-mental status examination when assessing memory impairment and perseverative behavior dis- decision-making capacity. J Geriatr Psychiatry criminate early Alzheimer’s disease from subcortical Neurol. 2010;23(1):3–8. vascular dementia. J Neurol Sci. 2005;229–230: 27. Nasreddine ZS, Phillips NA, Bédirian V, et al. The 75–9. Montreal Cognitive Assessment, MoCA: a brief 12. Wallin A, Milos V, Sjogren M, Pantoni L, Erkinjuntti screening tool for mild cognitive impairment. J Am T. Classifi cation and subtypes of vascular dementia. Geriatr Soc. 2005;53(4):695–9. Int Psychogeriatr. 2003;15(1):27–37. 28. Hachinski V, Iadecola C, Petersen RC, et al. National 13. Robinson RG, Spalleta G. Poststroke depression: a Institute of Neurological Disorders and Stroke- review. Can J Psychiatry. 2010;55(6):341–9. Canadian Stroke Network vascular cognitive impair- 14. American Psychiatric Association Committee on ment harmonization standards. Stroke. Nomenclature and Statistics. Diagnostic and statisti- 2006;37(9):2220–41. cal manual of mental disorders (DSM-IV). 4th ed. 29. Canning SJ, Leach L, Stuss D, Ngo L, Black SE. Washington, DC: American Psychiatric Association; Diagnostic utility of abbreviated fl uency measures in 1994. Alzheimer disease and vascular dementia. Neurology. 15. Chui HC, Victoroff JI, Margolin D, Jagust W, Shankle 2004;62(4):556–62. R, Katzman R. Criteria for the diagnosis of ischemic 30. Henry JD, Crawford JR, Phillips LH. Verbal fl uency vascular dementia proposed by the state of California performance in dementia of the Alzheimer’s type: Alzheimer’s Disease Diagnostic and Treatment a meta-analysis. Neuropsychologia. 2004;42(9): Centers. Neurology. 1992;42:473–80. 1212–22. 16. Roman GC, Tatemichi TK, Erkinjuntti T, et al. 31. Jefferson AL, Cahn-Weiner D, Boyle P, Paul RH, Vascular dementia: diagnostic criteria for research Gordon N, Moser D, Cohen RA. Cognitive predictors studies: report of the NINDS-AIREN International of changes in activities of daily living among patients Workshop. Neurology. 1993;43:250–60. with vascular dementia. Int J Geriatr Psychiatry. 17. Cosentino SA, Jefferson AL, Carey ME, et al. The 2006;21(8):752–4. clinical diagnosis of vascular dementia: a compari- 32. Jefferson AL, Paul RH, Ozonoff A, Cohen RA. son among four classifi cation systems and a proposal Evaluating elements of executive functioning as pre- for a new paradigm. Clin Neuropsychol. 2004; dictors of instrumental activities of daily living 18(1):6–21. (IADLs). Arch Clin Neuropsychol. 2006;21(4): 18. Goldstein LB, Bushnell CD, Adams RJ, et al. 311–20. Guidelines for the primary prevention of stroke: a 33. De Coene B, Hajnal JV, Gatehouse P, et al. MR of the guideline for healthcare professionals from the brain using fl uid-attenuated inversion recovery American Heart Association/American Stroke (FLAIR) pulse sequences. Am J Neuroradiol. Association. Stroke. 2011;42:1–68. 1992;13(6):1555–64. 19. Guidetti D, Casali B, Mazzei RL, Dotti MT. Cerebral 34. Kamada K, Kakeda S, Ohnari N, Moriya J, Sato T, autosomal dominant arteriopathy with subcortical Korogi Y. Signal intensity of motor and sensory corti- infarcts and leukoencephalopathy. Clin Exp Hypertens. ces on T2-weighted and FLAIR images: intraindivid- 2006;28:271–7. ual comparison of 1.5T and 3T MRI. Eur Radiol. 20. Hajjar I, Sorond F, Hsu Y-H, Galica A, Cupples LA, 2008;18(12):2949–55. Epub 2008 Jul 19. Lipsitz LA. Renin angiotensin system gene polymor- 35. Stankiewicz JM, Glanz BI, Healy BC, et al. Brain MRI phisms and cerebral blood fl ow regulation: the lesion load at 1.5T and 3T versus clinical status in mul- MOBILIZE Boston study. Stroke. 2010;41:635–40. tiple sclerosis. J Neuroimaging. 2011;21(2): e50–6. 21. Ogino A, Kazui H, Miyoshi N, et al. Cognitive impair- 36. Price CC, Jefferson AL, Merino JG, Heilman KM, ment in patients with idiopathic normal pressure Libon DJ. Subcortical vascular dementia: integrating 294 R. Paul et al.

neuropsychological and neuroradiological data. 38. Seno H, Ishino H, Inagaki T, Yamamori C, Miyaoaka Neurology. 2005;65(3):376–82. T. Comparison between multiple lacunar infarcted 37. Boone KB, Miller BL, Lesser IM, et al. patients with and without dementia in nursing homes Neuropsychological correlates of white matter lesions in shimane prefecture, Japan. Dement Geriatr Cogn in healthy elderly subjects: a threshold effect. Arch Disord. 2000;11:161–5. Neurol. 1992;49:549–54. Assessment in Acute Stroke Rehabilitation* 2 0

George M. Cuesta

Abstract Stroke is the third leading cause of death in the United States, preceded by cancer and heart disease. Stroke is the primary cause of adult disability in the USA according to the Centers for Disease Control and Prevention, and stroke survivors represent the largest diagnostic category of referrals to rehabilitation hospitals. Neuropsychologists who work in acute stroke rehabilitation settings require a broad range of skills. They must be knowledgeable and competent in neuropsychology, rehabilitation psychology, and health psychology in order to provide effective assistance to their three principal constituencies: stroke patients, their family caregivers, and the stroke rehabilitation treatment team. Neuropsychologists assist these constituencies by managing the physical, cognitive, behavioral, emotional, social, sexual, and vocational consequences of stroke. This chapter provides a primer on stroke and suggestions are provided for effective neuropsychological practice in the acute rehabilitation hospital setting.

Keywords Acute stroke ¥ Cerebrovascular disease ¥ Rehabilitation ¥ Recovery ¥ Cognitive remediation

* The views expressed in this chapter are those of the author and do not reﬂ ect the ofﬁ cial policy of the Department of Veterans Affairs or the US Government. G. M. Cuesta , Ph.D. () United States Department of Veterans Affairs , Manhattan Vet Center, Readjustment Counseling Service, Veterans Health Administration , 32 Broadway, Suite 200 , Manhattan , NY 10004 , USA e-mail: [email protected]

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 295 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_20, © Springer Science+Business Media, LLC 2013 296 G.M. Cuesta

Stroke is the third leading cause of death in the services for stroke patients are typically provided United States, preceded by cancer and heart dis- to those in the middle range of impairment. While ease. As of December 31, 2009, there were an those with milder strokes are frequently dis- estimated 616,067 deaths due to heart disease charged directly to home with outpatient therapy and 562,875 deaths due to cancer in the USA; or home care, those with more severe strokes who the death toll for stroke (cerebrovascular disease) cannot tolerate inpatient rehabilitation are dis- was 135,952 (Centers for Disease Control and charged to a long-term care facility with limited Prevention, CDC/National Center for Health rehabilitation therapy services. Statistics). Stroke is the primary cause of adult Neuropsychologists who work in acute stroke disability in the USA according to the Centers rehabilitation settings will ﬁ nd that providing for Disease Control and Prevention, and stroke assessment and intervention to this patient survivors represent the largest diagnostic cate- population demands a broad range of skills. They gory of referrals to rehabilitation hospitals [ 1 ] . must be knowledgeable and competent in neu- As a consequence of the accelerated aging of the ropsychology, rehabilitation psychology, and US population, stroke will remain a public health health psychology in order to provide effective problem with adverse personal, societal, and assistance to their three principal constituencies: economic implications. According to Caplan, stroke patients, their family caregivers, and rehabilitation services for stroke patients are the stroke rehabilitation treatment team. typically provided to those in the middle range Neuropsychologists assist these constituencies of impairment [ 2] . While those with milder by managing the physical, cognitive, behavioral, strokes are frequently discharged directly to emotional, social, sexual, and vocational conse- home with outpatient therapy or home care, quences of stroke. those with more severe strokes who cannot tolerate inpatient rehabilitation are discharged to a long-term care facility with limited rehabilitation Prevalence therapy services. An estimated 6,400,000 Americans, 20 years of age and older, have had a stroke (extrapolated to Introduction and Brief Literature 2006 using National Center for Health Statistics/ Review National Health and Nutrition Examination Survey 2003Ð2006 data). Overall stroke preva- Stroke is the third leading cause of death in the lence during the period from 2003 to 2006 was USA, preceded by cancer and heart disease. As estimated at 2.9% [3 ] . According to data from the of December 31, 2009, there were an estimated 2005 Behavioral Risk Factor Surveillance System 616,067 deaths due to heart disease and 562,875 of the Centers for Disease Control and Prevention, deaths due to cancer in the USA; the death toll for 2.7% of men and 2.5% of women age 18 and stroke (cerebrovascular disease) was 135,952 greater had a history of stroke. Among these, (Centers for Disease Control and Prevention, 2.3% were non-Hispanic white, 4.0% were non- CDC/National Center for Health Statistics). Hispanic black, 1.6% Asian/Paci ﬁ c Islanders, Stroke is the primary cause of adult disability in 2.6% were Hispanic of any race, 6.0% were the USA according to the Centers for Disease Native American Indian/Alaska Native, and 4.6% Control and Prevention, and stroke survivors rep- were admixed [4 ] . resent the largest diagnostic category of referrals to rehabilitation hospitals [ 1 ] . As a consequence of the accelerated aging of the US population, Incidence stroke will remain a public health problem with adverse personal, societal, and economic impli- On average, every 40 seconds, someone in the cations. According to Caplan [ 2 ] , rehabilitation USA has a stroke. In the USA alone, more than 20 Assessment in Acute Stroke Rehabilitation 297

700,000 people suffer a stroke each year, and cells and pose other threats to survival like about 2/3 of these individuals survive and require increased pressure on the brain or spasms in the rehabilitation [5 ] . The most recent data from the blood vessels; both of these conditions can be Heart Disease and Stroke Statistics 2010 Update, very dangerous for the patient. However, stud- a report from the American Heart Association ies suggest that those patients with hemorrhagic [6 ] , indicated that each year, about 795,000 peo- stroke have a greater chance for recovering ple experience a new or recurrent stroke. About function than those patients with ischemic 610,000 of these are fi rst attacks, and 185,000 are stroke [10 ] . recurrent attacks. The age-adjusted incidence of It is estimated that between 50% and 70% of fi rst ischemic stroke per 100,000 was 88 in patients recover functional independence after a whites, 191 in blacks, and 149 in Hispanics, stroke. However, between 15% and 30% of according to the data from the Northern Manhattan patients who survive either an ischemic or hem- Study [7 ] . The stroke incidence rate is higher for orrhagic stroke remain with some permanent men compared with women at younger ages but disability [10 ] . The National Institutes of Health not at older ages. The male-to-female incidence (NIH) devised a scoring system that helps predict ratio was 1.25 in those 55Ð64 years of age, 1.50 stroke severity and outcome by scoring the in those 65Ð74 years of age, 1.07 in those following 11 factors: levels of consciousness, 75Ð84 years of age, and 0.76 in those 85 years of gaze, visual fi elds, facial movement, motor func- age or greater [6 ] . tions in the upper and lower extremities, coordi- On average, every four minutes, someone nation, sensory loss, problems with language, dies of a stroke. Mortality data from 2006 indi- inability to articulate, and attention. In addition cated that stroke accounted for approximately 1 to use of the NIH Stroke Scale (NIHSS), described of every 18 deaths in the USA. In the decade above, measurement of brain injury using mag- from 1996 to 2006, the stroke death rate fell netic resonance imaging (MRI) and time (in 33.5%, and the actual number of stroke deaths hours) since onset of stroke symptoms to the time declined to 18.4%. More women than men die of the MRI brain scan are two additional factors of stroke each year due to the larger number of used to predict stroke severity and outcome [ 10 ] . elderly women. Women accounted for 60.6% of Up to 70% of patients with ischemic strokes who stroke deaths in the USA in 2006. The 2006 score less than 10 on the NIHSS have favorable overall death rate for stroke was 43.6 per outcome after 1 year. Only between 4% and 16% 100,000. Death rates were 41.7 for white males, of patients have favorable outcome if their NIHSS 67.1 for black males, 41.1 for white females, score is more than 20 [10 ] . and 57.0 for black females [ 8 ] . One question neuropsychologists frequently get from stroke patients and their families is, “What are my chances of having another stroke?” Prognosis The literature points out that the risk for recurrent stroke is highest within the fi rst few weeks and In 2009, there were 135,952 Americans who months. Risk for recurrent stroke is approxi- died as a result of stroke. However, mortality mately 14% in the fi rst year and about 5% there- rates are declining. During the fi rst year, over after. Speci fi c risk factors for early recurrence 75% of patients survive a fi rst stroke and over include the following: older age, evidence of half survive beyond 5 years [9 ] . Those patients blocked arteries (i.e., history of coronary artery who suffer ischemic strokes have a much better disease, peripheral artery disease, ischemic chance of survival than those with hemorrhagic stroke, or transient ischemic attack), hemorrhagic strokes. Among the ischemic stroke categories, or embolic stroke, diabetes, alcoholism, valvular embolic strokes pose the greatest threat to sur- heart disease, and atrial fi brillation [ 10 ] . When vival, followed by thrombotic and lacunar patients and their families are being educated strokes. Hemorrhagic strokes destroy brain about stroke recurrence, neuropsychologists can 298 G.M. Cuesta emphasize that preventive measures be instituted Risk Factors as soon as possible. These measures include encouraging patient compliance with medication Some risk factors for stroke are modifi able (e.g., for hypertension, hypercholesterolemia, diabetes, hypertension, diabetes mellitus, atrial fi brillation, and heart disease. Preventive measures also alcohol use, smoking) and are subject to external include encouraging the patient to make and control by changes in lifestyle. Manipulation of maintain lifestyle choices like quitting smoking, modi fi able risk factors may have dramatic effects reducing alcohol consumption, eating a more on the incidence, prevalence, economic effects, healthy diet, and getting more aerobic exercise. and personal costs of stroke. Devasenapathy and However, these behaviors are more challenging Hachinski [12 ] asserted that up to 75% of all to change and some may be physically impossi- strokes are preventable. Other researchers have ble (e.g., exercise) for some patients to change asserted that nearly 379,000 strokes could be pre- after a devastating stroke. vented each year through treatment of atrial fi brillation, cigarette smoking, hypertension, heavy alcohol consumption, and physical inactivity [13 ] . De fi nition of Stroke However, some of the risk factors for stroke are not modifi able. These include prior stroke, A stroke occurs when brain cells die as a conse- age, gender, race, ethnicity, and heredity. Stroke quence of inadequate blood perfusion. When risk increases with age. For example, the lifetime blood fl ow is interrupted, brain cells are robbed risk for stroke in adults over the age of 55 is of vital supplies of oxygen and nutrients. greater than 1 in 6 and doubles with each succes- Approximately 80% of strokes are caused by sive decade after age 55 [14 ] . blockage of an artery in the neck or brain. These are referred to as ischemic strokes. In ischemic strokes, blood fl ow is insuffi cient to maintain Clinical Signs and Symptoms of Stroke neurologic function, and infarction occurs when ischemia reaches a threshold to produce cell In general, onset of stroke symptoms is acute. death. The remaining 20% of strokes are caused According to the National Institute of Neurological by a blood vessel that bursts in the brain and Disorders and Stroke (NINDS), common pre- causes bleeding into or around the brain. These senting neurological symptoms include [15 ] : are called hemorrhagic strokes. A transient 1. Sudden numbness or weakness of the face, ischemic attack is an acute transient neurologi- arm, or leg on one side of the body, cal defi cit that typically lasts less than 1 hour 2. Sudden confusion, trouble speaking, or and is without persistent neurological abnor- understanding, mality or evidence of acute infarction on neu- 3. Sudden trouble seeing in one or both eyes, roimaging [11 ] . A silent stroke is a brain injury 4. Sudden trouble walking, dizziness, and loss of of vascular origin that is appreciated on neu- balance or coordination, and roimaging but is not associated with symptoms. 5. Sudden severe headache with no known cause. Silent strokes are frequently found during diagnostic neuroimaging of an acute stroke in patients with no known history of a prior Pathophysiology stroke. A lacunar infarct is a small cavity caused by a small deep cerebral infarct and is There are many different types of strokes, each most often associated with arterial hyperten- having a different cause. The two main types of sion. These appear predominantly in the basal stroke are ischemic stroke and hemorrhagic ganglia, thalamus, and white matter of the inter- stroke. The following is a basic description of nal capsule and the pons [ 11 ] . these stroke types and the four most common 20 Assessment in Acute Stroke Rehabilitation 299 causes of stroke (two of which are ischemic and vessel downstream. This type of stroke mecha- two of which are hemorrhagic). For a more nism causes rapid focal onset symptoms with detailed description of the pathophysiology of little opportunity for compensation by collateral stroke, the interested reader is referred to Barnett blood supply routes [2, 16 ] . et al. [16 ] . Hemorrhagic strokes are caused by a blood The pathophysiology of ischemic strokes is vessel that bursts either within the brain or just widely known. They are the most common type outside it. These strokes frequently result in dra- of stroke, contributing to more than 80% of all matic onset of symptoms. Hemorrhagic strokes stroke cases. They are caused by plaque buildup are typically classifi ed according to the anatomi- and blood clots that subsequently deprive parts of cal location of the bleeding. The main causes of the brain from adequate perfusion or blood fl ow, hemorrhagic strokes are systolic blood pressure, oxygen, and nutrients; this results in damage and age, and anticoagulation. High blood pressure is death of brain cells, tissue, and stroke. There are the main cause of both hemorrhagic and isch- many factors that affect the buildup of a blood emic strokes. Less common causes include cra- clot that results in stroke. The most common nial trauma, tumors, hypertensive hemorrhages, cause of ischemia and the infarction that follows and vasculitides, all of which lead to accumula- it is atherosclerosis, a nonin fl ammatory progres- tion of blood around the brain causing hemor- sive disease that begins in childhood, peaks rhagic stroke. between the ages of 50 and 70, and can affect any The third most common cause of stroke after artery in the body. Fatty deposits accumulate on thrombotic and embolic strokes is the primary the arterial wall. These deposits produce a throm- intracerebral hemorrhage. This hemorrhagic bus that over time gradually narrows the arterial stroke results from degeneration and rupture of a passage until the blood vessel becomes suf fi ciently penetrating cerebral artery, often due to hyperten- occluded to produce a stroke. Permanent damage sion. The blood rarely reaches the surface of the generally ensues with complete deprivation of cortex but enters the cerebrospinal fl uid in about blood fl ow beyond several minutes [ 2 ] . The like- 90% of the cases. Signifi cant compression of the lihood of a stroke is largely affected by several brain stem structures can be fatal [2, 16 ] . factors including age, family history, systolic The fourth most common cause of stroke is blood pressure, smoking, alcohol use/abuse, the subarachnoid hemorrhage (SAH). This hem- diet, myocardial disease, diabetes, and atrial orrhagic stroke results from rupture of a saccular fi brillation. Of these, age and systolic blood aneurysm. An aneurysm is a ballooning of an pressure are the most infl uential factors in isch- arterial wall due to congenital weakness in its emic strokes. structure. The ballooning further weakens the Another type of ischemic event is the lacunar blood vessel’s arterial wall, making it prone to stroke that occurs when small penetrating rupture and hemorrhage. In this type of hemor- branches of the major cerebral arteries become rhagic stroke, blood leaks into the subarachnoid clogged and result in a thrombotic infarction. space between the external surface of the brain These types of strokes frequently affect the basal and the arachnoid meningeal layer. This type of ganglia, internal capsule, thalamus, and the pons. stroke announces itself in an acute or gradual Location-speci fi c syndromes can result from manner depending on the size of the affected lacunar infarcts. These include pure motor or blood vessel and the rupture itself. When onset is sensory stroke, dysarthric stroke, and hemipare- rapid, the consequences are often severe and life- sis with ataxia [2 ] . threatening. The patient complains of a sudden The embolic stroke is produced by an abrupt and severe headache, and intracranial pressure interruption of blood supply by pieces of throm- dramatically elevates as a consequence of the bus that have broken loose from one part of the injection of blood into the brain from the ruptured blood vessel system and later lodged in a narrower vessel [2, 16 ] . 300 G.M. Cuesta

Table 20.1 Most common symptoms and signs of stroke and their reliability [17 ] Symptom or sign Prevalence (%) [18 ] Agreement among examiners (Kappa*) [19 ] Symptoms Acute onset 96 Good (0.63) [19 ] Subjective arm weaknessb 63 Moderate (0.59) [19 ] Subjective leg weaknessb 54 Moderate (0.59) [19 ] Self-reported speech disturbance 53 Good (0.64) [19 ] Subjective facial weakness 23 Ð Arm paresthesiac 20 Good (0.62) [19 ] Leg paresthesiac 17 Good (0.62) [19 ] Headache 14 Good (0.65) [19 ] Nonorthostatic dizziness 13 Ð Signs Arm paresis 69 Moderate to excellent (0.42Ð1.00) [19, 20 ] Leg paresis 61 Fair to excellent (0.40Ð0.84) [19, 20 ] Dysphasia or dysarthria 57 Moderate to excellent (0.54Ð0.84) [19, 20 ] Fair to excellent (0.29Ð1.00) [19, 20 ] Hemiparetic or ataxic gait 53 Excellent (0.91) [20 ] Facial paresis 45 Poor to excellent (0.13Ð1.00) [19, 20 ] Eye movement abnormality 27 Fair to excellent (0.33Ð1.00) [20 ] Visual ﬁ eld defect 24 Poor to excellent (0.16Ð0.81) [19, 20 ] a Kappa statistic: 0Ð0.20 = poor agreement; 0.21Ð0.40 = fair agreement; 0.41Ð0.60 = moderate agreement; 0.61Ð0.80 = good agreement; 0.81Ð1.00 = excellent agreement b Noted as “loss of power” [17 ] c Noted as “loss of sensation” [17 ] Information from references [18Ð 20 ]

Diagnosis of Stroke Physicians must quickly assess persons with suspected acute ischemic stroke because acute In general, diagnosis of stroke is beyond a neu- stroke therapies (i.e., thrombolysis) have a nar- ropsychologist’s scope of practice; nevertheless, row time window of effectiveness. One instru- knowing the decision-making process whereby ment that can assist the physician with rapid physicians make a stroke diagnosis can richly diagnosis of stroke is The National Institute of inform neuropsychological practice. According Health Stroke Scale (NIHSS) [ 22, 23 ] . The to Yew and Cheng [17 ] , the history and physical NIHSS is available at http://www.ninds.nih.gov/ examination remain the pillars of diagnosing doctors/NIH_Stroke_Scale.pdf. This scale was stroke. The most common historical feature of an designed to be completed within 5Ð8 min. ischemic stroke is acute onset; the most common The physician must determine the exact time physical fi ndings of ischemic stroke are focal of symptom onset since it is critical for determin- weakness and speech disturbance [ 18 ] . The most ing eligibility for thrombolysis. However, one common and reliable signs and symptoms of community-based study found that clinicians ischemic stroke are listed in Table 20.1 [17Ð 20 ] . agreed, to the minute, less than 50% of the time In a community-based study of diagnostic accu- [19 ] . Corroboration time of symptom onset with racy, primary care physicians practicing in an a known event or from a witness to the symptoms emergency setting had 92% sensitivity for diag- may help to improve this estimate. nosis of transient ischemic attack (TIA) and Neuroimaging must be completed in order to stroke [21 ] . reliably distinguish between ischemic stroke and 20 Assessment in Acute Stroke Rehabilitation 301 intracerebral hemorrhage. Both are characterized Multimodal magnetic resonance imaging (MRI) by acute onset of focal symptoms. However, sequences, especially diffusion-weighted imag- patients with intracerebral hemorrhage typically ing, have better resolution than CT and, there- have gradual worsening of symptoms after the fore, have better sensitivity for detecting acute abrupt onset. These worsening symptoms refl ect ischemic stroke. Figure 20.2 is a dramatic illus- the increasing size of the hematoma. Intracerebral tration of this point. hemorrhagic patients may also have decreased Patients with subarachnoid hemorrhage pres- level of consciousness. ent differently from intracerebral and ischemic The primary purpose of neuroimaging in a stroke patients. The most common symptom patient with suspected ischemic stroke is to rule described by the patient is having “the worst out the presence of other types of central ner- headache of my life.” According to Suarez et al. vous system lesions and to distinguish between [25 ] , other symptoms may include vomiting, sei- ischemic and hemorrhagic stroke. Figure 20.1 zures, meningismus, and decreased level of con- provides examples of intracerebral and suba- sciousness. These patients may not exhibit focal rachnoid hemorrhages on computed tomography signs given that bleeding occurs outside the brain. (CT) scans. CT scans are considered to be An exception to this is when an aneurysm bursts suf fi ciently sensitive at detecting mass lesions and bleeds into a focal location (e.g., a posterior (e.g., brain masses or abscesses) as well as detec- communicating artery aneurysm that compresses tion of acute hemorrhages. They may not, however, the third cranial nerve). be sensitive enough to detect ischemic stroke, Current guidelines for classifi cation of early especially when the stroke is small, acute, or in stroke severity recommend the use of the NIHSS the posterior fossa (e.g., brain stem and cerebel- [22 ] ; however, no trial data currently exists that lum areas) [ 17, 24] . The purpose of CT scan is to demonstrates that its use improves outcomes. It is rule out stroke mimics and to detect hemorrhage, one of the most common classifi cation tools however, not to rule in a diagnosis of ischemic available and provides a structured neurological stroke. A normal CT scan of the brain does not examination that has both diagnostic and prog- rule out the diagnosis of ischemic stroke. nostic values [ 22 ] . Yew and Cheng [17 ] suggested

Fig. 20.1 Head computed tomography (CT) scans showing (a ) intracerebral hemorrhages (arrows ) and ( b ) subarachnoid hemorrhages (arrows ). Note that acute hemorrhage appears hyperdense (white ) on a CT scan 302 G.M. Cuesta

Fig. 20.2 ( a ) Noncontrast computed tomography (CT) obtained shortly after the CT reveals a new extensive scan showing two hypodense regions indicating old infarction ( arrow) in the right-middle cerebral artery dis- infarctions in the distribution of the left-middle cerebral tribution not evident on the CT. Reprinted with permis- (long arrow ) and posterior cerebral arteries (short arrow ). sion from MedPix¨. Retrieved from http://rad.usuhs.edu/ (b ) Diffusion-weighted magnetic resonance imaging scan medpix

that, in general, combinations of signs and symp- T2-weighted and proton density-weighted images toms are more useful than any single fi nding. starting about 8 hours after onset, and it should These authors presented a helpful algorithm follow vascular distribution. Mass effect is usually derived from several consensus sources for the maximal at about 24 hours and starts about diagnosis of stroke (see Fig. 20.3 ). 2 hours after onset even in the absence of paren- The Internet Stroke Center [27 ] has an excel- chymal signal changes. In subacute stroke , lent summary of the computed tomography (CT) defi ned as 1 week or older, there is low signal on and magnetic resonance imaging (MRI) criteria T1-weighted and high signal on T2-weighted for infarction and hemorrhage; the interested images, and it should follow the vascular distri- reader is referred to that source for more detailed bution. Revascularization and bloodÐbrain barrier information. breakdown may cause parenchymal enhancement Brie fl y, in CT imaging of infarction , the with contrast agents. In old stroke, de fi ned as neuroradiologist will fi nd a focal hypodense area several weeks to years, there is low signal on T1 in cortical, subcortical, or deep gray or white and high signal on T2. Mass effect disappears matter, following the vascular territory or water- usually after one month. There is loss of tissue shed distribution. CT imaging of hemorrhage with large infarcts, and parenchymal enhance- will demonstrate a hyperdense image in white or ment fades after several months [27 ] . deep gray matter, with or without involvement of the cortical surface. Hematoma refers to a solid, homogeneously hyperdense image [27 ] . Poststroke Cognitive Impairment In MRI imaging of an acute stroke, the clinician will fi nd subtle low signal (or hypointense) Of primary concern to stroke neuropsychologists, on T1 imaging. According to the guidelines, this stroke rehabilitation psychologists, and other is often diffi cult to see at this stage. There is stroke rehabilitation specialists is the evaluation high signal (or hyperintense) on spin density or of cognitive impairment resulting from stroke. 20 Assessment in Acute Stroke Rehabilitation 303

Fig. 20.3 Algorithm for the History of recent abrupt onset of persistent focal diagnosis of acute stroke. neurologic deficit and no recent head trauma Information from references [19, 22, 26 ] Glucose fingerstick, screening tests, and electrocardiography

Blood glucose ≥ 63 mg per L (3.50 mmol per L)?

No Yes

Treat and reevaluate Consider other stroke mimics

Is clinical impression that of a stroke? (Consider use of a stroke scale.)

No Yes

Evaluate for other Head computed tomography or causes of symptoms magnetic resonance imaging

Mass, intracerebral hemorrhage and subarachnoid hemorrhage excluded?

No Yes

Treat as indicated Diagnosis of probable ischemic stroke

Up to 64% of persons who have a stroke will have epidemiology, neuropsychology, brain imaging, some degree of cognitive impairment [ 28 ] with neuropathology, experimental models, biomark- up to a third developing frank dementia [29Ð 31 ] . ers, genetics, and clinical trials to recommend Cognitive impairment that is caused by or associ- minimum, common, clinical, and research stan- ated with vascular factors has been called vascu- dards for the description and study of vascular lar cognitive impairment or VCI [32Ð 34 ] . cognitive impairment [ 35 ] . The Neuropsychology Prior to 2006, there were no commonly agreed Working Group of this convention was charged upon standards for identifying and describing with recommending test protocols that could be stroke patients with cognitive impairments, used in multicenter investigations of potential particularly in the early stages, and especially with patients with vascular cognitive impairment cognitive impairment related to vascular factors, (VCI). Three different protocols were developed or vascular cognitive impairment. In 2006, the by the Neuropsychology Working Group to serve National Institute for Neurological Disorders and three different purposes. One protocol required Stroke (NINDS) and the Canadian Stroke Network about 60-minutes of administration time, the (CSN) convened researchers in clinical diagnosis, second required about 30-minutes, and the third 304 G.M. Cuesta required only 5-minutes of administration time. Table 20.2 Differential diagnosis of stroke The 60-minutes protocol was developed for use Ischemic stroke in research studies. The 30- and 5-minutes proto- Hemorrhagic stroke cols were developed with clinical purposes in Craniocerebral/cervical trauma mind and will be further explained in the next Meningitis/encephalitis section on Neuropsychological Assessment Tech- Intracranial mass niques. The interested reader is referred to the Tumor Hachinski et al. [ 35 ] journal article for more Subdural hematoma detailed information. Seizure with persistent neurological signs Migraine with persistent neurological signs Metabolic Hyperglycemia (nonketotic hyperosmolar coma) Neuropsychological Assessment Hypoglycemia Techniques and Issues Post-cardiac arrest ischemia Drug/narcotic overdose Diagnosis of acute ischemic stroke is often Source: American Heart Association. Basic Life Support straightforward. The sudden onset of a focal for Healthcare Providers and Advanced Cardiac Life Support neurologic defi cit in a recognizable vascular From: Acute Ischemic Stroke: New Concepts of Care distribution with a common presentation, i.e., © 1998Ð1999 Genentech, Inc. All rights reserved hemiparesis, facial weakness, and aphasia, identifi es a common syndrome of acute stroke. However, there are differential diagnostic prob- therapists, physical therapists, speech and lan- lems because there are several subtypes of guage pathologists, recreational therapists, and a stroke, and some nonvascular disorders may neuropsychologist. have clinical pictures that appear identical to From the day of admission, frequent anxiety- strokes. Table 20.2 provides a listing of com- provoking concerns for family members/care- mon conditions that should be considered in the givers, rehabilitation team members, and differential diagnosis of stroke as delineated by clinicians are discharge planning and where the the Internet Stroke Center. patient will go after they complete the trial of In an acute rehabilitation setting, by the time acute rehabilitation. Alternatives include short- the patient arrives at the hospital, the diagnosis of term subacute rehabilitation (usually in long- stroke has usually been well established. term care facilities), home with homecare Typically, the stroke event occurred in the com- services, home with daycare services, or home munity while the patient was going about his nor- with outpatient care. Ideally, all of these alterna- mal everyday activities. The patient is taken to an tives share in common varying degrees of fre- acute care hospital where diagnosis is made by an quency and intensity of occupational therapy, emergency room physician or a stroke team, physical therapy, and speech therapy. The where available, and the patient is medically sta- answer to the discharge placement question bilized. In consultation with the stroke team, a depends on the severity of the functional limita- determination is made by family caregivers about tions (e.g., physical, cognitive, behavioral) pro- whether the patient can manage the signifi cant duced by the stroke, the amount of functional intensive intervention of an acute rehabilitation recovery the patient makes during acute reha- program. The patient is transferred to the acute bilitation, and the resources (i.e., time, fi nancial, rehabilitation hospital to begin orientation, assess- emotional) available to the family. ment, and treatment intervention from a team of Neuropsychologists working in an acute reha- multidisciplinary professionals. The team typi- bilitation setting are frequently consulted to cally includes a neurologist or physiatrist, nurses evaluate the cognitive and behavioral limitations and nursing aides, social workers, occupational of stroke patients. 20 Assessment in Acute Stroke Rehabilitation 305

Common referral questions for the neuropsy- caregivers. Additional key information to gather chologist working with stroke patients in the from collateral sources (e.g., family caregivers) acute rehabilitation setting include: includes a history of the patient’s premorbid level 1. Determining the cognitive strengths and weak- of functioning (e.g., occupation, education, social nesses of the patient, support, temperament). Initially, a short visit with 2. Determining capacity to consent to treatment, the patient might be helpful; in this visit, the neu- 3. Consultation regarding behavioral problems, ropsychologist introduces himself, explains the e.g., agitation, aggression, apathy. reason for the visit, begins to build rapport, elicits the patient’s informed consent for evaluation, and books a time to meet. The evaluation has already Cognitive Assessment begun since the visit provides the opportunity for the neuropsychologist to start gathering prelimi- Regarding determination of cognitive strengths nary information about the stroke patient’s behav- and weaknesses, family members and clinicians ior, cognition, abilities, and challenges. are frequently concerned about the patient’s abil- When selecting the instruments he will use, ity to manage activities of daily living and instru- the neuropsychologist takes care to consider the mental activities of daily living at home. The stroke patient’s obvious impairments, e.g., right neuropsychologist can provide the rehabilitation or left hemiparesis/plegia, right or left hemine- team and the patient’s caregivers with informa- glect/inattention, and receptive/expressive apha- tion from neuropsychological testing about the sia. Other patient conditions to be aware of, that cognitive abilities that have been spared and the can affect cognitive performance, are the patient’s problem areas that remain. Rarely are these cog- energy level and presence of depression. nitive diffi culties unaccompanied by behavioral For the stroke patient unencumbered by apha- issues. For example, a stroke patient may have sia with suf fi cient energy to withstand about impaired attention on neuropsychological testing 30 min of sustained cognitive activity, a standard that may be accounted for by destruction of atten- neuropsychological screening assessment can tion pathways in the brain and exacerbated by the include brief history taking and neuropsycho- presence of poststroke depression. The neuropsy- logical testing measures such as the one recom- chologist can use any and every source of infor- mended by the Neuropsychology Working Group mation available to determine impairments and in Hachinski et al. [35 ] . The 30-min protocol strengths. Properly administered, scored, and suggested by the Neuropsychology Working interpreted neuropsychological testing provides Group included the following neuropsychologi- valid and reliable quanti fi able information. In an cal test battery: semantic and phonemic fl uency acute rehabilitation setting, the neuropsycholo- [ 36] , Digit Symbol-Coding [ 37 ] , and the revised gist can observe the patient in occupational ther- Hopkins Verbal Learning Test [ 38 ] , in addition apy during a cooking task or a dressing task and to the Center for Epidemiologic Studies- make inferences about the patient’s attention and Depression Scale (CES-D) developed by the memory functioning based upon these observa- National Institute of Mental Health [ 39 ] and tions. Information from these observations can Neuropsychiatric Inventory [40 ] . The Trail augment neuropsychological testing results. Making Test A and B [ 41] and the Mini Mental When these observations are consistent with neu- State Examination (MMSE) [42 ] can supplement ropsychological testing results, they add to the the battery. ecological validity of the data. When time is short or the patient is encumbered Whenever possible, the neuropsychologist with decreased energy or short attention span, the should, fi rst, gather the facts about the stroke neuropsychologist can use the 5-min protocol rec- patient by reviewing his medical chart and obtain ommended by the Neuropsychology Working feedback about cognition and behavior from Group in Hachinski et al. [ 35] . The protocol con- the stroke rehabilitation team and from family sists of selected subtests from the Montreal 306 G.M. Cuesta

Cognitive Assessment. This test is available with depressed, frightened, or confused or might possess instructions in 34 different languages and norma- characterological features that account for their tive data at www.mocatest.org (MoCA) [ 43] . It behavior. Another variable for the neuro- includes a fi ve-word immediate and delayed psychologist to consider is the energy level of memory test, a six-item orientation task, and a the patient. Acute rehabilitation programs typi- one-letter phonemic fl uency test (the letter F). The cally require 3 hours a day of occupational ther- MoCA may be used without permission, free of apy and physical therapy. On top of this charge, for clinical or educational noncommercial requirement is about 45Ð60 minutes of speech purposes (Copyright Ziad Nasreddine, MD). therapy. Add to this intense schedule recreational Medical test results (e.g., computed tomogra- therapy programs, nursing care, meals, visits phy or magnetic resonance imaging of the brain) from the neuropsychologist, and family and are often included in the history and physical friend visits, and you have a regimen that can be report completed by the attending neurologist or very taxing for some patients who are already physical medicine and rehabilitation physician signifi cantly physically and emotionally com- upon the patient’s admission to the acute reha- promised by the stroke. bilitation hospital. These results can be easily Treatment refusal and the desire to leave the included in the neuropsychologist’s initial report hospital create stress not only for the treatment with reference to their source. Since diagnosis is team but also for the family caregivers who typi- typically already made by the attending physically want the patient to remain in the acute reha- cian, the neuropsychologist can focus on devel- bilitation hospital for treatment. In these cases, oping hypotheses about patterns of de fi cits and the attending neurologist or physiatrist will often how they may manifest. Consequently, neuropsy- request a consult from the neuropsychologist to chological assessment results can either con fi rm determine if the patient has the capacity to make or refute these hypotheses. These conclusions treatment decisions for himself or herself. and, more importantly, their functional implica- Determining capacity to make treatment deci- tions can be discussed in team meetings and sions can have the benefi cial effect of respecting recorded in the patient’s evaluation reports. the autonomy of the patient, logically seeking a Family members are a valuable source of solution, and documenting the reasonable action information about the patient’s premorbid taken in response to the problem. The details of (pre-stroke) functioning. Neuropsychologists how to conduct a formal capacity evaluation go can obtain information from reliable family beyond the scope of this chapter but in general members about the patient’s social, academic, include a careful review of the entire available and occupational functioning. This information medical record, a directed clinical interview with provides the neuropsychologist with a basis of the patient, or use of formal, structured assess- comparison for their current functioning. It is ment tools like the Aid to Capacity Evaluation suggested that the neuropsychologist integrate (ACE) [44 ] and the MacArthur Competence this information into the neuropsychological test- Assessment Tool (MacCAT) [45 ] . Grisso and ing report. A portion of the history section of the Appelbaum [45 ] developed an excellent formal report can be devoted to the patient’s premorbid structured assessment tool to evaluate capacity, functioning with appropriate references. and the reader is referred to that source for more detailed information. In cases where it is determined that the patient Capacity Assessment has the capacity to make decisions for himself and persists in their desire to leave hospital, then In acute rehabilitation settings, occasionally, the rehabilitation team will have few options but there will be patients who refuse to be treated or to concede to these wishes even though it is insist on going home, i.e., leave the hospital thought by the team that continued treatment will against medical advice. These patients might be be in the best interest of the patient. In an acute 20 Assessment in Acute Stroke Rehabilitation 307 rehabilitation setting, this usually means the gyms. A structured mental status examination patient leaves the hospital against medical advice combined with formal measures like the Beck or due to lack of motivation for treatment is dis- Depression Inventory Fast Screen for Medical charged to home or subacute treatment. In order Patients (BDI-FS) [ 46] or the Beck Anxiety to increase safety, the neuropsychologist can join Inventory (BAI) [ 47 ] can be used to assess for with the attending physician, the social worker, depression and anxiety, respectively. and nursing staff in providing the patient and the One way the neuropsychologist can effectively family caregivers with education about safety in use his time and the time of the stroke rehabilita- the home, prohibiting driving and use of other tion team is by having a once or twice weekly mechanical equipment, medication administra- behavioral management team meeting. The team tion/compliance, and prohibiting consumption of gathers at a speci fi c time and place and discusses alcohol and other illicit drugs. The stroke reha- the problem behaviors of the patient. The neuro- bilitation team will also need to coordinate the psychologist acts as the facilitator of the meeting assistance (e.g., home health care aide) and and the consultant. Each member of the stroke equipment (e.g., shower chair, wheel chair) that rehabilitation team working with the patient pro- will be needed at home. vides their feedback on the behavioral problems as experienced in their respective disciplines. It is strongly recommended that nursing has represen- Behavioral Assessment tation in these meetings. It has been the author’s experience that nursing aides provide valuable A common referral question for neuropsycholo- information about the patient’s behavior since gists working with stroke patients in an acute they work with them so intimately in otherwise rehabilitation setting is consultation regarding very private activities such as personal hygiene, behavioral problems. Poststroke depression, irri- eating, bathing, toileting, etc. Each member of tability, agitation, confusion, and aggression are the team describes what interventions they have just a few examples. Neuropsychologists are tried to alter the problem behavior. After each of called upon in these settings to provide assess- the team members have described problem behav- ment, treatment, and consultation about these iors and attempted interventions, the neuropsy- dif fi cult behaviors. One approach to assessment chologist then makes other intervention of these behaviors is multimodal. The neuropsy- suggestions based upon established guidelines. chologist can obtain information about the The author has found the practical guidelines patient’s behavior from a number of sources. from the Rehabilitation Institute of Chicago Feedback about the behaviors can be elicited Publication Series to be very helpful [48 ] . from each of the stroke rehabilitation team members working with the patient, including the occupational therapist, physical therapist, and Follow-Up/Recommendations speech therapist. Feedback from the patient’s family, nursing staff and nursing aides should not In terms of follow-up, the neuropsychologist be overlooked. Sometimes, there are inconsisten- working with stroke patients in an acute rehabili- cies in the patient’s behavior in the therapy gyms tation setting will typically know the discharge vs. on the nursing fl oor. For example, patients disposition of the patient. Discharge alternatives might angrily insist on getting help from, nursing include home with homecare services, home with staff for tasks they have demonstrated in the outpatient care or therapeutic day care, subacute occupational therapy gym they are capable of rehabilitation in a nursing home, or skilled nurs- completing independently. In addition to formal ing facility. In cases where contact with the and informal interaction directly with the patient, patient and family caregivers has been intensive, neuropsychologists can observe the patient’s it is recommended that the neuropsychologist be behavior on the nursing fl oor and in the therapy involved with discharge planning and coordinating 308 G.M. Cuesta of neuropsychological rehabilitation services. One day, while at work as a letter carrier for the For example, during the acute rehabilitation post offi ce, he fell ill and collapsed in the mail- admission, neuropsychological evaluation was room. Coworkers called 911, and he was taken to completed, a trial of cognitive remediation begun, the emergency department of the local medical and psychological readjustment counseling initi- center. The emergency physicians in consultation ated. The neuropsychologist, in cooperation with with the acute stroke team diagnosed a right the social worker, can make recommendations hemisphere ischemic stroke that left James with a and arrangements for the patient to obtain follow- left hemiparesis, left visual fi eld neglect, and dys- up neuropsychological evaluation 90 days and arthria. It was determined that onset of the symp- 12 months poststroke to monitor progress. The toms of stroke was within 3 hours, and therefore, neuropsychologist can also make recommenda- tissue plasminogen activator (tPA) was initiated tions and arrangements for continued cognitive to enhance blood fl ow. He remained in the acute remediation and counseling. In some cases, care hospital for about a week and was deter- depending on time, third party payment, and mined to be a good candidate for acute rehabilita- logistical constraints, the neuropsychologist may tion. Some factors that determined his candidacy be able to provide these services on an outpa- were relative youth, absence of aphasia, hemody- tient basis. namic stability, good social support from his wife Treatment and intervention recommendations and family, and his own positive motivation to get in-clude the following: follow-up (at 90 days and better. Factors that were potential obstacles to 12 months) neuropsychological evaluation to progress were suspected onset of poststroke monitor progress made in cognitive and psycho- depression and lack of education about stroke logical functioning, readjustment counseling to and its consequences. He was medically stabilized continue to assist the patient with the psychologi- and transferred to the acute rehabilitation center. cal consequences of stroke, referral to a psychia- James and his wife received orientation to the trist for prescription and management of stroke rehabilitation unit. The fi rst 48 hours at the psychotropic medication as indicated, and cogni- unit were dedicated to completing evaluations tive remediation to assist the patient with learning and assessments by the multidisciplinary team. strategies to compensate for impairments. Specifi c The neuropsychologist met with the patient and techniques for remediation of memory have been his wife and provided orientation to the role of suggested by Cuesta [ 49 ] . Reinforcement of edu- the neuropsychologist on the treatment team. A cation about stroke and its consequences for both time was booked for a neuropsychological screen- patient and family caregivers, recommendation ing evaluation. When James fi rst came to the and referral for respite care, and therapeutic con- of fi ce for the appointment, he began to sob uncon- sultation with the family caregivers, are also sug- trollably. So, therefore, the time was spent focus- gested. Neuropsychologists can be especially ing on treating his emotional well-being. Once he infl uential in improving the care of the patient by was able to compose himself, emotional support, attending to the emotional and education needs of encouragement, and education about stroke were the family caregivers. provided to the patient. The neuropsychologist queried James about symptoms of depression. The following symptoms of depression were Case Example acknowledged: early, middle, and late insomnia; loss of appetite with weight loss of about 10 lb James was a 42-year-old, right-hand dominant, since stroke onset; lethargy; decreased concentra- married, employed, domiciled, Caucasian man tion; anhedonia; dysphoric/depressed mood with who was status post a right hemisphere stroke. He affective lability; a sense of helplessness; and had a history of hypertension, hypercholester- decreased self-esteem and self-confi dence. The olemia, diabetes, and smoking. He also led a BDI-FS and BAI were administered, and he somewhat sedentary lifestyle prior to the stroke. endorsed depression at a moderate level of severity 20 Assessment in Acute Stroke Rehabilitation 309 and mild-moderate anxiety. The neuropsychologist the community for antidepressant medication recommended, and James agreed, to consider use management. Finally, arrangement for referral to of antidepressant medication, weekly individual a neuropsychologist in the community was made readjustment counseling, weekly stroke educa- for follow-up neuropsychological evaluation tion group, and weekly stroke support group. He 90 days poststroke. also agreed to neuropsychological evaluation of his cognitive functioning later in the fi rst week of his admission. His wife was very dedicated to Summary and Future Directions him and was able to be present for the greater part of the treatment day; this support was positively Neuropsychology work in an acute rehabilitation infl uential in James’ progress. She agreed to setting is challenging, exciting, and meaningful. attend the weekly family/caregiver stroke educa- Neuropsychologists that enjoy interacting with tion and support groups. On neuro psychological multidisciplinary teams will fi nd the work rich evaluation, James was administered the and rewarding. The work requires the clinician to 30-minutes protocol described above. Effort was go beyond the comfort zone of the classic role of adequate on testing, and he was motivated to neuropsychological evaluation and consultation. learn about his abilities and diffi culties. His intel- The successful neuropsychologist employed in ligence level was estimated to be in the average an acute rehabilitation setting with stroke patients range. Cognitive impairments (greater than will learn and implement the competencies of 2 standard deviations below the mean) were in rehabilitation psychology and health psychology. the areas of attention, speed of processing, and Some, but by no means exhaustive, directions visual hemi-inattention to the left side of space. for future research include more precise deter- Relative weaknesses (1Ð2 standard deviations mination of the predictive validity of neuropsy- below the mean) were in the areas of delayed chological measures. Increased precision in recall of verbal and visual information. Cognitive predictive validity of these tests can assist in remediation protocol was initiated. He responded establishing early prognosis and guiding treat- well to some of the strategies he learned to comment decisions [ 2 ] . Caplan [2 ] suggested that a pensate for problems with attention and memory. post-discharge placement algorithm developed For example, he used external memory aids as by Ween et al. [50 ] can be strengthened with the described by Cuesta [ 49 ] . He was observed to addition of neuropsychological data. reliably refer to his daily journal and written Improving the ecological validity of neuro- schedule to help him recall important events and psychological testing is another important area appointments. His depression was monitored, of future research. Neuropsychological tests and behavior was discussed in the weekly behav- with good ecological validity can aid in making ioral management team meeting. During the last reasonable and practical post-discharge recom- week of his 4-week stay, the 30-minutes protocol mendations related to functional activities such was readministered to determine progress made as driving, handling personal fi nances, and since admission. A family meeting was convened returning to school and work. Research collabo- with his wife, two young adult children, and his ration with other disciplines like occupational parents to provide them with feedback about therapy can be especially helpful in this functional progress made in rehabilitation and to endeavor. discuss discharge planning issues. Also, during A third important topic for future research is the last week of his admission, the neuropsychol- in the area of treatment effi cacy for the emotional ogist made arrangements, in cooperation with the and behavioral problems associated with stroke, stroke rehabilitation team’s social worker, for i.e., poststroke depression, anxiety, and other James to obtain individual psychotherapy for behavioral disturbances that adversely impact on depression from a psychologist in his commu- the rehabilitation potential of the patient. nity. Also, a referral was made to a psychiatrist in Behavioral/psychological treatment can be for 310 G.M. Cuesta individuals or groups and can take the form of ¥ Neuropsychologists in an acute stroke reha- psycho-education, skill building classes, and bilitation setting should take lead the behav- cognitive behavioral interventions. ioral management aspect of the acute stroke Neuropsychologists are an important part of rehabilitation program. One way to do this is the multidisciplinary treatment teams working in to have frequent, short (e.g., 30 minute) behav- acute rehabilitation settings with stroke patients. ioral management meetings with the multidis- Awareness and recognition of the importance of ciplinary team. the role of the neuropsychologist is increasing as ¥ Nursing aides can provide extremely valuable evidenced by the work of a task force of the behavioral observations about patients. They American Stroke Association [ 51 ] . Their report, work closely and intimately with the patients “Recommendations for the Establishment of when they are on the nursing unit, and they Stroke Systems of Care,” explicitly recognized can provide unique insights and observations. the place of neuropsychologists on the stroke These patient behaviors might not be demon- rehabilitation team. Neuropsychologists must strated in the physical therapy gym or occupa- cultivate evidence that demonstrates that their tional therapy gym. competencies, skills, knowledge, and abilities are ¥ When maladaptive behaviors are identifi ed essential to acute rehabilitation multidisciplinary and it is determined that the patient can reason teams working with stroke patients. and make judgments, it might be effective for What follows are some suggestions for neu- the patient to meet with the team so that ropsychologists working with acute rehabilita- maladaptive behavior can be communicated tion teams. These suggestions were lessons in a non-critical manner. Frequent visits to the learned and developed from the author’s own patient can build rapport and a foundation for experiences working in an acute rehabilitation future intervention and can ease the transition setting over the last 13 years. into rehabilitation. ¥ The neuropsychologist’s interactions with the patient’s family are a golden opportunity to Clinical Pearls obtain collateral information about the patient’s cognitive and behavioral function- ¥ Neuropsychologists should not see them- ing. Contact with the family is also an oppor- selves as having exclusive dominion over the tunity to alleviate some of their anxieties about assessment and treatment of the patient’s the patient’s behaviors and functioning and cognitive and behavioral problems. The other provide education about stroke and recovery. members of the team can provide valuable information about the patient’s functioning in these domains. References ¥ In addition to assessment of cognitive and emotional functioning, the neuropsychologist 1. Centers for Disease Control. Hospitalizations for on a stroke team can contribute to judgments stroke among adults aged over 65 years—United States, 2000. J Am Med Assoc. 2003;290:1023Ð4. about the patient’s suitability for rehabilitation, 2. Caplan B. Rehabilitation psychology and neuropsy- capacity to make decisions, psychological and chology with stroke survivors. In: Frank RG, Rosenthal social factors that affect recovery, advising M, Caplan B, editors. Handbook of rehabilitation psy- other members of the treatment team about chology. 2nd ed. Washington, DC: American Psychological Association; 2010. p. 63Ð94. neurobehavioral matters, educating patients 3. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, and their families about stroke and its conse- Dai S, De Simone G, Ferguson TB, Ford E, Furie K, quences, and making post-discharge referrals Gillespie C, Go A, Greenlund K, Haase N, Hailpern and recommendations for post-discharge S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, living [ 2 ] . Mozaffarian D, Mussolino M, Nichol G, Roger V, 20 Assessment in Acute Stroke Rehabilitation 311

Rosamond W, Sacco R, Sorlie P, Stafford R, Thom T, and validation of a stroke recognition instrument. Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J and Lancet Neurol. 2005;4(11):727Ð34. on behalf of the American Heart Association Statistics 19. Hand PJ, Haisma JA, Kwan J, et al. Interobserver Committee and Stroke Statistics Subcommittee agreement for the bedside clinical assessment of (2009). Heart disease and stroke statistics 2010 suspected stroke. Stroke. 2006;37(3):776Ð80. update. A report from the American Heart Association. 20. Goldstein LB, Simel DL. Is this patient having a Circulation. J Am Heart Assoc. doi: 10.1161/ stroke? J Am Med Assoc. 2005;293(19):2391Ð402. CIRCULATIONAHA.109.192667 . 21. Morgenstern LB, Lisabeth LD, Mecozzi AC, et al. A 4. Centers for Disease Control and Prevention (CDC). population-based study of acute stroke and TIA diag- Prevalence of stroke: United States, 2005. MMWR nosis. Neurology. 2004;62(6):895Ð900. Morb Mortal Wkly Rep. 2007;56:469Ð74. 22. Adams Jr HP, del Zoppo G, Alberts MJ, et al. 5 . http://ninds.nih.gov/disorders/stroke/poststrokere- Guidelines for the early management of adults with hab.htm. ischemic stroke: a guideline from the American Heart 6. National Heart, Lung, and Blood Institute. Incidence Association/American Stroke Association Stroke and Prevalence: 2006 Chart Book on Cardiovascular Council, Clinical Cardiology Council, Cardiovascular and Lung Diseases. Bethesda, MD: National Heart, Radiology and Intervention Council, and the Lung, and Blood Institute; 2006. Atherosclerotic Peripheral Vascular Disease and 7. White H, Boden-Albala B, Wang C, Elkind MS, Rundek Quality of Care Outcomes in Research Interdisciplinary T, Wright CB, Sacco RL. Ischemic stroke subtype inci- Working Groups: the American Academy of dence among whites, blacks, and Hispanics; the Northern Neurology affi rms the value of this guideline as an Manhattan Study. Circulation. 2005;111:1327Ð31. educational tool for neurologists [published correc- 8. National Center for Health Statistics. Health Data tions appear in Stroke. 2007;38(6):e38 and Stroke. Interactive File, 1981Ð2006. Hyattsville, MD: 2007;38(9):e96]. Stroke. 2007;38(5):1655Ð711. National Center for Health Statistics; 2006. 23. National Institute of Neurological Disorders and 9 . www.health central.com/heart-disease/stroke-000045_ Stroke. NIH Stroke Scale. 2003. http://www.ninds. 4-145.html. Accessed 16 Dec 2010. nih.gov/doctors/NIH_Stroke_Scale.pdf . Accessed 12 10. Baird AE, Dambrosia J, Janket S, Eichbaum Q, Dec 2010. Chaves C, Silver B, Barber PA, Parsons M, Darby D, 24. Mullins ME, Schaefer PW, Sorensen AG, et al. CT Davis S, Caplan LR, Edelman RR, Warach S. A three- and conventional and diffusion-weighted MR imag- item scale for the early prediction of stroke recovery. ing in acute stroke: study in 691 patients at presenta- Lancet. 2001;357(9274):2095Ð9. tion to the emergency department. Radiology. 11. Festa JR, Lazar RM, Marshall RS. Ischemic stroke 2002;224(2):353Ð60. and aphasic disorders. In: Morgan JE, Ricker JH, edi- 25. Suarez JL, Tarr RW, Selman WR. Aneurysmal suba- tors. Textbook of clinical neuropsychology. New rachnoid hemorrhage. N Engl J Med. 2006;354(4): York: Taylor & Francis; 2008. p. 363Ð83. 387Ð96. 12. Devasenapathy A, Hachinski V. Cerebrovascular dis- 26. Adams Jr HP, Bendixen BH, Kappelle LJ, et al. ease. In: Rizzo M, Eslinger PJ, editors. Principles and Classifi cation of subtype of acute ischemic stroke. practice of behavioral neurology and neuropsychol- De fi nitions for use in a multicenter clinical trial. ogy. Philadelphia: W.B. Saunders Company; 2004. TOAST. Trial of Org 10172 in Acute Stroke Treatment. p. 597Ð613. Stroke. 1993;24(1):35Ð41. 13. Gorelick PB. Stroke prevention: an opportunity for 27. Practice guidelines for the use of imaging in tran- ef fi cient utilization of health care resources during the sient ischemic attacks and acute stroke. A report of coming decade. Stroke. 1994;25:220Ð4. the Stroke Council, American Heart Association 14. Goldstein LB, Adams R, Becker K, Furberg CD, (1997). Gorelick PB, Hademenos G, et al. Primary preven- 28. Jin YP, DiLegge S, Ostbye T, Feightner JW, Hachinski tion of ischemic stroke: a statement for healthcare V. The reciprocal risks of stroke and cognitive impair- professionals from the Stroke Council of the American ment in an elderly population. Alzheimer’s Dement. Heart Association. Stroke. 2001;32(1):280Ð99. 2006 l;2(3):171Ð8. 15. “Know Stroke. Know the Signs. Act in Time”, 29. Barba R, Martinez-Espinosa S, Rodriguez-Garcia E, National Institute of Neurological Disorders and Pondal M, Vivancos J, Del Ser T. Post stroke demen- Stroke (NINDS). January 2008. NIH Publication No. tia: clinical features and risk factors. Stroke. 08-4872. 2000;31:1494Ð501. 16. Barnett HJM, Stein BM, Mohr JP, Yatsu FM, editors. 30. Pohjasvaara T, Erkinjuntti T, Vataja R, Kaste M. Stroke. Pathophysiology, diagnosis, and management. Dementia three months after stroke: baseline fre- 2nd ed. New York: Churchill Livingstone; 1992. quency and effect of different de fi nitions of dementia 17. Yew KS, Cheng E. Acute stroke diagnosis. Am Fam in the Helsinki Stroke Aging Memory Study (SAM) Physician. 2009;80(1):33Ð40. cohort. Stroke. 1997;28:785Ð92. 18. Nor AM, Davis J, Sen B, et al. The recognition of stroke 31. Tatemichi TK, Desmond DW, Stern Y, Sano M, in the emergency room (ROSIER) scale: development Mayeux R, Andrews H. Prevalence of dementia after 312 G.M. Cuesta

stroke depends on diagnostic criteria. Neurology. 42. Folstein MF, Folstein SE, McHugh PR, Fanjiang G. 1992;42:413. Mini-Mental State Examination: User’s guide. Odessa, 32. Hachinski VC, Bowler JV. Vascular dementia. FL: PAR; 2001. Neurology. 1993;43:2159Ð60. author reply 2160Ð2161. 43. Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau 33. Bowler JV, Hachinski VC, editors. Vascular cognitive S, Whitehead V, Collin I, Cummings JL, Chertkow H. impairment. Oxford and New York: Oxford University; The Montreal cognitive assessment, moca: a brief 2003. screening tool for mild cognitive impairment. J Am 34. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Geriatr Soc. 2005;53:695Ð9. Greiner PA, Markesbery WR. Brain infarction and the 44. Etchells E, Sharpe G, Elliott C, Singer PA. Bioethics clinical expression of Alzheimer’s disease. The Nun for clinicians: 3. Capacity. CMAJ. 1996;155:657Ð61. Study. J Am Med Assoc. 1997;277:813Ð7. 45. Grisso T, Appelbaum PS. Assessing competence to con- 35. Hachinski V, Iadecola C, Peterson RC, Breteler MM, sent to treatment: a guide for physicians and other health Nyenhuis DL, Black SE, Powers WJ, DeCarli C, professionals. New York: Oxford University; 1998. Merino JG, Kalaria RN, Vinters HV, Holtzman DM, 46. Beck AT, Steer RA, Brown GK. Beck depression Rosenberg GA, Wallin A, Dichgans M, Marler JR, inventory-fast screen for medical patients: manual. Leblanc GG. National Institute of Neurological San Antonio, TX: Psychological Corporation; 2000. Disorders and Stroke—Canadian Stroke Network 47. Beck AT, Steer RA. Beck anxiety inventory: manual. vascular cognitive impairment harmonization stan- San Antonio, TX: The Psychological Corporation dards. Stroke. 2006;37:2220Ð41. Harcourt Brace & Company; 1993. 36. Heaton RK, Miller SW, Taylor MJ, Grant I. Revised 48. Rothke SE, Berquist TF, Schmidt M, Landre NA, comprehensive norms for an expanded Halstead- Speizman R. Behavioral management strategies Reitan battery: demographically adjusted neuropsy- for working with persons with brain injury: a practi- chological norms for African American and Caucasian cal manual. Chicago: Rehabilitation Institute of adults. Lutz, FL: PAR; 2004. Chicago; 1998. 37. The Psychological Corporation. WAIS-III/WMS-III: 49. Cuesta GM. Cognitive rehabilitation of memory Updated Technical Manual. San Antonio: The following stroke. Theory, practice, and outcome. In: Psychological Corporation; 2002. Barnett HJM, Bogousslavsky J, Meldrum H, editors. 38. Brandt J, Benedict RHB. Hopkins Verbal Learning Ischemic stroke: advances in neurology, vol. 92. Test—revised. Odessa, FL: PAR; 2001. Philadelphia: Lippincott Williams & Wilkins; 2003. 39. Parikh RM, Eden DT, Price TR, Robinson RG. The sen- p. 415Ð21. sitivity and speci ﬁ city of the center for epidemiologic 50. Ween JE, Alexander MP, D’Esposito M, Roberts M. studies depression scale in screening for post-stroke Factors predictive of stroke rehabilitation outcome depression. Int J Psychiatry Med. 1988;18:169Ð81. in a rehabilitation setting. Neurology. 1996;47: 40. Cummings JL, Mega MS, Gray K, Rosemberg- 388Ð92. Thompson S, Gornbein T. The neuropsychiatric 51. Schwamm LH, Pancioli A, Acker III JE, Goldstein inventory: comprehensive assessment of psychopa- LB, Zorowitz RD, Shephard TJ, et al. Recommendations thology in dementia. Neurology. 1994;44:2308Ð14. for the establishment of stroke systems of care: 41. Army Individual Test Battery: Manual of directions Recommendations from the American Stroke and scoring. Washington, D.C.: War Department, Association’s Task Force on the Development of Adjutant General’s Of ﬁ ce; 1944. Stroke Systems. Stroke. 2005;36:690Ð703. Accurate Assessment of Behavioral Variant Frontotemporal Dementia 2 1

Amanda K. LaMarre and Joel H. Kramer

Abstract Behavioral variant Frontotemporal dementia (bvFTD) is a neurodegenerative syndrome characterized by profound changes in personality and behavior, including social disinhibition, loss of empathy, apathy and compulsive behaviors. While cognitive decline does occur (typically beginning with executive dysfunction), these issues tend to emerge mid-disease course, rather than early on. Onset is insidious, typically beginning between ages 45-65 and prevalence is equal to Alzheimer’s disease (AD) in individuals under the age of 65. Despite signiﬁ cant advancements in our understanding of bvFTD over the past 12 years, misdiagnosis remains common. For example, a signiﬁ cant subset of individuals with bvFTD initially receive a diagnosis of early-onset AD, or late life psychiatric disturbance. Given their expertise in the assessment of cognition, behavior and emotion, neuropsychologists can play an important role in the differential diagnosis and management of this disease. This chapter begins with an up-to-date discussion of the clinical, neuropathological and genetic features of the disease, and then moves into a review of the neuropsychological literature. A structured discussion of key aspects to cover in a neuropsychological assessment is provided, and a case example of a ‘typical’ bvFTD patient is presented.

Keywords Behavioral variant frontotemporal dementia • Diagnostic criteria • Neuropsychological assessment • Emotion • Social behavior • Clinical assessment

A. K. LaMarre, Ph.D. (*) • J. H. Kramer, Psy.D. Memory and Aging Center, University of California, San Francisco , Box 1207 , San Francisco , CA 94143-1207 , USA e-mail: [email protected] ; [email protected]

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 313 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_21, © Springer Science+Business Media, LLC 2013 314 A.K. LaMarre and J.H. Kramer

Behavioral variant frontotemporal dementia awareness [12– 15] . These changes are often (bvFTD) is one of three neurodegenerative dramatic, resulting in the dissolution of the indi- syndromes that are collectively referred to as vidual’s former self, such that partners and fami- frontotemporal dementia (FTD). Initially thought lies no longer recognize their loved one [ 11 ] . For to be rare, we now know that it is equally as com- example, individuals may begin to make mon as Alzheimer’s disease in individuals under impulsive decisions or actions, including such the age of 65 [ 1] and is the third most common behaviors as shoplifting, driving recklessly, or dementia after Alzheimer’s disease (AD) and physically assaulting others [ 12, 14, 16, 17 ] . dementia with Lewy bodies (DLB) [2 ] . While They might violate social norms by making estimates of the prevalence of FTD vary, popula- inappropriate sexual comments [ 18 ] or become tion-based studies in both the United States and emotionally cold and self-centered such that they United Kingdom estimate a sporadic occurrence no longer respond to others’ emotional needs or at around 3.3–3.5/100,000 in individuals between pain [19 ] . These changes often present in sharp 45 and 65 years of age [3, 4 ] . Age of onset is typi- contrast to their cognitive ability, which may cally in the presenium, though onset ranges con- remain relatively intact for some time. siderably from the 30s to 90s [1, 5, 6] . The usual duration of FTD ranges from 8 to 11 years [7 ] . Clinically, FTD is expressed as three main vari- Diagnostic Criteria for bvFTD ants [ 8 ] . BvFTD is characterized by profound and early changes in personality and behavior [ 8 ] . This Until recently, diagnosis of bvFTD has most often phenotype is most common and accounts for been made using the revised version of the Lund– approximately 70% of the clinical expression of Manchester criteria, which were reformulated by the disease [ 9 ] . As such, bvFTD will be the focus a consensus of specialists in the area of FTD in of this chapter. The other two variants are primary 1998 [8 ] . Considerable advancements in our progressive aphasic syndromes. The semantic vari- understanding of this disease over the past 12 years ant (svPPA) is associated with the loss of word has led to development of new criteria by the knowledge (e.g., semantic structure of language), International bvFTD Criteria Consortium [20 ] while the nonfl uent variant (nfPPA) is character- (Table 21.1 ). With these criteria, diagnosis of pos- ized by early disturbances in motor speech output sible bvFTD is based solely on clinical presenta- and loss of syntax (e.g., grammatical structure of tion. Patients must meet at least three of the six language) [ 8, 10 ] . These two variants account for following criteria: (1) early behavioral disinhibi- approximately 15% and 10% of the phenotypic tion, (2) early apathy/inertia, (3) early loss of expression of the disease, respectively [ 9 ] . Gender sympathy or empathy, (4) early perseverative, ste- distribution tends to vary by clinical syndrome. reotyped or compulsive behaviors, (5) hyperoral- Many studies fi nd a male bias in bvFTD and svPPA ity or dietary changes, and (6) a neuropsychological and a female bias in nfPPA [ 1, 5, 6 ] . pro fi le suggesting de fi cits on tasks of executive function with relative sparing of memory and visuospatial function. To meet criteria for proba- Earliest Signs of bvFTD ble bvFTD, a patient must meet criteria for possible bvFTD, exhibit signi fi cant functional decline, The earliest signs of disease in bvFTD are fre- and show evidence of frontal and/or temporal quently subtle personality and behavioral changes atrophy on structural MRI or CT, or hypometabo- that become increasingly pronounced as time lism on positron emission tomography (PET). goes on. These symptoms often include apathy or Sensitivity of the new criteria has recently been disinhibition, reduced emotional response, demonstrated via retrospective chart review of changes in personality or beliefs [ 11 ] , poor judg- pathologically confi rmed cases in a multisite ment, and impairment in personal and social study, and fi ndings suggest that the new criteria 21 Accurate Assessment of Behavioral Variant Frontotemporal Dementia 315

Table 21.1 International consensus criteria for bvFTD [ 20 ] I. Neurodegenerative disease The following symptom must be present for any FTD clinical syndrome: A. Shows progressive deterioration of behavior and/or cognition by observation or history (as provided by a knowledgeable informant) II. Possible bvFTD Three of the following behavioral/cognitive symptoms [A–F] must be present to meet criteria. These symptoms should occur repeatedly, not just as a single instance A. Early behavioral disinhibition a. Socially inappropriate behavior b. Loss of manners or decorum c. Impulsive, rash, or careless actions B. Early apathy or inertia a. Apathy: loss of interest, drive, or motivation b. Inertia: decreased initiation of behavior C. Early loss of sympathy or empathy a. Diminished response to other people’s needs or feelings: positive rating should be based on speci fi c examples that re fl ect a lack of understanding or indifference to other people’s feelings b. Diminished social interest, interrelatedness, or personal warmth: general decrease in social engagement D. Early perseverative, stereotyped, or compulsive/ritualistic behavior a. Simple repetitive movements b. Complex, compulsive, or ritualistic behaviors c. Stereotypy of speech E. Hyperorality and dietary changes a. Altered food preferences b. Binge eating, increased consumption of alcohol or cigarettes c. Oral exploration or consumption of inedible objects F. Neuropsychological pro fi le: executive/generation de fi cits with relative sparing of memory and visuospatial functions a. De fi cits in executive tasks b. Relative sparing of episodic memory (compared to degree of executive dysfunction) c. Relative sparing of visuospatial skills (compared to degree of executive dysfunction) III. Probable bvFTD A. Meets criteria for possible bvFTD B. Exhibits signi fi cant functional decline (by caregiver report or as evidenced by CDR or FAQ scores) C. Imaging results consistent with bvFTD a. Frontal and/or anterior temporal atrophy on CT or MRI b. Frontal hypoperfusion or hypometabolism on SPECT or PET IV. bvFTD with de fi nite FTLD pathology Criterion A and either Criterion B or C must be present to meet criteria A. Meets criteria for possible bvFTD B. Histopathological evidence of FTLD on biopsy or at postmortem C. Presence of known pathogenic mutation V. Exclusion criteria for bvFTD Criteria A and B must both be answered negatively for any bvFTD diagnosis. Criterion C can be positive for possible bvFTD but must be negative for probable bvFTD A. Pattern of de fi cits is better accounted for by other nondegenerative nervous system or medical disorders: e.g., delirium, cerebrovascular disease, cerebellar disorder, systemic disorders (e.g., hypothyroidism), or substance- induced conditions B. Behavioral disturbance is better accounted for by a psychiatric diagnosis, e.g., depression, bipolar disorder, schizophrenia, preexisting personality disorder C. Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process (e.g., genetic mutations, extensive PIB fi nding, CSF markers) 316 A.K. LaMarre and J.H. Kramer have greater sensitivity to the diagnosis of bvFTD, pathological diagnostic criteria for not only Pick’s compared to the previous criteria (0.85 vs. 0.52, disease and frontotemporal dementia and parkin- respectively) [ 20 ] . sonism linked to chromosome 17 (FTDP-17) but also for motor disorders such as progressive supranuclear palsy (PSP) and corticobasal degen- Neuroanatomy and Pathology eration (CBD) [36, 37] . Similarly, cases found to of bvFTD have FTLD-TDP may present alone or in combination with motor neuron disease (e.g., amyo- The hallmark symptoms of bvFTD strongly trophic lateral sclerosis; ALS) [38, 39 ] . There is re fl ect initial areas of neurodegeneration. A also a growing consensus that the behavioral syn- recent structural neuroimaging analysis in drome of bvFTD can be found in patients with patients in the earliest stages of bvFTD (Clinical PSP, CBD, and ALS [40– 42 ] . Dementia Rating Scale (CDR) = 0.5; mild dementia) suggests that initial degeneration occurs primarily in paralimbic structures such as the Genetics anterior cingulate cortex, frontoinsular region, dorsal anterior insula, and lateral orbitofrontal While sporadic cases are common in bvFTD, at cortex [21 ] , and disease staging of autopsy- least 30–40% of all cases appear to be genetic in confi rmed cases of bvFTD are consistent with nature [ 43 ] , with rates of autosomal dominant this fi nding [22 ] . These structures have been pattern of inheritance ranging from 10% to 30% widely implicated in human social function and [44, 45] . At this time, genetic mutations known awareness of the self [ 23 ] and are part of a neural to cause familial FTD have been found on three network thought to play a role in decoding the different chromosomes (three, nine, seventeen) emotional salience (visceral, homeostatic, hedo- [ 46 – 48 ]. By and large, the greatest proportion of nic value) of a stimulus in order to facilitate familial cases comes from individuals who have appropriate action [24 ] . As the disease progresses, mutations on two independent, but extremely close neurodegeneration occurs in widespread areas of locations on chromosome 17 [ 9, 49 ] . The fi rst the frontal and temporal lobes [25– 29 ] . was discovered in 1998 and was found to be BvFTD is caused by abnormal aggregation of caused by mutations in the microtubule-associated protein in the brain, referred to collectively as protein (“MAPT”) gene [50 ] . It is now known frontotemporal lobar degeneration (FTLD). The that MAPT codes for the protein tau, which as two most common pathologies associated with mentioned above, is a major pathological sub- bvFTD are FTLD with tau-positive inclusions type of bvFTD [51 ] . More recently, linkage (FTLD-tau) and FTLD with TDP-43 positive analysis in the same region of chromosome 17 inclusions (FTLD-TDP) [2, 30 ] , with a handful has shown that mutations in the gene coding for of additional proteins accounting for a very small the growth factor progranulin are associated proportion of bvFTD cases [ 30 ] . Under normal with bvFTD (PGRN ; [52 ] ). Unlike MAPT , these conditions, both tau and TDP-43 play important cases display TDP-43 inclusions rather than tau roles in neuronal cell structure and function [ 31, [53 ] , though the mechanistic link between pro- 32 ] . Under pathologic conditions, however, these granulin and TDP-43 has yet to be elucidated. proteins aggregate and accumulate in the cyto- Interestingly, any of the three clinical variants of plasm of neurons and glial cells and are associ- FTD may occur in familial forms of the disease; ated with neuronal death and atrophy [2, 30 ] . however, certain variants are more likely to be Advancements in our understanding of the expressed than others [9, 49, 54 ] . For example, underlying pathology of FTD over the last PGRN mutation carriers tend to develop symp- 10 years have also demonstrated links with dis- toms characteristic of bvFTD or nfPPA [ 55 ] . 1 eases not historically believed to be associated with changes in cognition and behavior [33– 35 ] . 1For a recent review on the genetics of FTD, please read For example, FTLD-tau includes cases fulfi lling See et al. [58 ] . 21 Accurate Assessment of Behavioral Variant Frontotemporal Dementia 317

Table 21.2 Disorders that may present with similar Differential Diagnosis neurobehavioral features to bvFTD Neurodegenerative Progressive supranuclear palsy Despite signi fi cant advancements in the fi eld, diseases Corticobasal syndrome diagnosis of bvFTD remains clinically challeng- Amyotrophic lateral sclerosis ing. BvFTD is commonly misdiagnosed as early Alzheimer’s disease onset AD, which is not surprising, given that AD Semantic variant primary is the most prevalent dementia syndrome. Many progressive aphasia symptoms of the two diseases overlap, including Huntington’s disease neuropsychiatric disturbance and executive dys- Lewy body dementia function [ 56, 57 ] . Patients with neurodegenera- Psychiatric disorders Bipolar disorder tive motor syndromes may also exhibit symptoms Major depression consistent with a diagnosis of bvFTD (or an FTD phenocopy aphasia variant) [ 40– 42] . As such, having a con- Psychopathy comitant syndrome such as PSP or ALS should Neurologic disorders Cerebrovascular accident Traumatic brain injury not be considered exclusionary for a diagnosis of bvFTD. Huntington’s disease may also mimic many of the behavioral and psychiatric distur- (i.e., targeting AD) can potentially exacerbate bances seen in bvFTD [59 ] . bvFTD symptoms ( Table 21.2 ). Patients with bvFTD may also be misdiag- Efforts to develop specifi c, disease-modifying nosed with a late-onset psychiatric disturbance. therapies for FTLD are advancing rapidly, Symptoms of disinhibition, euphoria, and poor focusing on the major proteins currently known judgment can mimic those of mania, while pro- to be involved in the pathogenesis of the dis- found apathy and eating disturbance might be ease. Clinical trials aimed at manipulating tau misconstrued as depression. Wooley and col- have already begun, while researchers are leagues [60 ] completed a retrospective chart actively working to develop agents that might review of 252 patients with neurodegenerative modify TDP-43 and PGRN levels. Testing the disease presenting to our clinic. Of the patients ef fi cacy of these medications greatly depends with bvFTD, 51% of patients had received a prior upon our ability to ensure homogenous samples diagnosis of a psychiatric disorder (e.g., major in clinical trials. As there are currently no depression, bipolar disorder, schizophrenia) com- defi nitive methods for determining pathology pared to 23% of patients with Alzheimer’s dis- prior to autopsy, predicting pathology antemor- ease (e.g., major depression, anxiety), suggesting tem remains a key challenge. Researchers are that the symptoms of bvFTD are particularly mis- actively working to better understand the clini- understood by mental-health-care providers. copathologic correlations relevant to each pro- A small subset of patients diagnosed with bvFTD tein currently believed to be involved in the have been characterized as “nonprogressive” or development of FTLD. “bvFTD phenocopies” due to the presence of a behavioral disturbance in the context of lack of notable atrophy on imaging or cognitive decline Review of Neuropsychological over time [61– 63 ] . As these individuals rarely Literature come to autopsy, the etiology of this subset of individuals is unclear. Careful characterization Despite obvious impairment in the patient’s and longitudinal follow-up will be important in behavior and judgment, researchers seeking to understanding how these individuals relate to the characterize a neuropsychological pro fi le speci fi c progressive form of bvFTD. The importance of to bvFTD have not been highly successful. accurate differential diagnosis cannot be over- Research is plagued with a number of signi fi cant stated. Treatments aimed at an alternate diagnosis issues that likely contribute to discrepancies in 318 A.K. LaMarre and J.H. Kramer the data, including the lack of universally applied forgetting. While some studies suggest that diagnostic criteria, variability in diagnostic ter- bvFTD patients improve considerably with cued minology, lumping together of all three clinical recall or recognition [ 72, 74, 75 ] , data from our variants of the disease, small sample sizes, and center suggest that this effect does not hold up lack of reporting of disease severity or symptom when bvFTD and AD subjects are matched for duration [ 64 ] . Issues can also arise due to test severity. Visual memory also appears to be rela- selection and interpretation issues, including the tively spared in bvFTD [ 70 – 72 ] . When both possibility that impaired performance on tests are visual and verbal memory are intact, this may help due to factors that are beyond what the test is strengthen diagnostic certainty that the patient meant to measure. For example, a study examin- does not have Alzheimer’s disease. ing qualitative features of performance on neu- These patterns of memory performance, ropsychological testing in bvFTD and AD found however, are not specifi c to bvFTD. Disorders that patients with bvFTD tend to perform poorly with frontal–subcortical involvement such as on tasks of visuoconstructive ability, not due to Parkinson’s disease and PSP may also demonstrate de fi cits in visual perceptive ability, but rather, similar patterns [76, 77 ] . LaMarre and colleagues due to perseverations and de fi cits in organiza- demonstrated that episodic memory declines lon- tional ability [ 65 ] . Moreover, behavioral mani- gitudinally at the same rate in bvFTD and AD, festations of the disease itself, including poor though mean scores at baseline were signi fi cantly motivation and distractibility, may contribute to different [ 78 ] . Nevertheless, relative preservation variability in cognitive performance scores. of episodic memory in bvFTD compared to AD Our current understanding of the neuropsy- remains one of the most reliable differences chology of bvFTD lies largely within the context between these diseases. of research seeking to improve differential diagnosis between neurodegenerative diseases. In most cases, the cognitive pro fi les of individuals Language with bvFTD and AD are compared, though efforts to delineate specifi c tasks or cognitive facets that Individuals with bvFTD do not experience the will reliably differentiate the two have been same types of changes in language that accom- unsuccessful. As such, relative test score patterns pany PPA variants of FTD; however, speech and between domains appear to be most informative language ability may refl ect notable changes. to differential diagnosis. There are often reductions in spontaneous speech; decreased verbal output (single words or decreased phrase length) can potentially prog- Memory ress to complete mutism [ 8, 79– 81 ] . Reiterative speech disorders can also occur, such as palila- Compared to patients with AD who exhibit severe lia, echolalia, verbal stereotypies, and automatic verbal and visuospatial episodic memory de fi cits speech [7, 8 ] . Despite these changes in verbal [66 – 69] , patients with bvFTD demonstrate a rel- output, examination of semantic and syntactical ative preservation in their episodic memory knowledge using measures of confrontation [ 65, 70 – 72 ] . The pattern is typically one of atten- naming, word/picture matching, and sentence uated learning with a disorganized or inef fi cient comprehension suggest that these aspects of lan- approach. For example, Glosser and colleagues guage remain relatively intact in bvFTD [ 65, 71, found that diffi culty with serial-order recall was 82, 83 ] . more common in individuals with bvFTD than in There have been few studies that have directly those with AD and svPPA [73 ] . Perhaps the most examined differential language patterns between salient difference between bvFTD and AD is that bvFTD and other diseases [80, 83, 84 ] . Rascovsky bvFTD patients tend to retain information over and colleagues [ 84 ] studied verbal fl uency in delays, while AD patients exhibit more rapid pathology-confi rmed cases of FTD and AD who 21 Accurate Assessment of Behavioral Variant Frontotemporal Dementia 319 were matched on age, education, and dementia to see executive defi cits manifest until later in the severity. When converted to z -scores based on an disease. It is now being demonstrated that some age-matched control sample, scores on semantic pathological subtypes of bvFTD do not necessar- fl uency in the AD group were signifi cantly lower ily exhibit signi fi cant DLPFC degeneration (e.g., than their scores on phonemic fl uency, while the TDP-43, Type II) [ 99 ] ; as such, one might hypoth- FTD patients performed poorly on both semantic esize that patients with this type of pathology will and phonemic fl uency. be less likely to demonstrate executive function de fi cits. Another reason why fi ndings have been Visuospatial inconsistent may be due to the fact that executive functions are a poorly de fi ned construct that Although several studies have found that patients encompass heterogeneous facets of cognition with bvFTD have visuoconstructional de fi cits on such as working memory, inhibition, and set par with AD when the fi gure is very complex shifting [69, 100, 101] . Moreover, they depend [ 70, 85, 86] , the vast majority of research heavily on lower-order aspects of cognition such indicates that visuoconstruction and visual per- as processing speed and visual perception. ceptual skills are better preserved in patients with It appears that any number of tasks may be sub- bvFTD relative to AD [ 65, 75, 79, 87 , 90 ] . sumed under this umbrella term and are often Dif fi culties can arise for bvFTD patients when discussed as if interchangeable. Within the the task relies heavily on top-down control of bvFTD neuropsychological literature, there spatial processing. For example, Possin and col- appears to have been little consideration and leagues [88 ] recently demonstrated that fi gure consistency regarding which component of exec- copy performance was signi fi cantly correlated utive function might be particularly impaired in with right parietal cortex volume in patients with bvFTD (working memory vs. inhibition), or con- AD, but not with right dorsolateral prefrontal sistency in the type of task chosen (e.g., Trail cortex (DLPFC) volume. The opposite relation- Making Test vs. Digit Span). ship was demonstrated in patients with bvFTD. Overall, it appears that “traditional” clinical We have also examined longitudinal data to show measures of executive function are not particu- that visuospatial function remains relatively larly sensitive early in the disease process. It is stable in bvFTD and svPPA groups but declines possible, however, that experimental measures of signi fi cantly in the AD group [78 ] . executive function may be more sensitive to subtle declines. For example, Krueger et al. [93 ] administered traditional tasks of executive func- Attention/Executive Functions in bvFTD tion, as well as a computerized Flanker task (measuring cognitive control) to patients with While intuitive, the claim that attention and exec- bvFTD and healthy control subjects. Patients utive functions are broadly and disproportion- were dichotomized into those who scored within ately impacted in bvFTD lacks strong empirical normal limits on standard tasks of executive func- support. Investigation of this domain using “tration and those who did not, and their scores on ditional” tasks of executive function has led to the Flanker task were compared. Interestingly, largely confl icting fi ndings. While some studies both bvFTD patient groups showed a signi fi cantly fi nd impairments in this domain [ 71, 91– 93 ] , oth- larger congruency effect (e.g., longer latency on ers do not [ 94– 96] . One reason for this discrep- incongruent vs. congruent trials) compared to the ancy likely relates to stage of disease at which normal control subjects [93 ] . These results sug- patients are assessed. As neurodegeneration gest that even those patients who perform well on begins in the ventromedial aspect of the frontal standard tasks of executive function may still lobe and moves dorsolaterally with disease pro- have subtle, yet perceptible defi cits in cognitive gression [21, 24, 25, 97, 98 ] , we would not expect control, if measured by the appropriate method. 320 A.K. LaMarre and J.H. Kramer

Another approach to measuring executive tively involved in bvFTD relative to other functioning in bvFTD has been to measure neurodegenerative disorders. process-oriented features of performance such as Studies examining social behavior in bvFTD errors. Kramer et al. found that overall error have found that these individuals tend to demon- scores on tasks of executive function discrimi- strate fl at affect, reduced initiative, and more nated between patients with bvFTD and AD [71 ] . perseveration than patients with other neurode- Rule violation errors may also be helpful in dis- generative diseases [ 109 ] . Other studies have also criminating between AD and bvFTD. Carey and found de fi cits in social pragmatics during conver- colleagues [102 ] found that despite similar achieve- sation [80 ] and poor social judgment compared ment scores on the Delis–Kaplan Executive to patients with primary progressive aphasia Function System Tower Task, patients with [110 ] . Changes in personality facets related to bvFTD made signifi cantly more rule violations interpersonal function have also been noted to compared to patients with AD and normal con- occur in bvFTD. For example, Rankin et al. dem- trols. Poor “online” detection of errors has also onstrated that agreeableness (one of the Big Five been shown to distinguish between bvFTD, CBS, personality traits) was not only decreased in and PSP [103 ] . bvFTD, but also signifi cantly related to right orb- Thompson et al. qualitatively analyzed error itofrontal cortex volumes [111 ] . types between patients with AD and bvFTD on Several researchers have found that patients multiple tasks from several different domains of with bvFTD have signi fi cantly less self-awareness cognition, including language, memory, visu- regarding their current personality and behavioral ospatial, and executive function. While several de fi cits [19, 112– 114] compared to patients with tests were signifi cantly different between the two other neurodegenerative diseases, such as AD. groups, overall, differences in the types of errors This lack of awareness or concern may be due, in made were best able to distinguish between AD part, to the emotion-processing defi cits that have and bvFTD on regression analysis (e.g., spatial been documented in bvFTD. While basic emotion errors vs. perseverations on a drawing task) [65 ] . processing such as the startle refl ex has been Examining errors is also important given that shown to remain intact in patients with bvFTD some researchers have found that patients with [ 115] , there are defi cits in more complex forms of bvFTD often perform faster on measures of exec- emotion such as self-conscious emotion, includ- utive function (e.g., Stroop Inhibition) than ing embarrassment, [ 115, 116] , emotional down- patients with AD, but also make signifi cantly more regulation [ 117 ] , recognition of emotions in others errors, indicating an imbalance in their ability to [19, 118– 121 ] , and ability to empathize with accurately make speed/error trade-offs [ 95, 96 ] . others [ 110, 113, 122 ] .

Social Behavior and Personality Complex Learning and Decision Making

The dorsolateral prefrontal cortex (DLPFC) The ventral and orbital medial regions of the degenerates in both AD and bvFTD, though this prefrontal cortex are also thought to be involved may occur at different stages in disease course in self-advantageous decision making and [97 ] . This likely explains why large group differ- adaptive responses to changing emotional or ences in executive functioning are not regularly social demands in the environment [ 106, 108 ] . demonstrated between the two diseases [ 89, 94, Researchers have begun to create experimental 104 ] . Investigations into social and emotional paradigms which are thought to tap these pro- function have produced more consistent results, cesses, including tasks which measure risk taking likely due to the fact that they are mediated by via computerized gambling programs (e.g., Iowa more anterior and ventral aspects of the prefron- Gambling Task) [ 123] and reversal learning tal cortex [ 105– 108] , areas that are more selec- tasks focused on reward and punishment [ 106 ] . 21 Accurate Assessment of Behavioral Variant Frontotemporal Dementia 321

Several researchers have found impairments on Onset and Progression these tasks in patients with bvFTD [ 92, 124– 126] ; however, these studies have not directly Has the onset been slow and insidious, or abrupt compared bvFTD to patients with other neurode- and explicit? Behavioral variant FTD is an insidi- generative diseases, so their utility for differen- ous disease that may begin many years before tial diagnosis is unclear. changes become obvious. Moreover, because the age of onset of bvFTD tends to be in the late 50s, the personality and behavior changes are often Summary of Neuropsychology misinterpreted as “mid-life” troubles. While Literature insidious change is common to most neurodegenerative disease, abrupt onset changes in personal- While the “classic” pattern of impaired attention ity and behavior are less likely to be bvFTD. and executive function with relative sparing of memory, language, and visuospatial function can occur in bvFTD, this pattern is not a constant and Nature of Change is just one of six symptoms (the other fi ve being social or behavioral) that de fi ne bvFTD. As such, As evidenced in the International Criteria for it is imperative that practitioners do not use evi- bvFTD [ 20 ] , changes in personality, emotional- dence of this neuropsychological pattern as ity, and social behavior are the most salient symp- justi fi cation for diagnosis of the disease in absence toms of bvFTD, and the six major symptoms of of other symptoms outlined in the International the International criteria can be used to structure Diagnostic Criteria [ 20 ] . the interview: 1 . Early behavioral disinhibiton . Has the person become socially, behaviorally, or cognitively Clinical Assessment of bvFTD disinhibited? Do they make inappropriate comments or engage in socially unacceptable A comprehensive evaluation of bvFTD should behaviors (e.g., fl atulence, nose picking)? Do include a clinical interview, neuropsychological they approach strangers and engage them in assessment, assessment of social and emotional conversations, or have new-onset gambling or function, and informant based measures. Given stealing? that cognition can be relatively preserved in the 2 . Early apathy / inertia . Does the patient demon- early stages of the disease, the history, informant strate a signifi cant loss of interest, drive, or report, and observable behavior seen throughout initiation of behavior? For example, those the assessment will likely be the most helpful patients who were once hardworking and information you gather. spontaneous may become passive and indif- ferent to the surrounding environment. They may also become disengaged in others around Interview them and show little interest in initiating or maintaining conversations. A well-structured clinical interview with a col- 3 . Early loss of empathy /sympathy . Does the lateral source is critical. The patients typically patient make hurtful or insensitive comments lack insight into the social, emotional, or behav- to others (e.g., make disparaging remarks ioral issues that are most germane to their care- about other’s weight or looks), seem not to givers and tend to deny problems. If the informant notice the pain or distress of others, lack emo- does not feel comfortable speaking frankly in tional warmth? front of the patient, one should consider conduct- 4 . New - onset compulsive /stereotyped behaviors . ing a separate interview. During the interview, Patients with bvFTD can manifest complex important areas to cover include: compulsions, such as counting or checking rituals 322 A.K. LaMarre and J.H. Kramer

or hoarding of useless items such as paper with a neuroradiologist or neurologist. Atrophy is napkins. They may also display simple motor or often asymmetric (right > left) and, in the early vocal stereotypies such as tapping, picking, lip middle stages, confi ned to the medial frontal and smacking, and repeating nonsensical phrases. anterior temporal lobes. With increasing disease 5 . Hyperorality or dietary changes . Changes in severity, more diffuse areas of these brain regions eating or hyperorality may occur as well, such degenerate, and more posterior areas including that a person may begin to consume alcohol in the parietal cortex become involved [22, 97, 98 ] . large quantities, take up smoking cigarettes, or Of note, atrophy of the hippocampus also occurs prefer to eat only fast food or sweets. Indeed, in bvFTD [21, 22 ] ; therefore, this fi nding should signi fi cant weight gain is common in bvFTD. not be used to support a diagnosis of AD rather Eating behaviors can also take on a compulsive than bvFTD. Clinically, structural magnetic reso- or rigid quality such as binge eating, eating nance imaging (MRI) is best for reviewing these only certain foods, or needing to be served fi ndings, though positron emission tomography meals at a particular time. (PET) scans may also reveal hypometabolism of 6 . Neuropsychological pro fi le (executive de fi cits the frontal and temporal lobes. While currently with relative preservation of memory and available only through research, PET imaging visuospatial function): does the patient seem that utilizes Pittsburg Compound B (PIB), a to have trouble completing complex tasks, or radioligand which binds to amyloid in the brain, doing two things at once, but can still drive, has been shown to be negative in bvFTD [97 ] . navigate around town, or remember conversations that occurred a few days earlier? As many patients will not have undergone neu- Cognitive Assessment ropsychological testing prior to your assessment, pointed “real-world” questions regarding In general, tests of global cognition such as attention/executive functions vs. memory and Folstein’s Mini Mental Examination (MMSE; visuospatial function can help get a better [ 127 ] ), the Blessed-Roth Dementia Rating Scale understanding of their cognitive pro fi le. [ 128 ] , or the Montreal Cognitive Assessment (MoCA; [ 129 ] ) can be insensitive to the subtle changes in cognition that occur early in bvFTD. Family History Indeed, some bvFTD patients in our clinic score 30/30 on the MMSE, despite signi fi cant behavioral Approximately 30–40% of all individuals with and social defi cits. Nevertheless, inclusion of a bvFTD have a strong family history of the disease. measure of global cognition is standard practice in Unfortunately, clear family histories are often dementia assessment. With its greater focus on ver- dif fi cult to elicit. There may be vague recollections bal fl uency and executive functions, the MoCA may that one of their grandparents was “senile” or had be better able to pick up on subtle defi cits in bvFTD, been diagnosed with a psychiatric disorder later in and is our measure of choice in this population. life. However, if a history reveals family members We fi nd that a short battery (approximately who exhibited signifi cant changes in personality 1–1.5 h) that examines all major cognitive and social behavior after the fi fth decade or who domains is a quick and useful way to help aid dif- had symptoms of motor disorder (e.g., ALS, PSP, ferential diagnosis without overtaxing the patient. CBS), these are potential clues that the individual While by no means invariable, the relative neu- may have a genetic form of the disease. ropsychological profi le of a patient with bvFTD tends to be one of spared visuospatial and language function and relatively better performance Neuroimaging than patients with AD on tests of episodic and semantic memory. Verbal fl uency is relatively If the patient has had neuroimaging, it will be better categorically than phonemically (though helpful to obtain the report or review the scan both may be attenuated due to economy of 21 Accurate Assessment of Behavioral Variant Frontotemporal Dementia 323 speech). We also recommend executive function atric behaviors that may occur in the context of tests that elicit and quantify performance errors dementia (e.g., anxiety, apathy, disinhibition, like rule violations, perseveration, environmental aberrant motor behavior). The informant is also dependency, impulsivity, and distractibility since asked to rate their level of distress by each symp- achievement scores have not been shown to reli- tom, which can be useful in helping structure ably differentiate between bvFTD and AD. feedback with the family. Extensive research investigating neuropsychiatric symptoms in dementia has been completed with the NPI [130 ] . Behavioral Observations Patients with bvFTD tend to have higher overall total scores on the NPI compared to AD, and the After neuropsychological evaluation, examiners domains of apathy, disinhibition, aberrant motor at our center complete a brief behavior-rating behavior, and appetite/eating changes appear to scale where patients are rated on a scale ranging best differentiate between bvFTD and AD from none, mild, moderate, and severe on the [131– 133 ] . following observable behaviors: agitation, stimulus boundedness, perseverations, decreased initi- Revised Self-Monitoring Scale [ 134 ] ation, motor stereotypies, distractibility, lack of This 13-item questionnaire measures an individ- social/emotional engagement, impulsivity, ual’s sensitivity and responsiveness to social socially inappropriate behavior, and impaired or cues. While the measure was initially designed fl uctuating levels of attention. Data from our cen- for self-report, this questionnaire is easily adapted ter suggest that perseverative and inappropriate to an informant-based questionnaire. behaviors and lack of social engagement signi fi cantly discriminate between patients with Interpersonal Reactivity Index [ 135 ] bvFTD and AD. In addition to providing impor- The empathic concern (EC) and perspective tak- tant diagnostic information, quantifying behav- ing (PT) subscales of the Interpersonal Reactivity iors systematically can also be helpful in Index (IRI) were designed to evaluate an indi- interpreting the neuropsychological data (e.g., vidual’s ability to empathize with others. The did the patient fully attend to the task, or were 7-item EC scale specifi cally measures an indi- they distracted and disinhibited?). vidual’s emotional response which results from the perception of another’s emotional state. The 7-item PT subscale measures an individual’s Informant-Based Measures tendency to spontaneously employ perspective taking in their typical social interactions. The inclusion of informant-based measures in your assessment can yield important information which, for one reason or another, was not gleaned Experimental Measures of Emotional/ on interview. These scales can provide invaluable Social Function information regarding social and emotional de fi cits experienced by the patient. There are a number of commercially available measures of emotional and social function that Neuropsychiatric Inventory [ 130 ] have been used to study defi cits in bvFTD, but we The Neuropsychiatric Inventory (NPI) is a screen- have found that many of these tasks are too long ing measure that is administered to the patient’s or attentionally demanding for our patients, and informant by the clinician and is a well-validated do not provide us with reliable information. We measure of neuropsychiatric symptoms common have found that the following two measures are in neurodegenerative disease. It was developed as well tolerated by our patients and provide diag- a way to quickly and accurately assess the fre- nostically valuable information. Both tasks are quency and severity of 12 different neuropsychi- in the fi nal stages of development and will be 324 A.K. LaMarre and J.H. Kramer published shortly. Copies can be obtained from Mr. R’s symptoms began insidiously around the developer, Dr. Katherine Rankin at the the age of 58. Previously kind and even tempered, University of California, San Francisco (UCSF; Mr. R became progressively more negative and [email protected] ). critical of others. His demeanor became sarcastic and socially inappropriate, telling off-color jokes Dynamic Affect Recognition Test in mixed company, and making loud derogatory (Rankin et al., personal communication) remarks about overweight individuals standing This test was designed to assess emotion recogni- nearby. He was more irritable and impatient when tion using dynamic, ecologically valid stimuli. driving, lashing out verbally against other drivers Individuals are asked to watch 12 brief (20 s) for perceived infractions. There were no reported vignettes of actors depicting one of six basic incidents of aggressive or violent behaviors. His emotions (happy, surprised, sad, angry, fearful, family reported an overall emotional blunting, and disgusted) with a semantically neutral script social withdrawal, and detachment from his fam- and choose the correct emotion. Comparison of ily, losing all interest in their lives. The patient’s performance between patients with AD and wife reported that if she did not plan activities, bvFTD at our center suggests that those with AD Mr. R would stand and stare out the window all perform comparably to normal controls, while day. His son noted that his previously strong those with bvFTD have signi fi cant de fi cits in interest in the upkeep of his car had dissipated their ability to accurately recognize emotions. over the prior 2 years. In addition, his diet drasti- cally changed from healthy, low-fat foods to pri- Social Norms Questionnaire (Rankin et al., marily junk food, candy, and large quantities of personal communication) coffee. His family reported a weight gain of over This simple, 22-item yes/no questionnaire was 20 pounds in the past 5 years. developed as a way to determine the degree to Mr. R’s family also reported a signi fi cant which patients understand and can accurately decline in function, such that he became unable identify implicit, but widely accepted social to follow through with paying bills, instead just boundaries dominant in US culture. The social leaving paperwork in piles around the house. His norms questionnaire (SNQ22) includes both wife was not aware of this issue until they began inappropriate (e.g., “Cut in line if you are in a receiving a series of notices. While previously hurry,” “Pick your nose in public,” and “Wear the handy around the home, Mr. R became unable to same shirt every day”) and generally acceptable complete familiar projects, such as hanging behaviors (e.g., “Tell a coworker your age,” doors, instead starting the job but then leaving it “Blow your nose in public,” and “Eat ribs with midstream. His family was also aware that Mr. your fi ngers”). Data from our center suggests that R’s job category at the police station changed compared to patients with AD, those with bvFTD once or twice in the 2 years before retirement for rate many behaviors as appropriate that normal reasons that were unclear to them, but which they adults would say are inappropriate. now believe may have had to do with his impairments. The patient’s family noted that Mr. R had Case History begun to engage in compulsive behaviors including emptying the recycling bin at home several History of Presenting Illness times a day, checking the lint trap in the dryer repeatedly, and collecting paper napkins from res- Mr. R is a 63-year-old, right-handed, retired taurants. He also engaged in repetitive behaviors policeman presenting for evaluation of personal- such as whistling and tapping his hands on the ity and behavioral changes. While Mr. R denies table for prolonged periods of time. He compul- any changes in his cognition or behavior, his wife sively scratches himself but no rash has been and son provided additional clinical history. noted. He continues to display loss of empathy 21 Accurate Assessment of Behavioral Variant Frontotemporal Dementia 325 and will laugh when other people get hurt. He will Neuropsychiatric Symptom Assessment often say repeatedly throughout the day, “everyone has lost their sense of humor!” or “where has Examination of the NPI subscales indicates that your sense of humor gone?” He is restless and the patient’s wife endorsed frequent symptoms of often wants to go somewhere; however, upon agitation, apathy, disinhibition, aberrant motor arriving at a new destination, he quickly wants to behavior, and changes in appetite/eating behavior go back home. The family did not endorse any that cause her signifi cant distress (NPI Total signi fi cant declines in his episodic memory, lan- Score: 60). guage, visuospatial, or motor function. Mr. R’s typical day consists of getting up, showering, and getting dressed. He requires Functional Evaluation reminders to bathe and groom himself. He will stand at a window for long periods of time and The patient’s Clinical Dementia Rating Scale report that his son has gone by or that he is waiting (CDR) total score was 1.0. His most signifi cant for somebody to arrive. He appears insatiable and impairments occurred in the domains of judg- will eat for extended periods of time if he is not ment and problem solving, home and hobbies stopped. Current medications include Lexapro and personal care. (20 mg/daily) and Simvastatin (20 mg/daily).

Imaging Results (Fig. 21.1 ) Social/Medical History Impressions and Formulation Mr. R has been married to his wife for 44 years. They have four adult children. He completed a Mr. R is a 63-year-old, retired policeman with a Master’s Degree in Sociology. He worked in law 5-year history of signifi cant personality and behav- enforcement for 30 years. According to his family, ior changes marked by disinhibited and socially he performed his job in an extremely professional inappropriate behavior, irritability, apathy and manner and was well respected. social withdrawal, poor executive functioning, Past medical history is signi fi cant for a history obsessive–compulsive activities, and hyperorality of hypercholesterolemia. He has never been with a 20-pound weight gain in the past fi ve years. hospitalized nor had any surgery. He has no On neuropsychological testing, his affect was history of head trauma, severe febrile illness, or notable for emotional blunting and mild irritabil- thyroid disease. ity. Overall, Mr. R demonstrated below average Family history is signifi cant for a mother who performance on free recall measures of verbal developed signs of signi fi cant cognitive dysfunc- and visual episodic memory. Verbal and visual tion around age 85 which was characterized mainly recognition memory were within normal limits. by memory loss and hallucinations. She died in His performance on measures of executive func- 2007 with a diagnosis of dementia. His father died tioning varied, ranging from impaired to average. at age 59 of a heart attack. There is no other known Of note, he made a total of 22 errors, which is family history of dementia, neurological or neuro- well above average compared to others in his age muscular disorders, or psychiatric illness. range. Global cognition, attention/working memory, language, and visuospatial function remain largely intact. Neuropsychological Test Summary Given his history of signifi cant emotional and behavioral changes, error-prone pattern of per- Please see Table 21.3 formance on measures of executive function and 326 A.K. LaMarre and J.H. Kramer

Table 21.3 Neuropsychological test summary Domain Test Raw score Range Global MMSE 29/30 Within normal limits (WNL) Attention/working Longest digit span forward 7 WNL memory Longest digit span backward 5 WNL Memory CVLT-II-SF trial 1–4 total 23/36 Below average CVLT-II-SF 10-min delay 6/9 Below average CVLT-II-SF cued recall 7/9 Below average CVLT-II-SF recognition 9/9; 1 false positive WNL Figure copy recall 10/17 Below average Figure copy recognition YES WNL Language Abbreviated BNT total 15/15 WNL Syntax comprehension 5/5 WNL Repetition 5/5 WNL Visuospatial Figure copy 15/17 WNL Object–number location matching 10/10 WNL Face perception 12/12 WNL Calculations 4/5 Below average Executive function Modi fi ed Trail Making Test (time) 64/120 Below average Modi fi ed Trail Making Test errors 4 – Design fl uency 11 Average Design fl uency errors 4 – “D” word fl uency (60 ) 3 Impaired “D” word errors 3 – Animal fl uency (60 ) 14 Below average Animal fl uency errors 2 – Stroop interference total 54 Average Stroop interference errors 9 – Affect naming 9/16 Impaired

Fig. 21.1 T2-weighted structural magnetic resonance worse on the right compared to left (image is oriented imaging (MRI) of Mr. R’s brain. Note the signifi cant vol- according to radiological convention; e.g., left = right, ume loss in the frontal and temporal lobes bilaterally, right = left) neuroimaging fi ndings of right > left degenera- In terms of treatment, Mr. R’s primary care tion of paralimbic frontal, temporal, and insular physician may want to consider prescribing structures, his pattern of fi ndings is most sugges- treatment with a selective-serotonin reuptake tive of a diagnosis of behavioral variant fronto- inhibitor (SSRI) in order to target his obsessive– temporal dementia. compulsive behaviors and irritability. However, 21 Accurate Assessment of Behavioral Variant Frontotemporal Dementia 327 anticholinesterase agents should not be pre- References scribed, as these have been known to exacerbate the irritability seen in frontotemporal dementia. 1. Ratnavalli E, Brayne C, Dawson K, Hodges JR. The I also recommend that Mr. R begin a program of prevalence of frontotemporal dementia. Neurology. vigorous physical activity, as exercise has been 2002;58(11):1615–21. shown to have neuroprotective properties. His 2. Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, entire family may want to consider attending a FTD Lee VM, Hatanpaa KJ, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar caregiver support group. Finally, despite intact degeneration: consensus of the consortium for fron- attention and visuospatial skills, it is strongly rec- totemporal lobar degeneration. Acta Neuropathol. ommended that Mr. R discontinue driving, in order 2007;114(1):5–22. to avoid the possibility of an untoward event. 3. Mercy L, Hodges JR, Dawson K, Barker RA, Brayne C. Incidence of early-onset dementias in Cambridgeshire, United Kingdom. Neurology. 2008;71(19):1496–9. Clinical Pearls 4. Knopman DS, Petersen RC, Edland SD, Cha RH, Rocca WA. The incidence of frontotemporal lobar degeneration in rochester, minnesota, 1990 through • FTD is fi rst and foremost a disease that dis- 1994. Neurology. 2004;62(3):506–8. rupts behavior and social function. 5. Johnson JK, Diehl J, Mendez MF, Neuhaus J, Shapira • Compared to AD, patients with bvFTD tend to JS, Forman M, et al. Frontotemporal lobar degenera- have little insight into their condition and are tion: demographic characteristics of 353 patients. Arch Neurol. 2005;62(6):925–30. more fl at, perseverative, inappropriate, and 6. Hodges JR, Davies R, Xuereb J, Kril J, Halliday G. emotionally dysregulated. Survival in frontotemporal dementia. Neurology. • Due to its pathological heterogeneity, bvFTD 2003;61(3):349–54. can present alone or in combination with other 7. Mendez M, Cummings J. Dementia: a clinical approach. Philadelphia: Butterworth Heinemann; diseases such as PSP, CBD, and ALS. 2003. • BvFTD is often misdiagnosed as late-onset 8. Neary D, Snowden JS, Gustafson L, Passant U, Stuss psychiatric disease or early onset AD. D, Black S, et al. Frontotemporal lobar degenera- • The presence of executive dysfunction in the tion: a consensus on clinical diagnostic criteria. Neurology. 1998;51(6):1546–54. absence of other major cognitive impairments 9. Pickering-Brown SM. The complex aetiology of is not speci fi c to bvFTD. frontotemporal lobar degeneration. Exp Neurol. • Neuropsychological testing should focus on 2007;206(1):1–10. relative patterns of performance vs. domain 10. Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, et al. Classi fi cation of pri- impairments. mary progressive aphasia and its variants. Neurology. • In the early stages of disease, process-oriented 2011;76(11):1006–14. features of performance such as rule-viola- 11. Miller BL, Seeley WW, Mychack P, Rosen HJ, Mena tions and errors appear to best discriminate I, Boone K. Neuroanatomy of the self: evidence from patients with frontotemporal dementia. between bvFTD and AD. Neurology. 2001;57(5):817–21. • Integration of history, behavioral observations, 12. Boxer AL, Miller BL. Clinical features of frontotem- imaging, social/emotional function, informant poral dementia. Alzheimer Dis Assoc Disord. questionnaires, and relative test scores in 2005;19 Suppl 1:S3–6. 13. Liu W, Miller BL, Kramer JH, Rankin K, Wyss- keeping with the disease are most important in Coray C, Gearhart R, et al. Behavioral disorders in coming to an accurate diagnosis. the frontal and temporal variants of frontotemporal • A multidisciplinary team approach, working dementia. Neurology. 2004;62(5):742–8. with a neurologist and other health-care pro- 14. Passant U, Elfgren C, Englund E, Gustafson L. Psychiatric symptoms and their psychosocial conse- fessionals, is most helpful in diagnosing this quences in frontotemporal dementia. Alzheimer Dis elusive disease. Assoc Disord. 2005;19 Suppl 1:S15–8. 328 A.K. LaMarre and J.H. Kramer

15. Shinagawa S, Ikeda M, Fukuhara R, Tanabe H. Initial 30. Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, symptoms in frontotemporal dementia and semantic Alafuzoff I, Kril J, et al. Nomenclature and nosology dementia compared with Alzheimer’s disease. for neuropathologic subtypes of frontotemporal Dement Geriatr Cogn Disord. 2006;21(2):74–80. lobar degeneration: an update. Acta Neuropathol. 16. Mendez MF, Chen AK, Shapira JS, Miller BL. 2010;119(1):1–4. Acquired sociopathy and frontotemporal dementia. 31. Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated Dement Geriatr Cogn Disord. 2005;20(2–3):99–104. neurodegeneration in Alzheimer’s disease and related 17. Miller BL, Darby A, Benson DF, Cummings JL, disorders. Nat Rev Neurosci. 2007;8(9):663–72. Miller MH. Aggressive, socially disruptive and anti- 32. Chen-Plotkin AS, Lee VM, Trojanowski JQ. TAR social behaviour associated with fronto-temporal DNA-binding protein 43 in neurodegenerative dis- dementia. Br J Psychiatry. 1997;170:150–4. ease. Nat Rev Neurol. 2010;6(4):211–20. 18. Miller BL, Cummings JL, Villanueva-Meyer J, Boone 33. Kertesz A, Martinez-Lage P, Davidson W, Munoz DG. K, Mehringer CM, Lesser IM, et al. Frontal lobe degen- The corticobasal degeneration syndrome overlaps eration: clinical, neuropsychological, and SPECT char- progressive aphasia and frontotemporal dementia. acteristics. Neurology. 1991;41(9):1374–82. Neurology. 2000;55(9):1368–75. 19. Rankin KP, Baldwin E, Pace-Savitsky C, Kramer 34. Kertesz A, McMonagle P, Blair M, Davidson W, JH, Miller BL. Self awareness and personality Munoz DG. The evolution and pathology of fron- change in dementia. J Neurol Neurosurg Psychiatry. totemporal dementia. Brain. 2005;128(Pt 9): 2005;76(5):632–9. 1996–2005. 20. Rascovsky K, Hodges JR, Knopman D, Mendez MF, 35. Irwin D, Lippa CF, Swearer JM. Cognition and amy- Kramer JH, Neuhaus J, et al. Sensitivity of revised otrophic lateral sclerosis (ALS). Am J Alzheimers diagnostic criteria for the behavioural variant of fron- Dis Other Demen. 2007;22(4):300–12. totemporal dementia. Brain. 2011;134(9):2456–77. 36. Tolnay M, Probst A. The neuropathological spec- 21. Seeley WW, Crawford R, Rascovsky K, Kramer JH, trum of neurodegenerative tauopathies. IUBMB Weiner M, Miller BL, et al. Frontal paralimbic network Life. 2003;55(6):299–305. atrophy in very mild behavioral variant frontotemporal 37. Lee VM, Goedert M, Trojanowski JQ. dementia. Arch Neurol. 2008;65(2): 249–55. Neurodegenerative tauopathies. Annu Rev Neurosci. 22. Broe M, Hodges JR, Scho ﬁ eld E, Shepherd CE, Kril 2001;24:1121–59. JJ, Halliday GM. Staging disease severity in patho- 38. Lillo P, Hodges JR. Frontotemporal dementia and logically con ﬁ rmed cases of frontotemporal demen- motor neurone disease: overlapping clinic-patholog- tia. Neurology. 2003;60(6):1005–11. ical disorders. J Clin Neurosci. 2009;16(9):1131–5. 23. Adolphs R. The social brain: neural basis of social 39. Mackenzie IR. The neuropathology of FTD associ- knowledge. Annu Rev Psychol. 2009;60:693–716. ated with ALS. Alzheimer Dis Assoc Disord. 24. Seeley WW, Menon V, Schatzberg AF, Keller J, 2007;21(4):S44–9. Glover GH, Kenna H, et al. Dissociable intrinsic 40. Josephs KA, Petersen RC, Knopman DS, Boeve BF, connectivity networks for salience processing and Whitwell JL, Duffy JR, et al. Clinicopathologic executive control. J Neurosci. 2007;27(9):2349–56. analysis of frontotemporal and corticobasal degen- 25. Rosen HJ, Gorno-Tempini ML, Goldman WP, Perry erations and PSP. Neurology. 2006;66(1):41–8. RJ, Schuff N, Weiner M, et al. Patterns of brain atro- 41. Lomen-Hoerth C, Anderson T, Miller B. The overlap phy in frontotemporal dementia and semantic of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology. 2002;58(2):198–208. dementia. Neurology. 2002;59(7):1077–9. 26. Perry RJ, Graham A, Williams G, Rosen H, 42. Strong MJ, Grace GM, Freedman M, Lomen- Erzinclioglu S, Weiner M, et al. Patterns of frontal Hoerth C, Woolley S, Goldstein LH, et al. Consensus lobe atrophy in frontotemporal dementia: a volumet- criteria for the diagnosis of frontotemporal cogni- ric MRI study. Dement Geriatr Cogn Disord. tive and behavioural syndromes in amyotrophic 2006;22(4):278–87. lateral sclerosis. Amyotroph Lateral Scler. 27. Salmon E, Kerrouche N, Herholz K, Perani D, Holthoff 2009;10(3):131–46. V, Beuthien-Baumann B, et al. Decomposition of meta- 43. Sikkink S, Rollinson S, Pickering-Brown SM. The bolic brain clusters in the frontal variant of frontotem- genetics of frontotemporal lobar degeneration. Curr poral dementia. Neuroimage. 2006;30(3):871–8. Opin Neurol. 2007;20(6):693–8. 28. Boccardi M, Sabattoli F, Laakso MP, Testa C, Rossi 44. Goldman JS, Farmer JM, Wood EM, Johnson JK, R, Beltramello A, et al. Frontotemporal dementia as Boxer A, Neuhaus J, et al. Comparison of family his- a neural system disease. Neurobiol Aging. tories in FTLD subtypes and related tauopathies. 2005;26(1):37–44. Neurology. 2005;65(11):1817–9. 29. Varrone A, Pappata S, Caraco C, Soricelli A, Milan 45. Seelaar H, Kamphorst W, Rosso SM, Azmani A, G, Quarantelli M, et al. Voxel-based comparison of Masdjedi R, de Koning I, et al. Distinct genetic rCBF SPET images in frontotemporal dementia and forms of frontotemporal dementia. Neurology. Alzheimer’s disease highlights the involvement of 2008;71(16):1220–6. different cortical networks. Eur J Nucl Med Mol 46. Gydesen S, Hagen S, Klinken L, et al. Imaging. 2002;29(11):1447–54. Neuropsychiatric studies in a family with presenile 21 Accurate Assessment of Behavioral Variant Frontotemporal Dementia 329

dementia different from Alzheimer and Pick disease. 61. Kipps CM, Nestor PJ, Fryer TD, Hodges JR. Acta Psychiatr Scand. 1987;76:276–84. Behavioural variant frontotemporal dementia: not all 47. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, it seems? Neurocase. 2007;13(4):237–47. Boxer AL, Baker M, Rutherford NJ, et al. Expanded 62. Mioshi E, Hodges JR. Rate of change of functional GGGGCC hexanucleotide repeat in noncoding abilities in frontotemporal dementia. Dement Geriatr region of C9ORF72 causes chromosome 9p-linked Cogn Disord. 2009;28(5):419–26. FTD and ALS. Neuron. 2011;72(2):245–56. 63. Davies RR, Kipps CM, Mitchell J, Kril JJ, Halliday 48. Sha S, Takada L, Rankin KP, Yokoyama JS, GM, Hodges JR. Progression in frontotemporal Rutherford NJ, Fong JC, et al. Frontotemporal dementia: identifying a benign behavioral variant by dementia due to C9ORF72 mutations: Clinical and magnetic resonance imaging. Arch Neurol. imaging features. 2012. Neurology, in press. 2006;63(11):1627–31. 49. Kumar-Singh S, Van Broeckhoven C. Frontotemporal 64. Wittenberg D, Possin KL, Rascovsky K, Rankin KP, lobar degeneration: current concepts in the light of Miller BL, Kramer JH. The early neuropsychologi- recent advances. Brain Pathol. 2007;17(1):104–14. cal and behavioral characteristics of frontotemporal 50. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich dementia. Neuropsychol Rev. 2008;18(1):91–102. S, Houlden H, et al. Association of missense and 65. Thompson JC, Stopford CL, Snowden JS, Neary D. 5 ¢ -splice-site mutations in tau with the inherited Qualitative neuropsychological performance charac- dementia FTDP-17. Nature. 1998;393(6686):702–5. teristics in frontotemporal dementia and Alzheimer’s 51. Lynch T, Sano M, Marder KS, Bell KL, Foster NL, disease. J Neurol Neurosurg Psychiatry. Defendini RF, et al. Clinical characteristics of a 2005;76(7):920–7. family with chromosome 17-linked disinhibition- 66. McKhann G, Drachman D, Folstein M, Katzman R, dementia-parkinsonism-amyotrophy complex. Price D, Stadlan EM. Clinical diagnosis of Neurology. 1994;44(10):1878–84. Alzheimer’s disease: report of the NINCDS-ADRDA 52. Baker M, Mackenzie IR, Pickering-Brown SM, Gass work group under the auspices of department of J, Rademakers R, Lindholm C, et al. Mutations in health and human services task force on Alzheimer’s progranulin cause tau-negative frontotemporal disease. Neurology. 1984;34(7):939–44. dementia linked to chromosome 17. Nature. 67. Welsh K, Butters N, Hughes J, Mohs R, Heyman A. 2006;442(7105):916–9. Detection of abnormal memory decline in mild cases 53. Mackenzie IR, Baker M, Pickering-Brown S, Hsiung of Alzheimer’s disease using CERAD neuropsycho- GY, Lindholm C, Dwosh E, et al. The neuropathol- logical measures. Arch Neurol. 1991;48(3):278–81. ogy of frontotemporal lobar degeneration caused by 68. Moss MB, Albert MS, Butters N, Payne M. mutations in the progranulin gene. Brain. 2006;129(Pt Differential patterns of memory loss among patients 11):3081–90. with Alzheimer’s disease, Huntington’s disease, and 54. Rabinovici GD, Miller BL. Frontotemporal lobar alcoholic Korsakoff’s syndrome. Arch Neurol. degeneration: epidemiology, pathophysiology, diagno- 1986;43(3):239–46. sis and management. CNS Drugs. 2010;24(5):375–98. 69. Lezak MD, Howieson DB, Loring DW. 55. Snowden JS, Pickering-Brown SM, Mackenzie IR, Neuropsychological assessment. 4th ed. New York: Richardson AM, Varma A, Neary D, et al. Progranulin Oxford University Press; 2004. gene mutations associated with frontotemporal 70. Hodges JR, Patterson K, Ward R, Garrard P, Bak T, dementia and progressive non-ﬂ uent aphasia. Brain. Perry R, et al. The differentiation of semantic demen- 2006;129(Pt 11):3091–102. tia and frontal lobe dementia (temporal and frontal 56. Johnson JK, Head E, Kim R, Starr A, Cotman CW. variants of frontotemporal dementia) from early Clinical and pathological evidence for a frontal vari- Alzheimer’s disease: a comparative neuropsycho- ant of Alzheimer disease. Arch Neurol. 1999;56(10): logical study. Neuropsychology. 1999;13(1):31–40. 1233–9. 71. Kramer JH, Jurik J, Sha SJ, Rankin KP, Rosen HJ, 57. Woodward M, Jacova C, Black SE, Kertesz A, Johnson JK, et al. Distinctive neuropsychological Mackenzie IR, Feldman H, et al. Differentiating the patterns in frontotemporal dementia, semantic frontal variant of Alzheimer’s disease. Int J Geriatr dementia, and Alzheimer disease. Cogn Behav Psychiatry. 2010;25(7):732–8. Neurol. 2003;16(4):211–8. 58. See TM, LaMarre AK, Lee SE, Miller BL. Genetic 72. Wicklund AH, Johnson N, Rademaker A, Weitner causes of frontotemporal degeneration. J Geriatr BB, Weintraub S. Word list versus story memory in Psychiatry Neurol. 2010;23(4):260–8. Alzheimer’s disease and frontotemporal dementia. 59. Rosenblatt A. Neuropsychiatry of Huntington’s dis- Alzheimer Dis Assoc Disord. 2006;20(2):86–92. ease. Dialogues Clin Neurosci. 2007;9(2):191–7. 73. Glosser G, Gallo JL, Clark CM, Grossman M. 60. Woolley JD, Khan BK, Murthy NK, Miller BL, Memory encoding and retrieval in frontotemporal Rankin KP. The diagnostic challenge of psychiatric dementia and Alzheimer’s disease. Neuropsychology. symptoms in neurodegenerative disease: rates of 2002;16(2):190–6. and risk factors for prior psychiatric diagnosis in 74. Gregory CA, Serra-Mestres J, Hodges JR. Early patients with early neurodegenerative disease. J Clin diagnosis of the frontal variant of frontotemporal Psychiatry. 2011;72(2):126–33. dementia: how sensitive are standard neuroimaging 330 A.K. LaMarre and J.H. Kramer

and neuropsychologic tests? Neuropsychiatry temporal dementia. Neuropsychologia. 2011; Neuropsychol Behav Neurol. 1999;12(2):128–35. 49(1):43–8. 75. Walker AJ, Meares S, Sachdev PS, Brodaty H. The 89. Rascovsky K, Salmon DP, Ho GJ, Galasko D, Peavy differentiation of mild frontotemporal dementia GM, Hansen LA, et al. Cognitive pro fi les differ in from Alzheimer’s disease and healthy aging by neu- autopsy-confi rmed frontotemporal dementia and ropsychological tests. Int Psychogeriatr. 2005; 17(1): AD. Neurology. 2002;58(12):1801–8. 57–68. 90. Blair M, Kertesz A, McMonagle P, Davidson W, 76. Salmon DP, Filoteo JV. Neuropsychology of cortical Bodi N. Quantitative and qualitative analyses of versus subcortical dementia syndromes. Semin clock drawing in frontotemporal dementia and Neurol. 2007;27(1):7–21. Alzheimer’s disease. J Int Neuropsychol Soc. 77. Kertesz A, McMonagle P. Behavior and cognition in 2006;12(2):159–65. corticobasal degeneration and progressive supranu- 91. Gregory C, Lough S, Stone V, Erzinclioglu S, Martin clear palsy. J Neurol Sci. 2010;289(1–2):138–43. L, Baron-Cohen S, et al. Theory of mind in patients 78. LaMarre AK, Bostrum A, Miller BL, Kramer JH. with frontal variant frontotemporal dementia and Differential rates of cognitive decline in bvFTD, Alzheimer’s disease: theoretical and practical impli- svFTD and AD. Dement Geriatr Cogn Disord. cations. Brain. 2002;125(Pt 4):752–64. 2010;30(Supp 1):62. 92. Torralva T, Kipps CM, Hodges JR, Clark L, 79. Blair M, Marczinski CA, Davis-Faroque N, Kertesz Bekinschtein T, Roca M, et al. The relationship A. A longitudinal study of language decline in between affective decision-making and theory of Alzheimer’s disease and frontotemporal dementia. mind in the frontal variant of fronto-temporal demen- J Int Neuropsychol Soc. 2007;13(2):237–45. tia. Neuropsychologia. 2007;45(2):342–9. 80. Rousseaux M, Seve A, Vallet M, Pasquier F, 93. Krueger CE, Bird AC, Growdon ME, Jang JY, Miller Mackowiak-Cordoliani MA. An analysis of commu- BL, Kramer JH. Confl ict monitoring in early fronto- nication in conversation in patients with dementia. temporal dementia. Neurology. 2009;73(5): Neuropsychologia. 2010;48(13):3884–90. 349–55. 81. Neary D. Dementia of frontal lobe type. J Am Geriatr 94. Gregory CA, Orrell M, Sahakian B, Hodges JR. Can Soc. 1990;38(1):71–2. frontotemporal dementia and Alzheimer’s disease be 82. Rogers TT, Ivanoiu A, Patterson K, Hodges JR. differentiated using a brief battery of tests? Int J Semantic memory in Alzheimer’s disease and the Geriatr Psychiatry. 1997;12(3):375–83. frontotemporal dementias: a longitudinal study of 95. Marra C, Quaranta D, Zinno M, Misciagna S, 236 patients. Neuropsychology. 2006;20(3):319–35. Bizzarro A, Masullo C, et al. Clusters of cognitive 83. Cotelli M, Borroni B, Manenti R, Ginex V, Calabria and behavioral disorders clearly distinguish primary M, Moro A, et al. Universal grammar in the fronto- progressive aphasia from frontal lobe dementia, and temporal dementia spectrum: evidence of a selective Alzheimer’s disease. Dement Geriatr Cogn Disord. disorder in the corticobasal degeneration syndrome. 2007;24(5):317–26. Neuropsychologia. 2007;45(13):3015–23. 96. Libon DJ, Xie SX, Moore P, Farmer J, Antani S, 84. Rascovsky K, Salmon DP, Hansen LA, Thal LJ, McCawley G, et al. Patterns of neuropsychological Galasko D. Disparate letter and semantic category impairment in frontotemporal dementia. Neurology. fl uency defi cits in autopsy-confi rmed frontotemporal 2007;68(5):369–75. dementia and Alzheimer’s disease. Neuropsychology. 97. Rabinovici GD, Seeley WW, Kim EJ, Gorno- 2007;21(1):20–30. Tempini ML, Rascovsky K, Pagliaro TA, et al. 85. Gasparini M, Masciarelli G, Vanacore N, Ottaviani Distinct MRI atrophy patterns in autopsy-proven D, Salati E, Talarico G, et al. A descriptive study on Alzheimer’s disease and frontotemporal lobar constructional impairment in frontotemporal demen- degeneration. Am J Alzheimers Dis Other Demen. tia and Alzheimer’s disease. Eur J Neurol. 2007;22(6):474–88. 2008;15(6):589–97. 98 Schroeter ML, Raczka K, Neumann J, von Cramon 86. Grossi D, Fragassi NA, Chiacchio L, Valoroso L, DY. Neural networks in frontotemporal dementia—a Tuccillo R, Perrotta C, et al. Do visuospatial and meta-analysis. Neurobiol Aging. 2008;29(3):418–26. constructional disturbances differentiate frontal vari- 99. Rohrer JD, Geser F, Zhou J, Gennatas ED, Sidhu M, ant of frontotemporal dementia and Alzheimer’s dis- Trojanowski JQ, et al. TDP-43 subtypes are associ- ease? An experimental study of a clinical belief. Int ated with distinct atrophy patterns in frontotemporal J Geriatr Psychiatry. 2002;17(7):641–8. dementia. Neurology. 2010;75(24):2204–11. 87. Diehl J, Kurz A. Frontotemporal dementia: patient 100. Strauss E, Sherman EMS, Spreen O. A compendium characteristics, cognition, and behaviour. Int J of neuropsychological tests: administration, norms, Geriatr Psychiatry. 2002;17(10):914–8. and commentary. 3rd ed. Oxford: Oxford University 88. Possin KL, Laluz VR, Alcantar OZ, Miller BL, Press; 2006. Kramer JH. Distinct neuroanatomical substrates and 101. Miyake A, Friedman NP, Emerson MJ, Witzki AH, cognitive mechanisms of fi gure copy performance in Howerter A, Wager TD. The unity and diversity of Alzheimer’s disease and behavioral variant fronto- executive functions and their contributions to 21 Accurate Assessment of Behavioral Variant Frontotemporal Dementia 331

complex “frontal lobe” tasks: a latent variable analy- frontotemporal lobar degeneration. Brain. sis. Cogn Psychol. 2000;41(1):49–100. 2006;129(Pt 9):2508–16. 102. Carey CL, Woods SP, Damon J, Halabi C, Dean D, 116. Sturm VE, Ascher EA, Miller BL, Levenson RW. Delis DC, et al. Discriminant validity and neuroana- Diminished self-conscious emotional responding in tomical correlates of rule monitoring in frontotem- frontotemporal lobar degeneration patients. Emotion. poral dementia and Alzheimer’s disease. 2008;8(6):861–9. Neuropsychologia. 2008;46(4):1081–7. 117. Goodkind MS, Gyurak A, McCarthy M, Miller BL, 103. O’Keeffe FM, Murray B, Coen RF, Dockree PM, Levenson RW. Emotion regulation defi cits in fronto- Bellgrove MA, Garavan H, et al. Loss of insight in temporal lobar degeneration and Alzheimer’s dis- frontotemporal dementia, corticobasal degeneration ease. Psychol Aging. 2010;25(1):30–7. and progressive supranuclear palsy. Brain. 118. Werner KH, Roberts NA, Rosen HJ, Dean DL, 2007;130(Pt 3):753–64. Kramer JH, Weiner MW, et al. Emotional reactivity 104. Nedjam Z, Devouche E, Dalla Barba G. and emotion recognition in frontotemporal lobar Confabulation, but not executive dysfunction dis- degeneration. Neurology. 2007;69(2):148–55. criminate AD from frontotemporal dementia. Eur J 119. Rosen HJ, Perry RJ, Murphy J, Kramer JH, Mychack Neurol. 2004;11(11):728–33. P, Schuff N, et al. Emotion comprehension in the 105. Beer JS, Heerey EA, Keltner D, Scabini D, Knight temporal variant of frontotemporal dementia. Brain. RT. The regulatory function of self-conscious emo- 2002;125(Pt 10):2286–95. tion: insights from patients with orbitofrontal dam- 120. Rosen HJ, Pace-Savitsky K, Perry RJ, Kramer JH, age. J Pers Soc Psychol. 2003;85(4):594–604. Miller BL, Levenson RW. Recognition of emotion in 106. Rolls ET. The functions of the orbitofrontal cortex. the frontal and temporal variants of frontotemporal Brain Cogn. 2004;55(1):11–29. dementia. Dement Geriatr Cogn Disord. 2004;17(4): 107. Hornak J, Bramham J, Rolls ET, Morris RG, 277–81. O’Doherty J, Bullock PR, et al. Changes in emotion 121. Kipps CM, Nestor PJ, Acosta-Cabronero J, Arnold after circumscribed surgical lesions of the orbitof- R, Hodges JR. Understanding social dysfunction in rontal and cingulate cortices. Brain. 2003;126 the behavioural variant of frontotemporal dementia: (Pt 7):1691–712. the role of emotion and sarcasm processing. Brain. 108. Zald DH, Andreotti C. Neuropsychological assess- 2009;132(Pt 3):592–603. ment of the orbital and ventromedial prefrontal cor- 122. Rankin KP, Kramer JH, Miller BL. Patterns of cogni- tex. Neuropsychologia. 2010;48(12):3377–91. tive and emotional empathy in frontotemporal lobar 109. Rankin KP, Santos-Modesitt W, Kramer JH, Pavlic degeneration. Cogn Behav Neurol. 2005;18(1): 28–36. D, Beckman V, Miller BL. Spontaneous social 123. Bechara A, Damasio AR, Damasio H, Anderson behaviors discriminate behavioral dementias from SW. Insensitivity to future consequences following psychiatric disorders and other dementias. J Clin damage to human prefrontal cortex. Cognition. Psychiatry. 2008;69(1):60–73. 1994;50(1–3):7–15. 110. Eslinger PJ, Moore P, Troiani V, Antani S, Cross K, 124. Torralva T, Roca M, Gleichgerrcht E, Bekinschtein Kwok S, et al. Oops! resolving social dilemmas in T, Manes F. A neuropsychological battery to detect frontotemporal dementia. J Neurol Neurosurg specifi c executive and social cognitive impairments Psychiatry. 2007;78(5):457–60. in early frontotemporal dementia. Brain. 2009;132(Pt 111. Rankin KP, Rosen HJ, Kramer JH, Schauer GF, 5):1299–309. Weiner MW, Schuff N, et al. Right and left medial 125. Gleichgerrcht E, Ibanez A, Roca M, Torralva T, Manes orbitofrontal volumes show an opposite relationship F. Decision-making cognition in neurodegenerative to agreeableness in FTD. Dement Geriatr Cogn diseases. Nat Rev Neurol. 2010;6(11): 611–23. Disord. 2004;17(4):328–32. 126. Rahman S, Sahakian BJ, Hodges JR, Rogers RD, 112. Ruby P, Schmidt C, Hogge M, D’Argembeau A, Robbins TW. Speci fi c cognitive de fi cits in mild fron- Collette F, Salmon E. Social mind representation: tal variant frontotemporal dementia. Brain. where does it fail in frontotemporal dementia? 1999;122(Pt 8):1469–93. J Cogn Neurosci. 2007;19(4):671–83. 127. Folstein MF, Folstein SE, McHugh PR. “Mini- 113. Eslinger PJ, Dennis K, Moore P, Antani S, Hauck R, mental state”. A practical method for grading the Grossman M. Metacognitive de fi cits in frontotempo- cognitive state of patients for the clinician. J Psychiatr ral dementia. J Neurol Neurosurg Psychiatry. Res. 1975;12(3):189–98. 2005;76(12):1630–5. 128. Blessed G, Tomlinson BE, Roth M. Blessed-roth 114. Bozeat S, Gregory CA, Ralph MA, Hodges JR. dementia scale (DS). Psychopharmacol Bull. Which neuropsychiatric and behavioural features 1988;24(4):705–8. distinguish frontal and temporal variants of fronto- 129. Nasreddine ZS, Phillips NA, Bedirian V, temporal dementia from Alzheimer’s disease? Charbonneau S, Whitehead V, Collin I, et al. The J Neurol Neurosurg Psychiatry. 2000;69(2):178–86. montreal cognitive assessment, MoCA: a brief 115. Sturm VE, Rosen HJ, Allison S, Miller BL, screening tool for mild cognitive impairment. J Am Levenson RW. Self-conscious emotion defi cits in Geriatr Soc. 2005;53(4):695–9. 332 A.K. LaMarre and J.H. Kramer

130. Cummings JL. The neuropsychiatric inventory: 133. Blair M, Kertesz A, Davis-Faroque N, Hsiung GY, assessing psychopathology in dementia patients. Black SE, Bouchard RW, et al. Behavioural mea- Neurology. 1997;48(5, Suppl 6):S10–6. sures in frontotemporal lobar dementia and other 131. Srikanth S, Nagaraja AV, Ratnavalli E. dementias: the utility of the frontal behavioural Neuropsychiatric symptoms in dementia-frequency, inventory and the neuropsychiatric inventory in a relationship to dementia severity and comparison in national cohort study. Dement Geriatr Cogn Disord. Alzheimer’s disease, vascular dementia and fronto- 2007;23(6):406–15. temporal dementia. J Neurol Sci. 2005;236(1–2): 134. Lennox RD, Wolfe RN. Revision of the self-moni- 43–8. toring scale. J Pers Soc Psychol. 1984;46(6): 132. Levy ML, Miller BL, Cummings JL, Fairbanks LA, 1349–64. Craig A. Alzheimer disease and frontotemporal 135. Davis MH. Measuring individual differences in dementias. Behavioral distinctions. Arch Neurol. empathy: evidence for a multidimensional approach. 1996;53(7):687–90. J Pers Soc Psychol. 1983;44(1):113–26. Movement Disorders with Dementia in Older Adults 2 2

Alexander I. Tröster and Nina Browner

Abstract Dementias associated with movement disorders are the second most common form of dementia in old age after Alzheimer’s disease. This chapter outlines the key neurological, neuropathological, neuroimaging, and neuropsychological features of two synucleinopathies (Parkinson’s disease dementia and dementia with Lewy bodies) and two tauopathies (corticobasal syndrome and progressive supranuclear palsy). Neuro- psychological evaluation of patients with movement disorders can be challenging, and some common pitfalls and suggestions for avoiding them are presented. Particular attention is paid to the type of information that must be elicited from medical records and the interview to plan an effective evaluation. Recommended instruments for the assessment and screening of cognition and psychiatric conditions, such as apathy and depression, are identiﬁ ed and some compensatory techniques are described. A case study is presented to illustrate the application of such instruments in the clinical setting.

Keywords Dementia with Lewy bodies • Parkinson’s disease • Corticobasal degeneration • Corticobasal syndrome • Basal ganglia • Progressive supranuclear palsy • Synucleinopathy • Tauopathy

A. I. Tröster , Ph.D. (*) Barrow Neurological Institute, 240 West Thomas Rd , Suite 301 , Phoenix , Az 85013 , USA e-mail: [email protected] N. Browner , M.D. Department of Neurology (CB 7025) , University of North Carolina School of Medicine , 170 Manning Drive, Suite 3128 , Chapel Hill , NC 27599-7025 , USA e-mail: [email protected]

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 333 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_22, © Springer Science+Business Media, LLC 2013 334 A.I. Tröster and N. Browner

In old age, the most common dementias associ- Epidemiology ated with movement disorders are Parkinson’s disease (PD) dementia (PDD), dementia with Parkinson’s Disease Dementia Lewy bodies (DLB), corticobasal degeneration and Dementia with Lewy Bodies (CBD), and progressive supranuclear palsy (PSP). These conditions can be broadly grouped Prevalence estimates of PD range from 18 to 418 according to their characteristic neuropathologic per 100,000 [ 2] . Annual incidence of PD has features as synucleinopathies (DLB and PDD) been estimated at 11 per 100,000, with inci- or tauopathies (CBD and PSP). Clinical neurop- dence increasing from 0 per 100,000 among those sychological test fi ndings by themselves are not 0–29 years old to 93 per 100,000 among those diagnostic, and differentiation between synucle- 70–79 years old [ 3 ] . A recent population-based inopathies and tauopathies might be easier than study in France reported an incidence of 263 per distinguishing among synucleinopathies or 100,000 person-years [ 4 ] . Dementia prevalence among tauopathies. Indeed, the neuropsycho- estimates in PD vary from 8% to 93%, depending logical features of PDD and DLB are often upon diagnostic criteria, sampling, and case indistinguishable even if subtle differences occa- ascertainment methods used. The most rigorous sionally emerge [ 1 ] , and for this reason are con- studies reveal a dementia prevalence of about 25% sidered together within this chapter. Similarly, among patients with PD [ 5 ] . Dementia incidence the tauopathies have considerable symptom is about 3% for persons with PD younger than overlap, and CBD can present clinically resem- 60 years and 15% for persons with PD older than bling PSP, and vice versa (and both can present 80 years [6– 8 ] . Advancing age, low education, and initially as a primary progressive aphasia). postural instability and gait disturbance (PIGD) Despite neuropsychological overlap among have been associated with increased dementia risk dementias associated with different movement in PD, among other factors (see Table 22.1 ). disorders, neuropsychological evaluation that The prevalence of DLB as distinguished from carefully weighs test results, neuroimaging and PDD remains to be adequately documented, but neurological fi ndings, interview information DLB is said to be the second most common cause about disease course, emergence of various of dementia, accounting for up to 20% of cases motor and non-motor symptoms (and their response to various treatments), and comorbidities can be helpful in supporting or ruling out a Table 22.1 Risk factors for dementia in Parkinson’s specifi c diagnosis. When patients with dementia disease [158 ] and a movement disorder are referred for neu- Demographic Disease Neurobe havioral ropsychological evaluation, the referral issue is variables variables variables often one of facilitating differential diagnosis Greater age Later onset Depression and determining if additional factors (e.g., Lower education Disease Poor performance depression, medications, or medical conditions) duration on tests of are producing cognitive compromise. Other Lower socioeco- Disease (a) Executive/ nomic status severity attention referral issues include patient selection for treat- Family history of Susceptibility (b) Verbal fl uency ment (e.g., as in PD patients being considered Parkinson’s to levodopa- for deep brain stimulation or DBS (patients with dementia induced dementia are evaluated and typically excluded as psychosis or candidates for DBS), documenting de fi cit pro- confusion gression with advancing disease (or improve- REM sleep (c) Visuoperceptual behavior ment with treatment), and characterization of disorder de fi cits to help determine potentially bene fi cial Akinetic-rigid (d) List learning interventions and compensatory strategies. symptoms 22 Movement Disorders with Dementia in Older Adults 335 coming to autopsy [ 9 ] . A review of six studies genetic risk factors, except older age [20 ] . No noted a DLB prevalence ranging from 0 to 5% adequate epidemiologic studies of neuropsycho- among the general population, and from 0 to 31% logical impairments in PSP have been conducted, among dementia cases [10 ] . A recent study and dementia prevalence estimates in PSP of reported an incidence of suspected DLB of 112 50–80% might be overestimates due to common per 100,000 person-years [4 ] . A study in the USA visual disturbances and information processing using formal diagnostic criteria for DLB reported speed abnormalities. A recent study with a sam- a similar incidence of about 0.1% in the popula- ple of over 300 patients observed impairments on tion and 3% among dementia cases [11 ] . the Dementia Rating Scale in 57% of patients, and on the Frontal Assessment Battery in 62% of cases [21 ] . Corticobasal Degeneration

Prevalence and incidence of CBD have not been Clinical and Neurological Presentation widely studied. Prevalence in Japan has been reported to be about 2 per 100,000 [ 12 ] to 9 per Parkinson’s Disease Dementia 100,000 [13 ] . A Russian study estimated age- and Dementia with Lewy Bodies standardized incidence at 0.02 per 100,000 person-years [ 14 ] . Dementia and neurobehav- Separate criteria have been proposed for PDD ioral abnormalities were thought to be rare in [22 ] and DLB [23 ] (see Tables 22.2 and 22.3 ). An CBD but are now accepted to be a common pre- essential feature differentiating PDD and DLB is senting problem depending perhaps on whether the time of onset of dementia in relation to onset patients initially present to movement disorder, of motor signs. When neurobehavioral symptoms dementia, or psychiatry clinics. Whereas one precede or occur within the fi rst 12 months of the study noted that at initial presentation, only motor signs, then a diagnosis of DLB is made. By 19% of 36 patients had “slight generalized cog- contrast, when cognitive symptoms have their nitive impairment” [ 15 ] , another study observed onset more than 12 months after the onset of par- that among 13 pathologically con fi rmed cases, kinsonism, then PDD is diagnosed. 69% had dementia at presentation [ 16 ] . The Parkinson’s disease dementia requires that a H1/H1 tau haplotype has been identifi ed as prior diagnosis of Parkinson’s disease has been heightening susceptibility to both CBD and made. Several criteria for PD diagnosis have been PSP (with the H2 haplotype perhaps being pro- proposed, but the most widely accepted are those tective) [17 ] , but no clear genetic etiology has of the UK Parkinson’s Disease Society Brain been identi fi ed. Bank (or Queen Square) criteria [24 ] . Diagnosis of PD requires the presence of a parkinsonian syndrome evidenced by bradykinesia and at least Progressive Supranuclear Palsy one of muscular rigidity, 4–6 Hz resting tremor, and postural instability not related to propriocep- The population prevalence of PSP is about 5 per tive, vestibular, visual, or cerebellar dysfunction. 100,000 [ 18 ] , but these estimates may be conser- The diagnosis of defi nite PD requires at least vative due to diagnostic inaccuracy or uncertainty three supportive features: unilateral onset, persis- and range from about 3 to 6 per 100,000. Annual tence of symptom asymmetry, progression of incidence of PSP is estimated at 5 per 100,000 symptoms, excellent response to levodopa, [19 ] in persons older than 50 years though a levodopa response sustained for 5 years, recent Russian study reported an age-standardized levodopa-induced dyskinesias, or a clinical incidence of 0.14 per 100,000 person-years [ 14 ] . course over 10 years. Exclusion of various condi- Neither incidence nor prevalence of PSP is tions capable of producing parkinsonism is strongly associated with any demographic or required. PD most often becomes symptomatic 336 A.I. Tröster and N. Browner

Table 22.2 Clinical diagnostic criteria for PDD (based on Emre et al. [22 ] ) Core features : (both required for probable or possible PDD) 1. Diagnosis of Parkinson’s disease per UK Parkinson’s Disease Society Brain Bank criteria 2. Dementia of insidious onset and slow progression in the presence of PD, de fi ned by: (a) Impairment of more than one domain of cognition (b) Impairment represents a decline from premorbid functioning (c) Impairment in day-to-day functioning not ascribable to motor or autonomic dysfunction Associated features : (typical cognitive pro fi le as outlined below in at least 2 of the 4 domains, and at least one of the behavioral symptoms required for diagnosis of probable PDD; atypical cognitive pro fi le in one or more domains allows for diagnosis of possible PDD, in which behavioral disturbance may or may not be present) 1. Cognition (a) Impaired attention which may fl uctuate within or across days (b) Impaired executive functions, e.g., planning, conceptualization, initiation, rule fi nding, set maintenance or shifting, bradyphrenia (c) Preserved language, though word- fi nding and complex sentence comprehension de fi cits may be present (d) Impaired memory, usually with bene fi t from cuing and better recognition than recall 2. Behavior (a) Apathy (b) Changes in mood and personality, including features of depression and anxiety (c) Delusions; commonly of the paranoid type (d) Hallucinations; usually visual, complex, and well formed (e) Excessive daytime sleepiness/somnolence Features making the diagnosis of PDD uncertain : (none of these features can be present when diagnosing probable PDD; one or both of these features can be present when diagnosing possible PDD) 1. Another abnormality capable of impairing cognition, but judged not to be the cause of the dementia (e.g., vascular disease on neuroimaging) 2. Time interval between onset of motor and cognitive symptoms is unknown Features suggesting another condition as causing the mental impairment : (if present, PDD cannot be diagnosed) 1. Cognitive and behavioral abnormality occurs solely in the context of other conditions, such as confusional state due to systemic disease or intoxication, or major depressive disorder 2. Features consistent with probable vascular dementia per NINDS-AIREN criteria during the sixth decade of life, but juvenile and as lawn mowers). In the case of DLB, cognitive young-onset forms occur. The most common ini- changes are also likely to be accompanied by tial cognitive complaint in both patients with complaints of visual distortions and hallucina- PDD and those with DLB may involve memory. tions and signs of possible rapid eye movement One study reported that 67% of PDD and 94% of (REM) sleep behavior disorder (RBD) (e.g., DLB patients initially complained of memory acting out dreams while asleep). problems [25 ] . However, patients may also initially complain of word-fi nding problems, diffi culty keeping up with conversations due to Corticobasal Degeneration slowness of thought, ineffi ciency with work, domestic chores and fi nancial management, as Because the clinical features of CBD can be pro- well as problems with concentration, indecisive- duced by conditions other than CBD, and patho- ness, and apathy [ 26 ] . In our experience, patients logically con fi rmed CBD can have heterogeneous and/or their care partners may also report fairly clinical presentations, it has been proposed that early in PDD that the patient has problems with corticobasal syndrome (CBS) be the preferred day-to-day and repair tasks with which they were term for conditions characterized by the core previously facile (e.g., sequencing of recipes, motor and cortical features of CBD regardless of trouble reassembling disassembled objects such etiology. In contrast, CBD has been proposed to 22 Movement Disorders with Dementia in Older Adults 337

Table 22.3 Revised clinical diagnostic criteria for DLB a sense of lack of ownership in the absence of (based on McKeith et al. [23 ] ) visual cues of the limb, involuntary purposeful Central feature : progressive cognitive decline that movements, or frank interference of one limb interferes with social and occupational function with the other’s execution of purposeful move- Core features : (any 2 = Probable DLB; any 1 = Possible ment. Patients often complain of clumsiness with DLB) fi ne fi nger movements and abnormal reaching 1. Fluctuating cognition movements. 2. Recurrent visual hallucinations 3. Spontaneous motor parkinsonism *Suggestive features : (1 or more + a core feature = Probable DLB, any 1 alone = Possible DLB) Progressive Supranuclear Palsy 1. REM sleep behavior disorder 2. Severe neuroleptic sensitivity PSP shares some pathological and clinical fea- 3. Decreased tracer uptake in striatum on SPECT tures with CBD and frontotemporal dementia dopamine transporter imaging or on MIBG (e.g., primary progressive aphasia). Although myocardial scintigraphy signs of PSP may be evident as early as age 40, Supportive features : (common but lacking diagnostic speci fi city) formal diagnosis typically occurs after age 60, 1. Repeated falls and syncope with particularly high incidence rates after age 80 2. Transient, unexplained loss of consciousness [ 19] . Only about 5% of cases have symptom 3. Systematized delusions onset before age 50. At the present time, there are 4. Hallucinations in other modalities no effective pharmacological or neurosurgical 5. Relative preservation of medial temporal lobe on CT treatments available for patients with PSP and or MRI scan survival rates range from approximately 5 to 6. Decreased tracer uptake on SPECT or PET imaging 10 years after diagnosis [28 ] . Research diagnos- in occipital regions tic criteria have been proposed wherein possible 7. Prominent slow waves on EEG with temporal lobe transient sharp waves PSP criteria have better sensitivity than specifi city, and probable PSP criteria have better speci fi city be reserved for neuropathologically distinct CBD than sensitivity [29 ] . The diagnosis of possible regardless of clinical presentation [27 ] . PSP requires a gradually progressive disorder CBD onset is usually in the sixth decade of beginning at age 40 or later, either vertical supra- life, and mean time to death from diagnosis is nuclear gaze palsy or both slowing of vertical about 7 years. CBD can present with either saccades and prominent postural instability in the predominantly motor or cognitive dysfunction. fi rst year of disease; other diseases that could Typical initial complaints include clumsiness, explain these features need to be excluded. stiffness, or jerkiness of an arm and less fre- Probable PSP requires vertical supranuclear gaze quently, clumsiness of a leg (stubbing one’s toes palsy, prominent postural instability, and falls in when walking). The most striking motor features the fi rst year of onset, and other features of pos- of CBD include markedly asymmetric, progressive, sible PSP. Defi nite PSP requires neuropathologic akinetic-rigid parkinsonism of gradual onset that confi rmation after criteria for possible or proba- responds minimally to levodopa, associated with ble PSP are met. focal dystonia with or without contractures, and The earliest symptoms in PSP are often imbal- hand, limb, gait, and speech apraxia. CBD is ance evident in falls, accompanied by greater sometimes accompanied by focal stimulus–sensitive axial than appendicular rigidity, impoverished myoclonus, usually involving the most affected postural refl exes, and dysarthria (commonly a limb and jerky action-induced tremor. Common hypophonic monotone). Other common fi ndings cortical signs in CBD include asymmetric are sloppy eating habits due to poor eye-hand ideational and ideomotor apraxia, cortical sen- coordination, nonspeci fi c visual dif fi culties, loss sory defi cits (e.g., astereognosis, agraphesthesia), of eye contact, and slowness of thought [ 30 ] . and alien hand syndrome. The latter may involve Resting tremor is unusual in PSP. Gait in individuals 338 A.I. Tröster and N. Browner with PSP tends to be wide based and unstable. de fi ned by neuronal loss and LB in the substantia Symmetric bradykinesia and a masked face with nigra. However, LB and LN are also found out- a seemingly perpetually startled expression side the substantia nigra. Braak et al. developed a (raised brow) are common. The earliest oculomo- 6-stage system [ 33 ] outlining the systematic pro- tor problem is typically a slowing of vertical sac- gression of LB pathology from preclinical PD cades and fast phases with the classic vertical through advanced PD. In the fi rst two stages (pre- gaze palsy (usually affecting downgaze before clinical), olfactory and brain stem regions show upgaze) occurring later. In terms of cognitive LB and LN, and by the time of clinical diagnosis changes, when present, patients may complain (usually at stage III or IV), the LB and LN extend early on of visual, concentration, or executive to midbrain, including the substantia nigra, basal problems. forebrain, transentorhinal cortex, and the hip- No universally accepted clinical subtypes or pocampal CA2 cell fi eld. In the fi nal two stages categories of PSP exist. A review of 103 autopsy- (V and VI), LB and LN become evident in corti- proven cases of PSP revealed that all but about cal association areas and eventually in much or 15% of cases could be categorized as belonging all of neocortex. to one of two clinical phenotypes: half the cases An instructive study evaluating the Braak had the traditional PSP syndrome (with gaze staging system is the prospective Sydney palsy and early postural instability) and one-third Multicenter Study of PD [ 34 ] . These researchers of cases had symptoms readily confused with found three phenotypes of patients: (1) a group Parkinson’s disease (PD) (asymmetric motor with early, prominent dementia and akinetic-rigid symptom onset, predominance of tremor among PD (corresponding clinically to DLB), (2) a motor signs, and moderate response to levodopa group of older PD patients (onset after 70 years) therapy) [31 ] . The prototypical cognitive impair- developing dementia in 3–10 years (correspond- ment was common in the traditional syndrome ing clinically to PDD) who have widespread but rare in the parkinsonian subtype. Although alpha-synuclein pathology, and (3) a younger PD disease onset for both variants is in the sixth to group (onset before 70 years) in which dementia seventh decade of life, traditional PSP syndrome occurs late in the disease (after 10–15 years) has a disease duration of approximately 6 years, and there is cell-loss dominant pathology with whereas PSP associated with more PD-like symp- lesser alpha-synuclein deposition. Another study toms has a duration of almost 12 years and, there- similarly found that PD patients developing fore, has a slower, less severe progression [32 ] . dementia late in the disease had less cortical Recognizing these different clinical subtypes is alpha-synuclein pathology but greater cholinergic not only important when considering PSP in the abnormalities than those developing dementia differential diagnosis but also for patient counsel- early on, whose pathology resembles more ing with regard to potential medication response strongly that of DLB [35 ] . and prognosis. A signifi cant number of persons with DLB are also found to have amyloid plaques at autopsy, although amyloid pathology is likely to be less Neuropathology implicated in PDD. One possibility for the somewhat divergent fi ndings obtained from studies of Parkinson’s Disease Dementia cerebrospinal fl uid (CSF) beta-amyloid markers and Dementia with Lewy Bodies and functional amyloid imaging in PDD is that CSF biomarker levels may refl ect biologic pro- The pathological feature of PDD and DLB is the cesses other than amyloid deposition in the brain. presence of aggregates of alpha-synuclein, in the Although PD is initially primarily associated form of Lewy bodies (LB; neuronal cytoplasmic with dopaminergic pathophysiology, other neu- inclusions) and Lewy neurites (LN; axonal and rotransmitter systems become involved with dendritic inclusions). Traditionally, PD has been disease progression, and both DLB and PDD 22 Movement Disorders with Dementia in Older Adults 339 involve signifi cant dysfunction of the dopamin- gies in the neurobehavioral features of PDD. ergic and cholinergic systems. Studies have shown an association between dementia and neocortical, medial temporal, and amygdala atrophy [ 36 ] . Findings of possibly Corticobasal Degeneration greater temporal, parietal, and occipital [37 ] or frontotemporal neocortical atrophy in DLB than The pathological hallmarks of CBD include bal- PDD [ 38 ] , and more marked posterior reductions looned neurons which are most numerous in in fractional anisotropy on diffusion tensor imag- frontoparietal cortex, but are also seen in the ing in DLB than PDD [39 ] , are limited by poten- anterior cingulate, amygdala, and insular cortex. tially confounding group differences in duration Tau-containing neuronal inclusions are evident in or severity of dementia or parkinsonism. cortex and striatum. The frontal and frontopari- [11C]PIB PET imaging provides an estimate etal cortices typically show asymmetric atrophy. of the brain’s beta-amyloid load. One study The pons, medulla, and dentate are also atro- reported increased PIB uptake (greater amyloid phied, and the caudate may appear fl attened. The deposition) in DLB but not PDD, and in a major- substantia nigra shows decreased pigmentation ity of DLB but few PDD patients [ 40 ] , but another and cell loss. Neuronal loss and gliosis, in addi- study found increased PIB uptake in similar, tion to being evident in frontoparietal cortex, are small proportions of DLB and PDD patients. PIB seen in basal ganglia, thalamus, subthalamic uptake was associated with higher ApoE4 preva- nucleus, dentate, and red nucleus. Ballooned and lence, dementia severity, and CSF Abeta 42 lev- achromatic neurons are most numerous in fron- els [ 41 ] . Cortical acetylcholinesterase (AChE) toparietal cortex but are also seen in the anterior activity has been imaged in vivo using [11C] cingulate, amygdala, and insular cortex. methyl-4-piperidinyl propionate (PMP) or [11C] methyl-4-piperidyl acetate (MP4A). Decreased AChE activity was associated with depression in Progressive Supranuclear Palsy PD/PDD [ 42] and with working memory and executive defi cits in PDD [ 43 ] . Small sample PSP, unlike PD, compromises the entire substan- studies concur that MP4A binding is reduced tia nigra, and dopaminergic depletion is compa- especially in posterior brain regions in PD and rable in caudate and putamen. Neuronal loss PDD, but the extent of the defi cit in PD vs. PDD and gliosis are evident in the globus pallidus, remains unclear [ 44, 45 ] . Dopaminergic imaging subthalamic nuclei, red nuclei, dentate, superior using PET and SPECT reveals reduced dopamine colliculi, and periaqueductal gray matter. transporter binding and fl uorodopa uptake in the Neuro fi brillary tangles (different from those seen striatum. Posterior (especially occipital) cerebral in AD), and neuropil threads, are observed in the blood fl ow and glucose metabolism is especially basal ganglia, brain stem, dentate, and the nucleus reduced in DLB and PDD [46, 47 ] . basalis of Meynert, which is a major cortical cholinergic output structure. Corticobasal Degeneration

Structural and Functional MRI typically reveals cortical atrophy, especially Neuroimaging Findings frontoparietal (see Fig. 22.1 ), and occasionally hypointense putaminal and hyperintense subcorti- Parkinson’s Disease Dementia cal white matter signals on T2-weighted images and Dementia with Lewy Bodies [48 ] . Volumetric MRI has shown parietal and callosal atrophy in CBD [ 49 ] . PET and SPECT Advances in structural and functional neuroim- fi ndings are consistent with presynaptic dop- aging using radioactive tracers are beginning to aminergic abnormalities in CBD, thus revealing confi rm and clarify the role of various patholo- asymmetric decrease in fl uorodopa uptake and 340 A.I. Tröster and N. Browner

Fig. 22.1 MRI scan in corticobasal degeneration (note asymmetric atrophy, especially frontoparietal)

Fig. 22.2 Sagittal T1-weighted MRI in progressive supranuclear palsy: note thinning of the midbrain tegmentum and tectum and frontal atrophy

dopamine transporter binding in caudate and puta- oculomotor signs (see Fig. 22.2 ) and superior men, with the side contralateral to the hemibody cerebellar peduncle atrophy, though putaminal most affected showing the greater reduction [50 ] . atrophy which is also seen in other forms of Mild reductions in acetylcholinesterase activity parkinsonism may be evident [ 48 ] . Cortical have been observed with PET imaging, especially (especially frontotemporal) atrophy also occurs, in frontal, parietal, and occipital cortex [51 ] . and frontal atrophy has been linked to scores on the Frontal Behavior Inventory [ 52 ] and executive dysfunction [ 53 ] . Reduced glucose metabo- Progressive Supranuclear Palsy lism on FDG PET is seen especially in the midbrain and mesial frontal cortex [ 54 ] . Imaging Structural MRI fi ndings supportive of a diagnosis of pre- and postsynaptic dopaminergic abnormal- of PSP include midbrain atrophy correlated with ities does not differentiate PSP from other forms 22 Movement Disorders with Dementia in Older Adults 341 of parkinsonism such as multiple system atrophy, been compared, but no differences were found but imaging of postsynaptic dopaminergic abnor- between these groups on the Identities and malities can be helpful in differentiating PSP Oddities task [25 ] . from PD [ 50 ] . Recently, PET imaging has revealed paracentral and thalamic reductions in Language acetylcholinesterase activity [51 ] . Patients with PDD have more impaired verbal fl uency than PD patients, but verbal fl uency may be similarly impaired in PDD and DLB [25 ] . Neuropsychological Hallmarks Visual confrontation naming is preserved in PD. While some found naming to be comparably Parkinson’s Disease Dementia impaired in PDD and DLB [ 25 ] , the relative pres- and Dementia with Lewy Bodies ervation of naming in DLB compared to AD may have diagnostic signi fi cance [59 ] . Occasionally Recent reviews comparing cognitive performance observed mild impairments in sentence compre- in PDD and DLB [1, 55 ] can be consulted for hension or repetition have been ascribed to atten- further detail and additional references. tion/executive limitations in PD [ 60 ] , but performance in PDD is typically not impaired on Attention and Working Memory comprehension and repetition tasks. Performance on simple attention tasks, such as span tasks, is preserved in PD, but as the disease Learning and Memory progresses, impairments may be observed even The relative integrity of recognition relative to on cued attention tasks. Working memory- free recall has been interpreted as indicative of a demanding tasks reveal impairments early in PD retrieval de fi cit in PD. It must be emphasized that [56 ] , and these de fi cits progress in PDD. Complex recognition is not necessarily intact in PD [61, (sustained, divided) attention tasks, such as 62 ] . Furthermore, memory pro fi les in PD are het- Stroop and visual cancellation tasks, are more erogeneous [ 63 ] , and semantic encoding may be likely than simple tasks to elicit attention impair- de fi cient [64, 65 ] , perhaps re fl ecting executive ment in DLB or PDD [25 ] . In comparison to defi cits or problems in the use of self-initiated PDD, DLB may involve greater impairments on rather than externally imposed learning strate- tasks such as WAIS-R Arithmetic, Stroop, and gies. PDD and DLB memory impairments are Trail Making tests [57 ] . similarly severe (but less severe than in AD) [ 25 ] . Nonetheless, qualitative aspects of memory Executive Functions impairment may clinically distinguish DLB and Executive defi cits may have particular impor- PDD [66 ] . Whereas DLB manifests poorer recall tance as harbingers of PDD. Planning, often and more rapid rates of forgetting, PDD makes assessed with Tower tasks, can be slowed or inac- more perseverative errors during list learning curate in PD, or even stimulus bound in PDD [66 ] . Remote memory may be impaired in PDD, [58 ] . Card sorting tests evaluating conceptualiza- but the temporal gradient of the loss is equally tion and maintenance and switching of set may severe across all past decades implicating a show patients with PD to (a) be slow to conceptu- retrieval de fi cit [67, 68 ] . alize, (b) have dif fi culty shifting set, and (c) lose set. Set-shifting defi cits are more apparent in patients Visuoperceptual and Spatial Functions with declining mental status and evident espe- Comparably severe de fi cits in PDD and DLB have cially when extra- rather than intra-dimensional been observed on numerous visuospatial and con- shifts are required. structional tasks, including pentagon copying, DLB and PDD patients perform poorly on BVRT stimulus matching, visual cancellation, card sorting tasks. PDD and DLB group perfor- visual discrimination, and space and object per- mance on card sorting and tower tests have not ception [ 25, 69, 70 ] . Profound dif fi culties with 342 A.I. Tröster and N. Browner

Fig. 22.3 Copies of a clock and cube by a 78-year-old patient with dementia with Lewy bodies (DLB) (Mattis Dementia Rating Scale Total Score 113/144)

visuospatial and constructional tasks, e.g., draw- tried at antidepressant dosages within the highest ing and copying of fi gures, are often evident even recommended range [ 72 ] . Similarly, it appears in mild to moderate DLB (see Fig. 22.3 ). that anxiety and depression frequently go unrecognized by clinicians treating PD [ 73 ] . Screening Neuropsychiatric Features for neuropsychiatric conditions is important, and The most recent version of the Diagnostic and recommendations for use of specifi c scales in Statistical Manual of Mental Disorders (DSM) various neuropsychiatric conditions by Movement [71 ] contains separate categories and criteria for Disorder Society task forces are provided in mood and anxiety disorders due to medical con- Table 22.4 . ditions (including PD). The PDD criteria [ 22 ] , Depression is common in PD, occurring in however, do not require a separate diagnosis of a about half of all patients, but reliable compari- mood disorder because the criteria recognize the sons of depression prevalence estimates for common coexistence of neuropsychiatric symp- PDD and DLB are not available. One study toms. Nonetheless, the presence of any neuropsy- reported major depression to occur in about chiatric feature is probably best documented 13% of patients with PDD and in about 19% of explicitly in the medical record and neuropsy- patients with DLB (29% of PDD and 34% of chological evaluation report so that adequate DLB had less severe forms of depression) [ 74 ] . treatment is undertaken. That depression is under- One meta-analysis reported a prevalence of treated in PD is evidenced by the fi nding that only 42% in PD studies using DSM criteria [ 75 ] , but one-third of depressed PD patients were receiving incidence and prevalence rates are higher in antidepressant treatment and that, among those research than community samples (about 50% with persistent depression, only 11% had been vs. 10%) [ 76 ] . 22 Movement Disorders with Dementia in Older Adults 343

Table 22.4 Recommended and suggested rating scales for the assessment of neuropsychiatric features in Parkinson’s disease Feature Recommended scales (stronger evidence) Suggested scales (weaker evidence) Depression [159 ] Screening (and recommended cutoff in PD): For patients with dementia (though Hamilton Depression Rating Scale (HAM-D, insuf ﬁ cient evidence): MADRS, 9/10), Beck Depression Inventory (BDI, GDS; Cornell Scale for Depression 13/14), Hospital Anxiety and Depression in Dementia (CSDD, 5/6) Scale (HADS, 10/11), Montgomery-Åsberg Depression Rating Scale (MADRS,14/15), Geriatric Depression Scale (GDS-30, 9/10; GDS-15, 4/5) Anxiety [160 ] None Beck Anxiety Inventory (BAI), HADS, Zung SAS, Zung ASI, STAI, HARS, Neuropsychiatric Inventory (NPI) anxiety section Apathy and anhedonia [ 161 ] Apathy Scale (Starkstein et al.); Uni ﬁ ed Apathy Evaluation Scale (AES; Parkinson’s Disease Rating Scale (UPDRS) Marin); Lille Apathy Rating Scale item 4 (motivation/initiative) (LARS); Neuropsychiatric Inventory (NPI) item 7; Snaith-Hamilton Pleasure Scale (SHAPS) Psychosis [162 ] Neuropsychiatric Inventory (NPI); Brief Parkinson Psychosis Rating Scale Psychiatric Rating Scale (BPRS); Positive and (PPRS); Parkinson Psychosis Negative Syndrome Scale (PANSS); Schedule Questionnaire (PPQ); Behavioral for Assessment of Positive Symptoms (SAPS) Pathology in Alzheimer’s Disease Rating Scale (Behave-AD); Clinical Global Impression Scale (CGIS) Sleep disturbances [163 ] Daytime sleepiness : Epworth Sleepiness Scale Daytime sleepiness : Inappropriate (ESS) Sleep Composite Score (ISCS); Overall sleep impairment : Parkinson’s Disease Stanford Sleepiness Scale (SSS) Sleep Scale (PDSS); Pittsburgh Sleep Quality Index (PSQI); Scales for Outcomes in Parkinson’s Disease (SCOPA-Sleep)

About 50% of patients with PD have signi fi cant ring more often in DLB than PDD, hallucinations symptoms of anxiety, and as many as 75% of (76% of DLB, 54% of PDD) and delusions (57% those patients with PD and depression may have of DLB, 29% of PDD) are of a similar quality in a comorbid anxiety disorder [ 77 ] . However, the both patient groups, with paranoid and phantom reported prevalence of actual anxiety disorders boarder delusions and well-formed visual hallu- (vs. symptoms) in PD ranges from 5% to 40% cinations being among the most prominent fea- [78 ] . Almost 20% of PD patients had generalized tures [74 ] . Apathy is another behavioral syndrome anxiety, 20% had a social phobia (with another that has been observed in both PDD and DLB. 20% experiencing signi fi cant social anxiety) [79 ] , and recurrent panic attacks may occur in up to 24% of levodopa-treated patients [ 80 ] . Corticobasal Degeneration Although patients with PD rarely meet the full DSM criteria for obsessive-compulsive disorder Attention and Working Memory (OCD), a considerable number have symptoms Impairments in digit span are not uniformly of OCD. Anxiety disorders occur with compara- observed [82 ] . Autopsy-con fi rmed CBD patients ble prevalence in PDD and DLB [74 ] , and one have been shown to have mild impairments in study reported that anxiety may occur in about digit span backward (but not forward span) at ini- two-thirds of patients with DLB [81 ] . tial neuropsychological evaluation about 3 years Psychosis is common in PDD and DLB (but after symptom onset, and more marked impair- more common than in PD) [74 ] . Although occur- ments (on average, more than 2 standard deviations 344 A.I. Tröster and N. Browner below normative means) by follow-up about to retrieval defi cits given poor recall but intact 2 years later [ 83 ] . In the same sample, profound recognition has been observed on remote memory impairments were noted on the Stroop interfer- tasks [88 ] . ence task at both evaluations. Visuoperceptual and Spatial Functions Executive Functions Poor drawing (constructional apraxia) is com- Executive dysfunction, as indicated by poor per- monly observed in CBD. Visuospatial impair- formance on tasks such as the WCST [ 84– 87 ] ments have also been observed [86, 91 ] . and Trail Making test [ 82, 88 ] , is common in CBD. Performance on executive tasks such as Neuropsychiatric Features “20 Questions” is more compromised in fronto- With respect to emotional and neuropsychiatric temporal dementia (FTD) than in CBD, and issues, the Neuropsychiatric Inventory (NPI) dis- therefore may be especially helpful in differenti- closed depression in 73% of CBD patients, but ating FTD from CBD [89 ] . apathy (40%), irritability (20%), and agitation (20%) also occur at considerable rates [ 98 ] . In Language comparison to PSP patients, CBD patients have Primary progressive aphasia can be a presenta- apathy less frequently, but depression and irritation of CBD [90 ] . The aphasia in CBD is most bility are more frequently reported. commonly non fl uent (about 56% of cases), followed in frequency by anomic aphasia (30%) [91 ] . Fluent and mixed cases were quite rare: Progressive Supranuclear Palsy each about 5–7% of cases. Performance on language tests in patients with the traditional CBD Cognitive defi cits are more likely to be evident presentation is somewhat inconsistent, but a key in the classical version of PSP (Richardson feature of the language problems in CBD is pho- syndrome) than in the parkinsonian subtype nologic [92 ] . Verbal fl uency is impaired [84 ] , [ 31, 99 ] . probably in large part due to the executive demands of those tasks [ 93 ] . Performance on Attention and Working Memory semantic memory tasks such as conceptual Verbal attention is often normal on elementary matching and visual confrontation naming [92 ] tests, but defi cits in visual attention are common and expressive vocabulary is relatively preserved in PSP [ 100] . Bradyphrenia is very common and and impaired in only a minority of patients [ 82, often severe in PSP [101 ] and should be consid- 94] . When naming is impaired, disproportionate ered when interpreting defi cits in higher-level bene fi t is derived from cuing, suggesting a retrieval cognitive functions. rather than semantic memory de fi cit [88, 94 ] . The apraxia in CBD is most often ideomotor, Executive Functions but ideational and limb kinetic apraxias do occur Executive dysfunction occurs early in PSP and is occasionally [84, 95– 97 ] . Patients most often hypothesized to arise from a deafferentiation of have dif fi culty demonstrating the use of tools or the basal ganglia and prefrontal cortex [102 ] utensils. though imaging also reveals correlations between frontal atrophy and executive de fi cits and frontal Learning and Memory behaviors [ 52, 103 ] . The executive de fi cits are Memory impairments in CBD involve both readily observed on brief bedside and cognitive encoding and retrieval de fi cits [84, 94 ] but may screening measures, such as the Frontal be rarer and milder than the apraxia and impair- Assessment Battery and the Mattis Dementia ments in executive functions [83 ] . Remote mem- Rating Scale (especially on the initiation/perse- ory impairment has been interpreted to be related veration subtest) [21 ] . De fi cits observed in CBD 22 Movement Disorders with Dementia in Older Adults 345 include compromised planning, problem solving Visuoperceptual and Spatial Functions [104 ] , and cognitive fl exibility [ 105 ] . Progression Oculomotor defi cits are a hallmark of PSP, with of defi cits in problem solving and cognitive impairment in voluntary vertical eye movements fl exibility may be especially rapid in PSP in com- considered a primary diagnostic feature. Other parison to other frontostriatal disorders [ 106 ] . neuro-ophthalmologic abnormalities occasionally Various frontal release signs can also be observed observed include blepharospasm and reduced in patients with PSP; for example, the “applause blinking frequency, all of which may interfere sign” (i.e., perseveration of clapping to com- with higher-level spatial cognition. Visuoperceptual mand) may be evident in as many as three-quarters abilities are also affected in PSP, including visual of PSP patients [107 ] and reliably differentiates search and scanning [106 ] , orienting [100 ] , track- PSP from PD and FTD [108 ] . ing, and attention, which may be correlated with more severe oculomotor de fi cits [122 ] . Even early Language in PSP, subtle abnormalities may be observed in Speech problems like dysarthria and hypophonia clock drawing (see Fig. 22.4 ). occur earlier [ 109 ] and are more common in PSP as compared to other movement disorders [110 ] . Neuropsychiatric Features Impairment in verbal fl uency follows the classic Apathy is the most common neuropsychiatric “subcortical” pattern of letter fl uency being more symptom in patients with PSP, perhaps refl ecting affected than category fl uency [111 ] , although pathology within medial pre-frontostriatal loops the effects of PSP on action (verb) fl uency [ 112 ] (see [ 123] ). Apathy prevalence in PSP may be as will be important to determine since PSP is associated with greater defi cits in naming verbs than nouns [113 ] . When present, de fi cits in confrontation naming of nouns may be attributable to visual misperceptions, rather than semantic memory de fi cits [ 114 ] . Patients with PSP may also display ideomotor apraxia (associated with left posterior frontal and subcortical volume loss) [115 ] , although it is less pronounced than in CBD [ 97] . Patients with PSP may present initially with primary progressive aphasia or nonfl uent aphasia [ 116– 118 ] .

Learning and Memory Episodic memory defi cits are present in PSP, but the severity of these defi cits is considerably less when compared to PDD, DLB, and AD [ 119] . Tests of episodic memory reveal a mixed encoding/retrieval pro fi le whereby free recall is impaired, but recognition discrimination is generally within normal limits [ 85 ] . Remote memory is largely unaffected [120 ] , Fig. 22.4 Clock drawn to command by a patient with progressive supranuclear palsy. Note the similarly sized though a mild defi cit in remote autobiographical clock hands, indecisiveness in placing the hand origin, memories (without a temporal gradient) has been and double perseveration (of 1 and 2) at the number “2.” observed and attributed to retrieval de fi cits [121 ] . The heart-shaped fi gure next to “2” appears to be a perse- Non-declarative learning and memory defi cits are veration of the circles indicating the origin of the hands. Also, the numbers are placed outside the clockface. The observed on measures of procedural learning but diffi culties seem most consistent with executive rather not perceptual priming [101 ] . than visuospatial dysfunction 346 A.I. Tröster and N. Browner high as about 90% [ 124 ] and is far more common nuclear palsy. Vascular dementia and some other and severe in PSP as compared to PD, which is conditions that can be associated with parkinso- more likely to present with depression, hallucina- nian features (e.g., normal pressure hydrocephalus, tions, and delusions [ 125 ] . Although apathy is Alzheimer’s disease) are discussed in separate sometimes misdiagnosed as depression, the latter chapters in this volume. does not present as a prominent neuropsychiatric feature of PSP [124 ] . Persons with PSP also exhibit behavioral signs of disinhibition [ 125 ] . As many Neuropsychological Assessment: as three-quarters of patients with PSP may evi- Practical Issues and Pointers dence changes in “personality” [ 107 ] , which can include increased irritability [125 ] . Given patients’ Review of the Medical Record possibly limited insight into their cognitive and behavioral de fi cits [126 ] , neuropsychiatric symp- Medical records should be reviewed as in any other toms often exacerbate caregiver stress and burden. neuropsychological evaluation. In the case of A summary of the neurological, radiological, and movement disorders, especially those presenting neuropsychological features of PDD, DLB, CBD, with dementias, this review is particularly impor- and PSP is provided in Table 22.5 . tant as it allows one to plan for an adequate examination and to anticipate factors that might interfere with standardized test administration. In addition Other Movement Disorders to the usual information gleaned from medical with Dementia records, record reviewing for patients with movement disorders should address the following: Several other movement disorders are associated • Age and age at onset of movement disorder with dementia. Huntington’s disease is an autosomal symptoms. dominant disorder associated with choreiform • Age at onset of cognitive changes, since this movements, dementia, and neuropsychiatric information may facilitate determination of disturbances. The disorder is not covered in detail PDD vs. DLB, and estimation of the rate of here since patients are typically younger. The cognitive decline (e.g., PSP is associated with dementia, however, is considered a prototypical especially rapid progression of executive “subcortical” dementia. Similarly, Sydenham’s de fi cits). chorea (St. Vitus’ dance), associated with group • Side of onset of movement disorder symptoms A beta-hemolytic streptococcal infection, is not such as tremor, rigidity, and bradykinesia and covered here as it usually presents in childhood. perceived asymmetry (PD and CBD often A form of parkinsonism, multiple system atro- have asymmetric profi les, whereas DLB and phy (MSA), not responsive to levodopa treat- PSP have more symmetric presentations, ment, is associated with cognitive impairments, especially axial motor symptoms). but rarely dementia, and reviews of this condi- • Nature of parkinsonian symptoms (e.g., tion’s neuropsychology have been offered else- tremor, rigidity, bradykinesia, postural insta- where [127 ] . Wilson’s disease, a genetic disorder bility, and gait disturbance) and presence of of copper metabolism, can be associated with non-parkinsonian motor features (e.g., dysto- dementia, but presentation is usually in child- nia, myoclonus, which may suggest a hood or young adulthood. It is of note that cere- tauopathy). brovascular disease can produce parkinsonism • Timing of antiparkinsonian and other medica- but vascular parkinsonism accounts for a small tions and when the patient is likely to be in the fraction of cases with parkinsonism coming to best motor “ON” state. autopsy [81 ] . Most cases are accounted for by • Presence of motor fl uctuations and their tim- Parkinson’s disease, multiple system atrophy, ing. Knowledge of fl uctuations (e.g., wearing corticobasal degeneration, and progressive supra- off, freezing) and involuntary movements Table 22.5 Summary of neurological, radiological, and neuropsychological characteristics of Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) Feature PDD DLB CBD PSP Clinical features Asymmetric onset of Tremor less common Markedly Axial rigidity dispro- rigidity, bradykinesia than in PDD and asymmetric rigidity; portionate to appen- or tremor; initially more postural than at parkinsonism is dicular rigidity; “en levodopa responsive rest; signs less minimally levodopa bloc” movement; other: but slow loss of asymmetric than in responsive. Other vertical gaze abnormal- levodopa responsive- PD/PDD signs: apraxia, alien ity; a small subset of ness; dementia onset limb, dystonia, PSP patient’s parkin- associated with myoclonus, jerky sonism may be initially postural instability tremor; cortical responsive to levodopa, and gait disturbance sensory de fi cits but mostly unresponsive to treatment MRI scan Little cortical Little cortical Posterior frontal and Frontal and midbrain atrophy atrophy; hippocampal atrophy; parietal cortex atrophy atrophy variable hippocampal atrophy is atrophy variable pronounced SPECT Mostly frontoparietal Posterior: Asymmetric Frontal-subcortical and PET and occipital occipital-parietal frontoparietal and hypoperfusion thalamic Attention/working Moderate impairment Moderate to severe Mild to moderate Mild to moderate memory/processing impairment; evident impairment impairment speed early Executive Moderate to severe Mild to moderate Normal to moderate Moderate to severe functions impairment impairment impairment impairment; evident early and typically rapidly progressive Language Normal to moder- Normal to moder- Apraxia dispropor- Normal to moderately ately impaired; ately impaired; tionate to expressive impaired; verbal fl uency impairment fl uency impairment and receptive fl uency impairment seen early, but visual is most common, but language impairment seen early confrontation naming some patients may and repetition have marked naming relatively intact until impairment like late in disease Alzheimer’s Visuospatial/ Mild to severe Moderate to severe Normal to moderate Mild to severe perceptual and impairment impairment; typically impairment impairment, perhaps constructional seen early secondary to gaze abnormalities; executive dysfunction may impact Learning and Mild to severe; Mild to severe; less Mild to moderate; Normal to moderate; memory affects mainly pronounced than in mainly retrieval often secondary to encoding and Alzheimer’s early on; de fi cits, some executive de fi cits retrieval, storage only storage (forgetting encoding problems; impacting encoding later in disease; less rates) variable; retrograde is not and/or retrieval pronounced than in remote memory temporally graded strategies Alzheimer’s; remote impairment variable memory impairment but typically no variable, but typically temporal gradient no temporal gradient and retrieval problems evident Neuropsychiatric Depression and Depression and Depression with Frequent apathy; Anxiety prominent; anxiety prominent; lesser apathy disinhibition and hallucinations (esp. hallucinations (esp. personality changes; visual); paranoid (esp. visual); paranoid (esp. depression less Othello) and phantom Othello) and phantom common boarder delusions boarder delusions 348 A.I. Tröster and N. Browner

(e.g., dyskinesia or dystonia) allows for plan- psychosocial information. In addition, it should ning and timing of the evaluation. be established whether there is a family history • Existence of pathological daytime sleepi- speci fi cally of dementias or movement ness or somnolence and time of occurrence disorders. (and REM sleep behavior disorder), and if A question that arises in interview is whether available, review of polysomnography stud- patients and care partners are accurate in report- ies. Such knowledge allows one to establish ing cognitive and other behavioral and functional at what time of day the patient is likely best changes. In the case of PD, accuracy of report tested and how much testing might reason- may vary with respect to the function being ably be undertaken in one appointment. reported upon. It has been found that patients are • Presence of marked tremor or apraxia that accurate reporters of disability, even in the pres- might interfere with tests with strong motor ence of cognitive compromise and depression demands. [ 128 ] . In contrast, in the case of memory impair- • Presence of visual problems (e.g., double ment, whereas the patient’s and care partner’s vision) or gaze abnormalities (especially in report is typically concordant and related to PSP) that might interfere with standard test patient scores on objective cognitive measures, administration. patient-care partner report discrepancies increase • Presence of marked attention fl uctuations as a function of patient cognitive impairment and (especially in DLB) that might yield spurious depression [ 129] . One study reported that care patterns of strengths and weaknesses across partners may focus on select aspects of cognitive cognitive tests. defi cit such as verbal recall [ 129 ] , but another • Existence of hallucinations (especially in study found good concordance between caregiver DLB) or affective disturbance that might report and patient’s objective performance on a compromise patient effort on testing or ability range of cognitive tasks, including those measur- to respond meaningfully. ing memory, executive function, language, and • Comorbid medical conditions, especially psychomotor speed [ 130 ] . A useful observation endocrine conditions such as thyroid dysfunc- to keep in mind is that patients, including those tion or diabetes (patients may need snack with PDD and DLB, may frequently complain of breaks to maintain adequate blood sugar memory disorders initially [25 ] , but what patients levels). describe as memory disorders may actually rep- • Utilization of medications with anticholin- resent other de fi cits. For example, reported trou- ergic effects that might impact concentration ble remembering names or words may refer to and memory (including not only agents used dysnomia, and a reported inability to recall how to treat tremor but also conditions such as uri- to operate equipment or machinery (e.g., sewing nary incontinence). machines, lawn mowers) may refer to executive • History of prior neurosurgical intervention for dysfunction. movement disorder (e.g., pallidotomy, deep During the interview, it is important to prepare brain stimulation, fetal tissue transplantation). the patient for evaluation. The patient’s anxiety If stimulators are present, determine current about evaluation should be allayed as far as pos- setting and known side effects (e.g., sible, and patients should be informed that they dysarthria). will probably fi nd some tasks easier than others and that variations in performance and skills are the norm rather than the exception. The patient Interview should be encouraged to report when they feel onset of dyskinesias or dystonias, or fl uctuations All information obtained from medical record in motor functions. Even if it is not possible to review should be veri fi ed during interview discontinue or take a break in evaluation, the along with the regularly obtained medical and presence of these features should be noted to 22 Movement Disorders with Dementia in Older Adults 349 facilitate later interpretation of test results. Several overviews of screening instruments Similarly, patients should be monitored for commonly used with or designed for PD have fatigue and especially in DLB, and some cases of recently been published [ 132, 133 ] . It should also PDD, the examiner should be alert to fl uctuations be borne in mind that recommendations made for in attention. cognitive assessment in PD by an American Academy of Neurology committee [ 134 ] are based on a now outdated literature review and Screening Instruments have limited relevance. Two commonly used screening instruments Frequently physicians and neuropsychologists not specifi cally designed for PDD and DLB are need to screen for cognitive impairment in per- the Mini-Mental State Exam (MMSE) [ 135, sons with movement disorders. While the use of 136] and the Dementia Rating Scale (DRS and screening instruments has been the subject of DRS-2) [137, 138] . More recently, the Montreal empirical investigation in PD and PDD, less Cognitive Assessment (MoCA) has been used attention has been paid to screening in PSP, CBD, in PD [139 ] . Patients with PD and other demen- and DLB. Thus, an important issue is how well tias make qualitatively different errors on the screening instruments perform in detecting cog- MMSE [ 140 ] . These qualitative differences nitive impairments in movement disorders. aside, the MMSE de-emphasizes working In comparison to full neuropsychological memory and executive functions and might lack evaluations, the advantages of cognitive screen- sensitivity to cognitive changes associated with ing instruments include their brevity, relatively subcortical-frontal dysfunction. This suspicion simple administration and scoring, patient was confi rmed by a study comparing PD patients acceptability, and limited expense. Cognitive with and without mild cognitive impairment screening can be helpful in deciding whether a (defi ned by a neuropsychological test battery). patient might require full neuropsychological The mean MMSE score of the mildly impaired evaluation. Possible disadvantages of screening group was only 1.5 points lower than that of the instruments include the limited information intact group, and in the normal range (mean 28.0, obtained, the use of cutoff scores that may not be standard deviation 2.1) [ 141 ] . The MMSE also adequately corrected for demographics and base appears to be less sensitive than the DRS to cog- rates, and limited sensitivity and specifi city for nitive defi cits in atypical parkinsonian syndromes use across a broad range of disorders. Another (Bak et al., 2005), and the Montreal Cognitive issue is that relatively few screening instruments Assessment (MoCA) [ 139 ] in PD [ 142 ] . have been developed for movement disorders, Nonetheless, the MMSE probably has adequate and the application of instruments primarily sensitivity and specifi city in detecting impair- developed for Alzheimer’s disease may have ment among unequivocally demented patients limited applicability given such instruments with PD (in whom screening may not be needed). emphasis on memory and relative neglect of Using DSM-IV dementia criteria as the “gold executive functions and working memory. standard,” a study of 126 PD patients found a Recently, more emphasis has been placed on MMSE cutoff of 23(dementia)/24(no dementia) developing instruments specifi cally for use with to have 98% sensitivity and 77% specifi city PD and PDD (and presumably such instruments [143 ] . Mean annual rate of change in the MMSE might have utility in other movement disorders), score is about 1 point for persons with PD with- but no instruments have been developed out dementia, but about 2–2.5 points for those specifi cally for PSP, CBD, and DLB. Recent with dementia [144 ] . studies of PSP and CBD have utilized generic The DRS’s sensitivity and speci fi city in detect- screening instruments such as the Dementia ing cognitive impairment in PD and related disor- Rating Scale (DRS), Addenbrooke Cognitive ders has not been adequately addressed, but Examination (ACE), and Frontal Assessment several studies show different score profi les in Battery (FAB) for screening [ 21, 131 ] . PD, PDD, DLB, and AD. One study reported that 350 A.I. Tröster and N. Browner whereas an AD group earned lower Memory sub- should also have utility with other movement test scores than a PD group with comparable disorders that can present with mild cognitive severity of cognitive impairment, the PD group compromise or dementia. attained lower Construction subtest scores. Discriminant function analyses using Memory, Initiation/Perseveration, and Construction subtest Selecting Neuropsychological Test scores correctly classi fi ed 75% of the sample Batteries for Movement Disorders [145 ] . The Construction and Initiation/ and Possible Test Modi fi cations Perseveration subtest scores of the DRS are the most helpful in distinguishing PD patients from As is the case for any neuropsychological evalua- healthy controls [ 146 ] . Though PDD and DLB tion, test selection should consider the patient’s may differ minimally in their DRS pro fi les (with condition or the differential diagnosis, the referral perhaps lower Conceptualization scores in DLB question(s), patient and caregiver concerns, the early on), Memory, Construction and Initiation/ normative and psychometric properties of the Perseveration scores best distinguish between tests (e.g., availability of alternate forms, test- PDD/DLB and AD [119 ] . retest reliability, validity for use in movement dis- Another generic dementia screening instru- orders and dementia), and the patient’s ability to ment with potential utility in PD is the cognitive tolerate and cooperate with the tests. When evalu- section of the Cambridge Examination for Mental ating patients with movement disorders, awareness Disorders (CAMCOG). Using a cutoff score of of the potential impact of various features of 80 points and below to identify dementia in PD, movement disorders (e.g., motor fl uctuations, one study reported the instrument to show 95% sleep disturbance and fatigability, choreiform and sensitivity and 94% speci fi city [143 ] . Cognitively dystonic dyskinesias, gaze palsy, apraxia, dysar- intact patients with PD (MMSE > 25) demon- thria, and hypersalivation) on test performance strate an average annual rate of change of about 4 needs to be considered (Table 22.6 ) . points on the revised version of the instrument Standard test administration methods may (CAMCOG-R) [147 ] . need to be modi fi ed when working with patients Two screening batteries for persons with with movement disorders. Downward gaze palsy, frontal and subcortical dysfunction have been as seen in PSP, makes it diffi cult for patients to published, including the Frontal/Subcortical voluntarily look down at test forms. In such cases, Assessment Battery (FSAB) [148 ] and the stimuli may be held up for the patient to see at Frontal Assessment Battery (FAB) [ 149 ] . The eye level, about 18” from the patient’s face. When latter has been used in studies of PD, but its impediments such as slurred speech are evident, psychometric properties still require further patients may be asked to repeat responses exploration. although this is frustrating to some patients, per- Several instruments specifi cally for use with haps necessitating testing over multiple brief ses- PD have been developed, including the Mini- sions. Hypophonia may be compensated for by Mental Parkinson (MMP) [ 150 ] , the Scales for an amplifi cation device. Tests requiring pointing Outcomes of Parkinson’s disease – Cognition rather than oral responses may be more appropri- (SCOPA-Cog) [ 151 ] , the Parkinson Neuro- ate for patients with speech impairment. psychometric Dementia Assessment (PANDA) A patient with tremor, dyskinesia, dystonia, or [ 152 ] , and the Parkinson’s Disease Cognitive apraxia may require help from the examiner when Rating Scale (PD-CRS) [153 ] . These instru- completing tests or questionnaires requiring writ- ments show promise but remain to be validated ing, circling of alternatives, or fi lling in of multiple in large, independent studies. No disease- choice blanks. Thus, such scales might be admin- speci fi c cognitive screening instruments have istered orally, with the examiner making the nec- been developed for use with DLB, PSP, or essary written notation. On some tasks, such as CBD, though instruments developed for PD card sorting or tower tests, the examiner may need 22 Movement Disorders with Dementia in Older Adults 351

Table 22.6 Neuropsychological tests commonly used in movement disorders with and without dementia Cognitive domain Test Premorbid estimates North American Adult Reading Test (NAART); Wechsler Test of Adult Reading (WTAR); Wide Range Achievement Test (WRAT); Advanced Clinical Solutions Test of Premorbid Functioning (TOPF) Neuropsychological screening Mattis Dementia Rating Scale (DRS); Mini-Mental Status Examination; Repeatable Battery for the Assessment of Neuropsychological Status (RBANS); Montreal Cognitive Assessment (MoCA); Parkinson’s Disease Cognitive Rating Scale (PD-CRS); Parkinson Neuropsychometric Dementia Assessment (PANDA); Scales for Outcomes of Parkinson’s Disease – Cognition (SCOPA-Cog); Cambridge Examination for Mental Disorders (Cognitive section) (CAMCOG); Addenbrooke Cognitive Examination (ACE) Intelligence Raven’s Progressive Matrices; Wechsler Abbreviated Scale of Intelligence (WASI); Wechsler Adult Intelligence Scale (WAIS) (recent editions) Attention and working memory Brief Test of Attention (BTA); Digit and Visual Span; Stroop Testa ; Digit Ordering Test; Letter Number Sequencing; Digit Symbol or Symbol Digit test Executive function Delis-Kaplan Executive Function Scale (DKEFS); Booklet Category Test; Trail Making Test (TMT)a ; Wisconsin Card Sorting Test (WCST); Tower of London (and various modi fi cations); Cambridge Neuropsychological Test Automated Battery; Verbal fl uency tests (phonemic, semantic, action) Memory Benton Visual Retention Test - recognition (BVRT-R); California Verbal Learning Test (CVLT/CVLT-II); Rey Auditory Verbal Learning Test (RAVLT); Selective Reminding Test; Rey Complex Figure Test (RCFT)a ; Wechsler Memory Scale (WMS) (recent editions)a ; Brief Visuospatial Memory Test (BVMT-R); Hopkins Verbal Learning Test (HVLT-R) Language and praxis Boston Naming Test (BNT); Controlled Oral Word Association Test (COWAT); Sentence Repetition; Token Test; Complex Ideational Material; Western Aphasia Battery subtests (including Apraxia) Visual and spatial perception and Benton Facial Recognition Test; Benton Judgment of Line Orientation (JLO); construction Hooper Visual Organization Test (VOT); Clock Drawing Motor/ fi ne motor Finger Tapping a ; Grooved Pegboarda Mood state Beck Anxiety Inventory (BAI); Beck Depression Inventory (BDI); Hamilton Depression Scale (HDS) or Inventory (HDI); The Neuropsychiatric Inventory (NPI); Pro fi le of Mood States (POMS); State-Trait Anxiety Inventory (STAI); Maudsley Obsessional-Compulsive Inventory; Yale-Brown Obsessive Compulsive Scale (YBOCS); Hospital Anxiety and Depression Scale (HADS), Montgomery-Åsberg Depression Rating Scale (MADRS); Cornell Scales for Depression in Dementia (CSDD) Quality of life, coping and stressors Parkinson’s Disease Questionnaire (PDQ); Medical Outcomes Study 36-item short form (SF-36); Sickness Impact Pro fi le (SIP); Coping Responses Inventory (CRI); Ways of Coping Questionnaire; Life Stressors and Social Resources Inventory (LISRES) a Note: Test may not be appropriate for patients with marked motor impairment to hold and move the cards or blocks/beads as In parkinsonian patients and patients with instructed by the patient (standard timing cannot dementia who have sleepiness or somnolence, be used in such cases). In general, tests with fatigue, severe motor “OFF” periods, or fre- signi fi cant motor demands are better avoided with quent fl uctuations, breaks will need to be taken. patients who have movement disorders. Though Although there may occasionally be a need to non-motor tasks might be administered when compare performances “ON” and “OFF” medi- patients have dyskinesias, the patient may still be cations, it is recommended that patients be distracted by these movements, and this needs to tested while on their antiparkinsonian medica- be considered in interpreting the test results. tions (though anticholinergics are best discon- 352 A.I. Tröster and N. Browner tinued and tapered prior to evaluation). In neurophysiologic dysfunction is, however, not patients with advanced movement disorders, advised, as this might lead to underestimation of testing during the off state is unnecessarily chal- anxiety [154 ] . PSP often features apathy, and lenging to patient and examiner, and the patient this should be assessed carefully. CBD, though may also experience increased dysphoria and also associated with a notable frequency of anxiety during off state, further complicating apathy, more often has depression. Although the test interpretation. questionnaires and scales recommended for PD neuropsychiatric evaluation have not been evaluated for the most part in other movement disor- Assessment of Neuropsychiatric ders, they seem reasonable choices in the absence Symptoms of other evidence.

Given the frequency with which affective and other neuropsychiatric symptoms occur in A Case of Possible Corticobasal movement disorders such as PDD, DLB, PSP, Degeneration (Corticobasal and CBD, information on these conditions Syndrome) should be obtained during medical record review and interview. In addition, it is often The case described was selected because it illus- helpful to quantify the severity of symptoma- trates the diffi culty one may have in clinically tology to document existence and severity of a differentiating CBD and PSP, both tauopathies. condition, and consequently, completion of A 66-year-old, right-handed, white man with various observer rating and self-report scales is 16 years of education was seen in consultation recommended. The various scales recom- at the request of a neurologist to facilitate dif- mended by the Movement Disorder Society ferential diagnosis and treatment decision mak- (MDS) are listed in Table 22.4 . ing. The patient had initially been diagnosed as One particular issue in PD, PDD, and other having Parkinson’s disease by a neurologist at movement disorders is that symptoms of an outside facility, based on left-sided cogwheel depression and anxiety may overlap with those rigidity and the presence of a very slight of the movement disorder. For example, sleep tremor. disturbance, psychomotor retardation, lack of The patient stated at evaluation that he had energy, stooped posture, masked facial expres- experienced some cognitive changes initially sion, dry mouth, and sexual dysfunction can be about 4–5 years prior to evaluation, more observed in PDD, DLB, PSP, and depression. speci fi cally noticing slowness of thought and Consequently, to improve diagnosis, it has diffi culty speaking at work (he had had a man- been suggested that early morning awakening, agement position overseeing data processing). anergia, and psychomotor slowing not be con- Though the patient had initiated a change in his sidered when diagnosing depression in PD. own job duties about 1.5 years prior to the Due to symptoms overlap, rating scales might evaluation, by the time of evaluation, he had overestimate depression in PD/PDD/DLB, and retired due to his cognitive problems. His wife in the case of PDD, empirically derived alter- had only noticed some cognitive changes in her nate cutoffs have been provided for several husband for the past year or so. He seemed to depression scales [ 127 ] . be reluctant to make decisions (although the Diagnosis of an anxiety disorder in PD is also quality of his decisions seemed adequate to the hindered by symptom overlap. Unfortunately, the wife), and she had noticed that her husband validity and reliability of anxiety rating scales had become avoidant of chores and had begun has not been widely studied. Elimination of anxi- to have dif fi culty with certain chores. For ety inventory items re fl ecting autonomic and example, when looking at tools to fi x some- 22 Movement Disorders with Dementia in Older Adults 353 thing, or at the lawn mower, he seemed uncer- recovered unaided after a few steps. Strength was tain what to do with the implements and 5/5 throughout. His cranial nerve exam was machines. He occasionally had trouble butter- largely unremarkable. His extraocular move- ing his toast, but otherwise was able to cut food ments were intact, but he had mild dif fi culty with and use utensils. smooth pursuits. Facial sensation and strength In addition, the patient about a year before was intact and symmetric. His sensory exam was evaluation had become more hesitant to drive, intact to light touch, temperature, and vibration had struck a mailbox, and consequently in all four extremities. Refl exes were 2+ and stopped driving. At evaluation, he reported symmetric throughout. Toes were downgoing that he had ceased driving due to what he bilaterally. described as dif fi culties with distance judg- The patient had had limited bene fi t from ment and perspective. antiparkinsonian medications (rasagiline and The patient had been treated for depression ropinirole) in the year before his evaluation. A with SSRIs for 6 months by his primary care phy- CT scan of the head done at an outside institu- sician about 2 years prior to this evaluation. His tion about 2 years prior to this evaluation was wife observed that her husband had been more interpreted as revealing of mild cerebral atro- easily frustrated and irritable than in the past, but phy given age. An MRI done about 10 months the patient perceived that his depression had been prior to evaluation was interpreted as revealing a reaction to perceived cognitive and motor of diffuse atrophy, greater on the right than changes, and the loss of a close friend. Recent left, and especially prominent in the frontal- mood was euthymic. parietal lobes. Regarding motor signs, the patient had had a Neuropsychological test results are presented mild, non-bothersome tremor for 12–15 years in Table 22.7 . Particularly evident were prior to evaluation (and there was a family dif fi culties with memory (recognition appeared history of this), but in the year before evaluation relatively preserved in comparison to free developed balance problems that he sometimes recall), fi ne visual motor coordination, dexterity referred to as “dizziness.” He had had 4 or 5 falls and speed, verbal fl uency, apraxia, processing without head injury. speed, and to lesser extent working memory. At the neurological evaluation, his score on Oral language comprehension was relatively the MoCA was 17/30, and declines were noticed intact, and executive dysfunction was mild. in memory, verbal fl uency, and executive and Signi fi cant affective distress was denied, and visuospatial functions. On his movement disor- the patient only reported mild symptoms of ders exam, resting tremor was absent, though depression. Overall, the neuropsychological mild postural tremor was observed in the right profi le of strengths and weaknesses in the con- arm. On fi nger-to-nose, he had mild intention text of progressive parkinsonism fairly unre- tremor on the right compared to the left. Mild sponsive to medication suggested a likely rigidity in the neck and mild-to-moderate rigidity tauopathy (note CBD was more strongly sug- in both upper and lower extremities were noted, gested than PSP, but the patient developed a greater on the left. Dysdiadochokinesis and mild gaze abnormality less than 1 year after evalua- bradykinesia was evident bilaterally, more so on tion). He also began to complain of clumsiness the left, and the patient had dif fi culty with recip- of the legs, and stubbing his toes especially rocal hand movements. Ideomotor apraxia was when climbing a curb. greater on the left. He had no diffi culty arising Interested readers are referred to a recently from a chair with his hands folded across his published neuropsychology casebook for detailed chest. Posture was slightly stooped. Observation case descriptions of other movement disorders of gait revealed good stride length but slightly with dementia, including PSP [ 155 ] , CBD [156 ] , reduced arm swing. On the retropulsion test, he and DLB [ 157 ] . 354 A.I. Tröster and N. Browner

Table 22.7 Neuropsychological test scores of a 66-year-old man with suspected corticobasal degeneration Standard score (index (I) or T-score) Test Raw score or percentile* Intelligence estimate Wechsler Test of Adult Reading (WTAR): Full Scale IQ estimate 48 121 (I) Cognitive screening Mattis Dementia Rating Scale (DRS-2): Total score (/144) 110 23 Attention/working memory/processing speed Wechsler Adult Intelligence Scale (WAIS-IV): Working Memory Index 83 (I) Wechsler Adult Intelligence Scale (WAIS-IV): Processing Speed Index 50 (I) Digit Span maxima 5 forward, 3 backward Spatial Span maxima 3 forward, 3 backward Trail Making Parts A and B (sec) 209, 300+ 15, 13 Stroop (SNST) Color and Color/Word (/112) 69, 29 <2* Executive function Wisconsin Card Sorting Test (WCST-64): Categories 1 6–10* (WCST-64): Trials to First Category 12 >16* (WCST-64): Perseverative Errors 12 41 Language 10 19 Letter Fluency (FAS) (words/180 s) Category Fluency(Animals) (words/60 s) 4 7 MAE Sentence Repetition (/14) 9 7* MAE Token Test (/44) 43 67* Motor speed/dexterity 48.1, 34.7 46, 30 Finger Tapping (dominant/nondominant hand) (average taps/10 s) Grooved Pegboard (dominant/nondominant hand) (sec) 243 (all pegs 18, 19 placed), 300+ (only 21 pegs placed) Apraxia 41 WAB Apraxia Exam (/60) Visuospatial/perceptual Benton Facial Recognition (/54) 32 (severe impairment) Judgment of Line Orientation (/30) 23 40* Clock Drawing 2/3 Verbal learning/memory Hopkins Verbal Learning Test-Revised (HVLT-R): Total Immediate Recall (/36) 14 22 Hopkins Verbal Learning Test-Revised (HVLT-R): Delayed (/12) 6 32 Hopkins Verbal Learning Test-Revised (HVLT-R): Recognition Discrimination 11–0 47 Index (recognition hits—false positives) (0–12) Brief Visuospatial Memory Test—Revised (BVMT-R): Total Immediate recall (/36) 10 29 Brief Visuospatial Memory Test—Revised (BVMT-R): Delayed (/12) 4 31 Brief Visuospatial Memory Test—Revised (BVMT-R): Recognition Discrimination 4–1 3–5* Index (recognition hits—false positives) (0-6) Brief Visuospatial Memory Test—Revised (BVMT-R): Copy (/12) 12 Mood state Pro fi le of Mood States (POMS): Tension-Anxiety 50 Pro fi le of Mood States (POMS): Depression 64 Pro fi le of Mood States (POMS): Anger-Hostility 43 Pro fi le of Mood States (POMS): Vigor-Activity <30 Pro fi le of Mood States (POMS): Fatigue-Inertia 39 Pro fi le of Mood States (POMS): Confusion-Bewilderment 66 22 Movement Disorders with Dementia in Older Adults 355

information, relevant responses, and pauses that Clinical Pearls allow better encoding of information. • In patients with movement disorders, it is crit- • When attempting to differentiate movement ical to enquire about vision. Abnormalities of disorders with dementia, consider carefully gaze and eye movements may be present and not only test scores but also qualitative fea- patients may have double vision and diffi culty tures of test performance as well as the onset, focusing or seeing test materials. evolution, and nature of motor symptoms. Also, keep in mind the base rate of disorders, their epidemiology, and typical age at onset and duration. Be familiar with the most typi- References cal neuroimaging fi ndings. • Bear in mind that patient terminology may not 1. Tröster AI. Neuropsychological characteristics of dementia with Lewy bodies and Parkinson’s disease correspond to reality when making complaints with dementia: differentiation, early detection, and of cognitive de fi cit. Thus, patients may com- implications for “mild cognitive impairment” and plain of memory problems but in fact refer to biomarkers. Neuropsychol Rev. 2008;18(1):103–19. aphasia or anomia (trouble recalling or pro- 2. Zhang ZX, Roman GC. Worldwide occurrence of Parkinson’s disease: an updated review. Neuroepide- ducing words) or executive dysfunction (an miology. 1993;12(4):195–208. inability to recall how to operate equipment 3. Bower JH, Maraganore DM, McDonnell SK, Rocca and machinery such as stoves, sewing WA. Incidence and distribution of parkinsonism in machines, and mowers). Olmsted County, Minnesota, 1976–1990. Neurology. 1999;52(6):1214–20. • The best way to ensure a smooth and effi cient 4. Perez F, Helmer C, Dartigues JF, Auriacombe S, evaluation is to be prepared for patient fatigue, Tison F. A 15-year population-based cohort study fl uctuations in attention and motor function, and of the incidence of Parkinson’s disease and demen- medication effects. These should be explored tia with Lewy bodies in an elderly French cohort. J Neurol Neurosurg Psychiatry. 2010;81(7): carefully in the medical record or when calling 742–6. the patient to schedule an appointment. 5. Aarsland D, Zaccai J, Brayne C. A systematic review • Patients often complain of trouble recalling of prevalence studies of dementia in Parkinson’s dis- people’s names, regardless of condition. We ease. Mov Disord. 2005;20(10):1255–63. 6. Biggins CA, Boyd JL, Harrop FM, Madeley P, recommend that patients use a cellular tele- Mindham RH, Randall JI, et al. A controlled, longi- phone or computer to append photos of tudinal study of dementia in Parkinson’s disease. acquaintances to contact information in the J Neurol Neurosurg Psychiatry. 1992;55(7):566–71. computer or telephone. This information, 7. Marder K, Tang MX, Cote L, Stern Y, Mayeux R. The frequency and associated risk factors for demen- including picture-name, can be reviewed prior tia in patients with Parkinson’s disease. Arch Neurol. to social encounters. Many of our patients 1995;52(7):695–701. have found this very helpful. Alternatively, 8. Mayeux R, Chen J, Mirabello E, Marder K, Bell K, they might review photo albums, although in Dooneief G, et al. An estimate of the incidence of dementia in idiopathic Parkinson’s disease. Neurology. our experience these contain too much infor- 1990;40(10):1513–7. mation and may include too few of the persons 9. McKeith IG. Dementia with Lewy bodies. Br commonly encountered. J Psychiatry. 2002;180:144–7. • Patients with movement disorders, with or with- 10. Zaccai J, McCracken C, Brayne C. A systematic review of prevalence and incidence studies of dementia out dementia, often have bradyphrenia and trou- with Lewy bodies. Age Ageing. 2005;34(6):561–6. ble keeping up with social discourse. We 11. Miech RA, Breitner JC, Zandi PP, Khachaturian AS, encourage them to engage in conversation in Anthony JC, Mayer L. Incidence of AD may decline small groups. One way to control the speed of the in the early 90s for men, later for women: The Cache County study. Neurology. 2002;58(2):209–18. fl ow of conversation is by questioning. Regular 12. Morimatsu M. Diseases other than Parkinson’s dis- questioning, without being annoying to other par- ease presenting with parkinsonism. Nippon Ronen ticipants in the conversation, allows processing of Igakkai Zasshi. 2004;41(6):589–93. 356 A.I. Tröster and N. Browner

13. Osaki Y, Morita Y, Kuwahara T, Miyano I, Doi Y. 29. Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Prevalence of Parkinson’s disease and atypical par- Duvoisin RC, et al. Clinical research criteria for the kinsonian syndromes in a rural Japanese district. diagnosis of progressive supranuclear palsy (Steele- Acta Neurol Scand. 2010;124:182–7. Richardson-Olszewski syndrome): report of the 14. Winter Y, Bezdolnyy Y, Katunina E, Avakjan G, NINDS-SPSP international workshop. Neurology. Reese JP, Klotsche J, et al. Incidence of Parkinson’s 1996;47(1):1–9. disease and atypical parkinsonism: Russian popula- 30. Jankovic J, Friedman DI, Pirozzolo FJ, McCrary JA. tion-based study. Mov disord. 2010;25(3):349–56. Progressive supranuclear palsy: motor, neurobehav- 15. Rinne JO, Lee MS, Thompson PD, Marsden CD. ioral, and neuro-ophthalmic fi ndings. Adv Neurol. Corticobasal degeneration. A clinical study of 36 1990;53:293–304. cases. Brain. 1994;117(Pt 5):1183–96. 31. Williams DR, de Silva R, Paviour DC, Pittman A, 16. Grimes DA, Lang AE, Bergeron CB. Dementia as the Watt HC, Kilford L, et al. Characteristics of two most common presentation of cortical-basal gangli- distinct clinical phenotypes in pathologically proven onic degeneration. Neurology. 1999;53(9):1969–74. progressive supranuclear palsy: Richardson’s syn- 17. Ludolph AC, Kassubek J, Landwehrmeyer BG, drome and PSP-parkinsonism. Brain. 2005;128(Pt Mandelkow E, Mandelkow EM, Burn DJ, et al. 6):1247–58. Tauopathies with parkinsonism: clinical spectrum, 32. O’Sullivan SS, Massey LA, Williams DR, Silveira- neuropathologic basis, biological markers, and treat- Moriyama L, Kempster PA, Holton JL, et al. Clinical ment options. Eur J Neurol. 2009;16(3):297–309. outcomes of progressive supranuclear palsy and 18. Nath U, Ben-Shlomo Y, Thomson RG, Morris HR, multiple system atrophy. Brain. 2008;131(Pt 5): Wood NW, Lees AJ, et al. The prevalence of pro- 1362–72. gressive supranuclear palsy (Steele-Richardson- 33. Braak H, Tredici KD, Rüb U, de Vos RA, Jansen Olszewski syndrome) in the UK. Brain. 2001;124 Steur EN, Braak E. Staging of brain pathology (Pt 7):1438–49. related to sporadic Parkinson’s disease. Neurobiol 19. Bower JH, Maraganore DM, McDonnell SK, Rocca Aging. 2003;24(2):197–211. WA. Incidence of progressive supranuclear palsy and 34. Halliday GM, McCann H. The progression of pathol- multiple system atrophy in Olmsted County, Minnesota, ogy in Parkinson’s disease. Ann N Y Acad Sci. 1976 to 1990. Neurology. 1997;49(5):1284–8. 2010;1184:188–95. 20. Nath U, Ben-Shlomo Y, Thomson RG, Morris HR, 35. Ballard C, Ziabreva I, Perry R, Larsen JP, O’Brien J, Wood NW, Lees AJ, et al. The prevalence of pro- McKeith I, et al. Differences in neuropathologic gressive supranuclear palsy (Steele-Richardson- characteristics across the Lewy body dementia spec- Olszewski syndrome) in the UK. Brain. 2001; trum. Neurology. 2006;67(11):1931–4. 124(Pt 7):1438–49. 36. Ibarretxe-Bilbao N, Tolosa E, Junque C, Marti MJ. 21. Brown RG, Lacomblez L, Landwehrmeyer BG, Bak MRI and cognitive impairment in Parkinson’s dis- T, Uttner I, Dubois B, et al. Cognitive impairment in ease. Mov Disord. 2009;24 Suppl 2:S748–53. patients with multiple system atrophy and progressive 37. Beyer MK, Larsen JP, Aarsland D. Gray matter atro- supranuclear palsy. Brain. 2010;133(Pt 8):2382–93. phy in Parkinson disease with dementia and demen- 22. Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts tia with Lewy bodies. Neurology. 2007;69(8): C, Mizuno Y, et al. Clinical diagnostic criteria for 747–54. dementia associated with Parkinson’s disease. Mov 38. Sanchez-Castaneda C, Rene R, Ramirez-Ruiz B, Disord. 2007;22(12):1689–707. Campdelacreu J, Gascon J, Falcon C, et al. 23. McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien Correlations between gray matter reductions and JT, Feldman H, et al. Diagnosis and management of cognitive de fi cits in dementia with Lewy Bodies and dementia with Lewy bodies: third report of the DLB Parkinson’s disease with dementia. Mov Disord. Consortium. Neurology. 2005;65(12):1863–72. 2009;24(12):1740–6. 24. Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ. 39. Lee JE, Park HJ, Park B, Song SK, Sohn YH, Lee What features improve the accuracy of clinical JD, et al. A comparative analysis of cognitive pro fi les diagnosis in Parkinson’s disease: a clinicopatho- and white-matter alterations using voxel-based dif- logic study. Neurology. 1992;42(6):1142–6. fusion tensor imaging between patients with 25. Noe E, Marder K, Bell KL, Jacobs DM, Manly JJ, Parkinson’s disease dementia and dementia with Stern Y. Comparison of dementia with Lewy bodies Lewy bodies. J Neurol Neurosurg Psychiatry. 2010; to Alzheimer’s disease and Parkinson’s disease with 81(3):320–6. dementia. Mov Disord. 2004;19(1):60–7. 40. Edison P, Rowe CC, Rinne JO, Ng S, Ahmed I, 26. Caballol N, Marti MJ, Tolosa E. Cognitive dysfunc- Kemppainen N, et al. Amyloid load in Parkinson’s tion and dementia in Parkinson disease. Mov Disord. disease dementia and Lewy body dementia measured 2007;22 Suppl 17:S358–66. with [11C]PIB positron emission tomography. 27. Lang AE. Corticobasal degeneration: selected devel- J Neurol Neurosurg Psychiatry. 2008;79(12):1331–8. opments. Mov Disord. 2003;18 Suppl 6:S51–6. 41. Maetzler W, Liepelt I, Reimold M, Reischl G, 28. Burn DJ, Lees AJ. Progressive supranuclear palsy: Solbach C, Becker C, et al. Cortical PIB binding in where are we now? Lancet Neurol. 2002;1(6):359–69. Lewy body disease is associated with Alzheimer- 22 Movement Disorders with Dementia in Older Adults 357

like characteristics. Neurobiol Dis. 2009;34(1): 56. Possin KL, Filoteo JV, Song DD, Salmon DP. Spatial 107–12. and object working memory defi cits in Parkinson’s 42. Bohnen NI, Kaufer DI, Hendrickson R, Constantine disease are due to impairment in different underlying GM, Mathis CA, Moore RY. Cortical cholinergic processes. Neuropsychology. 2008;22(5):585–95. denervation is associated with depressive symptoms 57. Mondon K, Gochard A, Marque A, Armand A, in Parkinson’s disease and parkinsonian dementia. Beauchamp D, Prunier C, et al. Visual recognition J Neurol Neurosurg Psychiatry. 2007;78(6):641–3. memory differentiates dementia with Lewy bodies 43. Bohnen NI, Kaufer DI, Hendrickson R, Ivanco LS, and Parkinson’s disease dementia. J Neurol Lopresti BJ, Constantine GM, et al. Cognitive cor- Neurosurg Psychiatry. 2007;78(7):738–41. relates of cortical cholinergic denervation in 58. Culbertson WC, Moberg PJ, Duda JE, Stern MB, Parkinson’s disease and parkinsonian dementia. Weintraub D. Assessing the executive function J Neurol. 2006;253(2):242–7. defi cits of patients with Parkinson’s disease: utility 44. Klein JC, Eggers C, Kalbe E, Weisenbach S, of the Tower of London-Drexel. Assessment. Hohmann C, Vollmar S, et al. Neurotransmitter 2004;11(1):27–39. changes in dementia with Lewy bodies and Parkinson 59. Ferman TJ, Smith GE, Boeve BF, Graff-Radford disease dementia in vivo. Neurology. 2010;74(11): NR, Lucas JA, Knopman DS, et al. Neuropsychological 885–92. differentiation of dementia with Lewy bodies from 45. Shimada H, Hirano S, Shinotoh H, Aotsuka A, Sato normal aging and Alzheimer’s disease. Clin K, Tanaka N, et al. Mapping of brain acetylcholin- Neuropsychol. 2006;20(4):623–36. esterase alterations in Lewy body disease by PET. 60. Grossman M, Carvell S, Stern MB, Gollomp S, Neurology. 2009;73(4):273–8. Hurtig HI. Sentence comprehension in Parkinson’s 46. Vernon AC, Ballard C, Modo M. Neuroimaging for disease: the role of attention and memory. Brain Lewy body disease: is the in vivo molecular imaging Lang. 1992;42(4):347–84. of alpha-synuclein neuropathology required and fea- 61. Breen EK. Recall and recognition memory in sible? Brain Res Rev. 2010;65(1):28–55. Parkinson’s disease. Cortex. 1993;29(1):91–102. 47. Teune LK, Bartels AL, de Jong BM, Willemsen AT, 62. Bronnick K, Alves G, Aarsland D, Tysnes OB, Eshuis SA, de Vries JJ, et al. Typical cerebral meta- Larsen JP. Verbal memory in drug-naive, newly bolic patterns in neurodegenerative brain diseases. diagnosed Parkinson’s disease. The retrieval defi cit Mov Disord. 2010;25(14):2395–404. hypothesis revisited. Neuropsychology. 2011;25(1): 48. Seppi K, Poewe W. Brain magnetic resonance imag- 114–24. ing techniques in the diagnosis of parkinsonian 63. Filoteo JV, Rilling LM, Cole B, Williams BJ, Davis syndromes. Neuroimaging Clin N Am. 2010;20(1): JD, Roberts JW. Variable memory profi les in 29–55. Parkinson’s disease. J Clin Exp Neuropsychol. 49. Groschel K, Hauser TK, Luft A, Patronas N, 1997;19(6):878–88. Dichgans J, Litvan I, et al. Magnetic resonance 64. Berger HJ, van Es NJ, van Spaendonck KP, Teunisse imaging-based volumetry differentiates progressive JP, Horstink MW, van ‘t Hof MA, et al. Relationship supranuclear palsy from corticobasal degeneration. between memory strategies and motor symptoms in Neuroimage. 2004;21(2):714–24. Parkinson’s disease. J Clin Exp Neuropsychol. 50. Tatsch K. Extrapyramidal syndromes: PET and 1999;21(5):677–84. SPECT. Neuroimaging Clin N Am. 2010;20(1):57–68. 65. Massman PJ, Delis DC, Butters N, Levin BE, Salmon 51. Hirano S, Shinotoh H, Shimada H, Aotsuka A, Tanaka DP. Are all subcortical dementias alike? Verbal N, Ota T, et al. Cholinergic imaging in corticobasal learning and memory in Parkinson’s and Huntington’s syndrome, progressive supranuclear palsy and fronto- disease patients. J Clin Exp Neuropsychol. temporal dementia. Brain. 2010;133(Pt 7):2058–68. 1990;12(5):729–44. 52. Cordato NJ, Pantelis C, Halliday GM, Velakoulis D, 66. Filoteo JV, Salmon DP, Schiehser DM, Kane AE, Wood SJ, Stuart GW, et al. Frontal atrophy correlates Hamilton JM, Rilling LM, et al. Verbal learning and with behavioural changes in progressive supranu- memory in patients with dementia with Lewy bodies clear palsy. Brain. 2002;125(Pt 4):789–800. or Parkinson’s disease with dementia. J Clin Exp 53. Paviour DC, Price SL, Jahanshahi M, Lees AJ, Fox Neuropsychol. 2009;31(7):823–34. NC. Longitudinal MRI in progressive supranuclear 67. Huber SJ, Shuttleworth EC, Paulson GW. Dementia palsy and multiple system atrophy: rates and regions in Parkinson’s disease. Arch Neurol. 1986;43(10): of atrophy. Brain. 2006;129(Pt 4):1040–9. 987–90. 54. Eckert T, Barnes A, Dhawan V, Frucht S, Gordon 68. Leplow B, Dierks C, Herrmann P, Pieper N, Annecke MF, Feigin AS, et al. FDG PET in the differential R, Ulm G. Remote memory in Parkinson’s disease diagnosis of parkinsonian disorders. Neuroimage. and senile dementia. Neuropsychologia. 1997;35(4): 2005;26(3):912–21. 547–57. 55. Metzler-Baddeley C. A review of cognitive impair- 69. Cormack F, Aarsland D, Ballard C, Tovee MJ. ments in dementia with Lewy bodies relative to Pentagon drawing and neuropsychological perfor- Alzheimer’s disease and Parkinson’s disease with mance in Dementia with Lewy Bodies, Alzheimer’s dementia. Cortex. 2007;43(5):583–600. disease, Parkinson’s disease and Parkinson’s disease 358 A.I. Tröster and N. Browner

with dementia. Int J Geriatr Psychiatry. 2004;19(4): corticobasal degeneration: comparison with progres- 371–7. sive supranuclear palsy and Alzheimer’s disease. 70. Mosimann UP, Mather G, Wesnes KA, O’Brien JT, Neurology. 1995;45(8):1477–83. Burn DJ, McKeith IG. Visual perception in Parkinson 85. Pillon B, Gouider-Khouja N, Deweer B, Vidailhet disease dementia and dementia with Lewy bodies. M, Malapani C, Dubois B, et al. Neuropsychological Neurology. 2004;63(11):2091–6. pattern of striatonigral degeneration: comparison 71. American Psychiatric Association. Diagnostic and with Parkinson’s disease and progressive supranu- Statistical Manual of Mental Disorders, Fourth clear palsy. J Neurol Neurosurg Psychiatry. 1995; Edition, Text Revision: DSM-IV-TR. Washington, 58(2):174–9. DC: American Psychiatric Association; 2000. 86. Soliveri P, Monza D, Paridi D, Radice D, Grisoli M, 72. Weintraub D, Moberg PJ, Duda JE, Katz IR, Stern Testa D, et al. Cognitive and magnetic resonance MB. Recognition and treatment of depression in imaging aspects of corticobasal degeneration and Parkinson’s disease. J Geriatr Psychiatry Neurol. progressive supranuclear palsy. Neurology. 1999; 2003;16(3):178–83. 53(3):502–7. 73. Shulman LM, Taback RL, Rabinstein AA, Weiner 87. Frasson E, Moretto G, Beltramello A, Smania N, WJ. Non-recognition of depression and other non- Pampanin M, Stegagno C, et al. Neuropsychological motor symptoms in Parkinson’s disease. Parkinsonism and neuroimaging correlates in corticobasal degen- Relat Disord. 2002;8:193–7. eration. Ital J Neurol Sci. 1998;19(5):321–8. 74. Aarsland D, Ballard C, Larsen JP, McKeith I. 88. Beatty WW, Scott JG, Wilson DA, Prince JR, A comparative study of psychiatric symptoms in Williamson DJ. Memory deﬁ cits in a demented dementia with Lewy bodies and Parkinson’s disease patient with probable corticobasal degeneration. with and without dementia. Int J Geriatr Psychiatry. J Geriatr Psychiatry Neurol. 1995;8(2):132–6. 2001;16(5):528–36. 89. Huey ED, Goveia EN, Paviol S, Pardini M, Krueger 75. Slaughter JR, Slaughter KA, Nichols D, Holmes SE, F, Zamboni G, et al. Executive dysfunction in fronto- Martens MP. Prevalence, clinical manifestations, eti- temporal dementia and corticobasal syndrome. ology, and treatment of depression in Parkinson’s Neurology. 2009;72(5):453–9. disease. J Neuropsychiatry Clin Neurosci. 2001; 90. Kertesz A, McMonagle P. Behavior and cognition in 13(2):187–96. corticobasal degeneration and progressive supranu- 76. McDonald WM, Richard IH, DeLong MR. clear palsy. J Neurol Sci. 2010;289(1–2):138–43. Prevalence, etiology, and treatment of depression in 91. Graham NL, Bak TH, Hodges JR. Corticobasal Parkinson’s disease. Biol Psychiatry. 2003;54(3): degeneration as a cognitive disorder. Mov Disord. 363–75. 2003;18(11):1224–32. 77. Schiffer RB, Kurlan R, Rubin A, Boer S. Evidence 92. Graham NL, Bak T, Patterson K, Hodges JR. for atypical depression in Parkinson’s disease. A J Language function and dysfunction in corticobasal Psychiatry. 1988;145(8):1020–2. degeneration. Neurology. 2003;61(4):493–9. 78. Walsh K, Bennett G. Parkinson’s disease and anxi- 93. Hohler AD, Ransom BR, Chun MR, Tröster AI, ety. Postgrad Med J. 2001;77(904):89–93. Samii A. The youngest reported case of corticobasal 79. Stein MB, Heuser IJ, Juncos JL, Uhde TW. Anxiety degeneration. Parkinsonism Relat Disord. 2003; disorders in patients with Parkinson’s disease. A J 10:47–50. Psychiatry. 1990;147(2):217–20. 94. Massman PJ, Kreiter KT, Jankovic J, Doody RS. 80. Vazquez A, Jimenez-Jimenez FJ, Garcia-Ruiz P, Neuropsychological functioning in cortical-basal Garcia-Urra D. “Panic attacks” in Parkinson’s ganglionic degeneration: Differentiation from disease. A long-term complication of levodopa Alzheimer’s disease. Neurology. 1996;46(3):720–6. therapy. Acta Neurologica Scandanavica. 1993; 95. Leiguarda R, Lees AJ, Merello M, Starkstein S, 87(1):14–8. Marsden CD. The nature of apraxia in corticobasal 81. Borroni B, Agosti C, Padovani A. Behavioral and degeneration. J Neurol Neurosurg Psychiatry. 1994; psychological symptoms in dementia with Lewy-bodies 57(4):455–9. (DLB): frequency and relationship with disease 96. Pharr V, Uttl B, Stark M, Litvan I, Fantie B, Grafman severity and motor impairment. Arch Gerontol J. Comparison of apraxia in corticobasal degenera- Geriatr. 2008;46(1):101–6. tion and progressive supranuclear palsy. Neurology. 82. Mimura M, White RF, Albert ML. Corticobasal 2001;56(7):957–63. degeneration: neuropsychological and clinical cor- 97. Soliveri P, Piacentini S, Girotti F. Limb apraxia in relates. J Neuropsychiatry Clin Neurosci. 1997;9(1): corticobasal degeneration and progressive supranu- 94–8. clear palsy. Neurology. 2005;64(3):448–53. 83. Murray R, Neumann M, Forman MS, Farmer J, 98. Litvan I, Cummings JL, Mega M. Neuropsychiatric Massimo L, Rice A, et al. Cognitive and motor features of corticobasal degeneration. J Neurol assessment in autopsy-proven corticobasal degener- Neurosurg Psychiatry. 1998;65(5):717–21. ation. Neurology. 2007;68(16):1274–83. 99. Srulijes K, Mallien G, Bauer S, Dietzel E, Groger A, 84. Pillon B, Blin J, Vidailhet M, Deweer B, Sirigu A, Ebersbach G, et al. In vivo comparison of Dubois B, et al. The neuropsychological pattern of Richardson’s syndrome and progressive supranuclear 22 Movement Disorders with Dementia in Older Adults 359

palsy-parkinsonism. J Neural Transm. 2011;118: nuclear palsy, and corticobasal degeneration. 1191–7. Neuropsychology. 2006;20(5):558–65. 100. Rafal RD, Posner MI, Friedman JH, Inhoff AW, 114. Podoll K, Schwarz M, Noth J. Language functions in Bernstein E. Orienting of visual attention in progres- progressive supranuclear palsy. Brain. 1991;114(Pt sive supranuclear palsy. Brain. 1988;111(Pt 2): 3):1457–72. 267–80. 115. Huey ED, Pardini M, Cavanagh A, Wassermann 101. Grafman J, Litvan I, Stark M. Neuropsychological EM, Kapogiannis D, Spina S, et al. Association of features of progressive supranuclear palsy. Brain ideomotor apraxia with frontal gray matter volume Cogn. 1995;28(3):311–20. loss in corticobasal syndrome. Arch Neurol. 102. Albert ML, Feldman RG, Willis AL. The ‘subcorti- 2009;66(10):1274–80. cal dementia’ of progressive supranuclear palsy. 116. Rohrer JD, Paviour D, Bronstein AM, O’Sullivan J Neurol Neurosurg Psychiatry. 1974;37(2):121–30. SS, Lees A, Warren JD. Progressive supranuclear 103. Josephs KA, Whitwell JL, Eggers SD, Senjem ML, palsy syndrome presenting as progressive nonfl uent Jack CR, Jr. Gray matter correlates of behavioral aphasia: a neuropsychological and neuroimaging severity in progressive supranuclear palsy. Mov analysis. Mov Disord. 2010;25(2):179–88. Disord. 2011;26:493–8. 117. Boeve B, Dickson D, Duffy J, Bartleson J, Trenerry 104. Monza D, Soliveri P, Radice D, Fetoni V, Testa D, M, Petersen R. Progressive nonfl uent aphasia and Caffarra P, et al. Cognitive dysfunction and impaired subsequent aphasic dementia associated with atypi- organization of complex motility in degenerative cal progressive supranuclear palsy pathology. Eur parkinsonian syndromes. Arch Neurol. 1998;55(3): Neurol. 2003;49(2):72–8. 372–8. 118. Mochizuki A, Ueda Y, Komatsuzaki Y, Tsuchiya K, 105. Millar D, Grif fi ths P, Zermansky AJ, Burn DJ. Arai T, Shoji S. Progressive supranuclear palsy pre- Characterizing behavioral and cognitive dysexecu- senting with primary progressive aphasia–clinico- tive changes in progressive supranuclear palsy. Mov pathological report of an autopsy case. Acta Disord. 2006;21(2):199–207. Neuropathologica (Berlin). 2003;105(6):610–4. 106. Soliveri P, Monza D, Paridi D, Carella F, Genitrini S, 119. Aarsland D, Litvan I, Salmon D, Galasko D, Wentzel- Testa D, et al. Neuropsychological follow up in Larsen T, Larsen JP. Performance on the Dementia patients with Parkinson’s disease, striatonigral degen- Rating Scale in Parkinson’s disease with dementia eration-type multisystem atrophy, and progressive and dementia with Lewy bodies: comparison with supranuclear palsy. J Neurol Neurosurg Psychiatry. progressive supranuclear palsy and Alzheimer’s dis- 2000;69(3):313–8. ease. J Neurol Neurosurg Psychiatry. 2003;74:1215–20. 107. Kaat LD, Boon AJ, Kamphorst W, Ravid R, 120. Pillon B, Dubois B, Ploska A, Agid Y. Severity and Duivenvoorden HJ, van Swieten JC. Frontal presen- speci fi city of cognitive impairment in Alzheimer’s, tation in progressive supranuclear palsy. Neurology. Huntington’s, and Parkinson’s diseases and progressive 2007;69(8):723–9. supranuclear palsy. Neurology. 1991;41(5):634–43. 108. Dubois B, Slachevsky A, Pillon B, Beato R, 121. Zarei M, Pouretemad HR, Bak T, Hodges JR. Villalponda JM, Litvan I. “Applause sign” helps to Autobiographical memory in progressive supranu- discriminate PSP from FTD and PD. Neurology. clear palsy. Eur J Neurol. 2010;17(2):238–41. 2005;64(12):2132–3. 122. Bak TH, Caine D, Hearn VC, Hodges JR. Visuospatial 109. O’Sullivan SS, Massey LA, Williams DR, Silveira- functions in atypical parkinsonian syndromes. Moriyama L, Kempster PA, Holton JL, et al. Clinical J Neurol Neurosurg Psychiatry. 2006;77(4):454–6. outcomes of progressive supranuclear palsy and mul- 123. Joel D. Open interconnected model of basal ganglia- tiple system atrophy. Brain. 2008;131(Pt thalamocortical circuitry and its relevance to the 5):1362–72. clinical syndrome of Huntington’s disease. Mov 110. Cordato NJ, Halliday GM, Caine D, Morris JG. Disord. 2001;16(3):407–23. Comparison of motor, cognitive, and behavioral fea- 124. Litvan I, Mega MS, Cummings JL, Fairbanks L. tures in progressive supranuclear palsy and Parkinson’s Neuropsychiatric aspects of progressive supranu- disease. Mov Disord. 2006;21(5):632–8. clear palsy. Neurology. 1996;47(5):1184–9. 111. Rosser A, Hodges JR. Initial letter and semantic 125. Aarsland D, Litvan I, Larsen JP. Neuropsychiatric category fl uency in Alzheimer’s disease, symptoms of patients with progressive supranuclear Huntington’s disease, and progressive supranuclear palsy and Parkinson’s disease. J Neuropsychiatry palsy. J Neurol Neurosurg Psychiatry. 1994;57(11): Clin Neurosci. 2001;13(1):42–9. 1389–94. 126. O’Keeffe FM, Murray B, Coen RF, Dockree PM, 112. Piatt AL, Fields JA, Paolo AM, Koller WC, Tröster Bellgrove MA, Garavan H, et al. Loss of insight in AI. Lexical, semantic, and action verbal fl uency in frontotemporal dementia, corticobasal degeneration Parkinson’s disease with and without dementia. J and progressive supranuclear palsy. Brain. Clin Exp Neuropsychol. 1999;21(4):435–43. 2007;130(Pt 3):753–64. 113. Cotelli M, Borroni B, Manenti R, Alberici A, 127. Tröster AI, Fields JA. Parkinson’s disease, progres- Calabria M, Agosti C, et al. Action and object nam- sive supranuclear palsy, corticobasal degeneration, ing in frontotemporal dementia, progressive supra- and related disorders of the frontostriatal system. In: 360 A.I. Tröster and N. Browner

Morgan JE, Ricker JH, editors. Textbook of clinical the detection of MCI and dementia in Parkinson dis- neuropsychology. New York: Psychology; 2008. p. ease. Neurology. 2009;73(21):1738–45. 536–77. 143. Hobson P, Meara J. The detection of dementia and 128. Brown RG, MacCarthy B, Jahanshahi M, Marsden cognitive impairment in a community population of CD. Accuracy of self-reported disability in patients elderly people with Parkinson’s disease by use of the with parkinsonism. Arch Neurol. 1989;46(9): CAMCOG neuropsychological test. Age Ageing. 955–9. 1999;28(1):39–43. 129. Sitek EJ, Soltan W, Wieczorek D, Robowski P, 144. Aarsland D, Andersen K, Larsen JP, Perry R, Slawek J. Self-awareness of memory function in Wentzel-Larsen T, Lolk A, et al. The rate of cogni- Parkinson’s disease in relation to mood and symp- tive decline in Parkinson disease. Arch Neurol. tom severity. Aging Ment Health. 2011;15:150–6. 2004;61(12):1906–11. 130. Naismith SL, Pereira M, Shine JM, Lewis SJ. How 145. Paolo AM, Tröster AI, Glatt SL, Hubble JP, Koller well do caregivers detect mild cognitive change in WC. Differentiation of the dementias of Alzheimer’s Parkinson’s disease? Mov Disord. 2011;26(1):161–4. and Parkinson’s disease with the Dementia Rating 131. Bak TH, Rogers TT, Crawford LM, Hearn VC, Scale. J Geriatr Psychiatry Neurol. 1995;8(3):184–8. Mathuranath PS, Hodges JR. Cognitive bedside 146. Brown GG, Rahill AA, Gorell JM, McDonald C, assessment in atypical parkinsonian syndromes. Brown SJ, Sillanpaa M, et al. Validity of the J Neurol Neurosurg Psychiatry. 2005;76(3):420–2. Dementia Rating Scale in assessing cognitive func- 132. Kulisevsky J, Pagonabarraga J. Cognitive impair- tion in Parkinson’s disease. J Geriatr Psychiatry ment in Parkinson’s disease: tools for diagnosis and Neurol. 1999;12(4):180–8. assessment. Mov Disord. 2009;24(8):1103–10. 147. Athey RJ, Porter RW, Walker RW. Cognitive assess- 133. Chou KL, Amick MM, Brandt J, Camicioli R, Frei ment of a representative community population with K, Gitelman D, et al. A recommended scale for cog- Parkinson’s disease (PD) using the Cambridge nitive screening in clinical trials of Parkinson’s dis- Cognitive Assessment-Revised (CAMCOG-R). Age ease. Mov Disord. 2010;25(15):2501–7. Ageing. 2005;34(3):268–73. 134. Miyasaki JM, Shannon K, Voon V, Ravina B, 148. Rothlind JC, Brandt J. A brief assessment of frontal and Kleiner-Fisman G, Anderson K, et al. Practice subcortical functions in dementia. J Neuropsychiatry Parameter: evaluation and treatment of depression, Clin Neurosci. 1993;5(1):73–7. psychosis, and dementia in Parkinson disease (an 149. Dubois B, Slachevsky A, Litvan I, Pillon B. The evidence-based review): report of the Quality FAB: a Frontal Assessment Battery at bedside. Standards Subcommittee of the American Academy Neurology. 2000;55(11):1621–6. of Neurology. Neurology. 2006;66(7):996–1002. 150. Mahieux F, Michelet D, Manifacier M-J, Boller F, 135. Folstein MF, Folstein SE, McHugh PR. Mini-mental Fermanian J, Guillard A. Mini-Mental Parkinson: state. A practical method for grading the cognitive fi rst validation study of a new bedside test con- state of patients for the clinician. J Psychiatr Res. structed for Parkinson’s disease. Behav Neurol. 1975;12(3):189–98. 1995;8:15–22. 136. Folstein MF, Folstein SE, Fanjiang G. Mini-Mental 151. Marinus J, Visser M, Verwey NA, Verhey FR, State Examination clinical guide. Lutz, FL: Middelkoop HA, Stiggelbout AM, et al. Assessment Psychological Assessment Resources; 2001. of cognition in Parkinson’s disease. Neurology. 137. Mattis S. Dementia Rating Scale-2. Lutz, FL: 2003;61(9):1222–8. Psychological Assessment Resources, Inc.; 2001. 152. Kalbe E, Calabrese P, Kohn N, Hilker R, Riedel O, 138. Mattis S. Dementia Rating Scale. Odessa, FL: Wittchen HU, et al. Screening for cognitive defi cits in Psychological Assessment Resources; 1988. Parkinson’s disease with the Parkinson neuropsycho- 139. Nasreddine ZS, Phillips NA, Bedirian V, metric dementia assessment (PANDA) instrument. Charbonneau S, Whitehead V, Collin I, et al. The Parkinsonism Relat Disord. 2008;14(2):93–101. Montreal Cognitive Assessment, MoCA: a brief 153. Pagonabarraga J, Kulisevsky J, Llebaria G, Garcia- screening tool for mild cognitive impairment. J Am Sanchez C, Pascual-Sedano B, Gironell A. Geriatr Soc. 2005;53(4):695–9. Parkinson’s disease-cognitive rating scale: a new 140. Jefferson AL, Cosentino SA, Ball SK, Bogdanoff B, cognitive scale speci fi c for Parkinson’s disease. Mov Leopold N, Kaplan E, et al. Errors produced on the Disord. 2008;23(7):998–1005. Mini-Mental State Examination and neuropsycho- 154. Higginson CI, Fields JA, Koller WC, Tröster AI. logical test performance in Alzheimer’s disease, isch- Questionnaire assessment potentially overestimates emic vascular dementia, and Parkinson’s disease. J anxiety in Parkinson’s disease. J Clin Psychol Med Neuropsychiatry Clin Neurosci. 2002;14(3):311–20. Settings. 2001;8(2):95–9. 141. Janvin C, Aarsland D, Larsen JP, Hugdahl K. 155. Tröster AI, Williams RC. Progressive supranuclear Neuropsychological pro fi le of patients with palsy. In: Morgan JE, Baron IS, Ricker JH, editors. Parkinson’s disease without dementia. Dement Casebook of clinical neuropsychology. New York: Geriatr Cogn Disord. 2003;15(3):126–31. Oxford University; 2011. p. 596–605. 142. Hoops S, Nazem S, Siderowf AD, Duda JE, Xie SX, 156. Lucas JA. A case of corticobasal syndrome. In: Stern MB, et al. Validity of the MoCA and MMSE in Morgan JE, Baron IS, Ricker JH, editors. Casebook 22 Movement Disorders with Dementia in Older Adults 361

of clinical neuropsychology. New York: Oxford rating scales in Parkinson’s disease: critique University; 2011. p. 559–66. and recommendations. Mov Disord. 2008;23(14): 157. Ferman TJ. Clinical and neuropathologic presenta- 2015–25. tion of dementia with Lewy bodies. In: Morgan JE, 161. Leentjens AF, Dujardin K, Marsh L, Martinez- Baron IS, Ricker JH, editors. Casebook of clinical Martin P, Richard IH, Starkstein SE, et al. Apathy neuropsychology. New York: Oxford University; and anhedonia rating scales in Parkinson’s disease: 2011. p. 550–8. critique and recommendations. Mov Disord. 158. Tröster AI, Woods SP. Neuropsychological aspects. 2008;23(14):2004–14. In: Pahwa R, Lyons KE, editors. Handbook of 162. Fernandez HH, Aarsland D, Fenelon G, Friedman Parkinson’s disease. 4th ed. New York: Informa; JH, Marsh L, Troster AI, et al. Scales to assess 2007. p. 109–31. psychosis in Parkinson’s disease: Critique and 159. Schrag A, Barone P, Brown RG, Leentjens AF, recommendations. Mov Disord. 2008;23(4): McDonald WM, Starkstein S, et al. Depression rat- 484–500. ing scales in Parkinson’s disease: critique and rec- 163. Hogl B, Arnulf I, Comella C, Ferreira J, Iranzo A, ommendations. Mov Disord. 2007;22(8):1077–92. Tilley B, et al. Scales to assess sleep impairment in 160. Leentjens AF, Dujardin K, Marsh L, Martinez- Parkinson’s disease: critique and recommendations. Martin P, Richard IH, Starkstein SE, et al. Anxiety Mov Disord. 2010;25(16):2704–16. Neuropsychological Considerations for Parkinson’s Disease Patients 2 3 Being Considered for Surgical Intervention with Deep Brain Stimulation

Paul J. Mattis , Chaya B. Gopin , and Kathryn Lombardi Mirra

Abstract In addition to their motor symptoms, patients diagnosed with idiopathic Parkinson’s disease (PD) often exhibit a subcortical pattern of cognitive impairment. Deep brain stimulation (DBS) is one of the treatments used to improve motor functioning in PD patients; however, studies focusing on the effects of DBS on cognition, mood, and behavior have produced mixed ﬁ ndings. This chapter reviews the history of various treatments for PD, the recent literature regarding DBS, and the neuropsychological outcomes in patients who undergo such surgery for the treatment of parkinsonian motor symptoms. DBS as a treatment for several other neurologic and psychiatric disorders is also discussed. In addition, case examples and recommendations for the neuropsychologist are presented.

Keywords Parkinson’s disease • Surgery • Ablative • Deep brain stimulation • Fetal transplantation • Gene therapy • Subcortical • Subthalamic nucleus • Globus pallidus

Introduction to Parkinson’s Disease P. J. Mattis () Center for Neurosciences, The Feinstein Institute Idiopathic Parkinson’s disease (PD) is a neurode- for Medical Research , Manhasset , NY , 11030 , USA generative disorder that is characterized by motor Department of Neurology , North Shore University symptoms, including resting tremor, bradykinesia, Hospital , Manhasset , NY , 11030 , USA muscle rigidity, and postural instability. Cognitive e-mail: [email protected] and behavioral disturbances are also common C. B. Gopin, Ph.D. • K. L. Mirra, Ph.D. to this disease and contribute to its functional Department of Neurology , North Shore University Hospital , Manhasset , NY , 11030 , USA disability [1– 3] . Onset is typically around age 65 years, although approximately 8% of individ- Department of Psychiatry , The Zucker Hillside Hospital , 75-59 263 rd Street , Glen Oaks , NY , 11004 , USA uals develop the illness “early,” between 21 and e-mail: [email protected] ; [email protected] 40 years of age [3 ] .

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 363 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_23, © Springer Science+Business Media, LLC 2013 364 P.J. Mattis et al.

The relationship between the development of in the forebrain that is lost due to the illness, PD and the gradual death of dopamine neurons, consistently reversing many of the key motor specifi cally in the substantia nigra pars compacta symptoms: akinesia, bradykinesia, and rigidity. (SNc), has been recognized since the 1950s However, it does not prevent the progression of [4– 6 ] . It is now known that symptoms of PD the disease, and for most patients, the ef fi cacy of manifest once a signi fi cant portion (approxi- the medication declines after 5 years of daily mately 60–70%) [ 7] of SNc dopaminergic cells treatment [ 14] . Long-term use of Levodopa is die, resulting in increased activity within the also hampered by treatment-induced motor com- motor circuitry (See [ 8 ] for a review). Speci fi cally, plications, such as dyskinesias and motor the diminished dopamine level in the SNc reduces fl uctuations [15 ] . Furthermore, nondopaminer- the inhibitory infl uence on the subthalamic gic symptoms (e.g., choking, drooling, sleep nucleus (STN), which then exerts excessive excit- disturbances, mood disorders, dementia) ulti- atory in fl uence on the globus pallidus pars interna mately start to emerge, contributing to the (GPi). This, in turn, contributes to increased inhi- disability of late-stage PD [ 16 ] . As such, alter- bition of thalamocortical neurons, which are nate treatments have been sought, including new responsible, in part, for the rhythmic tremors at surgical interventions. rest, inability to initiate/complete voluntary movements, and cogwheel rigidity associated with PD [9 ] . History of Surgical Treatments for PD Given the neural circuitry that has been implicated in PD, it is not surprising that patients often The use of surgical treatment to obtain symptom exhibit a subcortical pattern of cognitive impair- relief in PD dates back over a century (for detailed ment. The neuropsychological profi le of patients review see [11 ] and [17 ] ). In the early 1900s, with PD tends to reveal mild de fi cits in aspects of Victor Horsley and Henry Clark introduced basic executive functioning, memory, and visuospatial stereotactic neurosurgery techniques. After creat- functioning. Additionally, symptoms of depres- ing small openings in the skull, the researchers sion are frequently reported [ 10 ] . Language abili- were able to target specifi c brain structures that ties generally remain intact, although language they had previously identifi ed using a three- defi cits are occasionally reported and, in these dimensional Cartesian coordinate system. In instances, are largely secondary to executive dys- 1909, Horsley began to use ablative surgery function and/or motor impairment. The reader is through lesioning certain areas of the sensorimo- referred to Chap. 22 for a more comprehensive tor cortex [11 ] . Although this technique success- discussion of the neurocognitive impairment fully reduced the severity of resting tremors, associated with PD. additional impairment was evident in the performance of voluntary movements. The use of ablative surgery was further popularized in 1939 Treatment for PD when Bucy and colleagues implemented the technique to lesion the corticospinal tracts. Also in Overview 1939, Russell Meyers was the fi rst to operate on the basal ganglia through an open craniotomy Treatments for PD attempt to restore the motor procedure. Although effective in alleviating some circuit’s delicate balance, either through intro- of the motor symptoms, there was a high mortal- ducing dopaminergic medications that increase ity rate associated with the procedure, prompting the output of the substantia nigra or through sur- explorations for safer treatments [ 11 ] . In the late gical techniques that reduce the activity of the 1940s, Spiegal and colleagues and Leskell fur- STN or GPi [ 11– 13] . Levodopa, a dopamine sup- thered the use of stereotaxic techniques, resulting plement, is currently the gold standard of treat- in the implementation of relatively less invasive ment for PD [ 14 ] . Levodopa replaces dopamine approaches (for review, see [17 ] ). 23 Neuropsychological Considerations for Parkinson’s Disease Patients Being Considered… 365

In 1952, while conducting a pedunculotomy that the transplanted neurons would grow, connect, of a patient with PD, Irving Cooper accidentally and release DA, and thus, transplantation would interrupted fl ow in the anterior choroidal artery. enable the maintenance of a relatively steady To his surprise, the patient’s tremor and rigidity supply of dopamine to remain in the synaptic vastly improved postoperatively [ 18 ] . This acci- clefts [ 21, 22 ] . However, double-blind clinical dental fi nding prompted Cooper to deliberately trials produced mixed results [ 23 ] , and several use this procedure over the next several years to transplantations resulted in the development of alleviate PD motor symptoms [17 ] . unforeseen, severe, off-medication dyskine- Throughout the 1950s and 1960s, spurred by sias that warranted DBS intervention [ 24 ] . advancements in the understanding of PD neuro- Nevertheless, clinical improvement was noted for pathology, ablative surgeries were also widely patients who were 60 years of age or younger used. Destructive agents, such as alcohol, heat, or [23 ] , and the grafts were later found to remain cold, were introduced to a specifi ed location to viable 4 years postsurgery [ 25 ] . Further, there lesion the site [ 11 ] . Targeting speci fi c areas of the were no indications of cognitive decline follow- basal ganglia proved to be a relatively effective ing fetal tissue implantation [ 26 ] . At the time of and safe approach, leading to positive outcomes this chapter, a large-scale multicenter clinical and reduction of certain motor symptoms. trial in Europe is being undertaken (Principal Levodopa was fi rst introduced for the treatment Investigator: Roger Barker, M.D. from the of PD in 1968. The outcome was so promising that University of Cambridge); however, to date, the the use of surgical techniques decreased dramati- use of fetal nigral tissue transplantation for cally over the next several years [11, 17– 19 ] ; how- the alleviation of PD symptoms remains exclu- ever, in the late 1970s, it became evident that some sively an experimental treatment. patients became refractory to levodopa treatment over time. In other patients, treatment-induced motor complications and dyskinesias were Gene Therapy observed. These fi ndings, in conjunction with advancements in neuroimaging techniques and Gene therapy has become the focus of a few PD neurophysiological brain mapping, resulted in the treatment studies in recent years. Using modi fi ed reemergence of surgical intervention [11, 20 ] . viruses (vectors), genetic material is introduced Ablative techniques targeting the GPi and into the neurons within the motor circuit in the ventral intermediate nucleus of the thalamus hopes of reestablishing normal brain activity. (Vim) were frequently employed. Then, in the Recently, researchers have demonstrated that an early 1990s, deep brain stimulation (DBS) became AAV vector can be used safely to deliver the glu- an accepted and effective method of treatment [ 18 ] . tamic acid decarboxylase (GAD) gene directly Like ablative techniques, DBS treatment was into STN neurons [ 27 ] . There was no evidence of aimed at the above-mentioned targets (i.e., GPi, cognitive decline in these patients [ 28 ] . Given Vim) as well as the STN. Rather than destroying that reduced GABAergic input from the GP the targeted tissue through lesioning [17 ] , DBS increases the activity of the STN in PD patients introduced a reversible electrical impulse to the [29– 31 ] , Kaplitt and colleagues [ 27] hypothe- surrounding neuronal tissues near the target [18 ] . sized that the introduction of GAD, which cata- This technique will be discussed in detail below. lyzes the synthesis of GABA, would restore the delicate balance of neurotransmitters within the motor circuit. Indeed, prior studies conducted Fetal Transplantation in animals indicated that AAV-GAD improved brain function and PD-like symptoms without More recently, researchers began implanting causing toxic side effects [32– 35 ] . Although this fetal-stage neurons into the caudate-putamen or single study was not designed to assess the effec- substantia nigra of PD patients. It was hypothesized tiveness of the intervention, clinical outcomes 366 P.J. Mattis et al. were encouraging. Substantial improvements in Nevertheless, the infrequent occurrence of such both the “OFF” and “ON” states were observed, complications, coupled with the fact that the benefi ts beginning at 3 months after surgery and continuing of the surgery greatly outweigh the costs, ultimately until the end of the trial (i.e., 1 year postsurgery). led the FDA to approve DBS for the treatment of Randomized and placebo-controlled studies are medically intractable symptoms of movement dis- under way, and the data should be released in the orders in 2002 [ 9 ] . Since that time, thousands of coming year. This promising mode of treatment patients have undergone the procedure [37 ] . may prove to be the intervention of choice in the Investigators are still not entirely certain how future, as it does not require indwelling hardware the treatment works at the cellular level (for or frequent readjustments and may restore the review of the functional mechanism, see [39 ] ). motor network function to baseline through Micro-lesions from the procedure itself do pro- activity-dependent release of GABA [27 ] . duce motor network changes [ 40 ] , but these changes dissipate over time. It is also clear that the changes in motor circuitry with STN-DBS Deep Brain Stimulation (DBS) and those with levodopa administration have much in common but are not identical [ 41 ] . It has DBS involves the application of high-frequency been suggested that STN-DBS affects neuronal electrical stimulation directly into the neurons of membrane potentials and voltage-dependent the motor circuit. A burr hole is performed under calcium channels surrounding the pathologic cir- local anesthesia. Then, using stereotactic guid- cuitry [ 9 ] . In doing so, DBS may be altering the ance, stimulating quadripolar electrodes are fi ring pattern of STN neurons to immediately implanted using both direct MRI and CT target- produce a therapeutic effect at the electrode’s tip ing, as well as “indirect targeting” based on the [42, 43 ] . It is also possible that the stimulation is known locations of these targets relative to fi xed not affecting the cell bodies; rather, the axons midline structures (anterior and posterior com- carrying signals into the STN from other areas missure). Ventriculography, involving injection may be the target of the stimulation’s effects [ 9 ] . of contrast into the ventricular system, was rou- Support for this notion has been generated tinely used prior to the CT and MRI era and is through studies of animal models of PD, in which now used by only a few centers given the inva- optically stimulated cortical neurons, whose siveness of the procedure [ 36 ] . Thin wire elec- axons reach down to the STN, also diminish trodes are aimed at the target, and intraoperative PD-like signs [44 ] . stimulation is used to predict the effects of chronic Although the STN is currently the most sought stimulation, which assists in determining the fi nal out target for DBS, stimulation of other aspects site of electrode implantation [ 37 ] . Once the sig- of motor network, including the GPi [ 45 ] and nal strength and fi nal contact position have been Vim of the thalamus [46 ] , is also common. As the verifi ed, which typically occurs 1–2 days after scientifi c community learns more about the sub- surgery, one or two internal pulse generators are cortical pathophysiology of PD, target selection implanted under the skin in the subclavicular can be based more on the patient’s most disabling region near the collar bone [1 ] . These generators symptoms, medication response (including side create an open loop system in which electrical effects), and therapy goals [ 37 ] . Currently, DBS stimulation is delivered on a set, constant, pre- targeting the Vim is generally utilized to treat programmed schedule. Finally, three-dimensional only the contralateral tremor, without having computer tomography or MRI scans are per- impact on rigidity or bradykinesia [ 18 ] . As such, formed a few days later to confi rm the position of the Vim is not targeted as often as other structures the electrodes [9 ] . during DBS procedures. GPi DBS greatly reduces Risks associated with DBS surgery include air dyskinesias during the “ON” state, while STN- embolus, stroke, seizures, hemorrhage, hydro- DBS helps to alleviate some of the motor impair- cephalus, infections, and lead fractures [ 38 ] . ments during the “OFF” state [18 ] . Further, DBS 23 Neuropsychological Considerations for Parkinson’s Disease Patients Being Considered… 367 placement in the pedunculopontine nucleus has changes in psychomotor speed since performance been shown to be effective in reducing freezing on psychomotor tasks tends to remain stable or to of gait [47 ] . improve [54 ] . Several different explanations have been posited to explain this post-DBS cognitive weakness. Based on the activation of the left infe- Neuropsychological Outcome in rior frontal gyrus that was observed during neu- Patients Undergoing DBS roimaging studies of patients who underwent STN-DBS, Saint-Cyr and colleagues [ 55] hypoth- The improvement in motor functioning following esized that stimulating the STN may impact the DBS has been well documented [48 ] . In contrast, striato-thalamo-cortical circuit. This would then studies focusing on the effects of DBS on cogni- affect word generation, an ability that has been tion, mood, and behavior have yielded mixed localized to the left inferior frontal gyrus. fi ndings. It is possible that the variation in fi ndings Alternatively, it is plausible that the current used is due to differences in the treatment protocols to stimulate the STN may spread to adjacent cog- used at various centers. Other differences may nitive circuits [54, 56 ] , thereby disrupting the include the comparison groups used and the char- pathway associated with verbal fl uency. acteristics of the patient populations, as well as Decline in learning and memory has also been small sample sizes and variable amounts of time a consistent fi nding in DBS outcome studies; that elapsed until follow-up. An overview of however, the clinical signifi cance of these fi ndings these fi ndings are presented below. is questionable because the degree of decline may be limited [1 ] . Additionally, there is evidence to suggest that these abilities return to their pre-DBS Motor Outcome state as time elapses [50, 57, 58 ] . It is possible, therefore, that the reported declines in learning STN-DBS and GPi DBS have both been reported and memory are due to secondary factors (e.g., to improve the cardinal motor features of PD, edema, stimulator setting) and are not indicative including tremor, bradykinesia, rigidity, akinesia, of true impairment in these cognitive abilities. gait speed, stride length, lower limb joint move- Results of studies assessing the cognitive effects ments, postural instability, and levodopa-induced of STN-DBS in PD patients seem to suggest that the dyskinesia [37, 48, 49] . Further, DBS can reduce likelihood of decline is more frequently observed in levodopa-induced motor complications, such as older patients, who have a greater tendency to have prolonged “OFF ” periods and dyskinesias [50 ] . presurgical cognitive impairments than younger Although the long-term implications of these treat- patients [59 ] . However, Perriol and colleagues [60 ] ments are not fully appreciated, multiple studies of found that neither age at time of surgery, disease patients who are approximately 5 years posttreat- duration, or performance on a cognitive screen ment have suggested sustained ef fi cacy [51, 52 ] . (Dementia Rating Scale (DRS) total score), prior to surgery impacted outcome. Overall, preoperative cognitive de fi cits, confusion, and history of psycho- Cognitive Changes sis (induced by dopaminergic medication) were the factors that predicted cognitive outcome 12 months Findings regarding the cognitive changes associated after surgery [48, 61– 63 ] . with DBS vary widely (for review, see [37 ] ), with some studies reporting cognitive improvement, others revealing cognitive decline, and still others Psychosocial Changes and Quality showing no alterations in neurocognitive function- of Life ing. However, the most consistent fi nding is a mild decline in verbal fl uency, both phonemic and The fi ndings regarding psychiatric changes fol- semantic [53 ] , which cannot be accounted for by lowing surgery have also been mixed. Reductions 368 P.J. Mattis et al. in symptoms of depression and anxiety are With respect to other psychiatric symptoms, commonly described by patients [ 1 ] ; however, treatment with dopaminergic agents is a primary investigations that have focused on behavioral cause of hallucinations in PD [74 ] . Since treatment outcome have reported either no change in mood with DBS may lead to a decrease in pharmaco- symptoms [48, 59, 60 ] or signi fi cant psychological logical treatment, a reduction in these psychiatric disturbances and behavioral changes following symptoms can occur as a result. Interestingly, the DBS. Reported increases in mood symptoms existence of hallucinations presurgically does not were generally associated with dysthymia or appear to be a risk factor for the presence emotional lability [60, 64 ] . Yet, there are preliminary of these psychotic symptoms posttreatment reports documenting that patients have experi- [ 75, 76 ] . enced periods of mania/hypomania [65, 66 ] , Improvements in quality of life have been mirthful laughter [67 ] , and visual hallucinations reported for patients who underwent treatment [68 ] after undergoing DBS surgery. York and col- with DBS [77 ] as well as for their families [ 78 ] . leagues [59 ] reported that patients experienced Although reduced reliance on medications has slightly elevated levels of anxiety after under- been cited as the most common reason for these going DBS surgery, and this was observed to improvements [79 ] , advances in the ability to be highly correlated with disease duration [ 59 ] . perform activities of daily living (ADLs) have All other investigations conducted to date have also been reported [ 60, 70 ] . Further, improve- found that anxiety symptoms remain stable [ 69 ] ment in ADLs may be present even fi ve years or improve after the surgery is performed [70, 71 ] . posttreatment [79 ] . Nevertheless, the recovery of Mild improvements in obsessive-compulsive such abilities may not affect change in social symptoms and paranoid thoughts have also been adjustment. In fact, increased diffi culty in inter- documented [69 ] . personal relationships has been reported in some The factors associated with poor emotional patients postoperatively [52 ] . outcome are believed to be mediated by psychi- Several studies have demonstrated improve- atric state prior to the surgery. It has been ments in health status following DBS [ 80– 82 ] . reported that symptoms of depression that were Improvement has reportedly been noted in sleep present one year postsurgery were associated architecture, sleep ef fi ciency, and nocturnal with preexisting psychiatric disorders [60 ] . mobility; total sleep time and a reduction of sleep Additionally, advanced age seems to be associ- fragmentation and wakefulness after onset have ated with increased risk for postoperative mood also been demonstrated [83, 84 ] . disturbance [60 ] . York and colleagues [ 59 ] point out that such fi ndings may not be truly representative of the entire sample, as the indi- Published Recommendations for viduals who experience psychological distress Neuropsychologists may also be those who refuse to return for their follow-up evaluations. Given the varying cognitive, affective, and behav- Just as postsurgical depression appears to be ioral pro fi les of people diagnosed with PD, as associated with the presence of depressive symp- well as the neurocognitive changes that have been toms prior to surgery, patients who present with a reported in patients who have undergone DBS long-standing history of impulsivity (i.e., gam- surgery, neuropsychological assessments have bling behaviors) may be poor surgical candidates, become an essential component of pre-DBS as there has been some evidence to suggest that screening protocols at many medical centers [85 ] . these individuals are at increased risk for postop- The goal of such an evaluation is to aid in exclud- erative suicide attempts [72 ] . In contrast, symp- ing patients who have Parkinson’s plus syn- toms of impulsivity that have been induced by dromes (e.g., multiple systems atrophy, dopaminergic medications can be mitigated with progressive supranuclear palsy, corticobasal STN-DBS [73 ] . degeneration) and are therefore not expected to 23 Neuropsychological Considerations for Parkinson’s Disease Patients Being Considered… 369 bene fi t from surgery [86 ] , as well as patients with whether or not the patient is amnesic. The group preexisting cognitive deterioration or behavioral further states that measures of language should disorders that place them at increased risk for include the Boston Naming Test [ 89 ] , Controlled the exacerbation of their cognitive diffi culties if Oral Word Association Test (COWAT; [99 ] ), and they were to undergo DBS surgery [ 20, 55 ]. a measure of category fl uency. Benton’s Judgment Additionally, neuropsychologists have histori- of Line Orientation (JLO) and Facial Recognition cally played a role in the evaluation of cognitive [100 ] are suggested as appropriate visuospatial outcome postsurgery [38 ] . tasks, and the Stroop is used as a measure of In an effort to design a short (90 min) battery executive functioning [101 ] . that could be used to exclude atypical PD candidates from undergoing DBS, Pillon [ 85 ] suggested that neuropsychologists administer the Practice at North Shore: Long Island Mattis Dementia Rating Scale [ 87 ] as an estimate Jewish Health System of global cognitive functioning, the Grober and Buschke test [ 88 ] to investigate verbal memory, The Team and Their Roles the Boston Naming Test (BNT; [ 89 ] ), an apraxia examination [90 ] , and the Rey-Osterrieth PD patients who are considering DBS surgery at Complex Figure Copying (RCFT; [ 91 ] ) to assess our center, North Shore-Long Island Jewish “instrumental functions.” The author also recom- Health System (NSLIJ), undergo a comprehen- mends conducting a neuropsychiatric interview sive evaluation consisting of consultations with a and administering the Montgomery and Asberg neurologist who specializes in movement disor- Depression Rating Scale (MADRS; [92 ] ); the ders, a neurosurgeon who specializes in stereot- latter was specifi cally selected because it is sen- actic surgery, and a neuropsychologist. The goal sitive to changes in depressive symptoms over is to ensure that other treatments have been time [85 ] . exhausted and to identify candidates who will Others investigators have argued that the pre- bene fi t from the treatment and are physically, DBS battery must be more comprehensive. For cognitively, and emotionally able to tolerate all example, Okun and colleagues [38 ] report that in aspects of surgery and postoperative care. addition to the Dementia Rating Scale-Second In general, candidates are fi rst seen by the pro- Edition (DRS-II; [ 93 ] ) and the Mini-Mental State gram’s neurologist, and appointments with the Exam (MMSE; [94 ] ), neuropsychologists should neurosurgeon and neuropsychologist follow soon use the Wechsler Abbreviated Scales of thereafter; however, this sequence often varies. Intelligence (WASI; [95 ] ) to obtain an estimate of For example, a neurologist outside of the move- premorbid functioning. Okun’s treatment team ment disorder specialty may refer directly to neu- also recommends administering a digit span sub- rosurgery since this is the discipline through test, as well as the Paced Auditory Serial Addition which they would like their patients to receive Test (PASAT; [ 96] ), emphasizing the need to treatment. In addition, sometimes movement more directly assess basic attention, working disorder specialists refer directly to neuropsy- memory, and auditory information processing chology because they would like to understand speed, respectively. Although their battery the patient’s risk for cognitive decline, and the includes the Hopkins Verbal Learning Test- patient’s capacity to understand and tolerate the Revised (HVLT-R; [ 97 ] ), Okun and colleagues psychologically demanding procedure and [38 ] reportedly observed that many PD patients follow-up, prior to referring the patient to the perform poorly on such word list learning tasks. DBS program. As such, they also recommend administering During the preoperative evaluation, a patient’s the Logical Memory and Faces subtests from the levodopa response is carefully assessed using Wechsler Memory Scale-Third Edition (WMS- the levodopa challenge test. Although DBS has III; [98 ] ) to glean a better understanding of been shown to improve the motor complications 370 P.J. Mattis et al. of levodopa (e.g., reduce the amount of off-period experience an improvement in movement time, improve dyskinesias), levodopa-resistant symptoms, their inability to fulfi ll an unreason- features tend to persist despite treatment with able belief (e.g., return to tennis) increases the DBS. Therefore, a levodopa challenge test pro- risk that they will have a “catastrophic reaction.” vides information regarding the potential bene fi ts When there is an incongruity between patient and that the patient may obtain from DBS surgery. doctor expectations, additional patient education Those who respond well to the levodopa chal- is required so that the discrepancies can be lenge are predicted to have a better prognosis addressed directly. (e.g., fewer levodopa-resistant features) postsur- A comprehensive neuropsychological battery gery than those who respond poorly. is then administered in a single, extended session. Given that one of the main reasons for conducting a neuropsychological evaluation is to rule out Assessment Measures Utilized the presence of a primary progressive dementia, it is imperative that the assessment battery ade- Prior to the evaluation, the neuropsychologist quately evaluates a range of cognitive domains reviews the patient’s medical record, including including general cognition, attention/executive the neurologist and neurosurgeon’s consult notes functioning, learning, memory, language, visu- and the relevant brain scans when available (i.e., ospatial functioning, sensorimotor, and mood/ CT, MRI, FDG-PET). Patients also complete a personality. The Dementia Rating Scale-Second form prior to the assessment that documents Edition [ 93] is used to assist in distinguishing details of their developmental, educational, voca- patients with dementia from those without. tional, medical, and psychiatric history. At the Because it includes measures of attention and outset of each neuropsychological assessment, executive functioning, it is more sensitive than the patient and an informant (e.g., signifi cant the Mini-Mental State Exam [94 ] in assessing other, adult child) participate in a comprehensive various subcortical degenerative diseases [85 ] . clinical interview lasting approximately 30 min, Additionally, the WAIS-III [ 102 ] Block Design conducted to gather background information, and Similarities subtests are administered to gain a thorough understanding of current symp- measure current conceptual reasoning abilities. tomatology, and collect additional information Other subtests used at NSLIJ to assess atten- that may assist in making a differential diagnosis. tion and executive functioning include the During the course of the interview, the neuropsy- Repeating Numbers subtest from the Randt chologist discusses the patient’s reasons for con- Memory Test (RMT; [ 103] ) as a measure of basic sidering DBS at this time, understanding of the attention and working memory, the Symbol Digit surgical procedure and risks associated with the Modalities Test (SDMT; written and oral; [ 104 ] ) treatment and expected outcome of the surgery. as a measure of processing speed, and the Information regarding any potential social stres- Wisconsin Card Sorting Test-64 (WCST-64; sors that may impact the patient’s postoperative [105 ] ) as a measure of feedback utilization and outcome is also discussed in detail. Conveying an perseveration. Motor disinhibition is assessed understanding of treatment expectations is a key using a motor Go/No-Go task; bimanual and uni- element of the neuropsychological evaluation manual tasks of motor sequencing [ 106 ] are also because unreasonable expectations can result in a administered. In addition, both the patient and a negative emotional response, regardless of the family member complete the respective Frontal degree of motor improvement. Although all Systems Behavior Scale (FrSBe; [107 ] ) to pro- patients are informed about the likelihood of vide greater insight into the executive dysfunc- improvement and the types of symptoms that do tion that the patient is displaying in his or her and do not respond to treatment, some patients everyday life. continue to believe that the surgery is a panacea. Learning and memory are assessed for both Therefore, although such patients may indeed verbal and visual information. Immediate verbal 23 Neuropsychological Considerations for Parkinson’s Disease Patients Being Considered… 371 recall, learning over repeated presentations, and effective as it used to be because her ON states recall over a brief and extended delay period are occur less frequently and are weaker than they assessed using the California Verbal Learning were several years ago. She reports physical Test-Second Edition (CVLT-II; [ 108 ] ). The Brief symptoms, including balance dif fi culties leading to Visuospatial Memory Test-Revised (BVMT-R; falls (none have been serious to this point), tremor, [109 ] ) is used to provide comparable information and dystonia/dyskinesias, as well as increased regarding the patient’s visual learning and mem- diffi culty performing her activities of daily living ory abilities. independently. For the assessment of language skills, naming Case A reports that she is having occasional is evaluated using the BNT [ 89 ] , and phonemic diffi culty with her short-term memory, mainly and semantic fl uencies are appraised through the recalling the temporal details of events, and some COWAT (FAS; [100 ]) and animal naming, respec- word- fi nding dif fi culty. She explained that she tively. Auditory comprehension is assessed using feels “sharp” at times and “dull” at other times. the Commands subtest of the Boston Diagnostic According to her husband, Case A may take lon- Aphasia Examination (BDAE; [110 ] ). ger to recall details; however, he does not feel An understanding of the patient’s visual per- that she ever forgets information completely. ception/construction abilities is assessed using Medical history is otherwise signifi cant for the Hooper Visual Organization Test (HVOT; hypertension, cardiac arrhythmias, and arthritis. [111 ] ), Judgment of Line Orientation, and Facial Case A reports experiencing some depression Recognition [100 ] . Because praxis is only mildly and anxiety symptoms over the past few years, impaired in the non-demented PD patient, the but on exam, she endorsed only mild symptoms addition of an apraxia examination to the battery that were not considered to be clinically assists in making a differential diagnosis [85 ] . signi fi cant. Case A’s performance on the neurop- Finally, the severity of affective symptoms must sychological assessment battery is presented in be assessed because the presence of depressive Table 23.2 . symptoms has been shown to negatively impact recovery after DBS surgery [ 60 ] . In our center, the Beck Depression Inventory-Second Edition Case B: Brief Presenting Information (BDI-II; [112 ] ) and the Beck Anxiety Inventory (BAI; [113 ] ) are both administered. A list of the Case B is a 50-year-old man diagnosed with measures administered at our center is summa- Parkinson’s disease approximately 3 years prior rized in Table 23.1 . to the pre-DBS assessment, who mainly experiences a unilateral hand tremor that causes him distress and prevents him from performing tasks, Case Examples such as driving and working in construction. In response to questions about the surgical proce- Case A: Brief Presenting Information dure, Case B is unable to clearly state how the treatment will help him or articulate the possible Case A is a 71-year-old woman who was fi rst risks associated with the surgery. Further, his diagnosed with Parkinson’s disease approxi- expectations appear to be unrealistic, indicating mately 10 years prior to the pre-DBS assessment. that he will be “back to normal” and able to work She is interested in undergoing DBS surgery as and drive again. With respect to neuropsycho- she believes it may help make her ON/OFF cycles logical symptoms, he denies any cognitive more predictable, which will help improve her dif fi culties but indicates a history of depressive quality of life by making it possible for her to and anxious symptoms, with recent anxiety participate in enjoyable activities more often and regarding his health and inability to work. He is by enabling her to decrease some of her medica- divorced and currently lives alone. Case B has a tions. Case A feels her medication is no longer as long history of heavy alcohol abuse; he reports 372 P.J. Mattis et al.

Table 23.1 Measures used for pre-DBS assessment at North Shore-Long Island Jewish Health System Domain Measures administered General cognition Dementia Rating Scale-2 (DRS-2) National Adult Reading Test (NART) WAIS-III Block Design WAIS-III Similarities Attention/executive functioning Repeating Numbers (Randt Memory Test) Symbol Digit Modality Test Trail-Making Test Golden Stroop Wisconsin Card Sorting Test (WCST-64) Luria Motor Sequencing Tasks Motor Go/No-Go Frontal Systems Behavior Scale (FrSBe; self and family rating) Learning/memory California Verbal Learning Test-2 (CVLT-II) Brief Visuospatial Memory Test-Revised (BVMT-R) Language Boston Naming Test (BNT) Verbal Fluency Boston Diagnostic Aphasia Examination (BDAE)-Commands Visual perception/construction Benton Judgment of Line Orientation Benton Facial Recognition Hooper Visual Organization Test Sensorimotor Praxis Mood/personality Beck Depression Inventory-II (BDI-II) Beck Anxiety Inventory (BAI)

Table 23.2 Examination results for Case A, Case B, and Case C DBS candidate Case A Case B Case C Approved for DBS Failed prescreening Approved for DBS Domain Raw score Percentile Raw score Percentile Raw score Percentile General cognition DRS-2 total 139 41–59 122 3–5 134 19–28 Attention 36 60–71 33 11–18 35 41–59 Initiation/perseveration 37 60–71 31 6–10 36 41–59 Construction 6 41–59 6 41–59 6 41–59 Conceptualization 35 29–40 31 6–10 33 11–18 Memory 23 82–89 21 6–10 24 41–59 NART FSIQ = 126 FSIQ = 112 FSIQ = 122 WAIS-III Block design 28 50 29 25 29 37 Similarities 24 75 22 37 24 63 Attention/executive functioning Randt Memory Test—LSF; LSB 8; 7 91; 99 6; 4 34; 30 7; 5 37; 37 SDMT—Written; Oral 39; 50 53; 63 31; 38 3; 4 35; 44 21; 30 Trail-Making Test—A and B 33; 83 73; 68 46; 199 16; 4 73; 126 <1; 2 Golden Stroop Word 109 50 78 7 98 30 Color 79 50 42 1 57 7 Color/Word 58 91 23 1 25 3 Interference 12 88 −4.3 34 −11.04 14 (continued) 23 Neuropsychological Considerations for Parkinson’s Disease Patients Being Considered… 373

Table 23.2 (continued) DBS candidate Case A Case B Case C Approved for DBS Failed prescreening Approved for DBS Domain Raw score Percentile Raw score Percentile Raw score Percentile WCST-64 Categories 4 >16 3 >16 2 11–16 Perseverative errors 4 >99 12 25 19 8 Failure to maintain set 1 – 0 – 1 – Luria motor sequencing tasks Within normal limits Within normal limits Within normal limits Motor Go/No-Go Within normal limits Within normal limits Within normal limits FrSBe Raw score T = score Raw score T = score Raw score T = score Self—total (before; after) 97; 142 124; 146 113; 136 87; 111 65 41 Apathy 22; 53 99; >160 33; 52 74; 120 16 37 Disinhibition 34; 39 146; >160 28; 27 56; 54 16 30 Executive dysfunction 41; 50 128: 152 52; 57 100; 111 33 55 Family—total (before; after) 73; 86 114; 130 81 52 Apathy 24; 38 112; 156 27 54 Disinhibition 15; 16 84; 88 20 40 Executive dysfunction 34; 32 124; 120 34 57 Learning/memory Raw score Percentile Raw score Percentile Raw score Percentile CVLT-II total 41 46 29 7 29 7 (3, 7, 8, 11, 12) (3, 4, 6, 8, 8) (4,6,5,7,7) List B 6 70 3 7 4 30 Immediate recall (cued) 8 (9) 50 (30) 8 (7) 30 (16) 5 (5) 16 (2) Delayed recall (cued) 7 (8) 30 (16) 8 (7) 30 (16) 6 (7) 16 (16) Hits (false positives) 13 (5) 16 (3) 14 (10) 50 (2) 12 (2) 16 (50) Forced choice 16/16 – 16/16 – 16/16 – BVMT-R total 14 (3,5,6) 12 20 (6,7,7,) 21 15 (3,5,7,) 5 Learning 3 34 1 7 4 58 Delayed recall 7 34 7 14 5 4 Percent retention 117% >16 100% >16 71% 3–5 Hits (false positives) 5 (0) >16 (>16) 5 (0) 11–16 (>16) 6 (0) >16 (>16) Recognition discrimination 5 >16 5 11–16 6 >16 Copy 12/12 – 11/12 – 11/12 – Language BNT—correct (phonemic cues) 60 (N/A) 84 51 (3 of 9) 18 53 (5 of 7) 24 Verbal fl uency—phonemic; 54; 29 98; 25 47; 17 84; 1 32; 20 14; 34 semantic BDAE Commands 15 58 14 1 15 58 Visual perception/construction Judgment of line orientation 30 >86 21 22 21 22 Facial recognition 49 72–85 52 88–97 41 16–21 Hooper 20 12 25.5 53 21 16 Motor Apraxia exam Within normal limits Within normal limits Within normal limits Mood/personality BDI-II 5 Minimal 17 Mild 22 Moderate BAI 2 Normal 17 Moderate 17 Moderate 374 P.J. Mattis et al. drinking as many as 24 beers per night and notes and he works part time in security. Table 23.2 that he has at least one blackout per week. He outlines the results of Case C’s neuropsychologi- indicates that he has not had alcohol in 2 months cal assessment. as part of his preparation for surgery but reports a desire to resume his regular consumption of alcohol after undergoing DBS surgery. Table 23.2 Case A: Summary and Conclusions details the results of Case B’s neuropsychological assessment. Case A has identifi ed a realistic treatment outcome that matches her neurological state and has associated this outcome with a plausible change Case C: Brief Presenting Information in her life circumstances. There is little concern regarding Case A’s cognitive functioning. Case C is a 57-year-old man diagnosed with Attention, executive, learning, memory, and visu- Parkinson’s disease approximately 8 years prior to ospatial functions are all generally intact. Her the pre-DBS assessment, whose presenting physi- performance does reveal a mild weakness in ini- cal symptoms include excessive dyskinesias, “very tial encoding, and she reports diffi culties with brief” ON time, poor posture, and balance executive functions. However, she does not diffi culties. Case C was previously considered for exhibit rapid forgetting, and there is no evidence DBS surgery 4 years prior; however, it was deter- of a signifi cant anomia. This pattern is typical of mined that his psychiatric risk was too great, and his cognition in Parkinson’s disease. physical symptoms (just posture and balance com- In sum, the patient is entering into the process plaints at that time) are not considered to be univer- fully informed and fully aware of the surgical sally improved with the procedure. It was determined procedure, as well as its risks and possible that Case C had an adverse medication response to benefi ts. Her cognitive diffi culties are relatively Mirapex, and he was depressed, hypersexual, mild and in a pattern typical of Parkinson’s dis- engaging in excessive gambling, performing self- ease. Therefore, there is no evidence of a second- mutilation, and had passive suicidal ideation. When ary neurodegenerative disorder, and she is not at the medication was discontinued, he responded risk for greater than typical cognitive side effects. well, and the psychiatric symptoms subsided. In Finally, although she exhibits some mood issues, response to questions about the surgical procedure, she does not have a clinically signifi cant psychi- Case C is hoping to increase his ON time and atric disorder that would interfere with postsurgi- decrease the severity of his dyskinesias. He was cal quality of life or put her at risk for greater able to appropriately articulate the possible risks mood diffi culties. In such a case, participation in associated with the surgery, and he seemingly real- a series of psychotherapy sessions before and istic expectations regarding treatment outcome. after surgical intervention could be considered. With respect to neuropsychological symptoms, Case C reported that he has experienced a cognitive decline over the past 5–10 years, with a Case B: Summary and Conclusions more signi fi cant drop over the past 6 months. Symptoms include word- fi nding dif fi culty and Case B is experiencing signifi cant diffi culties confusion during his OFF state, including com- across multiple cognitive domains, with his great- prehension and memory problems. While he est impairment in complex attention and memory denied any changes in mood, he reported that he functions. This pattern of dysfunction is consis- has always been an anxious person, with some tent with the frontosubcortical dysfunction asso- depression since his divorce several years ago. ciated with Parkinson’s disease; however, the Although he is not receiving psychotherapy or degree of impairment is somewhat greater than psychopharmacologic treatment at the present expected in an individual his age, especially time, he has in the past. Case C currently lives in considering that the time since diagnosis is only residential housing, due to his psychiatric history, 3 years. It is very likely that his dif fi culties are 23 Neuropsychological Considerations for Parkinson’s Disease Patients Being Considered… 375 compounded by more diffuse brain dysfunction close relationships with his siblings who live associated with long-term alcohol abuse. Further, locally and see him regularly. Case C is reporting Case B exhibits mild to moderate mood diffi culties, signi fi cant, albeit mitigated, symptoms of depres- with greater anxiety than depressive symptoms. sion and anxiety that are currently not being Several issues should be considered in refer- treated directly and present some concern for the ence to his possible participation in surgical procedure. Therefore, it is strongly recommended intervention. First, Case B does not appear to that Case C participates in individual psychother- fully understand the procedure itself and the apy, as well as have a psychopharmacological associated risk, but more importantly, his expec- consultation, prior to moving forward with the tation for the treatment appears to be unrealistic. DBS procedure. These treatments will not only Second, he exhibits signifi cant cognitive and help address his long-standing affective symp- mood diffi culties. Finally, and most concerning, toms but will also provide him with an additional is his history of alcohol abuse. Given the patient’s support system while he engages in the process history and report during the exam, the prognosis of considering the procedure, undergoing the sur- for successful cessation is poor. If he is to be fur- gery, and recovering thereafter. Although Case C ther considered for surgical treatment, enrollment is experiencing signi fi cant cognitive de fi cits and in a formal substance abuse treatment program emotional symptoms, it was determined that he would be recommended, with the period of absti- would be considered a viable surgical candidate nence set by the surgical risk. with appropriate supports in place to monitor his psychiatric state. His medical risk for surgery is low, given his age and health, and a clini- Case C: Summary and Conclusions cal judgment was made in this case that the potential benefi t to his quality of life postopera- Case C is experiencing some diffi culties across tively is greater than his risk factors, considering multiple cognitive domains, with the area of that his symptoms are fully consistent with the greatest concern being executive functioning. He disease. is experiencing slowed processing speed, cognitive in fl exibility, and perseveration. More mild dif fi culties are apparent in memory and visuospa- Other Patient Populations Treated tial functioning, but performance in these domains with DBS and Clinical Considerations is in part implicated by his executive dysfunction. His memory dif fi culties are characterized by poor DBS has proven to be an effective method of learning and retrieval, but he has intact retention treatment for several other disorders, as well. In over time for information previously encoded. He fact, the FDA approved of this surgery for the has intact basic perceptual and construction abili- amelioration of symptoms associated with essen- ties, with dif fi culties in spatial processing and tial tremor (ET) 5 years before it was approved integration. Language functions are largely intact for use in PD patients. Since that time, DBS sur- with some retrieval dif fi culties apparent. In addi- gery has been used to mitigate the symptoms of tion, Case C is endorsing signifi cant emotional numerous movement and affective disorders. symptoms. Neuropsychologists continue to be an integral Overall, Case C’s pattern of cognitive part of the treatment team for these surgical diffi culties is fully consistent with what is seen in indications; however, there is less evidence on Parkinson’s disease. Despite the severity of defi cits, which to base clinical practice. In general, the role of there is no indication of a secondary neurological the neuropsychologist remains the same, assess- illness that would put him at risk for greater than ing the patients’ understanding of the procedure typical cognitive side effects from the DBS and quantifying the patients’ cognitive, behavioral, procedure. He exhibits realistic expectations for the and emotional status to aid in the prediction of procedure, has a strong support network, includ- outcome. However, the focus of course is different, ing living in a supported environment, and has especially in psychiatric indications. 376 P.J. Mattis et al.

DBS and Essential Tremor techniques such as habit reversal training are implemented. Because symptoms are often ET is a slowly progressive disease that is usually refractory to these various treatments and are fre- characterized by postural tremor; intention tremor quently reported to cause signifi cant distress, is seen in approximately half of ET patients, as various neurosurgical procedures have been well [114, 115 ] . These patients also have a disor- attempted to mitigate both motor and phonic tics der of tandem gait, which is usually mild. [122 ] . Among these procedures, DBS is consid- Propranolol and primidone tend to be the fi rst- ered to be an appropriate technique to use when line treatments, and in most cases, the symptoms TS symptoms are refractory to medications [ 121 ] , of ET can be treated solely with one or both of yet it has not yet been FDA approved. Part of the these medications [ 116 ] . As the illness pro- intralaminar nucleus of the thalamus, known as gresses, the frequency of the tremors tend to the centromedian-parafascicular complex (CM- decrease; however, their amplitude increases, PF), is considered to be the preferred target for exacerbating the resultant disability and DBS treatment of TS symptoms [ 123 ] , as stimu- signifi cantly impacting daily activities and qual- lation in this area has effectively allayed tics and ity of life. When the disease progression has improved the behavioral aspects of TS [124 ] . reached such a point, or when symptoms are not However, it has been suggested that stimulating properly managed with pharmacotherapy, DBS the GPi or the anterior limb of the internal of the ventralis intermedius nucleus (Vim) of the capsule may prove to be even more advantageous thalamus is often considered [ 37 ] . Outcome than DBS of the CM-PF for other behavioral studies have revealed that it is very likely that the features of the disorder [121 ] . Future studies pure postural tremor of the upper extremities will are necessary to ascertain which site should be improve after DBS of the ventralis intermedius/ targeted for which patients. zona incerta (for review, see [116 ] ). The success rate is slightly decreased if the patient presents with an intention tremor or a more proximal Major Depressive Disorder tremor predominates. In fact, only 50% of patients with intention tremors experience long-term More recently, DBS has been used to treat endog- improvement [ 117 ] . Results of outcome studies enous depression [ 42] . Like PD, major depres- further suggest that bilateral DBS may be consid- sive disorder (MDD) was initially treated using ered if head, voice, or trunk tremors are the main ablative surgeries until monoamine oxidase reason for surgery [ 118 ] , yet bilateral thalamo- inhibitors and tricyclic antidepressants were tomy is associated with high risks of complica- found to effectively improve depressive symp- tions and should not be conducted [119 ] . toms [ 125 ] . Nevertheless, a large number of patients diagnosed with depression remain refractory to these classes of medications and to the Tourette’s Syndrome selective serotonin reuptake inhibitors (SSRIs). Although electroconvulsive therapy (ECT) can According to the DSM-IV-TR [ 120 ] , Tourette’s be used to treat medically resistant depression, syndrome (TS) is a chronic, neurobehavioral dis- many patients are hesitant to undergo such a pro- order that is characterized by motor and phonic cedure due to the stigma associated with it [ 126 ] tics that persist for a minimum of 12 months. or because they are apprehensive that the ECT Patients who have been diagnosed with TS and may result in long-standing neurocognitive side who experience functional impairment in their effects [ 125] . This has spurred investigations ability to socialize are usually treated with neu- into the effectiveness of other nonpharmacologic roleptics, adrenergic agonists, and dopamine therapies, including vagus nerve stimulation, agonists [121 ] . Pharmacotherapy is often accom- transcranial magnetic stimulation, ketamine panied with behavioral treatment in which infusion therapy, and DBS (for review, see 23 Neuropsychological Considerations for Parkinson’s Disease Patients Being Considered… 377

[125, 127– 129 ] , respectively). Investigators who [143 ] or the inferior thalamic peduncle [ 144 ] can have studied the safety and effi cacy of DBS for also be effective in reducing or eliminating OCD the treatment of MDD symptoms have targeted a symptoms. wide array of areas, including the orbitofrontal cortex, anterior cingulate gyrus, corpus striatum, GP, subgenual cingulate, ventral capsule/ventral Conclusions striatum, ventral capsule/ventral commissure, nucleus accumbens, and inferior thalamic pedun- Over the past decade, DBS has proven to be an cle [129 ] . The various outcome studies that have effective treatment for several medically refrac- been conducted to date have been fairly compel- tory movement disorders and appears to have ling [130– 135 ] . Across investigations, treatment promising palliative effects for a variety of psy- resulted in sustained effects in most patients, and chiatric disorders. Although a number of investi- thus far, only minor complications from the gators have studied the neuropsychological surgery have been reported [125 ] . implications of DBS surgery in an effort to identify inclusionary and exclusionary criteria for the procedure, no consensus has been reached Obsessive-Compulsive Disorder regarding the degree of neurocognitive or psychiatric dysfunction that would render a patient DBS has also been used in the treatment of to be an inappropriate candidate [ 38 ] . Therefore, symptoms associated with obsessive-compulsive neuropsychologists must keep abreast of the ever disorder (OCD). An estimated 30–40% of patients increasing literature on this topic and create and diagnosed with OCD do not respond to medica- explicitly state the criterion to be used within tions, which frequently prompts off-label use of their program. alternative treatments [136 ] , including DBS. To date, the thalamic/capsular area seems to be the target of choice in the preliminary studies that have been conducted. Over a decade ago, Nuttin Clinical Pearls and colleagues [137 ] used DBS to treat six patients with severe OCD through implanting • Take the time to learn about PD, parkinsonian quadripolar electrodes into the anterior limb of disorders, and the disorders that can interfere the internal capsule. Of the four people who with treatment success. Without a clear under- continued in the study, three were reportedly standing of the natural history of cognitive and “much improved” and one remained “unchanged”; emotional symptoms in PD and other move- a follow-up study conducted 21 months postsur- ment disorders, it is diffi cult to interpret the gery indicated that individuals who had improved exam fi ndings. did not remit [ 138 ] . Further, the stimulation • Antiparkinson medication may need to be resulted in changes in regional activity, particu- withheld for the purposes of other assess- larly in the pons, as measured by fMRI, and lower ments, and this can potentially confound the frontal metabolism as seen on PET imaging, neuropsychological evaluation. Try to coordi- 3 months after surgery [ 139 ] . Other investigators nate the neuropsychological exam at a time who implanted the same location also reported when patients have taken their medications, that most patients were improved post-DBS [140, and they will be in the “ON” state. 141] . The right nucleus accumbens has also been • Do not restrict your differential diagnosis to the target of DBS surgery for the treatment of those disorders common to PD. PD is a disorder OCD [ 142] ; stimulation resulted in complete of mid- to late-adulthood, and each individual symptom remission 24–30 months after surgery has many risk factors that are related to his or in three of the four patients. Single case studies her genetic, environmental, emotional, and have suggested that stimulation of the caudate medical status, which are not necessarily a 378 P.J. Mattis et al.

result of the patient’s PD or common concerns • A hyperfocus on a single outcome speci fi c such as Alzheimer’s disease. to their environment. For example, a patient • Remember that the role of the neuropsycholo- may have a restriction in a hobby in which gist includes being a psychologist. Depression he or she needs to use a particular tool. and anxiety are symptoms of PD, not just a • Expectations that include environmental reaction to a disabling disease, and these changes, such as having better access to job dif fi culties affect quality of life. opportunities. • Although mood symptoms can potentially be treated with DBS in other brain regions, they are not treated by DBS in the STN, GPi, or References Vim. Mood symptoms can persist even after successful DBS for motor aspects of PD, 1. Woods SP, Fields JA, Troster AI. Neuropsychological resulting in threats to quality of life. sequelae of subthalamic nucleus deep brain stimula- • Expectations are everything. Just as mood dis- tion in Parkinson’s disease: a critical review. turbances limit treatment success, so do unre- Neuropsychol Rev. 2002;12:111–26. 2. Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts alistic expectations. The neuropsychologist C, Mizuno Y, et al. Clinical diagnostic criteria for plays a key role in assessing the patient’s dementia associated with Parkinson’s disease. Mov understanding of the anticipated postsurgical Disord. 2007;22:1689–707. outcome. Presurgical counseling and addi- 3. Pallone JA. Introduction to Parkinson’s disease. Disease-A-Month. 2007;53:195–9. tional education about treatment expectations 4. Olanow CW, Stern MB. Parkinson’s disease: unresolved may be needed. issues. Ann Neurol. 2008;64:S1–2. • Although the treatment team will take the 5. Rosenthal A. Auto transplants for Parkinson’s disease? patient’s level of motoric disability into Neuron. 1998;20:169–72. 6. Rothstein TL, Olanow CW. The neglected side of account in their fi nal decision, care must be Parkinson’s disease. Am Sci. 2008;96:218–25. taken to not let this factor bias your interpreta- 7. Youdim MB, Riederer P. Understanding Parkinson’s tion of the neuropsychological data. disease. Sci Am. 1997;1:52–9. • There are no pathognomonic signs for exclu- 8. DeLong M, Wichmann T. Update on models of basal ganglia function and dysfunction. Parkinsonism Relat sion and risk. However, the following are often Disord. 2009;15:S239–40. considered as negative fi ndings: 9. Torres G, Fraley GS, Hallas BH, Leheste JR, Phillippens • Generalized cognitive decline at a level that I. New frontiers in Parkinson’s disease therapy: deep brain is suggestive of dementia, for example, a stimulation. Kopf Carrier. 2010; 69:1–8. Retrieved from http://www.kop fi nstruments.com/Carrier/downlaod/car- Dementia Rating Scale less than 123. rier 69.pdf . • Pattern of cognitive de fi cits associated with 10. Fernandez HH, See RH, Gary MF, Bowers D, focal cortical dysfunction. Rodriguez RL, Jacobson C, Okun MS. Depressive • Memory performance suggesting greater symptoms in Parkinson disease correlate with impaired global and specifi c cognitive performance. defi cits in the retention of learned informa- J Geriatr Psychiatry Neurol. 2009;22:223–7. tion than in learning and retrieval. 11. Cozzens JW. Surgery for Parkinson’s disease. Disease- • Language diffi culties out of proportion to A-Month. 2007;53:227–42. executive de fi cits. 12. Henderson JM, Dunnett SB. Targeting the subthalamic nucleus in the treatment of Parkinson’s disease. • History of impulsive/obsessive behaviors Brain Res Bull. 1998;46:467–74. associated with disease onset and treat- 13. Pollak P, Benabid AL, Gross C, Gao DM, Laurent A, ment, such as pathological gambling. Benazzouz A, Hoffmann D, Gentil M, Perret J. Effects • History of suicidal ideation/attempts. of the stimulation of the subthalamic nucleus in Parkinson’s disease. Rev Neurol. 1993;149:175–6. • Major depressive disorder, or other axis I 14. Fahn S. How do you treat motor complications in psychiatric disorder, that has gone unrecog- Parkinson’s disease: Medicine, surgery, or both? Ann nized or intractable to treatment. Neurol. 2008;64:S56–64. • Speci fi c phobias related to medical 15. Schrag A, Quinn N. Dyskinesias and motor fl uctuations in Parkinson’s disease. A community-based study. procedures. Brain. 2000;123:2297–305. 23 Neuropsychological Considerations for Parkinson’s Disease Patients Being Considered… 379

16. Fox SH, Brotchie JM, Lang AE. Non-dopaminergic the human disorder. Ann N Y Acad Sci. 2003; treatments in development for Parkinson’s disease. 991:199–213. Lancet Neurol. 2008;7:927–38. 31. Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, 17. Rezai AR, Machado AG, Deogaonkar M, Azmi H, Tobin AJ. Two genes encode distinct glutamate decar- Kubu C, Boulis NM, et al. Surgery for movement boxylases. Neuron. 1991;7:91–100. disorders. Neurosurgery. 2008;62:S809–39. 32. Emborg ME, Carbon M, Holdern JE, During MJ, Ma 18. Espay AJ, Mandybur GT, Revilla FJ. Surgical Y, Tang C, Moirano J, Fitzsimons J, Roitberg BZ, treatment of movement disorders. Clin Geriatr Med. Tuccar E, Roberts A, Kaplitt MG, Eidelberg D. 2006;22:813–25. Subthalamic glutamic acid decarboxylase gene therapy: 19. Gildernberg PL. Management of movement disorders. changes in motor function and cortical metabolism. An overview. Neurosurg Clin N Am. 1995;6:43–53. J Cereb Blood Flow Metab. 2007;27:501–9. 20. Fields JA, Troster A. Cognitive outcomes after deep 33. Kaplitt MG, Leone P, Samulski RJ, Xiao X, Pfaff DW, brain stimulation for Parkinson’s disease: a review of O’Malley KL, During MJ. Long-term gene expres- initial studies and recommendations for future sion and phenotypic correction using adeno-associ- research. Brain Cogn. 2000;42:268–93. ated virus vectors in the mammalian brain. Nat Genet. 21. Cooper O, Astradsson A, Hallett P, Robertson H, 1994;8:148–54. Mendez I, Isacson O. Lack of functional relevance of 34. Lee B, Lee H, Nam YR, Oh JH, Cho YH, Chang JW. isolated cell damage in transplants of Parkinson’s dis- Enhanced expression of glutamate decarboxylase 65 ease patients. J Neurol. 2009;256:S310–316. improves symptoms of rat parkinsonian models. Gene 22. Olanow CW, Kordower JH, Freeman TB. Fetal nigral Ther. 2005;12:1215–22. transplantation as a therapy for Parkinson’s disease. 35. Luo J, Kaplitt MG, Fitzsimons HL, Zuzga DS, Liu Y, Trends Neurosci. 1996;19:102–9. Oshinsky ML, During MJ. Subthalamic GAD gene 23. Spencer DD, Robbins RJ, Naftolin F, Marek KL, therapy in a Parkinson’s disease rat model. Science. Vollmer T, Leranth C, Roth RH, Price LH, Gjedde A, 2002;298:425–9. Bunney BS, Sass KJ, Elsworth JD, Kier L, Majuch R, 36. Dormont D, Seidenwurm D, Galanaud D, Cornu P, Hoffer PB, Redmond DE. Unilateral transplantation Yelnik J, Bardinet E. Neuroimaging and deep brain of human fetal mesencephalic tissue into the caudate stimulation. Am J Neuroradiol, 2010; 15–23. nucleus of patients with Parkinson’s disease. N Engl J 37. Benabid AL, Chabardes S, Seigneuret E. Deep-brain Med. 1992;327:1541–8. stimulation in Parkinson’s disease: long-term effi cacy 24. Olanow CW, Fahn S. Fetal nigral transplantation as a and safety—What happened this year? Curr Opin therapy for Parkinson’s disease. In: Brundin P, Olanow Neurol. 2005;18:623–30. CW, editors. Restorative therapist in Parkinson’s dis- 38. Okun MS, Rodriguez RL, Miller AMK, Kellison I, ease. New York, NY: Springer Science + Business Kirsch-Darrow L, Wint DP, Springer U, Fernandez Media, LLC; 2006. p. 93–118. HH, Foote KD, Crucian G, Bowers D. Deep brain 25. Ma Y, Tang C, Chaly T, Greene P, Breeze R, Fahn S, stimulation and the role of the neuropsychologist. Freed C, Dhawan V, Eidelberg D. Dopamine Clin Neuropsychol. 2007;21:162–89. cell implantation in Parkinson’s disease: Long-term 39. Vitek JL. Deep brain stimulation: how does it work? clinical and 18 F-FDOPA PET outcomes. J Nucl Med. Cleveland Clinical J Med. 2008;75:S59–65. 2010;51:7–15. 40. Pourfar M, Tang C, Lin T, Dhawan V, Kaplitt MG, 26. Trott CT, Fahn S, Greene P, Dillon S, Win fi eld H, Eidelberg D. Assessing the microlesion effect of sub- Winfi eld L, Kao R, Eidelberg D, Freed CR, Breeze thalamic deep brain stimulation surgery with FDG RE, Stern Y. Cognition following bilateral implants of PET. J Neurosurg. 2009;110:1278–82. embryonic dopamine neurons in PD: a double blind 41. Asanuma K, Tang C, Ma Y, Dhawan V, Mattis P, study. Neurology. 2003;60(12):1938–43. Edwards C, Kaplitt MG, Feigin A, Eidelberg D. 27. Kaplitt MG, Feigin A, Tang C, Fitzsimons H, Mattis Network modulation in the treatment of Parkinson’s P, Lawlor PA, Bland RJ, Young B, Strybing K, disease. Brain. 2006;129:2667–78. Eidelberg D, During MJ. Safety and tolerability of 42. Chang J. Brain Stimulation for neurological and psy- gene therapy with an adeno-associated virus (AAV) chiatric disorders, current status and future direction. borne GAD gene for Parkinson’s disease: an open J Pharmacol Exp Ther. 2004;309:1–7. label, phase I trial. Lancet. 2007;369:2097–105. 43. Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, 28. Mattis P, Zgaljardic D, Feigin A. Neuropsychological Tkatch T, Meredith GE, Surmeier DJ. “Rejuvenation” functioning in pre-symptomatic but gene positive projects neurons in mouse models of Parkinson’s patients with Huntington’s disease. J Int Neuropsychol disease. Nature. 2007;447:1081–5. Soc. 2002;8:276. 44. Histed MH, Bonin V, Reid RC. Direct activation of 29. Obeso JA, Rodriguez-Oroz MC, Rodriguez M, sparse, distributed populations of cortical neurons by Marcias R, Alvarez L, Guridi J, Vitek J, Delong MR. electrical micro-stimulation. Neuron. 2009;63:508–22. Pathophysiologic basis of surgery for Parkinson’s 45. Volkmann J, Allert N, Voges J, Sturn V, Schnitzler A, disease. Neurology. 2000;55:S7–S12. Freund H. Long term results of bilateral pallidal 30. Wichmann T, DeLong MR. Pathophysiology stimulation in Parkinson’s disease. Ann Neurol. of Parkinson’s disease: the MPTP primate model of 2004;55:871–5. 380 P.J. Mattis et al.

46. Machado A, Rezai AR, Kopell BH, Gross RE, Sharan “on” STN or GPi stimulation in Parkinson’s disease. AD, Benabid A. Deep brain stimulation for Parkinson’s Neurology. 2000;55:411–8. disease: surgical technique and perioperative manage- 59. York MK, Dulay M, Macias A, Levin HS, Grossman ment. Mov Disord. 2006;21:S247–58. R, Simpson R, Jankovic J. Cognitive declines follow- 47. Schweder PM, Hansen PC, Green AL, Quaghebeur G, ing bilateral subthalamic nucleus deep brain stimula- Stein J, Aziz TZ. Connectivity of the pedunculopon- tion for the treatment of Parkinson’s disease. J Neurol tine nucleus in parkinsonian freezing of gait. Neurosurg Psychiatry. 2008;79:789–95. NeuroReport: For Rapid Communication of 60. Perriol MP, Krystkowiak P, Defebvre L, Blond S, Neuroscience Research. 2010;21:914–6. Destee A, Dujardin K. Stimulation of the subthalamic 48. Morrison CE, Borod JC, Perrine K, Beric A, Brin MF, nucleus in Parkinson’s disease: Cognitive and affec- Rezai A, Kelly P, Sterio D, Germano I, Weisz D, tive changes are not linked to the motor outcome. Olanow CW. Neuropsychological functioning follow- Parkinsoniam Relat Disord. 2006;12:205–10. ing bilateral subthalamic nucleus stimulation in 61. Hariz MI, Johansson F, Shamsgovara P, Johansson E, Parkinson’s disease. Arch Clin Neuropsychol. Hariz GM, Fagerlund M. Bilateral subthalamic 2002;19:165–81. nucleus stimulation in parkinsonian patient with pre- 49. St George RJ, Nutt JG, Burchiel KJ, Horak FB. A operative deﬁ cits in speech and cognition: Persistent meta-regression of the long-term effects of deep brain improvement in mobility but increased dependency: stimulation on balance and gait in PD. Neurology. A case study. Movement Disoders. 2000;15:136–9. 2010;75:1292–9. 62. Trepanier LL, Kumar R, Lozano AM, Lang AE, Saint- 50. Moro E, Scerrati M, Romito LMA, Roselli R, Tonali Cyr JA. Neuropsychological outcome of GPi pallido- P, Albanese A. Chronic subthalamic nucleus stimula- tomy and GPi or STN deep brain stimulation in tion reduces medication requirements in Parkinson’s Parkinson’s disease. Brain Cogn. 2000;42:324–47. disease. Neurology. 1999;53:85–90. 63. Perozzo P, Rizzone M, Bergamasco B, Castelli L, 51. Moro E, Hamani C, Poon Y, Al-Khairallah T, Lanotte M, Tavella A, Torre E, Lopiano L. Deep brain Dostrovsky JO, Hutchinson WD, Lozano AM. stimulation of the subthalamic nucleus in Parkinson’s Unilateral pedunculopontine stimulation improves disease: comparison of pre- and postoperative neu- falls in Parkinson’s disease. Brain. 2010;133:215–24. ropsychological evaluation. J Neurol Sci. 2001; 52. Schupbach WMM, Chastan N, Welter ML, Houeto 192:9–15. JL, Mesnage V, Bonnet AM, Czernecki V, Maltete D, 64. Smeding HMM, Speelman JD, Koning-Haanstra M, Hartmann A, Mallet L, Pidoux B, Dormont D, Navarro Schuurman PR, Nijssen P, Van Laar T, Schmand B. S, Cornu P, Mallet A, Agid Y. Stimulation of the sub- Neuropsychological effects of bilateral STN stimula- thalamic nucleus in Parkinson’s disease: a 5 year fol- tion in Parkinson’s disease: a controlled study. low up. J Neurol Neurosurg Psychiatry. 2005;76: Neurology. 2006;66:1830–6. 1650–44. 65. Funkiewiez A, Ardouin C, Caputo E, Krack P, Fraix 53. Parsons TD, Rogers SA, Broaten AJ, Woods SP, V, Klinger H, Chabardes S, Foote K, Benabid AL, Troster AI. Cognitive sequelae of subthalamic nucleus Pollak P. Long term effects of bilateral subthalamic deep brain stimulation in Parkinson’s disease: a meta- nucleus stimulation on cognitive function, mood, and analysis. Lancet Neurol. 2006;5:578–88. behaviour in Parkinson’s disease. J Neurol Neurosurg 54. Jahanshahi M, Ardouin CMA, Brown RG, Rothwell Psychiatry. 2004;75:834–9. JC, Obeso J, Albanese A, Rodriguez-Oroz MC, Moro 66. Kulisevsky J, Berthier ML, Gironell A, Gironell A, E, Benabid AL, Pollak P, Lomousin-Dowsey P. The Pascual-Sedano B, Molet J, Pares P. Secondary mania impact of deep brain stimulation on executive func- following subthalamic nucleus deep brain stimulation tion in Parkinson’s disease. Brain. 2000;123: for the treatment of Parkinson’s disease [abstract]. 1142–54. Neurology. 2001;56:S49. 55. Saint-Cyr JA, Trepanier LL, Kumar R, Lozano AM, 67. Krack P, Kumar R, Ardouin C, Limousin-Dowsey P, Lang AE. Neuropsychological consequences of McVicker JM, Benabid AL, Pollak P. Mirthful laugh- chronic bilateral stimulation of the subthalamic nucleus ter induced by subthalamic nucleus stimulation. Mov in Parkinson’s disease. Brain. 2000;123:2091–108. Disord. 2001;16:867–75. 56. Ashby P, Kim YJ, Kumar R, Lang AE, Lozano AM. 68. Diederich NJ, Alesch F, Goetz CG. Visual hallucina- Neurophysiological effects of stimulation through tions induced by deep brain stimulation in Parkinson’s electrodes in the human subthalamic nucleus. Brain. disease. Clin Neuropharmacol. 2000;23:287–9. 1999;122:1919–31. 69. Castelli L, Perozzo P, Zibetti M, Crivelli B, Morabito 57. Dujardin K, Defebvre L, Krystkowiak P, Blond S, U, Lanotte M, Cossa F, Bergamasco B, Lopiano L. Destee A. In ﬂ uence of chronic bilateral stimula- Chronic deep brain stimulation of the subthalamic tion of the subthalamic nucleus on cognitive func- nucleus for Parkinson’s disease: Effects on cognition, tion in Parkinson’s disease. J Neurol. 2001;248: mood, anxiety and personality traits. Eur Neurol. 603–11. 2006;55:136–44. 58. Pillon B, Ardouin C, Damier P, Krack P, Houeto JL, 70. Daniele A, Albanese A, Contarino MF, Zinzi P, Klinger H, Bonnet AM, Pollak P, Benabid AL, Agid Barbier A, Gasparini F, Romito LMA, Bentivoglio Y. Neuropsychological changes between “off” and AR, Scerrati M. Cognitive and behavioural effects of 23 Neuropsychological Considerations for Parkinson’s Disease Patients Being Considered… 381

chronic stimulation of the subthalamic nucleus in 84. Cicolin A, Lopiano L, Zibetti M, Torre E, Tavella A, patients with Parkinson’s disease. J Neurol Neurosurg Guastamacchia G, Terreni A, Makrydakis G, Fattori Psychiatry. 2003;74:175–82. E, Lanotte MM, Bergamasco B, Mutani R. Effects of 71. Witt K, Daniels C, Reiff J, Krack P, Volkmann J, deep brain stimulation on the subthalamic nucleus Pinsker MO, Krause M, Tronnier V, Kloss M, Schnitzler on sleep architecture in parkinsonian patients. Sleep A, Wojtecki L, Botzel K, Danek A, Hilker R, Sturm V, Med. 2004;5:207–10. Kupsch A, Karner E, Deuschl G. Neuropsychological 85. Pillon B. Neuropsychological assessment for man- and psychiatric changes after deep brain stimulation for agement of patients with deep brain stimulation. Parkinson’s disease: a randomized, multicentre study. Mov Disord. 2002;17:S116–22. Lancet Neurol. 2008;7:605–14. 86. Pillon B, Dubois B, Agid Y. Testing cognition may 72. Voon V, Krack P, Lang AE, Lozano AM, Dujardin K, contribute to the diagnosis of movement disorders. Schupbach M, et al. A multicentre study on suicide Neurology. 1996;46:329–33. outcome following subthalamic stimulation for 87. Mattis S. Dementia rating scale. Odessa, FL: Parkinson’s disease. Brain. 2008;131:2720–8. Psychological Assessment Resources; 1988. 73. Ardouin C, Voon V, Worbe Y, Abouazar N, Czernecki 88. Grober E, Buschke H. Genuine memory de ﬁ cits in V, Hosseini H, et al. Pathological gambling in parki- dementia. Dev Neuropsychol. 1987;3:13–36. non’s disease improves on chronic subthalamic 89. Kaplan EF, Goodglass H, Weintraub S. The Boston nucleus stimulation. Mov Disord. 2006;21:1941–6. Naming Test. 2nd ed. Philadelphia, PA: Lea and 74. Brun DJ, Troster AI. Neuropsychiatric complications Febiger; 1983. of medical and surgical therapies for Parkinson’s dis- 90. Heilman KM, Gonzalez Rothi LJ. Apraxia. In: ease. J Geriatr Psychiatry Neurol. 2004;17:172–80. Heilman KM, Valenstein E, editors. Clinical 75. Papapetropoulos S, Katzen H, Schrag A, Singer C, Neuropsychology. 2nd ed. Oxford, England: Oxford Scanlon BK, Nation D, Guevara A, Levin B. A ques- University; 2003. p. 215–35. tionnaire-based (UM-PDHQ) study of hallucinations 91. Meyers J, Meyers K. The Meyers scoring system for in Parkinson’s disease. BMC Neurol. 2008;8:21. the Rey Complex Figure and the Recognition Trial: 76. Yoshida F, Miyagi Y, Kishimoto J, Morioka T, Murakami professional manual. Odessa, FL: Psychological N, Hashiguchi K, Samura K, et al. Subthalamic nucleus Assessment Resources; 1995. stimulation does not cause deterioration of preexisting 92. Montgomery SA, Asberg MA. A new depression hallucinations in Parkinson’s disease patients. Sterotact scale designed to be sensitive to change. Br J Funct Neurosurg. 2009;87:45–9. Psychiatry. 1979;134:382–9. 77. Siderowf A, Jaggi JL, Xie SX, Loveland-Jones C, 93. Jurica PJ, Leitten CL, Mattis S. Dementia Rating Leng L, Hurtig H, Colcher A, Stern M, Chou KL, Scale-2: professional manual. Lutz: Psychological Liang G, Maccarone H, Simuni T, Baltuch G. Long- Assessment Resources; 2001. term effects of bilateral subthalamic nucleus stimula- 94. Folstein MF, Folstein SE, McHugh PR. Mini-mental tion on health-related quality of life in advanced state: a practical method for grading the cognitive Parkinson’s disease. Mov Disord. 2006;21:746–53. state of patients for the clinician. J Psychiatr Res. 78. Lezcano E, Gomez-Esteban JC, Zarranz JJ, Lambarri 1975;12:189–98. I, Madoz P, Bilbao G, Pomposo I, Garibi J. 95. Wechsler D. Wechsler Abbreviated Scales of Improvement in quality of life in patients with Intelligence. San Antonio, TX: Psychological advanced Parkinson’s disease following bilateral Corporation; 1999. deep-brain stimulation in subthalamic nucleus. Eur J 96. Gronwall DM. Paced Auditory Serial Addition Task: Neurol. 2004;11:451–4. a measure of recovery from concussion. Percept Mot 79. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix Skills. 1977;44:363–73. V, Ardouin C, Koudsie A, Limousin PD, Benazzouz 97. Brandt J, Benedict RHB. The Hopkins Verbal A, LeBas JF, Benabid AL, Pollak P. Five-year follow- Learning Test Revised: professional manual. up of bilateral stimulation of the subthalamic nucleus Odessa, FL: Psychological Assessment Resources; in advanced Parkinson’s disease. N Engl J Med. 2002. 2003;349:1925–34. 98. Wechsler D. Wechsler Memory Scale: manual. 3rd 80. Den Oudsten BL, Van Heck GL, De Vries J. Quality ed. San Antonio, TX: Psychological Corporation; of life and related concepts in Parkinson’s disease: a 1997. systemic review. Mov Disord. 2007;22:1528–37. 99. Benton AL, Hamsher K, Sivan AB. Multilingual 81. Diamond A, Jankovic J. The effect of deep brain stim- Aphasia Examination—Third Edition. 3rd ed. Iowa ulation on quality of life in movement disorders. City, IA: AJA Associates; 1983. J Neurol Neurosurg Psychiatry. 2005;76:188–1193. 100. Benton AL, Hamsher K, Varney NR, Spreen O. 82. Martinez-Martin P, Deuschl G. Effect of medical and Contributions to Neuropsychological Assessment. A surgical interventions on health-related quality of life clinical manual. New York, NY: Oxford University; in Parkinson’s disease. Mov Disord. 2007;22:757–65. 1983. 83. Antonini A, Landi A, Mariani C, DeNotaris R, Pezzoli 101. Golden CJ. Stroop Color and Word Test: a manual G. Deep brain stimulation and its effect on sleep in for clinical and experimental uses. Cleveland, OH: Parkinson’s disease. Sleep Med. 2004;5:211–4. Stoelting Co; 1978. 382 P.J. Mattis et al.

102. Wechsler D. Wechsler Adult Intelligence Scale. 121. Serrvello D, Sassi M, Porta M. Deep brain stimula- 3rd ed. San Antonio, TX: Psychological Corporation; tion in Tourette syndrome. Clin Neuropsychiatry. 1997. 2009;6:266–73. 103. Randt CT, Brown ER. Administration Manual: 122. Temel Y, Visser-Vandewalle V. Surgery in Tourette Randt Memory Test. Bayport, NY: Life Science syndrome. Mov Disord. 2004;19:3–14. Associates; 1983. 123. Houeto JL, Karachi C, Mallet L, Pillon B, Yelnik 104. Smith A. Symbol Digit Modalities Test: manual. Los J, Mesnage V, Welter ML, Navarro S, Pelissolo A, Angeles, CA: Western Psychological Services; 1982. Damier P, Pidoux B, Dormont D, Cornu P, Agid Y. 105. Kongs SK, Thompson LL, Iverson GL, Heaton RK. Tourette’s syndrome and deep brain stimulation. Wisconsin Card Sorting Test-64 Card Version. Lutz, J Neurol Neurosurg Psychiatry. 2005;76: 992–5. FL: Psychological Assessment Resources; 2000. 124. Servello D, Porta M, Sassi M, Brambilla A, 106. Luria AR. Higher Cortical Functions in Man. New Robertson MM. Deep brain stimulation in 18 patients York, NY: Basic Books; 1980. with severe Gilles de la Tourette syndrome refractory 107. Grace J, Malloy P. Frontal Systems Behavior Scale to treatment: the surgery and stimulation. J Neurol (FrSBe): professional manual. Lutz, FL: Neurosurg Psychiatry. 2008;79:136–42. Psychological Assessment Resources; 2001. 125. Alterman RL, Dumitriu D, Mathew S. Deep brain 108. Delis DC, Kramer JH, Kaplan E, Ober BA. California stimulation for major depressive disorder. Clin Verbal Learning Test-Second Edition, Adult Version Neuropsychiatry. 2009;6:259–65. manual. San Antonio, TX: The Psychological 126. Dowman J, Patel A, Rajput K. Electroconvulsive Corporation; 2000. therapy: attitudes and misconceptions. J Electro- 109. Benedict RHB. Brief Visuospatial Memory Test- convulsive Therapy. 2005;21:84–7. Revised: manual. Odessa, FL: Psychological 127. Daban C, Martinez-Aran A, Cruz N, Vieta E. Safety Assessment Resources; 1997. and efﬁ cacy of Vagus Nerve Stimulation in 110. Goodglass H, Kaplan E. Boston diagnostic aphasia treatment-resistant depression. A systematic review. examination. Philadelphia, PA: Lea and Febiger; 1983. J Affect Disord. 2008;110:1–15. 111. Hooper H. Hooper Visual Organization Test (HVOT). 128. Loo CK, MaFarquhar TF, Mitchell PB. A review of Los Angeles: Western Psychological Services; 1983. the safety of repetitive transcranial magnetic stimu- 112. Beck AT, Steer RA, Brown GK. BDI-II, Beck lation as a clinical treatment for depression. Int J depression inventory: manual. 2nd ed. Boston, MA: Neuropsychopharmacol. 2008;11:131–47. Harcourt Brace; 1996. 129. Price RB, Nock MK, Charney DS, Mathew SJ. 113. Beck AT, Steer RA. Beck anxiety inventory: manual. Effects of intravenous ketamine on explicit and San Antonio, TX: Psychological Corporation; 1990. implicit measures of suicidality in treatment-resis- 114. Deuschel G, Wenzelburger R, Lof ﬂ er K, Raethjen J, tant depression. Biol Psychiatry. 2009;66:522–6. Stolze H. Essential tremor and cerebellar dysfunc- 130. Jimenez F, Velasco F, Salin-Pascual R, Hernandez tion clinical and kinematic analysis of intention JA, Velasco M, Criales JL, Nicolini H. A patient tremor. Brain. 2000;123:1568–80. with a resistant major depression disorder treated 115. Louis ED, Ford B, Wendt KJ, Cameron G. Clinical with deep brain stimulation in the inferior thalamic characteristics of essential tremor: data from a com- peduncle. Neurosurgery. 2005;57:585–93. munity-based study. Mov Disord. 1998;13:803–8. 131. Mayberg HS, Lozano AM, Voon V, McNeely HE, 116. Deuschl G, Bain P. Deep brain stimulation for Seminowicz D, Hamani C, Schwalb JM, Kennedy trauma: patient selection and evaluation. Mov SH. Deep brain stimulation for treatment-resistant Disord. 2002;17:S102–11. depression. Neuron. 2005;45:651–60. 117. Pollak P, Benabid AL, Krack P, Lomousin P, 132. Schlaepfer TE, Lieb K. Deep brain stimulation for Benazzouz A. Deep brain stimulation. In: Jankovic treatment of refractory depression. Lancet. 2005; J, Tolosa E, editors. Parkinson’s disease and move- 366:1420–2. ment disorders. Baltimore, MD: Williams and 133. Lozano AM, Maybery HS, Giacobbe O, Hamani C, Wilkoins; 1998. p. 1085–102. Craddock RC, Kennedy SH. Subcallosal cingulated 118. Pahwa R, Lyons KL, Wilkonson SB, Carpenter MA, gyrus deep brain stimulation for treatment-resistant Troster AI, Searl JO, Overman J, Pickering S, Koller depression. Biol Psychiatry. 2008;64:461–7. WC. Bilateral thalamic stimulation for the treatment 134. Malone Jr DA, Doughtery DD, Rezai AR, Carpenter of essential tremor. Neurology. 1999;53:1447–50. LL, Friehs GM, Eskandar EN, Rauch SL, Rasmussen 119. Schuurman PR, Bosch DA, Bossuyt PM, Bonsel GJ, SA, Machado AG, Jubu CS, et al. Deep brain stimu- van Someren EJ, de Bie RM, Merkus MO, Speelman lation of the ventral capsule/ventral striatum for JD. A comparison of continuous thalamic stimulation treatment-resistant depression. Biol Psychiatry. and thalamotomy for suppression of severe tremor. 2009;65:267–75. N Engl J Med. 2000;342:461–8. 135. Wang X, Chang C, Geng N, Li N, Wang J, Ma J, Xue 120. American Psychiatric Association. Diagnostic and W, Zhao W, Wu H, Wang P, Gao G. Long-term effects statistical manual of mental disorders. 4th ed. of bilateral deep brain stimulation of the subthalamic Washington, DC: American Psychiatric Association; nucleus on depression in patients with Parkinson’s dis- 2000. p. 111–4. ease. Parkinsonism Relat Disord. 2009;15:587–91. 23 Neuropsychological Considerations for Parkinson’s Disease Patients Being Considered… 383

136. Lakhan SE, Callaway E. Deep brain stimulation for neuropsychological outcome in three cases. Acta obsessive-compulsive disorder and treatment-resistant Psychiatr Scand. 2003;107:275–82. depression: systematic review. BMC Research Notes. 141. Abelson JL, Curtis GC, Sagher O, Albucher RC, 2010;3:60. Harrigan M, Taylor SF, Martis B, Giordani B. 137. Nuttin B, Cosyns P, Demeulemeester H, Gybels J, Deep brain stimulation for refractory obsessive- Meyerson B. Electrical stimulation in anterior limbs of compulsive disorder. Biol Psychiatry. 2005;57: internal capsules in patients with obsessive-compulsive 510–6. disorder. Lancet. 1999;354:1526. 142. Sturm V, Lenartz D, Koulousakis A, Treuer H, 138. Nuttin BJ, Gabriels LA, Cosyns PR, Meyerson BA, Herholz K, Klein JC, Klosterkotter J. The nucleus Andreewitch S, Sunaert SG, Maes AF, Dupont PJ, accumbens: a target for deep brain stimulation in Gybels JM, Gilen F, Demeulemeester HG. Long-term obsessive-compulsive- and anxiety-disorder. J Chem electrical capsular simulation in patients with obsessive- Neuroanat. 2003;26:293–9. compulsive disorder. Neurosurgery. 2003;52:1263–72. 143. Aouizerate B, Cuny E, Bardinet E, Yelnik J, Martin- 139. Nuttin BJ, Gabriels LA, Cosyns PR, Meyerson BA, Guehl C, Rotge JY, Rougier A, Bioulac B, Tignol J, Andreewitch S, Sunaert SG, Maes AF, Dupont PJ, Mallet L, et al. Distinct striatal targets in treating Gybels JM, Gielen F, Demeulemeester HG. Long- obsessive-compulsive disorder and major depres- term electrical capsular stimulation in patients with sion. J Neurosurg. 2009;111:775–9. obsessive-compulsive disorder. Neurosurgery. 144. Jimenez F, Velasco F, Salin-Pascual R, Velasco M, 2008;62:966–77. Nicolini H, Velasco AL, Castro G. Neuromodulation 140. Gabriels L, Cosyns P, Nuttin B, Demeulemeester H, of the inferior thalamic peduncle for major depression Gybels J. Deep brain stimulation for treatment-refractory and obsessive compulsive disorder. Acta Neurochir. obsessive-compulsive disorder: psychopathological and 2007;97:S393–8. Idiopathic Normal Pressure Hydrocephalus 2 4

Lisa D. Ravdin and Heather L. Katzen

Abstract Idiopathic normal pressure hydrocephalus (INPH) is characterized by the clinical triad of gait disturbance, cognitive dysfunction, and urinary symptoms, observed in the context of enlargement of the cerebral ventricular system. Mean age of onset is approximately 60 years, which complicates the diagnosis since there is the potential for multiple age-related comorbidities in this population. Typically, gait disturbance is the presenting symptom that brings an individual to medical attention, but cognitive decline can be the initial symptom in some cases. NPH is an important diagnostic entity for the neuropsychologist working with older adults to be familiar with, since it is one of the few progressive cognitive disturbances that can be effectively treated. The current standard of care treatment is placement of a ventriculoperitoneal shunt, which can lead to reversal of symptoms, but shunt surgery is not without complications and careful patient selection is prudent. The neuropsychologist can be a key contributor in clinical settings for diagnostic considerations and in the evaluation of treatment response. In this chapter, we present a discussion of the clinical presentation and characteristic features of INPH, explore recent evidence-based diagnostic criteria, and provide guidelines for neuropsychological evaluation of INPH. A case example documenting post-shunt recovery of function is presented.

Keywords Normal pressure hydrocephalus • Gait disorders • Urinary symptoms • Executive dysfunction

L. D. Ravdin , Ph.D. () Department of Neurology & Neuroscience, H. L. Katzen , Ph.D. Weill Cornell Neuropsychology Service , Division of Neuropsychology, Department of Neurology , Weill Medical College of Cornell University , University of Miami Miller School of Medicine , New York Presbyterian Hospital , 428 East 72nd Street, 1120 NW 14th Street, Room 1337 , Miami , Suite 500 , New York, NY 10021 , USA FL 33136 , USA e-mail: [email protected] e-mail: [email protected]

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 385 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_24, © Springer Science+Business Media, LLC 2013 386 L.D. Ravdin and H.L. Katzen

multiple steps to make a 180° turn on command. Clinical Presentation In our experience, up to four steps is within the normal range and should not be considered an The clinical symptom triad of cognitive impair- indication of en bloc turning. INPH patients often ment, gait disorder, and incontinence is consid- require 5 or 6 steps and in some cases as many as ered the classic presentation of INPH, hence the 10–12 steps. In severe cases, patients with INPH well-known mnemonic “wacky, wobbly, and wet.” may be unable to turn at all without someone to However, contrary to clinical lore, it is now widely hold their hands and guiding them around. It is recognized that all three symptoms are not required important to note that in the very early stages of for diagnosis. Most commonly, disturbed gait is the disease, individuals may present with relatively the presenting symptom which brings the individ- normal turning but may go on to develop worsen- ual to medical attention, followed in frequency by ing gait and en bloc turning if left untreated. cognitive impairment and urinary symptoms [2, 3 ] . In rare instances, cognitive dysfunction can pre- date the onset of gait abnormalities in INPH [4 ] . Urinary Symptoms Nevertheless, variations in symptom presentation, with cognitive symptoms greater in severity than Urinary incontinence has not been well character- the disturbance in gait, should always raise the ized in INPH and is the least common symptom suspicion of comorbid disease (e.g., diagnosis of to be reported at the time of diagnosis. While both Alzheimer’s disease and INPH). frank incontinence is present in about half the cases, particularly in advanced stages, increased frequency and urinary urgency are far more com- Gait mon in the early stages of the disease. This is very important to note, as questions about urinary As described above, gait abnormalities are typi- symptoms need to extend beyond asking about cally the fi rst symptoms to become apparent and the presence or absence of frank incontinence. are the most readily recognized feature of INPH. Speci fi c follow-up questions regarding frequency The gait dysfunction in INPH has been described of urination and a sense of urgency should be as “magnetic,” “glue-footed,” “short-stepped,” or included and may reveal subtle bladder symptoms “shuf fl ing.” While the term “gait apraxia” has also that would otherwise go unreported. It is also not been used, this may not be accurate given the uncommon for patients to develop a “functional observation that many patients can execute correct incontinence,” where the gait disturbance may walking movements in a recumbent or supine interfere with successful toileting. Since they may position [ 5] . This clinical observation has been attribute occasional episodes of incontinence to qualitatively described in the literature and may their inability to walk fast enough to get to the differentiate INPH from other movement disorders, bathroom, they may not report these as bladder yet it has never been carefully studied. INPH symptoms unless speci fi cally asked. Bowel incon- patients typically present with complaints of tinence can also occur in the late stages of INPH. fatigue brought on by walking, diffi culty with chair and bed transfers, halting ambulation down a sloping surface, and inability to walk at an expected Cognitive Dysfunction pace [6 ] . Abnormal turning (“en bloc” turning) is also a characteristic feature of the gait abnormal- Cognitive defi cits in INPH range from subtle ity, with multiple steps being needed to turn in cognitive dysfunction to a frank dementia [ 7 ] . It place. It is notable that many standardized gait is estimated that INPH may be a contributing fac- scales employ a cutoff of greater than two steps to tor in to up to 6% of dementia cases [ 8 ] , yet that indicate abnormal turning; however, we have fi gure is likely an underestimate given the chal- found that many healthy older adults tend to take lenge of parceling out INPH in the context of 24 Idiopathic Normal Pressure Hydrocephalus 387 other dementing disorders. Early cognitive symp- presence of another disorder does not negate the toms can readily go undetected or can falsely be fact that INPH may contribute to the presenta- attributed to normal aging. In our experience, tion, and even more importantly, is not necessar- many high functioning patients do not report sub- ily a contraindication for treatment. In our jective cognitive changes early in the disease experience, many patients with comorbid neuro- course and perform well on global measures that degenerative conditions have been successfully are typically employed in neurology and neuro- treated for INPH. While the cognitive symptoms surgery clinics (e.g., MMSE, 3MS). However, typically do not show substantial improvements detailed neuropsychological assessment fre- post-shunt in patients with signifi cant comorbid quently reveals more subtle executive de fi cits and disease, improvements in gait can be associated psychomotor slowing, even when cognitive with increased independence in activities of daily symptoms are denied by the patient. living and can signifi cantly improve the patient’s In its purest form, the cognitive profi le associ- quality of life as well as make physical manage- ated with INPH re fl ects frontal systems dysfunc- ment easier for the caregiver. tion and can include reduced psychomotor and information processing speed, executive de fi cits, as well as compromised complex attention and Behavioral/Psychiatric Symptoms memory. [7, 9– 12 ] De fi cits in memory are characterized predominantly by dif fi culty acquiring Several case reports of psychiatric disturbances in new information and retrieval. This is typically association with INPH have appeared in the liter- secondary to de fi cits in the organization and ature, including depression [13, 14] , bipolar mania effi cient processing of information. Delayed [15 ] , psychosis [16, 17 ] , aggressivity [18, 19] , and recall is impaired but can often be prompted by obsessive–compulsive disorder [ 20 ] . Although cueing. Early cognitive compromise attributable atypical, psychiatric symptoms can emerge as a to INPH presents as mild frontal systems presenting feature and may complicate the diag- dysfunction. If unrecognized and left untreated, nostic process [ 17 ] . The pathogenesis of psychiat- cognitive symptoms may progress to a more ric presentations in INPH is not well understood. severe frontal dysexecutive syndrome. Lack of Symptoms may develop due to neurochemical treatment for a prolonged period may lead to the changes associated with the underlying brain dis- development of pro fi le that appears to be consis- order. In some cases, behavioral symptoms, such tent with a more generalized dementia. As true as depression, may be “reactive” or arise second- with other progressive dementing disorders, ary to the physical and mental disability. advanced untreated cases result in cognitive com- Nevertheless, it is important to recognize the promise indistinguishable from other forms of behavioral disturbances associated with INPH dementia. The presence of cortical de fi cits such since they may be refractory to conventional phar- as aphasia, agnosia, and alexia can be seen in the macological treatment and may, in some cases, be more advanced stages of INPH but likely signal responsive to shunt placement. Case reports have comorbid disease or alternate diagnoses if pres- suggested an improvement in specifi c psychiatric ent early on. As always, onset and duration of symptoms with shunt placement; however, this symptoms are critical factors to be considered in has not been systematically studied [16, 17 ] . the differential diagnosis. With regard to the cognitive pro fi le, there are many occasions in which the neuropsychological Demographics test results suggest involvement of not only frontal systems but a more widespread cognitive Symptoms of INPH typically develop with an decline that may indicate comorbid Alzheimer’s insidious onset in the sixth and seventh decade of disease (AD), vascular cognitive impairment, or life. [ 2, 21] It has been estimated that approxi- another neurodegenerative process. However, the mately one half of a percent of the population over 388 L.D. Ravdin and H.L. Katzen

65 suffers from NPH-related symptoms; however, the two conditions, the treating physician may few defi nitive incidence or prevalence studies of sometimes consider a trial of Levodopa ( l -dopa) INPH have been conducted. [ 22, 23] Many NPH to see if there is a clinical response. While there experts feel that this is an underestimate of the are some reports of INPH showing brief or partial true prevalence of this condition. A recent review response to l -dopa, this is atypical and may be of fi ve population-based studies from three coun- indicative of comorbid disease (i.e., PD). l -dopa tries revealed estimates ranging from 0.4% to treatment failures would rule out idiopathic PD, 3.0%, concluding that approximately 1% of the and these cases may then be directed to a tap test population will develop NPH by the age of 80 to prognosticate about shunt responsiveness. [ 24 ] . Although no large-scale epidemiological Other Parkinsonian syndromes may also be non- studies have been conducted, there does not appear responsive to l -dopa and tap test. to be a gender or racial predilection [ 25 ] . The vast INPH patients can also be misdiagnosed with majority of INPH cases are sporadic, yet detailed AD. Historically, gait disorder is more prominent linkage studies have not been performed. and noted to be the initial presenting feature in the majority of INPH cases, whereas cognitive decline is the predominant presenting feature in Pathophysiology AD. However, this notion may be in part due to the fact that objective cognitive testing was not The cause of ventricular enlargement in INPH is historically part of the diagnostic workup of poorly understood. A CSF absorption de fi cit in or INPH. Rather, basic mental status screening an imbalance between CSF production and absorp- instruments such as the MMSE were most fre- tion has been postulated; the exact pathophysio- quently used. The MMSE is not sensitive to fron- logic mechanism and specifi c neuroanatomic tal subcortical dysfunction, the pattern of substrates underlying the symptoms in INPH impairment most associated with INPH, and remain unknown. Ventricular dilatation may cause reports of normal mental status based on these disruption of descending periventricular fi bers screening measure do necessarily negate the pres- from the supplementary motor areas or compres- ence of cognitive de fi cits. sion of deeper subcortical circuits involving the Neuroimaging can be helpful in terms of the globus pallidus. It has been proposed that ventric- differential diagnosis of AD versus INPH. The ular enlargement may lead to increased vascular degree and pattern of ventricular enlargement is stretching, thereby decreasing compliance and key, but the differences are often subtle and are decreasing capacitance of the system [26, 27] . It not always interpreted accurately to an untrained has also been suggested that infarction in the deep eye. Scans revealing ventricular enlargement white matter fi bers leading to decreased periven- with cerebral atrophy greater than expected for tricular tensile strength could be a mechanism age are typically interpreted as consistent with underlying INPH [ 28, 29 ] . AD. In these cases, the ventricular changes are attributed to a secondary consequence of cerebral atrophy. When close inspection of the pat- Differential Diagnosis tern of ventricular enlargement reveals rounded frontal horns and marked enlargement of the The differential diagnosis of INPH often includes temporal horns and third ventricle, this would primary neurodegenerative disorders such as suggest the changes are not simply a consequence Parkinson’s disease (PD) and Alzheimer’s dis- of atrophy but rather that they are consistent with ease (AD). INPH. In these cases, the degree of ventricular Like PD, INPH presents with gait changes, enlargement is out of proportion to the cerebral motor slowing, and a pro fi le of frontal systems atrophy. The term hydrocephalus ex vacuo is dysfunction on cognitive testing. In particularly sometimes used to describe ventricular enlarge- challenging cases when it is diffi cult to differentiate ment in association with brain atrophy and can 24 Idiopathic Normal Pressure Hydrocephalus 389

Fig. 24.1 Imaging characteristics in INPH versus AD. atrophy in AD and (b ) ventriculomegaly without Comparison of AD and INPH on brain MRI. Axial images signi fi cant cortical atrophy in INPH show (a ) ventriculomegaly with signifi cant cortical be differentiated from INPH. Neuroimaging will Table 24.1 INPH differential diagnosis often be repeated over time to aid in diagnosis Neurodegenerative disorders Other conditions and to track disease progression or response to Alzheimer’s disease Spinal stenosis treatment; however, the presence or absence of Parkinson’s disease Noncommunicating ventricular changes does not always directly hydrocephalus correspond to changes in clinical symptoms or Vascular dementia HIV defi cits on formal testing. Axial MRI images of Dementia with Lewy bodies Lyme disease Frontotemporal dementia B de fi ciency an INPH and AD brain are shown in Fig. 24.1 . 12 There are several other conditions with vary- Spongiform encephalopathy Collagen vascular disorders ing etiologies that are common in aging popula- Corticobasal degeneration Neurosyphilis tions that can produce gait changes, bladder Multisystem atrophy Bladder spasticity symptoms, and cognitive dysfunction. Gait signs Progressive supranuclear palsy Osteoarthritis and symptoms can be associated with joint disorders such as hip, groin, or knee pain and other neurologic disorders (peripheral neuropathy and Evidence-Based Diagnostic Criteria spinal stenosis), as well as slowing and other gait changes that can be attributable to normal aging. In 2005, a set of evidence-based guidelines were There are a host of etiologies underlying cogni- published to aid in the diagnosis and management tive disorders in the elderly. A frontal systems dis- of INPH [30 ] . These guidelines recommend the turbance can be observed secondary to other classifi cation of INPH into “probable,” “possi- neurologic disorders (FTD and vascular disease), ble,” and “unlikely” cases based on data gathered psychiatric disorders (depression, bipolar), and a from clinical history, neuroimaging, physical multitude of other causes. Urinary symptoms are exam, and physiological criteria (see Table 24.2 ). also common in older adults and can present with urinary tract infections, diabetes, a variety of bladder conditions, prostate problems in men, and Probable INPH gynecological abnormalities in women. Table 24.1 shows a list of neurologic diagnoses that are often A diagnosis of “probable” INPH requires a his- considered in the differential diagnosis of INPH. tory of gait disturbance and at least one of the 390 L.D. Ravdin and H.L. Katzen other symptoms in the classic triad (cognitive or either (1) episodic or persistent urinary inconti- urinary). Also required is an insidious onset after nence not attributable to primary urological the age of 40 years, a suggestion of progression disorders, (2) persistent urinary incontinence or over time, a minimum duration of 3–6 months, urinary and fecal incontinence, or (3) two of the no antecedent event, and no evidence of another following: urinary urgency (frequent perception medical, neurologic, or psychiatric condition that of a pressing need to void), urinary frequency could fully explain the symptoms. (more than six voiding episodes in an average There must also be brain imaging (CT or MRI) 12-h period despite normal fl uid intake), or noc- performed after the onset of symptoms that indi- turia (the need to urinate more than two times in cates ventricular enlargement not entirely an average night). explained by cerebral atrophy or congenital In addition to the above requirements, a diag- enlargement. This can be quanti fi ed by an Evan’s nosis of “probable” INPH requires a CSF open- index of 0.3 or greater [ 31, 32 ] or some other ing pressure in the range of 5–18 mm Hg (or equivalent measurement of the ratio of ventricu- 70–245 mm H2 O) as determined by a lumbar lar size to cranial diameter. No evidence of mac- puncture or a comparable procedure. Pressures roscopic obstruction to CSF fl ow should be that are signifi cantly higher or lower than this observed. In addition, either enlargement of the range are not consistent with a “probable” INPH temporal horns of the lateral ventricles not fully diagnosis. accounted for by hippocampal atrophy, callosal angle of 40° or more, evidence of altered brain water content not attributable to microvascular Possible INPH ischemia or demyelination, or an aqueductal or fourth ventricular fl ow void on MRI must be The criteria required for a diagnosis of “possible” observable on brain imaging. INPH are somewhat less rigorous. The history The clinical examination must con fi rm the may indicate a subacute or indeterminate mode history criteria above including the presence of of onset, symptoms may be nonprogressive, dura- gait/balance disturbance as well as impairment in tion may be less than 3 months, and symptoms either cognition or urinary function. Gait and bal- may begin at any age after childhood. Also, as ance disturbance requires the presence of at least long as an antecedent event is not judged by the two of nine possible characteristics, including (1) clinician to be causally related to the onset, mild decreased step height, (2) decreased step length, head trauma, remote history of intracerebral hem- (3) decreased walking speed, (4) increased trunk orrhage, childhood and adolescent meningitis, or sway during walking, (5) widened standing base, other condition may be present. Further, a comor- (6) toes turned outward on walking, (7) retropul- bid neurologic, psychiatric, or medical condition sion, (8) turning requiring three or more steps for does not prohibit the INPH “possible” diagnosis, 180°, and (9) impaired walking balance. If cogni- as long as it is not thought to entirely explain the tive symptoms are present, they must not be presentation. The brain imaging must demon- attributed to another condition. The criteria strate ventricular enlargement consistent with specifi cally state that there must be a documented hydrocephalus but can show evidence of cerebral impairment in performance on a cognitive screen- atrophy or structural lesions that may in fl uence ing instrument or evidence of defi cits in at least ventricular size. Clinical fi ndings may include two cognitive domains (e.g., psychomotor func- gait disturbance or dementia alone, or inconti- tioning, fi ne motor speed, fi ne motor accuracy, nence and cognitive impairment without gait dis- attention, memory, executive functions, or behav- turbance. CSF opening pressure may be ioral/personality). To document symptoms in the unavailable or can be outside the defi ned range domain of urinary continence, patients must have (5–18 mm Hg or 70–245 mm H2 O). Table 24.2 Idiopathic normal pressure hydrocephalus classi fi cation: probable, possible, and unlikely categories Probable INPH Possible INPH Unlikely INPH I. Clinical fi ndings must include : I. Clinical fi ndings include :

a. Gait/balance disturbance a. Symptoms of either: 1. No evidence of consistent with NPH 1. Incontinence and/or cognitive ventriculomegaly b. Symptoms in at least one impairment in the absence of an 2. Signs of increased intracranial other domain (cognition, observable gait/balance disturbance pressure such as papilledema control of urination) 2. Gait disturbance or dementia alone 3. No component of the clinical

c. Insidious onset (versus b. Reported symptoms may: triad of INPH is present acute) after 40 years of age 1. Have subacute or indeterminate 4. Symptoms fully explained by d. Minimum symptom mode of onset other causes (e.g., spinal duration of 3–6 months 2. Be nonprogressive or not clearly stenosis)

e. Evidence suggesting progressive progression of symptoms 3. Begin at any age after childhood over time 4. Have <3 months or unknown duration

f. No antecedent neurologic, 5. Follow remote events that in the psychiatric, or general judgment of the clinician are not medical conditions likely to be causally related (e.g., mild suf fi cient to explain in the head trauma, history of intracerebral presentation hemorrhage, childhood/adolescent meningitis, or other conditions) 6. Coexist with other neurologic, psychiatric, or general medical disorders but in the judgment of the clinician not entirely explained by these conditions II. Brain imaging (CT or MRI ) II. Brain imaging (CT or MRI ) must show must show : ventricular enlargement consistent with hydrocephalus but can be associated with: a. Enlargement of the a. Evidence of cerebral atrophy suf fi cient ventricular system not to potentially explain ventricular size entirely attributable to b. Structural lesions that may in fl uence cerebral atrophy or ventricular size congenital enlargement b. No macroscopic obstruction to CSF fl ow c. At least one of the following supportive features 1. Enlargement of the temporal horns of the lateral ventricles not entirely attributable to hippocampal a trophy 2. Callosal angle > 40° 3. Evidence of altered brain water content, including periventricular signal changes (CT/MRI) not attributable to microvascular ischemic changes or demyelination 4. An aqueductal or fourth ventricular fl ow void on MRI III. Physiological : CSF III. Physiological : Opening pressure opening pressure in the range measurement not available or pressure of 5–18 mm Hg outside range required for probable INPH

(or 70–245 mm H2 O) Details regarding speci ﬁ c gait, cognitive, and urinary symptoms necessary for diagnosis are reviewed elsewhere [30 ] INPH idiopathic normal pressure hydrocephalus, CT computed tomography, MRI magnetic resonance imaging, CSF cerebrospinal ﬂ uid, SPECT single-photon emission computed tomography 392 L.D. Ravdin and H.L. Katzen

Unlikely INPH repeat test or referral for another type of CSF drainage procedure may be helpful. Given the An improbable or “unlikely” INPH diagnosis is high false-negative rate, lack of tap test response simply defi ned by a presentation in which there is does not completely rule out a diagnosis of INPH (1) no evidence of ventriculomegaly, (2) no signs nor does it preclude shunt responsiveness [30 ] . of increased intracranial pressure such as papille- External lumbar drainage (ELD) is a more dema, (3) no component of the clinical triad, and prolonged CSF drainage procedure in which (4) symptoms explained by other causes (e.g., larger volumes of fl uid are removed, typically spinal stenosis). over several days. CSF is typically drained at a rate of 10 cc/h through a catheter placed temporarily in the lumbar region. ELD has been shown Clinical Evaluation to have good prognostic value with a sensitivity of 50–100%, speci fi city of 60–100%, and posi- Routine clinical evaluation for INPH includes tive predictive value of 80–100% [ 33 ] . If there is clinical history and neurologic examination, bed- a strong suspicion of INPH and the tap test is side assessment of mental status, gait evaluation, negative or equivocal, the ELD procedure may be and structural brain imaging. Without additional considered. Until recently, ELD had only been procedures, research indicates a 46–61% response performed at a limited number of sites in the rate to surgical treatment [ 33 ] . Consensus guide- USA, yet, a growing number of clinical research lines [30 ] also recommend lumbar puncture, CSF settings have implemented it as part of the stan- drainage, and outfl ow resistance studies, as well dard presurgical workup. It is important to note as neuropsychological testing. While functional that this procedure requires hospitalization and brain imaging, urodynamic studies, video or com- can be associated with complications such as puterized gait evaluation, and other laboratory infection or nerve root irritation, and the clinical investigations may provide additional information decision of whether or not to conduct ELD should in some case, these were deemed as lacking be considered on case-by-case basis. As with a suf fi cient evidence to include as part of the INPH tap test, detailed assessment of gait, cognition, consensus criteria [ 30 ] . and urinary symptoms should be performed to Interestingly, CSF tap test is not required objectively assess response. The postdrainage according to the consensus criteria, but it is the neuropsychological evaluation and standardized most widely used diagnostic test performed to gait assessment are key factors in determining prognosticate shunt responsiveness. The proce- response. The neuropsychologist plays an inte- dure, also called a large volume lumbar puncture, gral role in these evaluations by providing objec- involves removal of approximately 50 cc of CSF. tive data regarding changes in performance. Improvement in clinical symptoms following a tap test is associated with an increased likelihood of a positive surgical outcome; however, this Treatment Response technique has also been found to have a high false-negative rate [ 34– 36 ] . While the standard of Response following shunt placement for INPH care has typically been for the clinician to make varies dramatically, with reported improvement subjective observations of the patient’s gait and rates ranging from 30% to 96% [ 37 ] . While treat- mental function following tap test, these methods ment response rates for INPH are traditionally have inherent bias. More objective detailed clini- thought to be lower than in secondary forms of cal assessment should be performed both before hydrocephalus, a recent study found that this tap test and about 2–4 h after CSF removal to can be explained primarily by the fact that INPH evaluate change. The pre- and posttap assessment patients frequently have comorbid disease. should include standardized gait and cognitive With favorable preconditions (e.g., low comor- assessment. In the event of equivocal results, a bidity), INPH patients were shown to have an 24 Idiopathic Normal Pressure Hydrocephalus 393 approximately 80% chance of good outcome, improvement [7, 12] . Others have suggested that even among patients with advanced age [38 ] . the more severe impairments may be more likely While the insertion of a shunt is a relatively to be refractory to treatment, but this has not been minor neurosurgical procedure, morbidity rates empirically studied. In our experience, even have been reported to be approximately 30% patients with subtle cognitive compromise show [39 ] . Major complications have been reported to objective improvement in cognitive functioning occur in about 10%, and minor complications and report an overall sense of improved cognitive occur in approximately 14% of patients [ 40 ] . ef fi ciency. In severely impaired patients that are Common complications include intracerebral basically untestable before surgery, there are hemorrhage, subdural effusions, subdural hema- sometimes changes in affect and in the ability to tomas, infection, shunt malfunction, over drain- participate in basic aspects of the evaluation that age, and hypotensive headaches. provide qualitative evidence of improvement. Although all three symptoms in the clinical Another methodological issue that contributes triad can show dramatic improvement following to our limited understanding about the recovery treatment, a substantial number of patients show of speci fi c cognitive functions in INPH is that incomplete resolution of one or more of the most investigations lack a control group, making symptoms. In general, gait is reported to be the it diffi cult to disentangle practice effects from a earliest and most frequent symptom to improve. true treatment effect. One recent study used com- Research has suggested that both a greater dura- parison data from a control sample and found tion of symptoms prior to intervention and the post-shunt improvement on most tasks; however, existence of comorbid disease are factors associ- effects of prior exposure to test material could ated with poorer outcome. Also, there is agree- not be examined since the controls were only ment that if left untreated or inadequately tested at one time point [ 44 ] . We recently evalu- managed, INPH often progresses to a severe state ated 12 INPH patients and nine controls with of impairment and dependency, resulting in comprehensive neuropsychological testing at markedly compromised mobility as well as a full- baseline and at 6-month follow-up [ 45 ] . The blown dementia. While all three symptoms in the INPH group showed greater improvement than clinical triad are not required for a diagnosis, sev- controls on a timed test of mental tracking and eral studies have shown that the presence of the sequencing (Trail Making B). INPH caregivers complete triad is associated with better outcome also reported improved activities of daily living following treatment [41, 42 ] . (ADLs) and reduced caregiver distress, suggest- There has been great variability in the litera- ing functional and quality of life improvements ture regarding recovery of cognitive functions. for both the shunt responder and their caregiver. Some studies report no change in mental status, while others suggest improvement in up to 90% of patients. Con fl icting fi ndings may be explained Neuropsychological Assessment by variations in the depth of cognitive examination and the way in which cognitive improvement A neuropsychologist may encounter INPH in the is de fi ned, as well as length of study follow-up context of a diagnostic evaluation, follow-up intervals. Several studies have documented assessment to track changes over time, an exami- improvement in overall mental status using nation to help establish response to intervention screening measures, but there is less agreement (tap test, ELD, shunt), or for research purposes. about whether speci fi c cognitive de fi cits may Detailed cognitive testing is recommended, par- respond differentially to treatment [ 2, 7, 43 ] . It ticularly in patients with more subtle abnormali- has been shown that patients with overt dementia ties, since screening measures and bedside testing exhibit clear gains in mental status following sur- may not pick up these mild defi cits. Mental status gery, whereas patients with more subtle impair- screening tests have poor sensitivity to the sub- ment in executive skills tend to show less striking cortical pattern of cognitive dysfunction typically 394 L.D. Ravdin and H.L. Katzen observed in INPH [46 ] . Repeat neuropsychologi- review of past medical and surgical history is also cal assessment is useful in monitoring disease an important part of the evaluation. progression and response to treatment or may be used to help identify shunt malfunction. Fatigue, both physical and mental, can contribute to Selection of Neuropsychological reduced performance, and we have found that Measures obtaining the patient’s best performance is most readily accomplished when conducting the exam As always, selection of tests will vary based on in two sessions. the nature of the referral and the patient’s presentation. Most initial referrals are for diagnostic purposes or for characterization of the extent of Taking the Clinical History cognitive impairment. In these cases, a relatively comprehensive battery should be employed that Cognitive dif fi culties, including de fi cits in insight mirrors that of a typical memory disorders evalu- and/or memory, may interfere with a patient’s ation, especially since comorbid conditions may ability to provide a complete and accurate his- need to be ruled out. When more specifi c referral tory. It is therefore critical for the clinician to questions, such as assessing potential response to gather history and background information from intervention (tap test, ELD, shunt), are at hand, a a collateral source. A well-informed caregiver or more selective battery can be implemented. A third party who is knowledgeable about the sample neuropsychological battery for use in patient’s premorbid and current level of function- NPH is listed in Table 24.3 . This is a core group ing should be interviewed. of tests that we have found to be sensitive to In order to understand the disease presentation changes in NPH and that we use in our NPH and course, one should ascertain whether the research program. onset of symptoms was acute or insidious, whether Not surprisingly, many of the traditional the symptoms have been static or progressive, and neuropsychological measures of higher cortical the severity of defi cits and degree with which they functions are unchanged in the posttap session or impact everyday functioning. Since INPH does immediately following surgery, but measures of not have a known antecedent cause by defi nition, processing and motor speed often show improve- inquiries regarding potential precipitating factors ments. We have found that measures of upper should be made to rule out SNPH. Although extremity motor speed can be helpful in deter- familial occurrence of INPH is rare, other herita- mining response to tap test [47 ] , particularly since ble conditions should be ruled out. Family history there are many cases where lower extremity questions should focus on neurodegenerative dis- motor functioning is severely compromised and orders such as PD, AD, Huntington’s disease, and cannot be formally assessed with standard gait other neurologic conditions that are often consid- scales (i.e., the patient is unable to ambulate ered in the differential diagnosis. Falls are com- without assistance). The recommended battery mon, and questions about gait changes should for assessing change pre- to post-CSF drainage also inquire about head injuries or loss of con- (tap test or ELD) is heavily weighted toward sciousness that may have occurred during those motor and psychomotor tests in order to maxi- events. Detailed questions about subtle bladder mize the ability to realize small gains over the symptoms need to be addressed with particular short term. Many of these tests are standardized attention to frequency and urgency as well as measures that are regularly used in neuropsycho- frank incontinence. Personal and family psychiat- logical clinics. Two less well-known measures ric histories should also be reviewed since behav- that we have incorporated into our battery that ioral symptoms can sometimes appear or be have not been well standardized, but provide exacerbated in INPH. As always, a standard excellent qualitative data, are the Line Tracing 24 Idiopathic Normal Pressure Hydrocephalus 395

Test and the Serial Dotting Test [ 48 ] . These two assessment should always be done on the same psychomotor speed and precision tests shown in day as the spinal tap. Although there is limited Fig. 24.2 have been demonstrated to be sensitive data regarding the optimal time for measuring to change in NPH [47 ] . posttap performance, and there are likely great We have found that to minimize fatigue and to individual differences in the response peak, the optimize performance, the pretap evaluation majority of experts suggest conducting the post- should be done on a day prior to the day of the tap assessment between 2 and 4 h after the spinal tap, preferably 1 or 2 days before and removal of spinal ﬂ uid [49 ] . Not uncommonly, always within 1 week if possible. The posttap family members report improved gait and sometimes improved attentiveness within 24 h after the tap test. We recommend routinely contacting Table 24.3 Core neuropsychological battery for repeat assessment in INPH patients the day after the tap to obtain this type of qualitative data. Post-shunt evaluations can also Global cognitive measures (i.e., Dementia Rating Scale [50 ] or 3MS [1 ] ) be useful to evaluate response to treatment and in Boston Naming Test [51 ] some cases help determine whether there may be Controlled Oral Word Association [52 ] a shunt malfunction. For example, if a patient Hopkins Verbal Learning Test—Revised [53 ] that initially demonstrated a clear response post- Wechsler Adult Intelligence Scale IV [54 ] (Digit Span) shunt developed a reemergence of symptoms, Trail Making Test A and B [55 ] neuropsychological assessment may be helpful in Symbol Digit Modalities Test [56 ] documenting the nature and severity of the change Grooved Pegboard Test [55 ] to provide evidence of a possible shunt obstruc- Finger Tapping Test [55 ] tion or other type of shunt malfunction. Repeated Line Tracing Test [57 ] assessments post-shunt can be useful in docu- Serial Dotting Test [57 ] menting recovery of function, as illustrated in the Gait scale [2 ] (videotaping of gait is helpful) case example provided below.

Fig. 24.2 Line tracing and serial dotting 396 L.D. Ravdin and H.L. Katzen

Management of NPH is accomplished with a on select measures administered as part of the multidisciplinary approach to patient care. The research protocol is provided below. neuropsychologist is a key member of the team and can play an important role in the diagnostic process, prognosticating about candidacy for Baseline Results treatment and monitoring recovery of function. A case example that demonstrates neuropsycholog- The pattern of baseline cognitive test scores ical assessment of recovery of function post- refl ected signifi cant decline from premorbid func- shunt is presented below. tioning, which was estimated to be in the high average range. Mr. X demonstrated borderline to impaired performance on two global cognitive Case Example: Recovery of Function screening measures (3MS = 82/100; DRS Following Shunt total = 118/144). Detailed neuropsychological testing revealed impairments in memory, semantic A brief summary is provided for Mr. X, an fl uency, executive functions, visuospatial abilities, 82-year-old right-handed gentleman who under- processing speed, and motor skills (domi- went of a series of neuropsychological assess- nant > nondominant). Attention, confrontation ments before and after shunt placement naming, and phonemic fl uency were intact. (baseline and follow-up post-shunt exams at 2, Overall, the observed pattern of performance 5, and 8 months). The patient initially presented revealed moderate frontal subcortical dysfunction, with severe gait disturbance, moderate cogni- and this was interpreted as consistent with INPH. tive decline, and mild urinary symptoms of approximately 1 year’s duration with a reportedly progressive course. Neuroimaging report- Follow-Up Results edly revealed prominent ventriculomegaly out of proportion to cerebral atrophy. The patient Comparison of baseline and post-shunt evalua- was diagnosed with INPH and underwent shunt tions suggested considerable improvement in placement. cognition as evidenced by signifi cant gains on a At the time of diagnosis, Mr. X enrolled in a global scale of cognitive functioning (see clinical research protocol, which included base- Fig. 24.3). Several measures of motor speed and line and post-shunt neuropsychological and gait dexterity, rapid motor processing, and mental evaluations. A brief summary of his performance tracking demonstrated moderate improvement

100

85 3MS 80

70 Baseline 2 months 5 months 8 months Time point

Fig. 24.3 Case example of post-shunt change in Modi fi ed Mini-Mental Exam (3MS) 24 Idiopathic Normal Pressure Hydrocephalus 397 over time (see Fig. 24.4). Moderate improvement walked 10 m in 20.5 s and 23 steps. At the fi nal was also observed on verbal fl uency and memory follow-up visit 8 months postsurgery, Mr. X by the 8-month follow-up exam (see Fig. 24.5 ). walked 10 m in 10 s and 9 steps, a clinically Dramatic improvement in gait was observed clini- signi fi cant improvement. Not all cognitive mea- cally as well as documented on a standardized sures refl ected improvement; defi cits persisted on gait scale (see Fig. 24.6 ). At baseline, Mr. X some tasks of psychomotor speed, and relative

Fig. 24.4 Case example of 1.00 post-shunt change in motor and psychomotor tests 0.50 0.00

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Trails A Grooved Pegboard- Serial Dotting Dom Trails B Line Tracing Finger Tap-Dom

Fig. 24.5 Case example 1.00 of post-shunt change in ﬂ uency and memory tests 0.50

0.00

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Phonemic Fluency Total Learning

Semantic Fluency Delay Recall 398 L.D. Ravdin and H.L. Katzen

15 NPH Gait 10

0 Baseline 2 months 5 months 8 months Time point

Fig. 24.6 Case example of post-shunt change in NPH Gait Scale. Note : Higher scores indicate greater impairment weaknesses (low average performance) were evi- • The gold standard for gait assessment in INPH dent on measures of motor dexterity, semantic is typically a neurologist’s subjective assess- fl uency, and learning. Consistent with anecdotal ment of gait; the neuropsychologist can bring reports and information from the literature, the a unique set of skills that provide objective earliest and most prominent gains post-shunt were measures of response. changes in gait, with improvements in cognition • In cases where gait is severely compromised evolving over the extended recovery period. or postdrainage changes are subtle, tests which rely on the integrity of upper extremity motor functioning can provide additional data to Clinical Pearls inform management. • Consistent with the literature demonstrating a • Comorbidity is common in INPH but does not high false-negative rate for tap tests, we have preclude shunt candidacy or response. seen INPH patients with negative tap test • Post-shunt improvements in gait can lead to respond to shunt. increased independence in activities of daily • ELD can be superior to tap test for prognosti- living as well as improved quality of life, even cating about shunt responsiveness, but it may if cognition remains compromised. Increased not be appropriate for all patients and it is only mobility reduces the burden of physical man- performed at specialty centers. agement for the caregiver. • Many INPH patients can execute correct walking movements in a recumbent or supine posi- References tion, potentially differentiating the gait dysfunction of INPH from other movement 1. Teng EL, Chui HC. The Modi fi ed Mini-Mental State disorders. (3MS) examination. J Clin Psychiatry. 1987;48:314–8. 2. Boon AJ, Tans JT, Delwel EJ, et al. Dutch normal- • When inquiring about urinary symptoms, ask pressure hydrocephalus study: prediction of outcome about urgency and frequency, since not all after shunting by resistance to out fl ow of cerebrospinal patients have frank incontinence. fl uid. J Neurosurg. 1997;87:687–93. • Despite reports of intact cognition as asse ssed 3. Boon AJ, Tans JT, Delwel EJ, et al. Dutch Normal- Pressure Hydrocephalus Study: the role of cerebro- by bedside mental status testing, many patients vascular disease. J Neurosurg. 1999;90:221–6. with INPH exhibit frontal systems dysfunction 4. Ravdin LD, Katzen HL. Idiopathic normal pressure on detailed neuropsychological testing. hydrocephalus. In: Morgan JE, Baron IS, Ricker JH, 24 Idiopathic Normal Pressure Hydrocephalus 399

editors. Casebook of clinical neuropsychology. 21. Mori K. Management of idiopathic normal-pressure Oxford University Press: New York; 2010. hydrocephalus: a multiinstitutional study conducted 5. Fisher CM. Hydrocephalus as a cause of disturbances in Japan. J Neurosurg. 2001;95:970–3. of gait in the elderly. Neurology. 1982;32:1358–63. 22. Casmiro M, Benassi G, Cacciatore FM, D’Alessandro 6. Knutsson E, Lying-Tunell U. Gait apraxia in normal- R. Frequency of idiopathic normal pressure hydro- pressure hydrocephalus: patterns of movement and cephalus. Arch Neurol. 1989;46:608. muscle activation. Neurology. 1985;35:155–60. 23. Trenkwalder C, Schwarz J, Gebhard J, et al. Starnberg 7. Iddon JL, Pickard JD, Cross JJ, Grif fi ths PD, Czosnyka trial on epidemiology of Parkinsonism and hyperten- M, Sahakian BJ. Speci fi c patterns of cognitive impair- sion in the elderly. Prevalence of Parkinson’s disease ment in patients with idiopathic normal pressure and related disorders assessed by a door-to-door sur- hydrocephalus and Alzheimer’s disease: a pilot study. vey of inhabitants older than 65 years. Arch Neurol. J Neurol Neurosurg Psychiatry. 1999;67:723–32. 1995;52:1017–22. 8. Casmiro M, D’Alessandro R, Cacciatore FM, Daidone 24. Conn H. Normal pressure hydrocephalus (NPH): R, Calbucci F, Lugaresi E. Risk factors for the syndrome more about NPH by a physcian who is the patient. of ventricular enlargement with gait apraxia (idiopathic Clin Med. 2010;10:1–4. normal pressure hydrocephalus): a case-control study. J 25. Marmarou A, Bergsneider M, Relkin N, Klinge P, Neurol Neurosurg Psychiatry. 1989;52:847–52. Black PM. Development of guidelines for idiopathic 9. Caltagirone C, Gainotti G, Masullo C, Villa G. normal-pressure hydrocephalus: introduction. Neurophysiological study of normal pressure hydro- Neurosurgery. 2005;57:S1–3. discussion ii-v. cephalus. Acta Psychiatr Scand. 1982;65:93–100. 26. Greitz D, Hannerz J, Rahn T, Bolander H, Ericsson A. 10. Klinge P, Berding G, Brinker T, Schuhmann M, Knapp MR imaging of cerebrospinal fl uid dynamics in health WH, Samii M. PET-studies in idiopathic chronic and disease. On the vascular pathogenesis of commu- hydrocephalus before and after shunt-treatment: the nicating hydrocephalus and benign intracranial hyper- role of risk factors for cerebrovascular disease (CVD) tension. Acta Radiol. 1994;35:204–11. on cerebral hemodynamics. Acta Neurochir Suppl. 27. Sklar FH, Diehl JT, Beyer Jr CW, Clark WK. Brain 2002;81:43–5. elasticity changes with ventriculomegaly. J Neurosurg. 11. Merten T. Neuropsychology of normal pressure 1980;53:173–9. hydrocephalus. Nervenarzt. 1999;70:496–503. 28. Bradley Jr WG, Whittemore AR, Watanabe AS, Davis 12. Thomsen AM, Borgesen SE, Bruhn P, Gjerris F. Prognosis SJ, Teresi LM, Homyak M. Association of deep of dementia in normal-pressure hydrocephalus after a white matter infarction with chronic communicating shunt operation. Ann Neurol. 1986;20:304–10. hydrocephalus: implications regarding the possible 13. Price TR, Tucker GJ. Psychiatric and behavioral manifes- origin of normal-pressure hydrocephalus. AJNR Am J tations of normal pressure hydrocephalus. A case report Neuroradiol. 1991;12:31–9. and brief review. J Nerv Ment Dis. 1977;164:51–5. 29. Tullberg M, Hultin L, Ekholm S, Mansson JE, 14. Rosen H, Swigar ME. Depression and normal pressure Fredman P, Wikkelso C. White matter changes in nor- hydrocephalus. A dilemma in neuropsychiatric differ- mal pressure hydrocephalus and Binswanger disease: ential diagnosis. J Nerv Ment Dis. 1976;163:35–40. speci fi city, predictive value and correlations to axonal 15. Schneider U, Malmadier A, Dengler R, Sollmann WP, degeneration and demyelination. Acta Neurol Scand. Emrich HM. Mood cycles associated with normal 2002;105:417–26. pressure hydrocephalus. Am J Psychiatry. 30. Relkin N, Marmarou A, Klinge P, Bergsneider M, Black 1996;153:1366–7. PM. Diagnosing idiopathic normal-pressure hydroceph- 16. Lying-Tunell U. Psychotic symptoms in normal-pres- alus. Neurosurgery. 2005;57:S4–16. discussion ii-v. sure hydrocephalus. Acta Psychiatr Scand. 1979;59: 31. Evans WA. An encephalographic ratio for estimating 415–9. ventricular enlargement and cerebral atrophy. Arch 17. Pinner G, Johnson H, Bouman WP, Isaacs J. Psychiatric Neurol Psychiatry. 1937;93:1–7. manifestations of normal-pressure hydrocephalus: a 32. Williams MA, Razumovsky AY, Hanley DF. short review and unusual case. Int Psychogeriatr. Evaluation of shunt function in patients who are never 1997;9:465–70. better, or better than worse after shunt surgery for 18. Crowell RM, Tew Jr JM, Mark VH. Aggressive NPH. Acta Neurochir Suppl. 1998;71:368–70. dementia associated with normal pressure hydroceph- 33. Marmarou A, Bergsneider M, Klinge P, Relkin N, alus. Report of two unusual cases. Neurology. Black PM. The value of supplemental prognostic tests 1973;23:461–4. for the preoperative assessment of idiopathic normal- 19. McIntyre AW, Emsley RA. Shoplifting associated pressure hydrocephalus. Neurosurgery. 2005;57:S17– with normal-pressure hydrocephalus: report of a case. 28. discussion ii-v. J Geriatr Psychiatry Neurol. 1990;3:229–30. 34. Vanneste JA. Three decades of normal pressure hydro- 20. Abbruzzese M, Scarone S, Colombo C. Obsessive- cephalus: are we wiser now? J Neurol Neurosurg compulsive symptomatology in normal pressure Psychiatry. 1994;57:1021–5. hydrocephalus: a case report. J Psychiatry Neurosci. 35. Malm J, Kristensen B, Karlsson T, Fagerlund M, 1994;19:378–80. Elfverson J, Ekstedt J. The predictive value of cere- 400 L.D. Ravdin and H.L. Katzen

brospinal ﬂ uid dynamic tests in patients with th idio- 46. Tombaugh TN, McIntyre NJ. The mini-mental state pathic adult hydrocephalus syndrome. Arch Neurol. examination: a comprehensive review. J Am Geriatr 1995;52:783–9. Soc. 1992;40:922–35. 36. Bret P, Chazal J, Janny P, et al. Chronic hydrocephalus 47. Tsakanikas D, Katzen H, Ravdin LD, Relkin NR. in adults. Neurochirurgie. 1990;36 Suppl 1:1–159. Upper extremity motor measures of Tap Test response 37. Klinge P, Marmarou A, Bergsneider M, Relkin N, in normal pressure hydrocephalus. Clin Neurol Black PM. Outcome of shunting in idiopathic normal- Neurosurg. 2009;111:752–7. pressure hydrocephalus and the value of outcome 48. Klinge P, Ruckert N, Schuhmann M, Dorner L, assessment in shunted patients. Neurosurgery. Brinker T, Samii M. Neuropsychological testing to 2005;57:S40–52. discussion ii-v. improve surgical management of patients with chronic 38. Kiefer M, Meier U, Eymann R. Does idiopathic nor- hydrocephalus after shunt treatment. Acta Neurochir mal pressure hydrocephalus always mean a poor Suppl. 2002;81:51–3. prognosis? Acta Neurochir Suppl. 2010;106:101–6. 49. Katzen H, Relkin N. Normal pressure hydrocephalus: 39. Vanneste J, Augustijn P, Dirven C, Tan WF, Goedhart a review. In: Geldmacher D, editor. Other dementias. ZD. Shunting normal-pressure hydrocephalus: do the Delray Beach: Carma Publishing; 2008. beneﬁ ts outweigh the risks? A multicenter study and 50. Mattis S. Dementia Rating Scale: professional manual. literature review. Neurology. 1992;42:54–9. Odessa: Psychological Assessment Resources; 1988. 40. Wilson RK, Williams MA. The role of the neurologist 51. Goodglass H, Kaplan E. The assessment of aphasia in the longitudinal management of normal pressure and related disorders. 2nd ed. Philadelphia: Lea and hydrocephalus. Neurologist. 2010;16:238–48. Febiger; 1987. 41. Black PM. Idiopathic normal-pressure hydrocephalus. 52. Spreen O, Benton AL. Neurosensory Centory Results of shunting in 62 patients. J Neurosurg. 1980; Comprehension Examination for Aphasia (NCCEA). 52:371–7. Victoria: University of Victoria; 1969. 42. Hebb AO, Cusimano MD. Idiopathic normal pressure 53. Benedict RHB, Schretlen D, Groninger L, Brandt J. hydrocephalus: a systematic review of diagnosis and Hopkins verbal learning test-revised: normative data outcome. Neurosurgery. 2001;49:1166–84. discussion and analysis of inter-form and test-retest reliability. 84–6. Clin Neuropsychol. 1998;12:43–55. 43. Raftopoulos C, Deleval J, Chaskis C, et al. Cognitive 54. Wechsler D. WAIS-IV manual. New York: The recovery in idiopathic normal pressure hydrocepha- Psychological Corporation; 2008. lus: a prospective study. Neurosurgery. 1994;35:397– 55. Reitan RM, Wolfson D. The Halstead-Reitan neurop- 404. discussion -5. sychological test battery. Tucson: Neuropsychological 44. Hellstrom P, Edsbagge M, Blomsterwall E, et al. Press; 1985. Neuropsychological effects of shunt treatment in idio- 56. Smith A. Symbol digit modalities test manual. Los pathic normal pressure hydrocephalus. Neurosurgery. Angeles: Western Psychological Services; 1973. 2008;63:527–35. discussion 35-6. 57. Klinge P, Rückert N, Weißenborn K, Dörner L, Samii 45. Katzen H, Ravdin LD, Assuras S, Heros R, Kaplitt M, M, Brinker T, A practical neuropsychological test Schwartz TH, Fink M, Levin BE, Relkin NR. Post- battery for measurement of cognitive and motor func- shunt cognitive and functional improvement in idio- tion in patients with Normal-pressure hydrocephalus pathic Normal Pressure Hydrocephalus (iNPH). (NPH). Poster at the 3rd International Hydrocephalus Neurosurgery. 2011;68(2):416–9. Workshop. Kos: Greece; May 17–20, 2001. Episodic and Semantic Memory Disorders 2 5

Taylor Kuhn and Russell M. Bauer

Abstract In its most pure form, the human amnesic syndrome involves a disabling impairment in new learning accompanied by some degree of impairment in aspects of remote memory in the context of relatively normal intellectual ability, language, and attention span. Neuropsychological research has clearly shown that lesions within the brain’s extended memory system (medial temporal lobe, diencephalon, and basal forebrain) produce anterograde amnesia while leaving other aspects of memory (retrieval of general knowledge, vocabulary, names) relatively intact. The episodic–semantic distinction has been useful in explaining key characteristics of the human amnesic syndrome. This chapter provides a framework for characterizing the distinction between “episodic” and “semantic” memory, and discusses the clinical features and assessment of disordered function in each of these two domains.

Keywords Episodic memory • Semantic memory • Amnesia • Memory systems • Neurobehavioral assessment

It has been nearly fi ve decades since the famous impairment in new learning accompanied by patient H.M., who represents a paradigmatic case some degree of impairment in aspects of remote of the human amnesic syndrome, was fi rst memory in the context of relatively normal intel- described in the literature. In its most pure form, lectual ability, language, and attention span. The the human amnesic syndrome involves a disabling hallmark feature, anterograde amnesia , involves “recent” memory; the essential feature of the defi cit is that the patient is impaired in the conscious, deliberate recall of information initially T. Kuhn , M.S. • R. M. Bauer , Ph.D., ABPP () learned after illness onset. In cases where remote Department of Clinical and Health Psychology , memory is impaired (retrograde amnesia ), the University of Florida , PO Box 100165 HSC , Gainesville , FL 32610-1065 , USA defi cit is often temporally graded or time-limited e-mail: [email protected] fl .edu ; [email protected] fl .edu and is generally worse for memories acquired in

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 401 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_25, © Springer Science+Business Media, LLC 2013 402 T. Kuhn and R.M. Bauer

Table 25.1 Diseases and problems producing disorders long-term memory, along with ubiquitous evi- of episodic and semantic memory dence from neuropsychological investigations of Disorders of episodic Disorders of semantic brain-damaged patients, gave rise to a variety of memory memory two-component models of memory, each attempt- Alzheimer’s disease (early) Alzheimer’s disease ing to characterize spared versus impaired mem- (mid/late) ory function in amnesia. In 1972, Tulving [ 3 ] fi rst Amnesic mild cognitive Semantic dementia impairment distinguished between two memory systems Stroke (PCA, thalamic Herpes simplex (“episodic” and “semantic” memory). Although perforators) encephalitis these two systems differ in content (episodic Aneurysm rupture/repair Neurosyphilis memory has come to be synonymous with mem- (ACoA) ory for specifi c events and their context, while Cerebral anoxia Stroke (MCA, PCA, semantic memory involves general knowledge), cortical) the core difference involves the subjective expe- Wernicke–Korsakoff Focal retrograde amnesia syndrome rience of remembering associated with each sys- Herpes simplex and HSV-6 Dissociative (psycho- tem. Episodic memories are accompanied by an encephalitis genic) amnesia experience of autobiographical remembering (in Autoimmune limbic Tulving’s terms, self-knowing or “autonoetic”), encephalitis while semantic memories lack this quality and Traumatic brain injury are accompanied by a feeling of “knowing” rather Transient global amnesia than “remembering.” Over time, the episodic– (TGA) Electroconvulsive therapy semantic distinction has been useful in explain- (ECT) ing key characteristics of the human amnesic Dissociative (psychogenic) syndrome. amnesia recent time periods than it is for memories Spared Function in Amnesia acquired in the very remote past. Neuropsychological research has clearly Many authors have argued that selective impair- shown that lesions within the brain’s extended ment of episodic, but not semantic, memory memory system (medial temporal lobe, dien- accounts for the fi nding that amnesic patients cephalon, and basal forebrain) produce antero- retain substantial intellectual, linguistic, and grade amnesia while leaving other aspects of social skill despite profound impairments in the memory (retrieval of general knowledge, vocabu- ability to recall speci fi c information encountered lary, names) relatively intact. This chapter focuses in prior learning episodes [4– 6 ] . on one way of characterizing this difference, the distinction between “episodic” and “semantic” memory, and discusses the clinical features and Retrograde Amnesia assessment of disordered function in each of these two domains. A list of disorders producing The episodic–semantic distinction may explain primary impairments in episodic or semantic temporally graded retrograde amnesia [4 ] . Cermak memory is provided in Table 25.1 . suggested that, as biographical material ages, it becomes progressively more semantic. Through retelling, it becomes less tied to speci fi c recollec- The Episodic–Semantic Distinction tive episodes and increasingly incorporated into one’s personal/family history or “folklore.” More The episodic–semantic distinction has historical recent memories are less likely to have been retold roots dating back to William James [ 1 ] . Hebb’s or elaborated beyond their original form and thus [2 ] proposed distinction between short-term and may retain more of a distinct episodic quality. 25 Episodic and Semantic Memory Disorders 403

If amnesia re fl ects a selective impairment in epi- Although it is tempting to regard anterograde sodic memory, then memories from more remote amnesia as “episodic” and retrograde amnesia/ time periods would be relatively more semantic remote memory disturbance as “semantic,” evi- and relatively spared as a result of this process. dence supports the view that both episodic and semantic memories can exist within each of these compartments. With respect to amnesia, MTT pre- Anatomy of Memory dicts that MTL damage will result in impairment of both recent and remote episodic memories, with The episodic–semantic distinction is broadly more extensive damage leading to more extensive consistent with anatomic facts. Lesions to the impairment. Although early studies with amnesic brain’s extended memory system (hippocampus/ patients such as H.M. reportedly found largely medial temporal lobe, diencephalon, and basal intact remote memory, recent reevaluations sup- forebrain) predominantly produce episodic mem- port the existence of more extensive retrograde ory impairment, while cortical lesions to anterior amnesia than previously thought (e.g., [ 9 ] .). temporal and parietal cortices tend to produce semantic memory impairments [ 7 ] . This distinction is further elucidated within a contemporary Double Dissociation Between Episodic clinico-anatomic model of human memory called and Semantic Memory “Multiple Trace Theory” (MTT; [ 8 ] ) that is remi- niscent of Cermak’s [ 4 ] ideas. MTT posits that as If the episodic–semantic distinction re fl ects a long as memories retain their episodic quality general principle of brain organization, then these (e.g., autobiographical mode of recollection, domains of memory should show double disso- context dependency, sensory-perceptual vivid- ciation in cases of focal brain disease. While data ness), they remain hippocampus dependent. Each described above provide ample evidence that epi- time an episodic memory is retrieved, it is subse- sodic memory can be impaired in the absence of quently re-encoded within the hippocampus and a defi cit in semantic memory [ 3 ] , what about the by dynamic networks of activation between the opposite? There have been several case reports hippocampus and cortical processing areas. demonstrating impaired semantic retrieval in the Activation of these networks leads to formation absence of a de fi cit in episodic/autobiographical of multiple traces in a network that becomes retrieval [10 – 12 ] ] . Several well-described cases increasingly distributed with each recollective of focal retrograde amnesia (i.e., disproportion- episode. As a result, older episodic memories ately impaired retrograde memory with relatively (i.e., those that have been retrieved numerous spared anterograde memory) have also contrib- times in different contexts) are more widely dis- uted to our understanding of the relationship tributed within the MTL than are recent ones, and between episodic and semantic memory [ 13 – 19 ] . different structures/regions within the MTL come In some cases [18 ] , a distinction within remote to make their own contribution. Moreover, as the memory has been found in which the patient is distributed network widens via multiple encod- impaired in retrieval of general knowledge but ings, it eventually can become independent of the unimpaired in retrieval of remote autobiographi- hippocampus and supported solely by neocortex. cal events. Damage to the anterior temporal These memories lose their context dependency or cortex is involved in most cases of focal retrograde autobiographic quality over time to the extent to amnesia, and damage to limbic-diencephalic which they have been retrieved in multiple con- structures contributes to impairment in remote texts. By this process, some episodic memory “autobiographical” memory. However, not all can gradually become “semantic” in quality. cases of focal retrograde amnesia are clearly Thus, semantic memory results at least in part suggestive of an episodic–semantic distinction, from gradual transfer of memory from hippocam- since careful analysis of the memory loss in some pus-dependent networks to cortical ones. cases reveals equivalent impairments in remote 404 T. Kuhn and R.M. Bauer autobiographical memory and factual knowledge loss (retrograde amnesia). Depending upon [20 ] . Finally, there is also ample evidence that a etiology, remote memory loss can be worse for developmental impairment in episodic memory more recent time periods, confi ned to a specifi c does not preclude the acquisition of factual time period or nonspecifi c [ 7 ] . As mentioned earlier, knowledge or language competence during the classic amnesic syndrome is most commonly development [ 21] . The acquisition of semantic accompanied by relative sparing of intellectual knowledge is largely independent from episodic and attentional ability, language, and other per- memory processes and takes place through formance domains that rely on established knowl- spared cortical regions subjacent to the hip- edge. Memory function that is not dependent on pocampi [21 ] . conscious, explicit recollection (i.e., implicit Although dissociations have been reported, memory) is also relatively spared. amnesics can have both episodic and semantic impairments [22– 26 ] . For example, Cermak et al. Etiology [23 ] found that Korsakoff patients had dif fi culty Serious episodic memory loss is a common prob- generating words from “conceptual” semantic lem in clinical neuropsychological evaluations memory (“name a fruit that is red”). Butters and and has considerable localizing signifi cance. It is colleagues [22 ] similarly found Korsakoff amne- also a helpful diagnostic fi nding since it is a dis- sics to be de fi cient on a verbal fl uency task. tinguishing feature of several neurological disor- A fundamental problem is that episodic and ders. Episodic memory disorders impair semantic memories are not easily dissociable functional capacity along a spectrum of severity, behaviorally [ 24 ] and may in some circumstances with only the most severe types qualifying as involve activation of the same or similar structures “amnesic.” Below, we review some of the more in functional imaging studies [ 27 ] . One confound important disorders. is that they interact in complex ways (e.g., episodic learning can have a stimulating effect on seman- Mild Cognitive Impairment tic search rate; [28 ] ). Recently, the concept of mild cognitive impair- As indicated earlier, multiple trace theory ment (MCI) was introduced to describe older provides a contemporary reformulation of the adults with a memory complaint in the context of episodic–semantic memory distinction within a normatively impaired memory, intact activities functional-anatomic account of the activity of the of daily living, generally intact cognitive func- hippocampal system. From the perspective of tion, and no dementia [ 29, 30] . At least three multiple memory systems accounts of spared and subtypes of MCI are widely recognized, includ- impaired function, MTT offers a promising way ing amnesic, multi-domain (encompassing more to conceptualize episodic and semantic memory than one cognitive area), and single-domain as points on a processing continuum. Of equal nonamnesic, forms [ 30 ] . The primary importance importance, it provides a neurobiologically real- of the MCI concept relates to its role as a possible istic model of memory dissociations that accounts prodromal stage of dementia. Longitudinal stud- for a large amount of clinical and research data. ies indicate that approximately 10–15% of patients with MCI convert to Alzheimer’s disease each year, compared to overall conversion rates Disorders of Episodic Memory of 1–2% in cognitively normal elders [ 31 ] . Behavioral markers and concurrent presence of Clinical Features entorhinal and hippocampal atrophy appear to most strongly predict eventual conversion [ 32 ] . The primary clinical features of episodic memory It is important to note that MCI encompasses disorders have already been described and involve both objective evidence and subjective report impairment in new learning (anterograde amne- (often including an informant) of age-related sia) and at least some degree of remote memory memory impairment. Many objectively normal 25 Episodic and Semantic Memory Disorders 405 adults may complain of memory loss, particularly Vascular Disease if they are in intellectually demanding positions. Stroke can produce amnesia when critical areas The isolated presence of a memory complaint are infarcted. Strokes affecting the posterior cere- without objective evidence may indicate the pres- bral artery territory (posterior medial temporal ence of depression or adjustment dif fi culties that lobe and retrosplenial cortex; [45 ] ) and the thal- are themselves worthy of independent clinical amic penetrating arteries [ 46 ] have been impli- attention. By the same token, depression, anxiety, cated, as has basal forebrain amnesia from and other neuropsychiatric symptoms that may anterior communicating artery aneurysm hemor- give rise to a subjective memory complaint are rhage or surgery [ 47 ] . Infarction of the fornix quite common in MCI [33 ] . with or without basal forebrain lesions can also present with isolated amnesia [ 48, 49 ] . In vascu- Degenerative Disorders lar cases, the onset of amnesia is abrupt. Many degenerative dementias such as Pick’s, Improvement is variable, and patients may be left Huntington’s, and Parkinson’s disease eventually with serious permanent defi cits, even following affect memory, but Alzheimer’s disease (AD) ini- small infarctions. tially manifests with an episodic memory impairment [34 ] . Nearly all of the neural systems Cerebral Anoxia thought to be important in memory are affected Depending upon the degree and duration of isch- by AD, including the medial temporal lobe emia and/or hypoxia, neuronal loss may be wide- [ 35– 37 ] , basal forebrain [ 38 ] , thalamus [ 39 ] , and spread or very focal. Amnesia has been reported neocortex. Memory impairment in Alzheimer’s following cardiac arrest in which the only patho- disease primarily affects episodic memory fi rst logical feature identifi ed was loss of neurons in but may also affect some aspects of semantic fi eld CA1 of the hippocampus [50 ] . Issues related memory such as verbal fl uency [ 40 ] . Eventually, to characterizing the extent of damage from anoxic semantic memory is more severely affected, as or ischemic insults have been reviewed [51 ] . are other cognitive domains including language, visuoperceptual ability, and executive function. Wernicke–Korsakoff Syndrome While the memory defi cit seen in AD and other Alcoholic Korsakoff syndrome most frequently cortical dementias primarily involves episodic develops after years of alcohol abuse and nutri- memory, signifi cant loss of semantic memory can tional de fi ciency [52– 54] but can also result from be seen in a variant of frontotemporal dementia, chronic avitaminosis secondary to malabsorption so-called semantic dementia [ 41, 42 ] . Thus, the syndromes [ 55] or in patients who refuse to eat in memory loss found in AD and frontotemporal the context of a psychiatric disorder [56 ] . Patients dementia is not as “pure” as in other forms of fi rst undergo an acute stage of the illness, amnesia and takes place in the context of broader Wernicke’s encephalopathy, in which symptoms cognitive decline. Semantic dementia is dis- of confusion, disorientation, oculomotor dysfunc- cussed more fully below. tion, and ataxia are present. After this resolves, amnesia can persist as a permanent symptom. Effects of Anticholinergic Medication Severe anterograde amnesia and an extensive, Many commonly used medications have temporally graded retrograde amnesia are charac- signifi cant central anticholinergic actions, includ- teristic features. Substantial defi cits in memory ing antihistamines commonly used in nonpre- encoding, coupled with signs of frontal executive scription sleep and allergy medications, some and visuospatial dysfunction are common. antidepressants, and medications used to manage urinary frequency and incontinence. Herpes Simplex and HSV-6 Encephalitis Anticholinergic drugs can impair memory [ 43 ] , Herpes simplex causes infl ammation and necro- and withdrawal of these medications in patients sis, particularly in the orbitofrontal and inferior with memory defi cits may result in dramatic temporal regions. It thus involves limbic structures, improvement in memory [44 ] . including the hippocampus, parahippocampal 406 T. Kuhn and R.M. Bauer gyrus, amygdala and overlying cortex, the polar known neoplasm, can have a more selective limbic cortex, cingulate gyrus, and the orbitof- limbic encephalitis that often responds to immu- rontal cortex [34 ] . Patients may present with per- notherapy with steroids, IVIG, or plasma sonality change, confusion, headache, fever, and exchange [68 ] . A syndrome of amnesia, psycho- seizures and are often amnesic. Prompt treatment sis, seizures, and central hypoventilation pro- with antiviral agents can control the illness, and gressing to coma has been attributed to antibodies full recovery is possible. However, damage to the that react with NMDA receptors [71 ] , and this aforementioned structures often leaves the patient syndrome may respond dramatically to immu- with severe anterograde and retrograde amnesia. notherapy. Although fi rst described in associa- The amnesic syndromes in patient D.R.B. (also tion with neoplasms, only 60% of a large series known as Boswell; [57 ] ) and patient S.S. [ 58, 59 ] had cancer [72 ] , and the same syndrome has have been particularly well characterized. Recent now been reported in children, many without reports indicate that herpes simplex infection can neoplasms [73 ] . Similar autoantibodies have occasionally lead to a syndrome of focal retro- been identifi ed in patients with epilepsy and grade amnesia that is described more completely systemic lupus [ 74 ] . below [13, 60, 61] . Human herpes virus-6 (HHV- 6) also can target the limbic system and present Trauma with amnesic syndromes, confusion, sleep disor- Following closed head injury, patients may have ders, and seizures [ 62 ] . Hokkanen and Launes an acute anterograde and retrograde amnesia, [63 ] review other infectious agents that can leave the duration of which correlates with the sever- residual neuropsychological sequelae, including ity of the injury as measured by the Glasgow memory loss. Coma Scale or the duration of unconsciousness [75 ] . The duration of posttraumatic amnesia Autoimmune Limbic Encephalitis (memory for ongoing events after trauma) is a This condition usually presents with personality good predictor of long-term functional outcome change, agitation, and amnesic symptoms. It [76– 78 ] . The retrograde amnesia typically was fi rst described as a paraneoplastic syndrome improves along with improvement in antero- [64– 67] , but it can also occur in patients without grade amnesia, providing evidence that a neoplasm [68 ] . Over the past decade, several retrieval de fi cit is responsible for the portion of autoantibodies have been associated with differ- the retrograde memory loss that recovers. ent forms of limbic encephalitis (see [ 69, 70 ] ). Residual memory impairment is usually a fea- Neuronal antibodies (Hu, Ma2, CV2/CRMP5, ture of broader cognitive and attentional impair- amphiphysin, and atypical intracellular antibod- ment, but it can be prominent with severe ies) in patients with various neoplasms (small injuries [79, 80 ] . Pathological changes are vari- cell and non-small cell lung cancer, testicular able and widespread. Memory dysfunction may tumors, thymomas, and others) have been asso- be caused by anterior temporal lobe contusions, ciated with an infl ammatory disorder affecting temporal lobe white matter necrosis, or diffuse neurons throughout the neuraxis but often with axonal disruption [ 75, 81] . Cases of focal retro- particular intensity in limbic structures includ- grade amnesia in the relative absence of a new ing the hippocampus. Although the pathogene- learning defect have been reported after closed sis is autoimmune, response to immunotherapy head trauma [ 15, 16 ] . is usually poor. However, patients with Ma-2 antibodies in association with testicular cancers Transient Global Amnesia often improve after surgery. Patients with anti- This distinctive form of amnesia begins suddenly bodies to voltage-gated potassium channels and typically resolves within a day [82– 85 ]. A (VGKC), sometimes associated with thymoma severe impairment in new learning and patchy or small cell lung cancer, but more often without loss of information learned prior to onset is seen. 25 Episodic and Semantic Memory Disorders 407

The patient often asks repetitive questions and Dissociative (Psychogenic) Amnesias may be aware of the memory defi cit. After reso- Psychologically induced loss of memory may be lution, neuropsychological testing is usually nor- normal, as in amnesia for events of childhood mal except for amnesia for the episode [ 84 ] . [114– 116] or for events during sleep [ 117 ] . Although the etiology of transient global amne- Alternatively, they may be pathological, as in the sia (TGA) is unclear, epilepsy [ 86– 88 ] , emo- amnesias associated with dissociative states, mul- tional stress [ 89 ] , occlusive cerebrovascular tiple personality, or with simulated amnesia [118– disease [ 90, 91] , migrainous vasospasm [ 83 , 92, 94 ] 120] . A striking loss of personal autobiographical head trauma [95 ] , vertebro basilar dyscontrol memory is a hallmark of functional amnesia, and [82 ] , and venous insuf fi ciency [96 ] have all been amnesia for one’s own name (in the absence of mentioned as possibilities. There are now many aphasia or severe cognitive dysfunction in other reports of small diffusion-weighted imaging spheres) is seen exclusively in this form of mem- (DWI) abnormalities in CA1 of the hippocampus ory loss. Retrograde loss is often disproportionate in patients with TGA within the fi rst 48 h [ 97– 100 ] ; to anterograde amnesia, and some patients will these lesions typically are transient [ 101, 102 ] demonstrate loss of skills or other procedural and are more likely to be evident after 24–48 h of memories typically retained by organic amnesic symptom onset (and hence, after resolution in patients. Some studies have reported dispropor- the majority of patients). The striking predilec- tionate loss of “personal” as opposed to “public” tion of these punctate lesions for the lateral hip- information in the retrograde compartment [121 ] , pocampus leaves little doubt as to their relevance a fact that is discussed in terms of the episodic– to the clinical fi ndings; however, their pathogen- semantic distinction by Reinhold and Markowitsch esis remains enigmatic. Although the DWI char- [ 122] . A good general review is provided by acteristics are suggestive of ischemia, patients Kihlstrom and Schacter [123 ] . with TGA do not appear to be at greater risk for cerebrovascular disease than controls [ 83, 103 ] . Epileptic TGA [ 104, 105 ] usually has a shorter Disorders of Semantic Memory duration, is more likely to recur, and may be associated with EEG abnormalities. Clinical Features

Electroconvulsive Therapy In contrast to the patient with episodic memory Used for relief of depression, electroconvulsive impairment, the patient with semantic memory loss therapy (ECT) can produce rapidly recovering fi nds it dif fi cult to retrieve and use previously anterograde and temporally limited retrograde stored factual, linguistic, or perceptual knowledge. amnesia [106– 108 ] . More severe impairment is The impairment may affect the comprehension or seen after bilateral versus unilateral application. production of words, concepts, facts, semantic The anterograde defect is related in severity to relationships, and general knowledge. Episodic the number of treatments and is characterized memory, though not entirely normal, is relatively by rapid forgetting and poor delayed recall spared, and the patient typically has no great dis- [109 ] . Substantial, often complete, recovery ability in learning and retrieving knowledge of takes place in the few months after treatment ongoing day-to-day events. A closer look at the ends [ 107, 110, 111 ] . The retrograde amnesia pattern of disruption over time reveals that the appears to be temporally limited, involving only loss of semantic knowledge initially affects the the few years prior to treatment onset. It, too, ability to retrieve specifi c exemplars within broad recovers almost completely in the months after categories and the patient may be capable eventu- treatment [112, 113] . Though the data is by no ally of identifying only typical items that show means clear, some authors have suggested that high family resemblance of their parent category. ECT-induced memory loss models bilateral The disorder affects naming, language compre- temporal lobe disease [ 109 ] . hension, expressive and receptive vocabulary, 408 T. Kuhn and R.M. Bauer and fact retrieval. Behavioral changes coincident profi le and associated comorbidities. However, with semantic loss may occur and may include all of these diseases are associated with rela- withdrawal, a reduction in interests, or the devel- tively intact somatosensory and motor abilities, opment of new preferences for food or activity procedural memory, verbal abilities, and visu- [124 ] , but these are not typically predominant ospatial skills. As such, knowledge of the features or reasons for referral. disease course, outcome, neurologic and neu- Although disorders of semantic memory are ropsychological profi le, and treatment are all typically nonspecifi c (i.e., do not differentially necessary in order to successfully complete a affect specifi c semantic categories), several well- differential diagnosis and provide effective described cases of category-speci fi c semantic medical care to affected patients. All three of defi cits have left little doubt that selective loss of these diseases affect the neural substrates that semantic memory exists. Warrington and Shallice mediate semantic memory, primarily the tem- [ 125 ] reported four cases of category-speci fi c poral cortex. Both lateral and medial structures semantic loss for living versus nonliving things of the temporal lobe that are involved in the after partial recovery from herpes simplex encoding, consolidation, and retrieval of encephalitis. Since Warrington and Shallice’s ini- semantic information can be affected. The tial demonstration, a large literature has accumu- semantic memory impairment seen in these lated showing that selective impairment of living conditions is briefl y reviewed below. things is most common [ 126 ] . Substantial literature has examined the implications of category Semantic Dementia speci fi city for understanding the organization of Semantic dementia (SD) is one of three promi- semantic memory. While these cases are most nent subtypes of frontotemporal dementia (pro- consistent with a categorical, meaning-based gressive non fl uent aphasia and behavioral organization of the memory store, other data variant are the others), which results from fron- either indicate that category specifi city can be totemporal lobar degeneration. Patients with accommodated within a modality-speci fi c seman- SD may present with word- fi nding dif fi culties, tic network affecting visually based category dis- aphasia, anomia, visual associative agnosia, or tinctions [127 ] or which outright favor a more impaired understanding of semantic words and interactive, modality-speci fi c view [128 ] . images. Pathologically, most patients have Category specifi city is relatively rare (fewer than ubiquitin-positive, tau-negative inclusion 150 reported cases exist) and is most common bodies, though some may have pathology con- after herpes simplex encephalitis. It is not com- sistent with Pick’s disease or Alzheimer’s monly seen in degenerative conditions that disease [124, 131 ] . produce semantic memory impairments, including The most prominent early feature in semantic Alzheimer’s disease [ 129 ] and semantic demen- dementia is the reduction of expressive vocabu- tia [130 ] . lary, commonly described as a “loss of memory for words” [132, 133 ] . Episodic memory problems Etiology may also be present but are typically mild in Semantic memory impairments are seen in a comparison [134 ] . Receptive vocabulary also variety of disease states, with the most com- deteriorates, though changes may be subtle mon causes being degenerative disease (seman- initially. As the disease progresses, spontaneous tic dementia variant of frontotemporal speech becomes increasingly anomic, with word- dementia, mid-stage Alzheimer’s disease) or a fi nding pauses and substitution of more generic post-acute outcome of CNS infection (herpes words (e.g., “thing”) for specifi c lexical items simplex encephalitis; HSVE). These diseases [124 ] . Many patients with SD also have defective affect semantic memory differently and each person knowledge, manifested in impairments in presents with a unique neuropsychological naming people, generating information about 25 Episodic and Semantic Memory Disorders 409 them from their names or faces, and, in severe episodic memory impairments typically exceed cases, recognizing the identity of faces or deter- semantic memory impairments in early AD, mining whether they are familiar [124 ] . while the reverse is true of SD. Tests of other functions (e.g., visuospatial function) differen- Alzheimer’s Disease (Later Stages) tially affected in AD versus SD might prove use- AD begins focally in the transentorhinal cortex of ful in differential diagnosis. The Adlam et al. [ 40 ] the temporal lobe, affecting the hippocampus study suggests that, despite some semantic mem- early in the disease. As the disease progresses, ory impairment in AD [ 141, 142 ] and episodic pathological features move in a posterior and lat- memory diffi culties in SD [ 143 ] , the two groups eral fashion to affect the lateral temporal lobe, can be differentiated when measures of the two basal forebrain, thalamus, and neocortex of the types of memory are combined with measures of parietal and frontal lobes, ultimately affecting visuospatial ability. virtually all areas thought to be important for memory. Because of increasing cortical involve- Herpes Simplex Encephalitis ment later in the disease, a broad spectrum of HSE is an acute in fl ammation and necrosis of the neuropsychological defi cits may eventually brain resulting from a herpes simplex virus-1 emerge. In the later stages of the disease, execu- strain infection of the limbic structures, including tive function, language, and even postural stabil- the hippocampus, parahippocampal gyrus ity and gait may be affected. amygdala and overlying cortex, polar limbic cor- Semantic memory impairment in AD may be tex, cingulate gyrus, and the orbitofrontal cortex. re fl ected in reduced receptive vocabulary and HSE often presents acutely with fever, personal- reduced ability to retrieve and understand words ity changes, confusion, seizures, hemiparesis, [135 ] . The impairment is greater for more recently and headaches. In the post-acute period, HSE is acquired words than for words learned earlier in associated with a range of neuropsychological life [136 ] , which has been postulated to result impairments owing to the typically bilateral, from the richer semantic embeddedness of earlier- though sometimes asymmetrical, medial, and lat- acquired words [137, 138 ] . A recent study sug- eral temporal lobe involvement. Remote memory gested that this effect was related to the degree of is typically impaired with a “fl at” temporal gradi- involvement in left anterior temporal neocortex as ent [144 ] . Episodic and semantic memory can measured by voxel-based morphometry [139 ] . both be profoundly impaired, including the abil- How does the semantic impairment in AD ity to retrieve remote autobiographical informa- compare to that of SD? A recent longitudinal tion [61 ] . Classic amnesic syndromes after HSE study by Xie et al. [ 140] showed that, while SD have been reported by McCarthy and Warrington and AD patients were not different early in the [145 ] and Cermak [58, 59 ] . disease, the semantic impairment in SD eventu- Some HSE cases suffer a more restricted ally outstripped that seen in AD later on. In this impairment of semantic memory, often in the form study, the SD patients performed more poorly of a category-speci fi c de fi cit. Most commonly than AD on semantic memory at all time points, reported are patients who have selective impair- whereas measures of episodic memory, initially ment in accessing information pertaining to “liv- worse in AD, eventually converged as the dis- ing things” [ 146] , though the opposite has been eases progressed. A recent study suggested that found and methodological issues in defi ning “cat- SD patients performed more poorly than AD egory speci fi city” may be useful for the clinician to patients on word sorting and naming tests from consider [147 ] . The fact that category specifi city the Cambridge Semantic Memory Test (CMST), is seen more commonly after HSE (which pre- though the overall test was not able to differenti- dominantly affects anteromedial temporal cortex) ate the groups [40 ] . Particularly, in early stages of than it is in SD (which involves more anterolat- the disease, substantial overlap in defi cits might eral temporal cortex) is intriguing. Noppeney exist. However, it is reasonable to postulate that et al. [148 ] suggest that the medial temporal 410 T. Kuhn and R.M. Bauer cortex may represent semantic categories that are acute onset suggests an infectious, vascular, or more interrelated (in their words, “tightly traumatic origin. HSE can occur at any time point packed”) in semantic space, while the lateral across the adult lifespan whereas dementia typi- temporal cortex might play a more general cally begins primarily after the age of 40. Within semantic role. the degenerative disorders, a younger age of onset has been associated with SD which has a mean Other Etiologies age of onset of 59 or FTD which has a mean age Other forms of brain disease can produce seman- of onset of 63 [150 ] . Although there are excep- tic memory defi cits (e.g., neurosyphilis, stroke), tions, AD tends to onset later. The mean age of usually in the context of other impairments that onset of AD is 68, with early onset de fi ned as that correlate with the site of damage. Capitani et al. which begins prior to the age of 60 and late onset [149 ] found that 12 of 18 patients with left pos- that which begins after 65 years of age [ 151 ] . terior cerebral artery stroke involving the fusi- Acute onset of febrile illness followed by more form gyrus displayed semantically based naming chronic semantic memory impairment should defi cits and 5 showed distinct category suggest an infectious process such as HSE. specifi city. Half of the left PCA patients showed Conversely, gradual, progressive impairment of additional de fi cits in verbal semantic knowl- semantic memory most likely signals a neurode- edge. Unlike the majority of HSE cases, who generative process. HSE can remit and often does showed differential impairments for animals, so in a pattern of alternative remission and some of the left PCA patients showed distinct relapse. HSE can be effectively treated, and when impairments in naming plants, with relative treated, survival is assured in the signifi cant sparing of animals. Other cases are the result of majority of cases. However, survivors can be left trauma affecting orbitofrontal and anterolateral with a range of impairments from complete temporal regions or re fl ect comorbid symptoms recovery to mild impairment from restricted of serious neurologic disturbances (e.g., brain impairment of language or memory to severe tumor). In general, the clinician should be aware dementia [152 ] . In terms of independent activities of the fact that most patients with signifi cant of daily living (IADLs), patients with AD will be semantic memory impairments have (typically initially impaired by episodic memory failure, bilateral) damage to the lateral anterior tempo- while those with SD or HSE may lose the ability ral lobe or parietotemporal association cortex, to follow customary routines or to understand and should clinically evaluate semantic memory key concepts such as fi nances. The pattern of loss with appropriate tests in any patient who has should be ascertained during the clinical interview damage within these regions. and should inform test selection during the neuropsychological examination. While a fi xed battery of tests is attractive due Clinical Examination to broad applicability to research databases and to ease of comparison with existing norms and Pre-examination interview of the patient sus- already evaluated patient populations, it is not pected of having semantic memory impairment is common to include comprehensive tests of critical and offers insight into the broad cognitive semantic memory in standard neuropsychologi- domain in which impairment is suspected. Critical cal batteries. In the patient suspected of semantic data include age, mode of onset (acute vs. insidi- memory impairment, a well-validated battery of ous), progression of cognitive decline, duration, tests, the Cambridge Semantic Memory Test and degree of impairment in activities of daily (CSMT) Battery, can be used to parse semantic living. The onset of the impairment should be from autobiographical memory impairment and clearly determined along with its course (remit- can determine whether the impairment is modal- ting, stable, or progressive). An insidious onset ity or category specifi c. Good normative data suggests a dementia such as AD or SD-FTD. An exists. However, while the CSMT is useful for 25 Episodic and Semantic Memory Disorders 411 evaluation of the type and nature of semantic enough time. Since speed of memory retrieval memory de fi cits, it is not suf fi ciently sensitive to is often a sign of a degraded semantic memory differentiate advanced AD from SD [ 40 ] . system, relaxing time constraints allows the cli- Additionally, research has shown that the Four nician to investigate the boundaries of a patient’s Mountains Test, a compilation of a topographical capability. Although many other factors are perception task with a topographical short-term involved, improvement with relaxation of time memory task and a nonspatial perception and constraints suggests some defi cit in semantic related short-term memory task, is a sensitive access, while lack of improvement may indicate measure than can be used to distinguish AD from a loss of semantic representations. FTD [ 153] . These authors showed that patients SD is the primary cause of semantic language with AD and amnesic MCI were impaired on the impairment in FTD. Language should be fully topographical short-term memory task but not assessed to rule out other forms of FTD (e.g., on perception when compared to the FTD partici- behavioral variant, progressive nonfl uent apha- pants. While the non-topographical task revealed sia). The concomitant, equal impairment of pro- no group differences, this task suggests that duction and comprehension may distinguish SD short-term memory for topographical informa- from progressive nonfl uent aphasia. Standardized tion can be impaired in AD, regardless of stage aphasia batteries (Western Aphasia Battery, of disease, and is therefore a useful diagnostic Boston Diagnostic Aphasia Examination) pro- measure [ 153 ] . vide an overview of performance that can be The neuropsychologist should be aware that supplemented by individual tests of naming differential diagnosis depends critically on the (Boston Naming Test), auditory comprehension relative patterning of semantic memory defi cits (Token Test), semantic processing (Pyramids and compared to other aspects of the performance Palm Trees, a subtest of the Cambridge Semantic pro fi le. SD will tend to exhibit semantic language Memory Test), grammar and syntax (Test for impairments and executive dysfunction early in Recognition of Grammar), repetition (Western the disease in the context of intact visuospatial Aphasia Battery), fl uency (Controlled Oral Word skills and relatively intact episodic memory. By Association, DKEFS Fluency), and tests of writ- the time AD patients exhibit disabling semantic ing and reading. SD patients have been shown to memory impairments, their episodic memory exhibit more signifi cant impairment on the problems will be quite signifi cant, but they may Boston Naming Test than either FTD or AD show relatively preserved language and visuospa- patients [154 ] . The COWA is particularly useful, tial skills and varying executive function that as research suggests that temporal lobe-damaged declines as a function of disease progression. patients and AD patients perform worse on HSE-related semantic memory defi cits more semantic fl uency measures (e.g., fruits/vegeta- commonly are category speci fi c, such that selection bles) than on letter fl uency (e.g., S). Patients with of standard neuropsychological tests may be frontal lobe disease tend to perform worse on let- insuffi cient to disclose their defi cit. Standardized ter fl uency than on semantic fl uency, due to the tests of semantic memory are critical in evaluating increased demand on strategic retrieval processes these patients. HSE affects executive functioning [155 ] . However, this discrepancy was observed while leaving language and visuospatial skills only when fruits and the letter S were used. No primarily intact. group differences were observed when animals Regardless of the preferred type of battery, and the letter F were compared. This fi nding special considerations and techniques should illustrates the necessity of a broad assessment of be employed when assessing potential semantic language so that such potential confounds may memory defi cits. “Testing the limits” should be be more fully understood. employed when working with patients who do In cases where remote memory/knowledge is not perform the tasks in the allotted time but affected, the assessment should be suf fi ciently who are capable of completing the tasks given thorough to enable an understanding of the type 412 T. Kuhn and R.M. Bauer of memory impaired (autobiographical vs. sary, develop in-house tests to informally assess semantic), time of memory impaired (remote vs. for this possibility if more extensive, standard- retrograde vs. anterograde amnesia), and whether ized tests of semantic memory are unavailable or not the memory defi cit is context specifi c. Assessing executive function can be useful for First, it must be established that the memory further differentiating SD-FTD from AD. impairment is one of semantic memory rather Common measures include Wisconsin Card Sort than autobiographical memory. This can be Test (WCST), The Delis–Kaplan Executive achieved by using such batteries as the Wechsler Functioning Scales, the Category Test, the Stroop Memory Scale (WMS-IV), which are composed Color Word Test, and measures of motor organi- of measures designed to assess the full range of zation and inhibition (Luria’s contrasting pro- memory domains. Additional standardized mea- grams, Go–No Go, recursive fi gures and serial sures of episodic memory include the Hopkins hand sequences). Ideally, executive functioning Verbal Learning Test, the California Verbal should be assessed as part of any neuropsycho- Learning Test—II, the Rey Complex Figure, the logical evaluation and is important in the investi- Continuous Visual Memory Test, and the Brief gation of semantic memory impairment. As Visual Memory Test—Revised. Focused mea- executive function is primarily mediated by fron- sures which assess either autobiographical or tal lobe structures, and SD is a subset of frontal semantic memory are available as well. For lobar degeneration, executive dysfunction is remote autobiographical memory, the Crovitz common in SD patients. However, this does not task (“describe an event from your past that necessarily distinguish SD from AD or HSE, involved a ‘ fl ag’”), the Autobiographical Memory since some executive dysfunction should be Interview [156 ] , or Squire’s TV Test [ 157 ] may expected in association with all etiologies we be useful, though clinicians are cautioned about have discussed, particularly in later disease the lack of precise normative data. General tests stages. HSE often presents with comorbid per- of vocabulary (WAIS-IV) are useful, as are tests sonality changes and alterations in conscious- of factual event knowledge that require patients ness, and later-stage AD frequently involves to identify famous faces (Famous Faces Task; personality changes, disinhibition, emotional Presidents Test) or to show knowledge of well- lability, and apathy. known public events from different decades that were not part of their personal life experience (Boston Remote Memory Battery). By assessing Other Neurodiagnostic Considerations the patient’s ability to recognize and recall information that is not bound to their own life-event In most cases, neuropsychologists who are memory, these tasks measure defi cits in semantic asked to evaluate patients with episodic and memory. While semantic memory can be impaired semantic memory disorders will function within in AD and SD, episodic, autobiographical knowl- an interdisciplinary team that includes specialty edge is an early sign of AD. Both episodic and physicians (neurologists, psychiatrists, neuro- semantic memory can be impaired in varying surgeons). It is obvious that the neurobehav- extents in HSE. Semantic memory impairments ioral workup of these patients should supplement that are not language bound in terms of either available neurodiagnostic information from perception or production and are also not context the neurologic and physical exam, laboratory speci fi c are more likely the result of AD. Both studies, and neuroradiologic investigations. FTD and AD have been shown to be impaired on Neuroimaging data suggest that both SD and verbal memory tasks; AD may be more likely to HSE involve pathological changes in similar, display visual memory de fi cits [154 ] . HSE and though not identical regions. HSE often results focal stroke are the most likely disorders to pro- in bilateral anterior temporal damage extending duce a category-speci fi c semantic memory into the amygdala and may include gray matter impairment, and the clinician should, if neces- atrophy in the medial structures of the anterior 25 Episodic and Semantic Memory Disorders 413 temporal lobe and the insula. These medial can be added to a preponderance of evidence structures are relatively spared in SD; atrophy during a dementia consensus debate. Parallel is more commonly observed in the lateral tem- developments in the genetics and neurohis- poral cortex, either unilaterally or bilaterally. tochemistry of frontotemporal dementia are The hallmark of early onset AD is focal hip- beginning to elucidate specifi c genetic and pocampal atrophy that is often readily apparent immunohistochemical markers that might be on MRI. Finally, genetic testing can add infor- useful in the differential diagnosis of SD and mative but not de fi nitive data to a diagnostic other FTD variants [ 158 ] . profi le. Carriers of the apolipoprotein E e 4 As has been demonstrated, there are numerous allele (APOE e 4) have been found to be at etiologies of acquired and degenerative semantic increased risk for developing AD; the APOE e 2 memory impairment, each with a unique disease allele has been suggested to serve a protective onset, course and neuropsychological pro fi le, and effect against the development of AD. Simply numerous tools to measure and evaluate these having an APOE e 4 allele does not denote defi cits. Thorough understanding and implemen- future development of AD, but this information tation of appropriate measures, as well as educated

Table 25.2 Evaluation of episodic and semantic memory disorders Domain Test Norms AFPa ? Reference Episodic/recent memory Verbal memory WMS-IV Logical Memory √ √ Wechsler et al. [ 159 ] Hopkins Verbal Learning Test-Revised √ √ Benedict et al. [ 160 ] California Verbal Learning Test—II √ √ Delis et al. [ 161 ] Rey Auditory Verbal Learning Test √ √ Schmidt [ 162 ] Nonverbal WMS-IV Visual Reproduction √ √ Wechsler et al. [ 159 ] memory Rey Complex Figure √ √ Meyers and Meyers [163 ] Brief Visual Memory Test √ √ Benedict [ 164 ] Continuous Visual Memory Test √ √ Trahan and Larrabee [ 165 ] Prospective Cambridge Test of Prospective Memory √ √ Wilson et al. [ 166 ] memory Episodic/remote Crovitz Paradigm Crovitz and Schiffman [167 ] memory Autobiographical Memory Interview +/− √ Kopelman et al. [156 ] TV Test, Remote events test Squire and Slater [157 ] Semantic Cambridge Semantic Memory Test √ PPT b Adlam et al. [40 ] memory WAIS-IV Vocabulary, Information √ √ Wechsler et al. [ 168 ] Language/ Western Aphasia Battery—Revised √ √ Kertesz [ 169 ] semantic Boston Diagnostic Aphasia Examination √ √ Goodglass et al. [ 170 ] processing Boston Naming Test √ √ Goodglass et al. [ 170 ] Controlled Oral Word Association √ √ Benton et al. [ 171 ] DKEFS Fluency √ √ Delis et al. [ 172 ] Test for Reception of Grammar √ √ Bishop [ 173 ] Reading, Writing Tests Various available Executive Wisconsin Card Sorting Test √ √ Grant and Berg [ 174 ] functioning Booklet Category Test √ √ DeFilippis and McCampbell [175 ] Delis–Kaplan Executive Functioning √ √ Delis et al. [ 172 ] Scales Stroop Test √ √ Stroop [ 176 ] Luria Motor Programming Luria [177 ] a Denotes whether test is available for purchase on the commercial market b The Pyramid and Palm Trees Test (a subtest of the CSMT) is commercially available 414 T. Kuhn and R.M. Bauer and concise interaction between health care References providers, is essential for the proper evaluation, diagnosis, and treatment of amnesic syndromes. 1. James W. The principles of psychology. New York: Dover; 1890. 2. Hebb DO. The organization of behavior: a neuropsy- Clinical Pearls chological theory. New York: Wiley; 1949. 3. Tulving E. Episodic and semantic memory. In: Tulving E, Donaldson W, editors. Organization of • Evaluation of patients with suspected epi- memory. New York: Academic; 1972. p. 381–403. sodic or semantic memory disorders 4. Cermak LS. The episodic-semantic distinction in should always include the participation of amnesia. In: Squire L, Butters N, editors. a collateral informant who can verify the Neuropsychology of memory. New York: Guilford Press; 1984. p. 55–62. patient’s report, which may appear accurate 5. Kinsbourne M, Wood F. Short-term memory pro- to the naïve examiner. cesses and the amnesic syndrome. In: Deutsch D, • Examination of the patient with episodic Deutsch JA, editors. Short-term memory. New York: memory impairment should be capable of sep- Academic; 1975. p. 258–91. 6. Weingartner H, Grafman J, Boutelle W, Kaye W, arating encoding, retention, and retrieval pro- Martin P. Forms of cognitive failure. Science. cesses through the use of multiple tests. 1983;221:380–2. • Virtually any neurologic disorder above the 7. Bauer R, Reckess G, Kumar A, Valenstein E. cervical vertebrae can affect episodic memory Amnesic disorders. In: Heilman KM, Valenstein E, editors. Clinical neuropsychology. 5th ed. New York: function; diagnosis typically relies on inter- Oxford University Press; 2011. disciplinary evaluation. 8. Moscotitch M, Rosenbaum RS, Gilboa A, Addis • Although the commonly used neuropsycho- DR, Westmacott R, Grady CL, et al. Functional neu- logical tests are capable of screening for roanatomy of remote episodic, semantic, and spatial memory: A unifi ed account based on multiple trace aspects of semantic memory dysfunction theory. Journal of Anatomy. 2005;207:35–66. (e.g., vocabulary, fl uency measures), system- 9. Steinvorth S, Levine B, Corkin S. Medial temporal atic evaluation of semantic memory disor- lobe structures are needed to re-experience remote ders will typically require the use of instru- autobiographical memories: Evidence from H.M. & W.R. Neuropsychologia. 2005;43:479–96. ments speci fi cally designed for this purpose 10. De Renzi E, Liotti M, Nichelli P. Semantic amnesia (see text). with preservation of autobiographic memory. A case • Episodic memory is most affected by disease report. Cortex. 1987;23(4):575–97. processes affecting the medial temporal lobe, 11. Grossi D, Trojano L, Grasso A, Orsini A. Selective “semantic amnesia” after closed-head injury. A case diencephalon, and basal forebrain, while report. Cortex. 1988;24(3):457–64. semantic memory is most affected by cortical 12. Yasuda K, Watanabe O, Ono Y. Dissociation between dysfunction. semantic and autobiographic memory: a case report. • Episodic and semantic memories are distin- Cortex. 1997;33(4):623–38. 13. Carlesimo GA, Sabbadini M, Loasses A, Caltagirone guished primarily as different modes of C. Analysis of the memory impairment in a post- retrieval; episodic memory has an autobio- encephalitic patient with focal retrograde amnesia. graphical character, while semantic mem- Cortex. 1998;34(3):449–60. ory does not. 14. Hodges JR, McCarthy RA. Loss of remote memory: a cognitive neuropsychological perspective. Curr • The clinician should keep in mind that the Opin Neurobiol. 1995;5(2):178–83. episodic–semantic memory distinction is not 15. Hunkin NM, Parkin AJ, Bradley VA, Burrows EH, the same as the recent–remote memory dis- Aldrich FK, Jansari A, Burdon-Cooper C. Focal ret- tinction. Episodic memories can be quite old rograde amnesia following closed head injury: a case study and theoretical account. Neuropsychologia. and retrieved from the remote compartment, 1995;33(4):509–23. just as new semantic memories are acquired 16. Kapur N, Ellison D, Smith MP, McLellan DL, all of the time ( Table 25.2 ). Burrows EH. Focal retrograde amnesia following bilateral temporal lobe pathology. A neuropsycho- 25 Episodic and Semantic Memory Disorders 415

logical and magnetic resonance study. Brain. 33. Monastero R, Mangialasche F, Camarda C, Ercolani 1992;115(Pt 1):73–85. S, Camarda R. A systematic review of neuropsychi- 17. Kapur N, Young A, Bateman D, Kennedy P. Focal atric symptoms in mild cognitive impairment. retrograde amnesia: a long term clinical and neu- J Alzheimers Dis. 2009;18:11–30. ropsychological follow-up. Cortex. 1989;25(3): 34. Damasio AR, Tranel D, Damasio H. Amnesia caused 387–402. by herpes simplex encephalitis, infarctions in basal 18. Markowitsch HJ, Calabrese P, Neufeld H, Gehlen W, forebrain, Alzheimer’s disease, and anoxia/ischemia. Durwen HF. Retrograde amnesia for world knowledge In: Boller F, Grafman J, editors. Handbook of neu- and preserved memory for autobiographic events. ropsychology. Amsterdam: Elsevier; 1989. p. A case report. Cortex. 1999;35(2):243–52. 149–66. 19. O’Connor M, Butters N, Miliotis P, Eslinger P, 35. Hyman BT, Van Hoesen GW, Damasio AR, Barnes Cermak LS. The dissociation of anterograde and ret- CL. Cell speci fi c pathology isolates the hippocampal rograde amnesia in a patient with herpes encephali- formation in Alzheimer’s disease. Science. tis. J Clin Exp Neuropsychol. 1992;14(2):159–78. 1984;225:1168–70. 20. Kapur N. Syndromes of retrograde amnesia: a con- 36. Jack CR, Petersen RC, Xu Y, O’Brien PC, Smith ceptual and empirical synthesis. Psychol Bull. GE, Ivnik RJ, et al. Rate of medial temporal lobe 1999;125(6):800–25. atrophy in typical aging and Alzheimer’s disease. 21. Vargha-Khadem F, Gadian DG, Watkins KE, Neurology. 1998;51:993–9. Connelly A, Van Paesschen W, Mishkin M. 37. Scott SA, DeKosky ST, Scheff SW. Volumetric atro- Differential effects of early hippocampal pathology phy of the amygdala in Alzheimer’s disease: quanti- on episodic and semantic memory. Science. tative serial reconstruction. Neurology. 1997;277(5324):376–80. 1991;41:351–6. 22 Butters N, Granholm E, Salmon E, Grant I, Wolfe J. 38. Whitehouse PJ, Price DL, Clark AW, Coyle JT, Episodic and semantic memory: a comparison of DeLong MR. Alzheimer disease: evidence for selec- amnesic and demented patients. J Exp Clin tive loss of cholinergic neurons in the nucleus baslis. Neuropsychol. 1987;9:479–97. Ann Neurol. 1981;10:122–6. 23 Cermak LS, Reale L, Baker E. Alcoholic Korsakoff 39. Xuereb JH, Perry RH, Candy JM, Perry EK, Marshall patients’ retrieval from semantic memory. Brain E, Bonham JR. Nerve cell loss in the thalamus in Lang. 1978;5:215–26. Alzheimer’s disease and Parkinson’s disease. Brain. 24. Squire LR, Zola SM. Episodic memory, semantic mem- 1991;114:1363–79. ory, and amnesia. Hippocampus. 1998;8(3):205–11. 40. Adlam A-L, Patterson K, Bozeat S, Hodges JR. The 25. Verfaellie M, Cermak LS. Acquisition of generic Cambridge Semantic Memory Test Battery: detec- memory in amnesia. Cortex. 1994;30(2):293–303. tion of semantic defi cits in semantic dementia and 26. Zola-Morgan S, Cohen NJ, Squire LR. Recall of Alzheimer’s disease. Neurocase. 2010;16:193–207. remote episodic memory in amnesia. 41. Bozeat S, Lambon Ralph MA, Patterson K, Garrard Neuropsychologia. 1983;21:487–500. P, Hodges JR. Non-verbal semantic impairment in 27. Schacter DL, Wagner AD, Buckner RL. Memory semantic dementia. Neuropsychologia. systems of 1999. In: Tulving E, Craik FIM, editors. 2000;38:1207–15. The Oxford handbook of memory. New York: 42. Davies RR, Halliday GM, Xuereb JH, Kril JJ, Oxford University Press; 2000. p. 627–43. Hodges JR. The neural basis of semantic memory: 28. Loftus EF, Cole W. Retrieving attribute and name evidence from semantic dementia. Neurobiol Aging. information from semantic memory. J Exp Psychol. 2009;30(12):2043–52. 1974;102:1116–22. 43. Drachman DA, Leavitt J. Human memory and the 29. Petersen RC, Stevens J, Ganguli M, Tangalos EG, cholinergic system. A relationship to aging? Arch Cummings JL, DeKosky ST. Practice parameter: Neurol. 1974;30:113–21. early detection of dementia: mild cognitive impair- 44. Womack KB, Heilman KM. Tolterodine and mem- ment (an evidence-based review): report of the Quality ory: dry but forgetful. Arch Neurol. 2003;60:771–3. Standards Subcommittee of the American Academy 45. Benson DF, Marsden CD, Meadows JC. The amne- of Neurology. Neurology. 2001;56:1133–42. sic syndrome of posterior cerebral artery occlusion. 30. Petersen RC. Mild cognitive impairment: aging to Acta Neurol Scand. 1974;50:133–45. Alzheimer’s disease. New York: Oxford University 46. Graff-Radford NR, Tranel D, Van Hoesen GW, Brandt Press; 2004. JP. Diencephalic amnesia. Brain. 1990;113:1–25. 31. Petersen RC. Mild cognitive impairment: transition 47. Volpe BT, Hirst W. Amnesia following the rupture and between aging and Alzheimer’s disease. Neurologia. repair of an anterior communicating artery aneu- 2000;15:93–101. rysm. J Neurol Neurosurg Psychiatry. 1983;46:704–9. 32. Devanand DP, Liu X, Tabert MH, Pradhaban G, 48. Part SA, Hahn JH, Kim JI, Na DL, Huh K. Memory Cuasay K, Bell K, et al. Combining early markers defi cits after bilateral anterior fornix infarction. strongly predicts conversion from mild cognitive Neurology. 2000;54:1379–82. impairment to Alzheimer’s disease. Biol Psychiatry. 49. Renou P, Ducreux D, Batouche F, Denier C. Pure and 2008;64:871–79. acute Korsakoff syndrome due to a bilateral anterior 416 T. Kuhn and R.M. Bauer

fornix infarction: A diffusion tensor tractography 66. Martin RC, Haut MW, Goeta Kreisler K, Blumenthal study. Arch Neurol. 2008;65:1252–53. D. Neuropsychological functioning in a patient with 50. Zola-Morgan S, Squire LR, Amaral DG. Human paraneoplastic limbic encephalitis. J Int Neuropsychol amnesia and the medial temporal region: enduring Soc. 1996;2(5):460–6. memory impairment following a bilateral lesion lim- 67. Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, ited to fi eld CA1 of the hippocampus. J Neurosci. Posner JB, Dalmau J. Paraneoplastic limbic enceph- 1986;6:2950–67. alitis: neurological symptoms, immunological 51. Squire LR, Zola SM. Ischemic brain damage and fi ndings and tumor association in 50 patients. Brain. memory impairment: a commentary. Hippocampus. 2000;123:1481–94. 1996;6(5):546–52. 68. Bien CG, Schulze-Bonhage A, Deckert M, Urbach 52. Butters N. Alcoholic Korsakoff’s syndrome: an H, Helmstaedter C, Grunwalt T, Schaller C, Elger update. Semin Neurol. 1984;4:226–44. CE. Limbic encephalitis not associated with neo- 53. Butters N, Cermak LS. Alcoholic Korsakoff’s syn- plasm as a cause of temporal lobe epilepsy. drome: an information processing approach to Neurology. 2000;55:1823–8. amnesia. New York: Academic; 1980. 69. Dalmau J, Bataller L. Clinical and immunological 54. Victor M, Adams RD, Collins GH. The Wernicke- diversity of limbic encephalitis: a model for parane- Korsakoff Syndrome. Philadelphia: F.A. Davis oplastic neurological disorders. Hematol Oncol Clin Co.; 1971. North Am. 2006;20:1319–35. 55. Becker JT, Furman JMR, Panisset M, Smith C. 70. Darnell RB, Poser JB. Autoimmune encephalopathy Characteristics of the memory loss of a patient with (editorial). Ann Neurol. 2009;66:1–2. Wernicke-Korsakoff’s syndrome without alcohol- 71. Nokura K, Yamamoto H, Okawara Y, Koga H, ism. Neuropsychologia. 1990;28:171–9. Osawa H, Sakai K. Reversible limbic encephalitis 56. Newman ME, Adityanjee A, Sobolewski E, Jampala caused by ovarian teratoma. Acta Neurol Scand. VC. Wernicke-Korsakoff amnestic syndrome sec- 1997;95:367–73. ondary to malnutrition in a patient with schizoaffec- 72. Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, tive disorder. Neuropsychiatry Neuropsychol Behav Peng X, Lai M, et al. Anti-NMDA-receptor encepha- Neurol. 1998;11(4):241–4. litis: Case series and analysis of the effects of anti- 57. Damasio AR, Eslinger PJ, Damasio H, Van Hoesen bodies. Lancet Neurol. 2008;7:1091–98. GW, Cornell S. Multimodal amnesic syndrome fol- 73. Florance NR, Davis RL, Lam C, Szperka C, Zhou L, lowing bilateral temporal and basal forebrain Ahmad S, Campen CJ, Moss H, Peter N, Gleichman damage. Arch Neurol. 1985;42:252–9. AJ, Glasere CA, Lynch DR, Rosenfeld MR, Dalmau 58. Cermak LS. The encoding capacity of a patient with J. Anti-N-methyl-D-aspartate receptor (NMDAR) amnesia due to encephalitis. Neuropsychologia. encephalitis in children and adolescents. Ann Neurol. 1976;14(3):11–326. 2009;66:11–8. 59. Cermak LS, O’Connor M. The anterograde and retro- 74. Levite M, Ganor Y. Autoantibodies to glutamate grade retrieval ability of a patient with amnesia due to receptors can damage the brain in epilepsy, systemic encephalitis. Neuropsychologia. 1983;21:213–34. lupus erythematosus and encephalitis. Expert Rev 60. Fujii T, Yamadori A, Endo K, Suzuki K, Fukatsu R. Neurother. 2008;8:1141–60. Disproportionate retrograde amnesia in a patient 75. Levin HS. Memory de fi cit after closed head injury. with herpes simplex encephalitis. Cortex. 1999; In: Boller F, Grafman J, editors. Handbook of 35(5):599–614. neuropsychology, vol. 3. Amsterdam: Elsevier; 1989. 61. Tanaka Y, Miyazawa Y, Hashimoto R, Nakano I, p. 183–207. Obayashi T. Postencephalitic focal retrograde amne- 76. Ownsworth T, McKenna K. Investigation of factors sia after bilateral anterior temporal lobe damage. related to employment outcome following traumatic Neurology. 1999;53(2):344–50. brain injury: a critical review and conceptual model. 62. Wainwright MS, Martin PL, Morse RP, Lacaze M, Disabil Rehabil. 2004;26:765–83. Provenzale JM, Coleman RE, Morgan MA, Hulette 77. Ponsford J, Draper K, Schonberger M. Functional C, Kurtzberg J, Bushnell C, Epstein L, Lewis DV. outcome 10 years after traumatic brain injury: Its Human herpes virus 6 limbic encephalitis after stem relationship with demographic, injury severity, and cell transplantation. Ann Neurol. 2001;50:612–9. cognitive and emotional status. J Int Neuropsychol 63. Hokkanen L, Launes J. Neuropsychological seque- Soc. 2008;14:233–42. lae of acute-onset sporadic viral encephalitis. 78. Ponsford JL, Olver JH, Curran C, Ng K. Prediction Neuropsychol Rehabil. 2008;17(4–5):450–77. of employment status 2 years after traumatic brain 64. Corsellis JA, Goldberg GJ, Norton AR. “Limbic injury. Brain Inj. 1995;9:11–20. encephalitis” and its association with carcinoma. 79. Russell WR, Nathan PW. Traumatic amnesia. Brain. Brain. 1968;91:481–96. 1946;69:290–300. 65. Khan N, Wieser HG. Limbic encephalitis: a case 80. Whitty CD, Zangwill OL, editors. Amnesia. London: report. Epilepsy Res. 1994;17(2):175–81. Butterworths; 1977. 25 Episodic and Semantic Memory Disorders 417

81. Vannorsdall TD, Cascella NG, Rao V, Pearlson GD, 99. Woolfenden AR, O’Brien MW, Schwartzberg RE, Gordon B, Schretlen DJ. A morphometric analysis Norbash AM, Tong DC. Diffusion-weighted MRI in of neuroanatomic abnormalities in traumatic brain transient global amnesia precipitated by cerebral injury. J Neuropsychiatry Clin Neurosci. 2010;22: angiography. Stroke. 1997;28:2311–4. 173–81. 100. Bartsch T, Deuschl G. Transient global amnesia: 82. Caplan LB. Transient global amnesia. In: Frederiks functional anatomy and clinical implications. Lancet JAM, editor. Handbook of clinical neurology, vol. 1. Neurol. 2010;9:205–14. Amsterdam: Elsevier; 1985. p. 205–18. 101. Sedlaczek O, Hirsch JG, Grips E, Peters CN, Gass 83. Hodges JR, Warlow CP. Syndromes of transient amne- A, Wöhrle J, Hennerici M. Detection of delayed sia: towards a classifi cation. A study of 153 cases. focal MR changes in the lateral hippocampus in tran- J Neurol Neurosurg Psychiatry. 1990;53:834–43. sient global amnesia. Neurology. 2004;62:2165–70. 84. Kritchevsky M. Transient global amnesia. In: Boller 102. Toledo M, Pujadas R, Grivé E, Álvarez-Sabin J, F, Grafman J, editors. Handbook of neuropsychol- Quintana M, Rovira A. Lack of evidence for arterial ogy, vol. 3. Amsterdam: Elsevier; 1989. p. 167–82. ischemia in transient global amnesia. Stroke. 85. Kritchevsky M, Squire LR, Zouzounis JA. Transient 2008;39:476–9. global amnesia: characterization of anterograde and 103. Miller JW, Petersen RC, Metter EJ, Millikan CH, retrograde amnesia. Neurology. 1988;38:213–9. Yanagihara T. Transient global amnesia: clinical char- 86. Bilo L, Meo R, Ruosi P, de Leva MF, Striano S. acteristics and prognosis. Neurology. 1987;37:733–7. Transient epileptic amnesia: an emerging late-onset 104. Kapur N. Transient epileptic amnesia—a clinical epileptic syndrome. Epilepsia. 2009;50 Suppl 5: update and reformulation. J Neurol Neurosurg 58–61. Psychiatry. 1993;56:1184–90. 87. Fisher CM. Transient global amnesia: precipitating 105. Butler CR, Zeman A. A case of transient epileptic activities and other observations. Arch Neurol. amnesia with radiological localization. Nat Clin 1982;39:605–8. Pract Neurol. 2008;4:516–21. 88. Fisher CM, Adams RD. Transient global amnesia. 106. Sackeim HA. The cognitive effects of electroconvul- Trans Am Neurol Assoc. 1958;83:143–5. sive therapy. In: Moos WH, Gamzu ER, Thal LJ, 89. Olesen J, Jørgensen MB. Leao’s spreading depres- editors. Cognitive disorders: pathophysiology and sion in the hippocampus explains transient global treatment. New York, NY: Marcel Dekker; 1992. p. amnesia: a hypothesis. Acta Neurol Scand. 183–228. 1986;73:219–20. 107. Semkovska M, McLoughlin DM. Objective cogni- 90. Heath fi eld KWG, Croft PB, Swash M. The syn- tive performance associated with electroconvulsive drome of transient global amnesia. Brain. therapy for depression: a systematic review and 1973;96:729–36. meta-analysis. Biol Psychiatry. 2010;15:568–77. 91. Shuping JR, Rollinson RD, Toole JF. Transient 108. Squire LR. A stable impairment in remote memory global amnesia. Ann Neurol. 1980;7:281–5. following electroconvulsive therapy. Neuropsycho- 92. Caplan L, Chedru F, Lhermitte F, Mayman C. logia. 1975;13:51–8. Transient global amnesia and migraine. Neurology. 109. Squire LR. ECT and memory dysfunction. In: Lerer 1981;31:1167–70. B, Weiner RD, Belmaker RH, editors. ECT: basic 93. Schmidtke K, Ehmsen L. Transient global amnesia mechanisms. Washington, DC: American Psychiatric and migraine. A case control study. European Neurol. Press; 1984. p. 156–63. 2008;40:9--14. 110. Squire LR, Chace PM. Memory functions six to nine 94. Tosi L, Righetti CA. Transient global amnesia and months after electroconvulsive therapy. Arch Gen migraine in young people. Clin Neurol Neurosurg. Psychiatry. 1975;32:1157–64. 1997;99:63–65. 111. Squire LR, Slater PC. Electroconvulsive therapy 95. Haas DC, Ross GS. Transient global amnesia trig- and complaints of memory dysfunction: a prospective gered by mild head trauma. Brain. 1986;109:251–7. three-year follow-up study. Br J Psychiatry. 1983; 96. Chung C-P, Hsu H-Y, Chao A-C, Chang F-C, Sheng 142:1–8. W-Y, Hu H-H. Detection of intracranial venous 112. Squire LR, Chace PM, Slater PC. Retrograde amne- refl ux in patients of transient global amnesia. sia following electroconvulsive therapy. Nature. Neurology. 2006;66:1873–7. 1976;260:775–77. 97. Alberici E, Pichiecchio A, Caverzasi E, Farina LM, 113. Squire LR, Slater PC, Miller P. Retrograde amnesia Persico A, Cavallini A, Bastianello S. Transient following ECT: Long-term follow-up studies. Arch global amnesia: hippocampal magnetic resonance Gen Psychiatry. 1981;38:89–95. imaging abnormalities. Funct Neurol. 114. Eacott MJ, Crawley RA. Childhood amnesia: on 2008;23:149–52. answering questions about very early life events. 98. Ay H, Furie KL, Yamada K, Koroshetz WJ. Memory. 1999;7(3):279–92. Diffusion-weighted MRI characterizes the ischemic 115. Usher JA, Neisser U. Childhood amnesia and the lesion in transient global amnesia. Neurology. beginnings of memory for four early life events. 1998;51:901–3. J Exp Psychol Gen. 1993;122(2):155–65. 418 T. Kuhn and R.M. Bauer

116. Wetzler SE, Sweeney JA. Childhood amnesia: a 133. Thompson SA, Patterson K, Hodges JR. Left/right conceptualization in cognitive-psychological terms. asymmetry of atrophy in semantic dementia: behav- J Am Psychoanal Assoc. 1986;34(3):663–85. ioural cognitive implications. Neurology. 117. Roth T, Roehrs T, Zwyghuizen Doorenbos A, 2003;61:1196–203. Stepanski E, Wittig R. Sleep and memory. 134. Hodges JR, Graham KS. Episodic memory: insights Psychopharmacol Ser. 1988;6:140–5. from semantic dementia. Phil Trans R Soc Lond: B 118. Markowitsch HJ. Functional neuroimaging correlates Biol Sci. 2001;356:1423–34. of functional amnesia. Memory. 1999;7(5–6):561–83. 135. Altmann LJ, McClung JS. Effects of semantic 119. Kessler J, Markowitsch HJ, Huber M, Kalbe E, impairment on language use in Alzheimer’s disease. Weber-Luxenburger G, Kock P. Massive and persis- Semin Speech Lang. 2008;29:18–31. tent anterograde amnesia in the absence of detect- 136. Cuetos F, Herrera E, Ellis AW. Impaired word recog- able brain damage: anterograde psychogenic amnesia nition in Alzheimer’s disease: the role of age of or gross reduction in sustained effort? J Clin Exp acquisition. Neuropsychologia. 2010;48:3329–34. Neuropsychol. 1997;19(4):604–14. 137. Johnston RA, Barry C. Age of acquisition in semantic 120. Kopelman MD. Amnesia: organic and psychogenic. processing of pictures. Mem Cognit. 2005;33:905–12. Br J Psychiatry. 1987;150:428–42. 138. Juhasz BJ. Age of acquisition effects in word and pic- 121. Kapur N. Amnesia in relation to fugue states— ture identifi cation. Psychol Bull. 2005;131:684–712. distinguishing a neurological from a psychogenic 139. Venneri A, McGeown WJ, Heitanen H, Guerrini C, basis. Br J Psychiatry. 1991;159:872–7. Ellis AW, Shanks MF. The anatomical basis of 122. Reinhold N, Markowitsch HJ. Retrograde episodic semantic retrieval defi cits in early Alzheimer’s memory and emotion: a perspective from patients disease. Neuropsychologia. 2008;46:497–510. with dissociative amnesia. Neuropsychologia. 140. Xie SX, Libon DJ, Wang X, Massimo L, Moore P, 2009;47:2197–206. et al. Longitudinal patterns of semantic and episodic 123. Kihlstron JF, Schacter DL. Functional amnesia. In: memory in frontotemporal lobar degeneration and Boller F, Grafman J, editors. Handbook of neuropsy- Alzheimer’s disease. J Int Neuropsychol Soc. chology, vol. 2. 2nd ed. Amsterdam: Elsevier; 2000. 2010;16:278–86. p. 409–27. 141. Adlam A-LR, Bozeat S, Arnold R, Watson P, Hodges 124. Hodges JR, Patterson K. Semantic dementia: a JR. Semantic knowledge in mild cognitive impairment unique clinicopathological syndrome. Lancet and mild Alzheimer’s disease. Cortex. 2006;42:675–84. Neurol. 2007;6:1004–14. 142. Hodges JR, Patterson K. Is semantic memory consis- 125. Warrington EK, Shallice T. Category speci fi c semantic tently impaired early in the course of Alzheimer’s impairments. Brain. 1984;107:829–54. disease? Neuroanatomical and diagnostic implica- 126. Capitani E, Laiacona M, Mahon B, Caramazza A. tions. Neuropsychologia. 1995;33:441–59. What are the facts of semantic category-specifi c 143. Scahill VL, Hodges JR, Graham KS. Can episodic defi cits? A critical review of the clinical evidence. memory tasks differentiate semantic dementia from Cogn Neuropsychol. 2003;20:213–62. Alzheimer’s disease? Neurocase. 2005;11:441–51. 127. Farah MJ, McClelland JI. A computational model of 144. Kopelman MD, Stanhope N, Kingsley D. Retrograde semantic memory impairment: modality speci fi city amnesia in patients with diencephalic, temporal and emergent category specifi city. J Exp Psychol. lobe, or frontal lesions. Neuropsychologia. 1991;120:339–57. 1999;37:939–58. 128. Thompson-Schill SL, Aguirre GK, D’Esposito M, 145. McCarthy RA, Warrington EK. Actors but not scripts: Farah MJ. A neural basis for category and modality the dissociation of people and events in retrograde specifi city of semantic knowledge. Neuropsychologia. amnesia. Neuropsychologia. 1992;30(7):633–44. 1999;37:671–6. 146. Gainotti G. What the locus of brain lesion tells us 129. Tippett LJ, Meier SL, Blackwood K, Diaz-Asper C. about the nature of the cognitive defect underlying Category speci fi c de fi cits in Alzheimer’s disease: category-specifi c disorders: a review. Cortex. fact or artifact? Cortex. 2007;43:907–20. 2000;36:539–59. 130. Lambon Ralph MA, Lowe C, Rogers TT. Neural 147. Laws KR, Sartori G. Category de fi cits and paradoxical basis of category-specifi c semantic defi cits: evidence dissociations in Alzheimer’s disease and herpes sim- from semantic dementia, HSVE, and a neural net- plex encephalitis. J Cogn Neurosci. 2005;17:1453–9. work model. Brain. 2007;130:1127–37. 148. Noppeney U, Patterson K, Tyler LK, Moss H, 131. Davies RR, Kipps CM, Mitchell J, Kril JJ, Halliday Stamatakis EA, Bright P, Mummery C, Price CJ. GM, Hodges JR. Progression in frontotemporal Temporal lobe lesions and semantic impairment: a dementia: identifying a benign behavioral variant by comparison of herpes simplex virus encephalitis and magnetic resonance imaging. Arch Neurol. semantic dementia. Brain. 2007;130:1138–47. 2006;63:1627–31. 149. Capitani E, Laiacona M, Pagani R, Capasso R, 132. Pijnenburg YA, Gillissen F, Jonker C, Scheltens P. Zampetti P, Miceli G. Posterior cerebral artery Initial complaints in frontotemporal lobar degenera- infarcts and semantic category dissociations: a study tion. Dement Geriatr Cogn Disord. 2004;17:302–6. of 28 patients. Brain. 2009;132:965–81. 25 Episodic and Semantic Memory Disorders 419

150. Johnson JK, Diehl J, Mendez MF, Neuhaus J, Shapria 162. Schmidt M. Rey Auditory and Verbal Learning Test: JS, et al. Frontotemporal lobar degeneration: demo- a handbook. Los Angeles: Western Psychological graphic characteristics of 353 patients. Arch Neurol. Services; 1996. 2005;62:925–30. 163. Meyers JE, Meyers KR. Rey Complex Figure Test 151. Saunders AM, Strittmatter WJ, Schmechel D, et al. and Recognition Trial. Odessa, FL: Psychological Association of apolipoprotein E allele epsilon 4 with Assessment Resources; 1995. late-onset familial and sporadic Alzheimer’s disease. 164. Benedict R. Brief Visuospatial Memory Test-Revised Neurology. 1993;43:1467–72. professional manual. Odessa, FL: Psychological 152. Pietrini V, Nertempi P, Vaglia A, Revello MG, Pinna Assessment Resources, Inc.; 1997. V, Ferro-Milone F. Recovery from herpes simplex 165. Trahan DE, Larrabee GJ. Continuous Visual Memory encephalitis: selective impairment of speciﬁ c seman- Test. Odessa, FL: Psychological Assessment tic categories with neuroradiological correlation. Resources; 1988. J Neurol Neurosurg Psychiatry. 1988;51:1284–93. 166. Wilson AB, Shiel A, Foley J, Smslie H, Groot Y, 153. Bird CM, Chan D, Hartley T, Pijnenburg YA, Rossor Hawkins K, Watson P. Cambridge Test of Prospective MN, Burgess N. Topographical short-term memory Memory (CAMPROMPT). San Antonio, TX: differentiates Alzheimer’s disease from frontotem- Pearson Assessments; 2005. poral lobar degeneration. Hippocampus. 2010;20: 167. Crovitz HF, Schiffman H. Frequency of episodic 1154–69. memories as a function of their age. Bull Psychonom 154. Kramer J, Jurik J, Sha S. Distinctive neuropsycho- Soc. 1974;4:517–8. logical pattern in frontotemporal dementia, semantic 168. Wechsler D, Coalson DL, Raiford SE. Wechsler dementia, and Alzheimer’s disease. Cogn Behav Adult Intelligence Test: fourth edition technical Neurol. 2003;16:211–8. and interpretive manual. San Antonio: Pearson 155. Hodges JR, Patterson K, Ward R, Garrard P, Bak T, Assessments; 2008. Perry R, Gregory C. The differentiation of semantic 169. Kertesz A. Western aphasia battery-revised. San dementia and frontal lobe dementia (temporal and Antonio, TX: Pearson Assessments; 2006. frontal variants of frontotemporal dementia) from 170. Goodglass H, Kaplan E, Barresi B. Boston Diagnostic early Alzheimer’s disease: a comparative neuropsy- Aphasia Examination. 3rd ed. San Antonio, TX: chological study. Neuropsychol. 1999;13:31--40. Pearson Assessments; 2000. 156. Kopelman MD, Wilson BA, Baddeley A. 171. Benton AL, Hamsher K deS, Sivan A. Multilingual Autobiographical memory interview. Oxford: Aphasia Examination. 3rd ed. Iowa City, IA: AJA Pearson Assessments; 1990. Associates; 1994. 157. Squire LR, Slater PC. Forgetting in very long term 172. Delis DC, Kaplan E, Kramer J. Delis-Kaplan memory as assessed by an improved questionnaire Executive Function Scale. San Antonio: technique. J Exp Psychol. 1975;104:50–4. Psychological Corporation; 2001. 158. Seelaar H, Rohrer JD, Pijnenburg YAL, Fox NC, 173. Bishop D. Test for the reception of grammar—sec- van Swieten JC. Clinical, genetic and pathological ond edition (TROG-2). Sydney, AU: Pearson heterogeneity of frontotemporal dementia: a review. Assessments; 2003. J Neurol Neurosurg Psychiatry. 2010. doi:10.1136/ 174. Grant DA, Berg EA. A behavioral analysis of the jnnp. 2010.212225 . degree of reinforcement and ease of shifting to new 159. Wechsler D, Holdnack JA, Drozdick LW. Wechsler responses in a Weigl-type card sorting problem. Memory Scale, fourth edition. Technical and inter- J Exp Psychol. 1948;38:404–11. pretive manual. San Antonio, TX: Pearson 175. DeFilippis NA, McCampbell E. Booklet Category Assessments; 2009. Test. 2nd ed. Odessa, FL: Psychological Assessment 160. Benedict RHB, Schretlen D, Groninger L, Brandt J. Resources; 1997. Hopkins Verbal Learning Test-Revised: Normative 176. Stroop JR. Studies of interference in serial verbal data and analysis of inter-form and test-retest reli- reactions. J Exp Psychol. 1935;18:643–62. ability. Clin Neuropsychol. 1998;12:43–55. 177. Luria AR. Higher cortical functions in Man. New 161. Delis DC, Kramer JH, Kaplan E, Ober BA. California York: Basic Books; 1966. Verbal Learning Test—second edition (CVLT-II). San Antonio, TX: Psychological Corporation; 2000. Epilepsy and Aging 2 6 Brian D. Bell and Anna Rita Giovagnoli

Abstract Epilepsy is the third most common neurological disorder of old age and a substantial public health problem. As the elderly population rises, the elderly will account for a large percentage of all new-onset seizures. However, while the study of epilepsy in adults in general has led to major advances in neuropsychology, epilepsy in the aged has been one of the more neglected areas within the ﬁ eld. Geriatric epilepsy is now an emerging ﬁ eld for all health-care practitioners, including neuropsychologists. Patient management requires assessment and treatment of cognitive and functional impairment and psychological issues. A thorough assessment of cognitive function is essential in discriminating epilepsy from classic progressive dementias and for assessing functioning prior to treatments for seizures once they are diagnosed. Neuropsychological assessment plays an important role to characterize cognitive impairments, reveal preserved abilities, help monitor medication treatment, track for coexistence of MCI or dementia, and assess for emotional distress.

Keywords Epilepsy ¥ Aging ¥ Memory ¥ Executive functions ¥ Brain plasticity ¥ Comorbitities ¥ Antiepileptic drugs

B. D. Bell , Ph.D. () Charles Matthews Neuropsychology Laboratory, Department of Neurology, Uni versity of Wisconsin School of Medicine and Public Health , MFCB, 1685 Highland A. R. Giovagnoli , M.D., Ph.D. Ave , Madison , WI 53705-2281 , USA Department of Clinical Neurosciences , W.S. Middleton Memorial Veterans Hospital , Neuropsychology Laboratory, Carlo Besta Madison , WI , USA Neurological Institute , Milan , Italy e-mail: [email protected] e-mail: [email protected]

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 421 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_26, © Springer Science+Business Media, LLC 2013 422 B.D. Bell and A.R. Giovagnoli

dence across the world due to variations in diag- Background nostic defi nition, socioeconomic status, access to health care and environmental exposures [ 7 ] . Seizures and Epilepsy Defi ned Furthermore, prevalence and incidence may be underestimated in geographic areas where the A seizure is a sudden, transitory event character- condition is greatly stigmatized. Gender-specifi c ized by positive or negative mental or physical disparity (higher incidence in males than females) symptoms associated with neuronal discharge is small [8, 9 ] . The classic rule that epilepsy is and electroencephalographic (EEG) changes. In most common in the fi rst 10 years of life has 1981, the International League Against Epilepsy changed. In fact, older adults now have the high- (ILAE) classi fi ed two major categories of seizure est prevalence of epilepsy per decade of any age type, characterized by either partial or general- group [10 ] . ized onset [ 1 ] . Partial (focal) seizures begin in a local area of the brain and are further subdivided into simple partial (no alteration in conscious- Seizures in Older Adults: A Growing ness) and complex partial seizures (CPS) (altera- but Understudied Problem tion of consciousness). Generalized seizures may have partial onset with secondary generalization Because the world’s population is aging and the (there is a clinical aura or an EEG focal discharge) risk of acute symptomatic seizures, epilepsy, and or generalized onset (involving the entire brain SE is highest in older adults, the number of older simultaneously). In some cases, seizure type may adults with epilepsy is rising [ 11Ð 15] . By the remain unclassi fi able. Seizure symptoms vary year 2025, greater than 30% of the population of across the life span, with more challenging diag- many developed countries will be older than 60, nostic demands in older adults. and at that point, the aged population will account Epilepsy is defi ned by recurrent (two or for a high percentage of all new-onset seizures more) epileptic seizures, unprovoked by any [16, 17 ] . This is due in part to increases in long- immediate identi fi ed cause [2Ð 4 ] . Idiopathic term survival after acute neurological insults and epilepsies generally have a genetic basis and the likelihood of correct diagnosis compared to onset during childhood, symptomatic epilepsies past decades. In the USA, epilepsy affects nearly are caused by brain lesion, and cryptogenic epi- 1.5% of those ³ 65 years old, and the prevalence lepsies have an unknown cause that potentially is higher in nursing homes (exceeding 5%). could be identi fi ed with suf fi cient investigation [2 ] . Epilepsy is now the third most common neuro- Multiple seizures occurring in a 24-h period or logical disorder of old age, and it is therefore not an episode of status epilepticus (SE) are consid- surprising that it has been described as a substan- ered a single event for diagnostic purposes. A tial public health problem [10, 12, 14, 18Ð 26 ] . single unprovoked seizure does not constitute Despite the rising prevalence of epilepsy in epilepsy, nor do isolated febrile seizures, neo- older adults, epilepsy and aging issues have natal seizures, or acute symptomatic seizures received limited attention in both human and provoked by acute systemic illness, intoxica- animal research [ 27Ð 29] . While the study of tion, or substance abuse or withdrawal [ 5 ] . epilepsy in children and young adults has led to Seizure classi fi cations and terminology are major advances in neuropsychology [ 30, 31 ] , undergoing revision by the ILAE to incorporate epilepsy and aging are thought to be one of the advances in neuroimaging, genomics, and more neglected areas of research within the fi eld molecular biology [ 4 ] . of neuropsychology [ 32] . This may be because Although epilepsy is the most common neuro- older patients with epilepsy have been infre- logical condition overall (average prevalence 1%) quently referred to neuropsychologists. This pat- [ 6 ] , there are disparities in its prevalence and inci- tern is likely to change with the advancing wave 26 Epilepsy and Aging 423 of baby boomers and increasing recognition of Seizure and Epilepsy Etiologies in Older geriatric seizures and their morbidity. Adults Geriatric epilepsy is an emerging fi eld for all health-care practitioners, including neuropsy- Stroke chologists, who can make a key contribution to Stroke is the most common cause of new-onset the care of older adults with suspected epilepsy. seizures and epilepsy in older adults, accounting In addition to diagnosis and use of medications, for 30Ð50% of all epilepsies in this group. Stroke- medical management requires assessment of cog- related seizures can be divided into early onset nitive and behavioral impairments, as well as and late onset, which refl ect different etiopatho- social or psychological problems that are caused genesis. The 5-year risk of developing a post- not only by epilepsy-related brain dysfunction stroke seizure is roughly 10%, and about one-third but also by chronic pathology and aging itself of those with seizures will develop epilepsy [46Ð [11, 18, 33Ð 37 ] . Abnormalities in cognition are 49 ] . The risk of poststroke seizures might be relatively common in patients with epilepsy, higher after a longer follow-up period [14, 23 ] . including affected older adults [ 38Ð 41 ] . Leading Moreover, mild cerebrovascular disease may be epileptologists have emphasized that a thorough the etiology of epilepsy even in some patients assessment of cognitive function is essential in with cryptogenic epilepsy [ 11, 14, 15, 22 ] . In a discriminating epilepsy-related impairment from study of US veterans, stroke and dementia had an dementia, and should be conducted prior to additive effect. Older adults with a combination the initiation of treatment for newly diagnosed of stroke and dementia were four times as likely seizures [22, 42 ] . to have epilepsy as those without either condition There are two broad groups of older adults [21 ] . with seizures, those who come to old age having Seizure risk is highest in severe, disabling had epilepsy since earlier in life and those who strokes, in hemorrhagic strokes, and in those with experience the onset of seizures or epilepsy at an cortical involvement [20, 26, 44, 47 ] . Further, the advanced age in the context of either an acute relationship between stroke and epilepsy is bidi- medical or neurological illness (stroke, tumor, rectional, in that individuals with late-onset sei- trauma, infection, metabolic abnormality, or drug zures are at higher risk of an initial stroke, owing interaction) or a non-acute setting, perhaps to a coexistence of vascular risk factors such as including the aging process itself [ 11, 13, 14, 28, hypertension, ischemic heart disease, diabetes, 32] . Across the full age range, the majority of sei- and antiepileptic drug (AED)-related alteration zures are cryptogenic, while 33Ð50% of seizures of folate metabolism. When a late-onset seizure have an unknown etiology in the elderly [ 7, 43 ] . occurs after a stroke, the possibility of a new These fi gures may decrease as diagnostic proce- cerebrovascular accident should be investigated. dures improve [12, 21, 22, 44 ] . The possibility of a decline in cognition also Many conditions can cause seizures in older should be investigated, especially in the case of adults. Cerebrovascular disease, dementia, tumor, late-onset recurrent seizures or SE [ 50 ] . It has and head trauma are the brain disorders most been recommended that older adults with new- often associated with new-onset epilepsy in onset seizures undergo a thorough cerebrovascular older adults. A fundamental distinction is made workup [ 23 ] . between epileptic seizures and non-epileptic seizures that occur due to other neurological attacks TIA such as migraine, sleep-related disorders, and Transient ischemic attacks (TIAs) are rarely narcolepsy or to a medical condition such as car- associated with seizures. TIAs usually can be diac syncope, paroxysmal abdominal pain, meta- differentiated from seizures, because negative bolic derangement, respiratory compromise, or motor phenomena such as hemiparesis are quite alcohol abuse [45 ] . uncommon in seizures. However, “inhibitory 424 B.D. Bell and A.R. Giovagnoli seizures” do occur, most often characterized by high in patients with AD and Down syndrome, aphasia or dysarthria. An aphasic disturbance affecting up to 56% of cases [55 ] . Experimental that has a sudden onset and then remains stable studies have shown that high levels of b -amyloid, until its subsequent gradual resolution is more the main constituent of AD plaques, and the apo- likely to be a TIA [ 15 ] . A normal EEG is expected lipoprotein e 4 allele, a genetic risk factor for AD, in TIA, whereas the EEG is likely to be abnor- were associated with seizures [ 56 ] , supporting mal in “inhibitory seizures,” showing diffuse the clinical evidence of association between AD slowing or intermittent rhythmic delta activities. and epilepsy. An additional factor is the poten- In about two-thirds of inhibitory seizures tially proconvulsant effect of acetylcholinesterase patients, the negative symptoms are associated inhibitors, which are used in the treatment of with some degree of confusion or a subsequent dementia. partial retrograde amnesia for the event, whereas New-onset epilepsy in older adults sometimes focal vascular insults do not usually produce may cause cognitive decline leading to an incor- confusion [ 15, 50 ] . rect diagnosis of dementia. Further, AED treatment (e.g., valproate) may provoke reversible Alzheimer’s Disease and Other chronic cognitive impairment that can also be Degenerative Dementias misdiagnosed as dementia [57 ] . Thus, if dementia There is no evidence that seizure risk is elevated and epilepsy start together, then it is probable that in patients with mild cognitive impairment (MCI), dementia is a consequence of epilepsy or AED which can represent prodromal Alzheimer’s dis- treatment, rather than an expression of AD. ease (AD) [51 ] . Studies of the prevalence of sei- Dementia with Lewy bodies (DLB) can be zures in patients with AD have led to con fl icting associated with seizures. Reports on EEG in DLB results. One investigation reported that from 10 have been con fl icting, but recent diagnostic to 17% of patients with autopsy-con fi rmed AD guidelines indicate EEG abnormalities are sup- presented with unprovoked seizures after disease portive of the diagnosis. In one study that exam- onset [52 ] . On the other hand, a recent multi-site ined EEG abnormalities, a “Grand Total EEG” study of 453 patients indicated unprovoked sei- index was derived from six variables: rhythmic zures are a “quite uncommon feature” in AD, background activity, diffuse slow-wave activity, although more common than in the general reactivity, paroxysmal activity, focal abnormali- elderly population [53 ] . CPS, including those ties, and sharp-wave activity. The patients with with secondary generalization, are the most com- DLB had a higher index than patients with AD, mon type of seizure in AD [51, 53 ] . It is possible and DLB was identifi ed with a sensitivity of 72% that CPS are sometimes underdiagnosed because and a specifi city of 85% using an EEG cutoff AD patients may be unaware of sudden changes score. The association between DLB and this or not able to report subjective symptoms, while EEG abnormality was independent of age and caregivers may fi nd it diffi cult to distinguish MMSE score [58 ] . behavioral alterations caused by seizures and Frontotemporal lobe dementia (FTD) appears fl uctuations in behavior related to dementia [ 53 ] . to be rarely associated with seizures [51, 54, 59 ] . It should also be kept in mind that demented However, a family has been reported with a novel patients sometimes exhibit orofacial movements, phenotype characterized by a combination of outbursts of temper, wandering, fl uctuating con- early onset and rapidly progressive FTD, parkin- fusion, and memory lapses that may not neces- sonism, and epileptic seizures [60 ] . sarily be seizure related [15 ] . Seizures are most common in the advanced Alcohol and Drugs, Brain Tumor, Head stages of AD, but early age of onset also is asso- Trauma, and HIV/AIDS ciated with greater risk of seizures, perhaps The peak incidence of initial seizures related to because of its association with gene mutations alcohol withdrawal occurs late in life [ 25 ] . About [20, 23, 51, 53, 54] . The frequency of seizures is 10% of seizures in older adults are associated 26 Epilepsy and Aging 425 with use of alcohol or prescription drugs, and sei- can lead to deleterious side effects, while lack of zures sometimes occur after withdrawal from appropriate treatment in undiagnosed geriatric certain sedative medications following chronic epilepsy patients can have dire consequences. use [15 ] . Two other neurological disorders com- Many older patients’ new-onset seizures are not monly seen by neuropsychologists, brain tumor diagnosed or there is a signi fi cant delay to diag- and head trauma, account for some cases of epi- nosis, with a mean time to correct diagnosis in one lepsy in older adults. Seizures are the fi rst sign of study of more than 18 months [11, 15, 19Ð 22, 62 ] . a brain tumor in 50% of older patients [ 23 ] . In the In general, reasons for diffi culty in securing a sei- case of head trauma, an age of 65 years or greater zure diagnosis in older adults include (1) atypical is one of the factors that increase the risk of post- or nonspecifi c presentation or semiology of par- traumatic epilepsy. Also, a sizable minority of tial seizures; (2) absence of classic symptoms individuals with HIV or AIDS is more than due to relative infrequency of tonicÐclonic sei- 50 years old, and this percentage is increasing. zures; (3) coexisting cognitive impairment that Seizures in this group usually occur later in the may lead to an incomplete history, underreporting disease process, resulting from mass lesions of of events, or failure to recognize transitory confu- various etiologies, or due directly to cerebral HIV sional states; (4) absence of witnesses due to infection [15 ] . patient living alone and/or being retired; (5) low sensitivity and/or specifi city in diagnostic investigations such as interictal EEG or ECG; (6) Clinical Issues decreased continuity of patient/physician relationships; and (7) the absence of specialists in the Diagnostic Challenges diagnostic process [ 20, 22, 26, 59, 63, 64 ] . Because it can be dif fi cult for physicians to dif- The diagnosis of epilepsy mainly rests on the ferentiate seizures from various other conditions, patient’s history and should be considered in any neuropsychologists are likely to evaluate patients patient who suffers from recurrent attacks of con- who have not yet received a defi nitive diagnosis. sistently or relatively stereotyped involuntary It also is important to keep in mind that two behavior or subjective experience. Specifi c diag- different disorders may coexist in the same nostic criteria depend on the seizure type, while patient [65 ] . general diagnostic points broadly support an epi- The etiology, semiology or clinical presenta- lepsy diagnosis. The fi rst step is to defi ne a criti- tion, and prognosis of a seizure disorder often cal symptom or fi xed combination of symptoms differ between younger and older patients. In (seizure diagnosis), the second is to establish the fact, “novel diagnostic paradigms” have been nature of the seizure (epileptic versus non-epileptic), recommended because of the diverse etiologies and the third is to determine the cause of seizures and atypical presentations of seizures in the or epilepsy (symptomatic, idiopathic, cryptogenic). elderly [15, 20, 22, 59 ] (cf. [62 ] ). Tables 26.1 and As for EEG, no diagnostic test can absolutely 26.2 [59 ] present some common characteristics con fi rm or exclude epilepsy unless the registration of seizures in older adults and clues to the of epileptiform discharges is contemporaneous to diagnosis, respectively. Generalized tonicÐclonic seizure symptoms. Other contributory diagnostic seizures can occur in older adults, including pri- techniques include neuroimaging, ambulatory mary generalized seizures that reemerge in old electrocardiography (ECG), orthostatic blood age after initial occurrence in early life [22 ] . pressure management, tilt table testing, hemato- About two-thirds of geriatric seizures have a logical and biochemical pro fi les, and thyroid focal onset, with or without secondary general- function testing [61 ] . ization. Focal motor seizures are the most fre- Seizures are both underdiagnosed and over- quently reported type of partial seizure. However, diagnosed in speci fi c subgroups of older adults this may refl ect not only a real occurrence but [11, 20, 22] . Unnecessary treatment with AEDs also the diffi culty in collecting details about the 426 B.D. Bell and A.R. Giovagnoli

Table 26.1 Characteristics of epilepsy in older adults There is often a lack of speci fi c clinical signs Partial epilepsy is most common of epilepsy in older adults. In a study of individuals New-onset frontal lobe seizures more common than older than 60 years who had a mean duration of temporal lobe seizures partial epilepsy of 44 years, many demonstrated Motor or sensory symptoms more common than progressively less elaborate and briefer sei- psychic symptoms zures over the course of their lives [69 ] . Auras Auras less common and may present in a nonspeci fi c are uncommon and often nonspecifi c when they way (e.g., dizziness) Automatisms less common than in young adults occur, and automatisms and secondary general- Secondary generalization less common ization also are relatively uncommon. A distur- Prolonged postictal state can occur bance of consciousness accompanied by a blank Status epilepticus appears to be more common than in stare may be the only manifestation of a CPS in young adults an older adult [ 12, 15, 22 ] . Postictal symptoms Focal slowing on EEG less likely to be indicative of result from seizure-induced reversible alterations in epilepsy neuronal function. Both the postictal focal motor de fi cits and confusional state can be prolonged in Table 26.2 Clues to the possibility of epileptic seizures older patients, with the former lasting for hours in older adults [59 ] and the latter for days. The prolonged post-ictal Confusional state with sudden onset and end confusion may even be mistaken for dementia Rhythmic muscular contractions in a focal territory [15, 20, 22, 23, 26, 32 ] . Paroxysmal behavior disorder with or without a focal neurological sign Transient Epileptic Amnesia Versus Impairment of consciousness Transient Global Amnesia A prior history of epilepsy Transient epileptic amnesia (TEA), also called Focal slow waves on interictal EEG epileptic amnesic syndrome, is a specifi c and probably underdiagnosed type of TLE that seizure semiology in older people who may fail tends to have a late onset [37, 70Ð 72 ] . It usually to report psychic symptoms [ 66 ] . CPS in particu- strikes in the sixth or seventh decade of life and is lar account for about 40% of all seizures in the associated with recurrent, abrupt, transient, and aged population [14, 15, 19, 22, 61, 67 ] . relatively severe anterograde memory distur- CPS with a mesial temporal lobe onset are bance (median duration = 30Ð60 min). Cognition most common in young adults and often are asso- is otherwise generally intact during the occur- ciated with an aura, disturbance of conscious- rence of the amnesic event. TEA may be associ- ness, behavioral arrest, oral-facial and limb ated with an abnormal EEG, especially a automatisms, and a period of post-ictal confusion sleep-deprived EEG, and is almost always respon- of seconds to minutes. Secondary generalization sive to an AED such as carbamazepine. Before also is relatively common. It also should be noted treatment is instituted, TEA tends to occur upon that widespread volumetric changes on imaging awakening and sometimes is associated with and cognitive defi cits are common in this group other temporal lobe symptomatology such as [ 39 ] , and older patients with long-standing olfactory hallucinations, oral automatisms, or temporal lobe epilepsy (TLE) also can be brief unresponsiveness. But transient amnesia expected to show impairment in more domains may be the sole ictal symptom. Interictal memory than memory. While new-onset temporal lobe impairment is commonly reported by TEA seizures can occur quite late in life [ 68 ] , new- patients and may not resolve with treatment. onset CPS in older adults is most likely to be Although standard memory testing might reveal extratemporal, often originating in the frontal only subtle dif fi culty, some TEA patients report lobe. This is at least in part due to the link between considerable problems with remote memory anterior frontal cortical areas and stroke. loss and accelerated long-term forgetting (ALF). 26 Epilepsy and Aging 427

In the latter, information tends to be recalled nor- lar, nonconvulsive and partial complex SE can mally for a day or more, but then fades at an present as prolonged confusion or unusual behav- accelerated rate compared to healthy controls. ior such as lethargy, agitation, automatisms, or The subjective report of this phenomenon by a mild personality change, which may prevent a subset of TEA patients has been confi rmed by timely diagnosis in elderly patients. When non- means of innovative memory assessment over convulsive SE is suspected, an EEG should be long intervals [ 73 ] . ALF may re fl ect a problem performed so that, if it is confi rmed, treatment with a late stage of memory consolidation and can be provided quickly [75 ] . perhaps a disturbance restricted to the hippocampus bilaterally. Thus, epilepsy should be ruled out Non-epileptic Paroxysmal Syndromes in patients with credible reports of intermittent There is a range of disorders with symptoms that and clear-cut amnesic attacks, ALF, and/or iso- can cause or mimic a seizure, including cerebro- lated retrograde amnesia [37, 70, 72, 74 ] . vascular, cardiovascular, endocrine/metabolic, A late life onset of transient memory loss is infectious, sleep, migraine, and psychiatric characteristic of both TEA and transient global conditions. The main differential diagnosis in amnesia (TGA). TGA is not an epileptic event older adults is convulsive syncope. Syncope is and so is associated with a normal EEG or slowing loss of consciousness due to an acute decrease in only, tends to last longer than TEA, and is usually cerebral blood fl ow, and if it is prolonged, con- a one-time event [ 37, 70 ] . Table 26.3 lists charac- vulsions may occur. This type of seizure may teristics of TEA versus TGA and TIA. result from a cardiac cause (heart block, ventricular tachycardia, ventricular fi brillation, asymmet- Status Epilepticus ric septal hypertrophy, aortic stenosis), carotid It is noteworthy that 30% of fi rst seizures in older sinus hypersensitivity, or vasovagal attack. adults present as SE [ 75 ] , de fi ned as any seizure Clinical observation (e.g., heart rate, blood pres- lasting more than 30 min or intermittent seizures sure, skin vegetative signs) facilitates diagnosis. lasting for more than 30 min during which the Whether or not an attack is observed, diagnosis is patient does not regain consciousness [76 ] . Stroke aided by simultaneous EEG and ECG. is the most common etiology of SE in older adults Other causes of non-epileptic seizures include [47 ] . Two main types of SE are distinguished: sleep-related disorders such as sleep attacks (irre- generalized (convulsive, nonconvulsive) and par- sistible episodes of sleep), cataplexy (sudden loss tial (simple, complex). Incidence of SE is sub- of postural tone sparing consciousness, often stantially higher in older adults in comparison to stimulated by strong emotions such as fear), sleep younger ages, and mortality is elevated in older paralysis (lasting a few minutes on awakening or adults, particularly in patients with brain anoxia when falling to sleep), hypnagogic hallucina- [ 77, 78] . SE is often underdiagnosed. In particu- tions, and REM behavior disorders. Diagnosis is

Table 26.3 Differential diagnosis of transient epileptic amnesia (TEA), transient global amnesia (TGA), and transient ischemic attack (TIA) TEA TGA TIA Duration <1 h 4Ð6 h Variable Ictal amnesia Retro-anterograde Dense anterograde, variable Not well characterized retrograde Other symptoms Sometimes olfactory hallucinations, Headache, nausea Focal neurological de fi cits automatisms, brief loss of awareness Recurrence ~Monthly Rare Not well characterized Interictal memory Includes accelerated long-term No permanent de fi cits Risk of permanent de fi cits forgetting, remote memory loss from strokes Note: Adapted with permission from Zeman and Butler [37 ] 428 B.D. Bell and A.R. Giovagnoli based on a characteristic history and the typical approximately 75% of PNES patients are women, EEG pattern showing sleep-onset REM. Another but this ratio may decrease signifi cantly in late- differential condition is migraine which may onset (>age 55) patients [ 82, 83 ] . In addition, it cause sudden loss of consciousness owing to appears that a history of sexual abuse, which is brainstem vasomotor changes. Clinical history relatively common in early-onset PNES patients, and EEG may easily discriminate epilepsy and is rare in late-onset patients, who are more likely migraine, although patients with migraine may to have severe physical health problems (e.g., show EEG epileptic abnormalities and some cardiovascular illness) and report health-related patients can be affected of course by both disor- traumatic experiences. Older-onset patients also ders. When a seizure is caused by electrolyte seem to be less likely to have baseline psychiatric imbalance, febrile illness, or hypoglycemia or disturbances [83 ] . hyperglycemia, chronic AED treatment is not In general, PNES may be longer than average required after the condition is successfully treated epileptic seizures (>2 min), have motor features [20, 79 ] . with a gradual onset and a fl uctuating course, and be associated with thrashing, violent movements, Psychogenic Non-epileptic Seizures side-to-side head movements, asynchronous Psychogenic non-epileptic seizures (PNES) are movements, and closed eyes. Other possible signs sudden involuntary attacks of sensation, move- of PNES include crying or speaking during sei- ment, autonomic alteration, or complex behavior, zures, noninvolvement of the face during gener- such as anesthesia, crying, bizarre postural alized movements, no seizures during sleep, changes, hyperventilation, or sudden fear expres- stronger seizures when the staff is present, resis- sion, that are not caused by cortical discharges, tance when trying to open the patient’s eyes, and although they may, in some cases, perfectly frequent hospitalizations. A history of multifac- mimic epileptic seizures. PNES are pseudo- eted symptoms and features that are unusual for neurological manifestations of psychological dis- epilepsy and an absence of incontinence, tongue tress or psychiatric disorders (conversion, laceration, and self-injury support this diagnosis. somatization). After Charcot’s de fi nition of hys- PNES patients also are more likely to recall tero-epilepsy and later terms such as pseudo-sei- details from the unresponsive period compared to zures or hysterical seizures, the term PNES has patients with epilepsy [15 ] . been preferred. PNES appear to be about as com- At the group level, epilepsy and PNES patients mon in older as in younger adults and sometimes typically perform similarly on neuropsychologi- can have an onset late in life [ 62, 80 ] . Diagnosis cal testing. However, symptom validity tests and of PNES requires differentiation not only from personality measures can help with differential epileptic seizures but also other forms of non- diagnosis. When present in young adult PNES epileptic episodes. Video-EEG recording docu- patients, neuropsychological impairment is often menting the absence of epileptiform discharges a function of suboptimal motivation during the during an event is the gold standard for diagnosis assessment or an emotional disturbance. For of PNES. In the absence of ictal EEG, no single example, PNES patients tend to perform worse symptom, clinical sign, or demographic variable than those with epilepsy on the Portland Digit allows for the diagnosis of PNES. Differential Recognition Test and Word Memory Test. While diagnosis is important to prevent unnecessary there is no single psychological pro fi le that AED treatment, iatrogenic complications, and differentiates PNES from epilepsy, extreme scores delayed referral to adequate psychiatric on the Hs and Hy scales of the MMPI-2 are more treatment. common in PNES patients [82, 84 ] . Initial work Some studies suggest that PNES represents with the MMPI-2-RF suggests that the RC1 approximately one-half of the non-epileptic sei- (Somatic Complaints) correctly classifi es about zures identifi ed during video-EEG monitoring in two-thirds of epilepsy and PNES patients. In addi- patients over age 60 [80, 81 ] . In younger adults, tion, two newly created supplementary scales 26 Epilepsy and Aging 429

(PNES Physical Complaints and PNES Attitudes) mon and not necessarily related to onset of epi- show promise, as they provided slightly better lepsy. For other abnormalities, computerized accuracy in correctly classifying 73% of patients tomography (CT) scans can reveal tissue con- [ 85 ] . Careful assessment of personality style and trasts such as the presence of blood, calcifi ed psychopathology, emotionalÐbehavioral distress lesions, and encephalomalacia, whereas mag- symptoms, pre-illness life and medical events, netic resonance (MRI) is more effective in iden- personal resources, and coping attitudes plays a tifying subtle changes in tissue density such as role in determining the psychic origin of PNES, as glial tumors or hippocampal changes [ 11, 14, well as in de fi ning epilepsy-related psychological 19, 32, 80] . CT- and MRI-detected brain lesions disorders which in relatively rare cases can result are not a necessary or suf fi cient criterion for in coexistence of non-epileptic seizures. epilepsy. However, in older patients, the detection of a focal brain lesion represents a signifi cant EEG diagnostic criterion that supports diagnosis Discharges on EEG are not rare in older patients when typical clinical and EEG signs are present without epileptic seizures, and interictal epilepti- [59 ] . In particular, in older patients with SE or form activity is present on routine EEG only in a prolonged behavior/mental symptomatology of minority of patients with onset of seizures after uncertain origin (e.g., nonconvulsive SE versus age 60 [ 86 ] . Benign EEG variants that are most metabolic failure), CT and MRI are important common in older adults include subclinical rhyth- emergency measures [ 90 ] . mic electrical discharges of adulthood (SREDA), wicket spikes, and small sharp spikes [ 64, 75 ] . Nevertheless, EEG often can be helpful in the Antiepileptic Drug Treatment diagnostic process [59, 63, 68, 87 ] , including extended/ambulatory EEG and long-term inpa- AEDs are the most common treatment for epi- tient video-EEG monitoring. The latter tends to lepsy, while other approaches may be applied in be underused in older adults, as they account for patients with drug-resistant seizures. Major drug about 5% of video-EEG inpatient admissions selection criteria (i.e., the seizure type to be [62, 64 ] . Long-term monitoring (typically lasting treated and side effects) are considered in the 3Ð5 days) can be cost effective and especially context of individual patient characteristics in valuable in diagnosing recurrent spells, classify- order to determine the probable relative ef fi cacy ing epilepsy, and determining candidates for epi- and tolerability of a drug. This process has lepsy surgery [ 22, 61, 62, 75, 80, 88, 89 ] . become more complex as many new AEDs have Long-term video-EEG does require precautions been introduced to clinical practice in the last few to be in place for prevention of falls and prompt decades, requiring systematic trials to determine detection and treatment of adverse events; ter- ef fi cacy in the individual patient. tiary epilepsy centers generally offer the highest Epilepsy usually is diagnosed after two or level of experience and care [89 ] . more unprovoked seizures occur [ 14] . The question of whether a physician should begin treatment with an AED immediately after a fi rst Brain Imaging seizure is controversial. Studies have demonstrated that deferring treatment until more than In recent years, brain imaging of course has one seizure has occurred does not adversely become more sophisticated, allowing for vari- affect the long-term remission rate. However, it ous structural and functional studies. For the has been recommended that treatment be insti- most part, these techniques have been applied tuted after a single unprovoked seizure, espe- for the diagnosis of younger, drug-resistant epi- cially in the context of a history of stroke, lepsy patients or to experimental study designs. because of the high risk of subsequent seizures Age-related changes on brain imaging are com- and their potential serious consequences, includ- 430 B.D. Bell and A.R. Giovagnoli

Table 26.4 AED use in older adults ications [ 26, 79, 91, 93 ] . Medication side effects AED selection depends on comorbid conditions, may be dose dependent or drug specifi c, and the co-medications, and expected side effects spectrum of side effects may differ from that seen Increased vulnerability to side effects and toxicity in younger patients. The pharmacokinetics Increased likelihood of failing medication trials due to (absorption, distribution, and metabolism) and adverse effects pharmacodynamics (receptor function) of AEDs Slower, more gradual titration and lower dosage generally are different in older adults, who are recommended Serum drug concentrations tend to vary more susceptible to the adverse side effects of AED combined with another medication may amplify these drugs and toxicity, as well as interactions adverse effects common to both with other types of medications. Older adults are often more susceptible to AED-induced cognitive side effects, ataxia, and dizziness, with a sec- ing falls, fractures, etc. [ 22, 45, 47, 50 ] . ondary increased tendency to confusion and falls. Fortunately, up to 80% of patients who develop The coexistence of various medical (e.g., cardiac, epilepsy in old age are rendered seizure free with hepatic or renal failure, obesity), neurological AED treatment [ 22, 44 ] , with better outcome (e.g., sleep-related disorders, migraine), or psy- when an AED is started within 2 years of the fi rst chiatric comorbidities (e.g., depression, psycho- seizure compared to after 2 years [ 61 ] . sis, anxiety) may be a factor in choosing a Taking into account the selection criterion of particular AED. For instance, valproate and the seizure type, the narrow-spectrum AEDs pregabalin are associated with weight gain; val- (e.g., carbamazepine, gabapentin, lacosamide, proate and topiramate may be effective in oxcarbazepine, phenobarbital, phenytoin, migraine; levetiracetam, primidone, phenobarbi- pregabalin, primidone, tiagabine), which are tal, topiramate, and zonisamide may contribute to typically effective in partial seizures with or worsen depression; levetiracetam, phenobarbital, without secondary generalization, are primary and primidone may cause behavioral reactions; choices in the treatment of late-onset epilepsy in carbamazepine and valproate may have positive older adults. However, broad-spectrum AEDs psychotropic effects; and many AEDs (in partic- (e.g., lamotrigine, levetiracetam, rufi namide, ular phenobarbital, primidone, topiramate) may topiramate, valproate, zonisamide), effective cause cognitive defi cits. Detailed discussions of both in partial and generalized seizures, are use- AED risks and bene fi ts in older adults are pro- ful when diagnosis is uncertain. Older adults are vided elsewhere [14, 19, 22, 23 ] . more likely than younger patients to become Comorbidities in older adults are also related seizure free with low AED doses [12 ] . to the use of other medications that may impli- Characteristics of AED use in older adults are cate pharmacological interactions and co-toxic- listed in Table 26.4 . ities. Co-medications can alter the absorption, AEDs rank fi fth among all drug categories in distribution, and metabolism of AEDs, effects capacity to elicit adverse side effects in older which increase the risk of either toxicity or adults. In a recent survey, 64% of a sample of therapeutic failure [ 79 ] . Common medications elderly community dwelling patients with intrac- that interact with AEDs include warfarin, table partial epilepsy listed medication side digoxin, theophylline, cyclosporine, and corti- effects as an illness-related concern [ 91 ] . AED costeroids. Because depression and anxiety are adherence among elderly patients often is subop- common in patients with epilepsy, the procon- timal, and this is associated with increases in both vulsive properties of tricyclic antidepressants seizures and health-care costs [92 ] . It is worth have to be considered. All tricyclic antidepres- keeping in mind that compliance may be affected sants can lower seizure threshold; seizures by ability to afford an AED; elderly individuals caused by these drugs typically are generalized are more likely to rely on government insurance tonicÐclonic [20 ] . It has been estimated that and may have to pay out of pocket for some med- 33% of the pharmaceutical expenditure by older 26 Epilepsy and Aging 431 adults is for over-the-counter products. Some lepsy surgery in patients more than 50 years old over-the-counter allergy, weight loss, and [101, 102] and two recent studies addressing memory aids may also have proconvulsive surgery in those more than 60 years old [ 42, 98 ] properties [14, 20 ] . suggest older patients often are viable candi- In line with the conclusions of the ILAE [94 ] , dates for epilepsy surgery. One study [ 42 ] a low dose of lamotrigine, gabapentin, or car- described postsurgical seizure and neuropsy- bamazepine has been recommended for treatment chological outcome in TLE patients with a mean of poststroke seizures [ 50 ] . A few recent studies age of 56 and a mean duration of epilepsy of have described the effectiveness and tolerability 33 years. Seizure outcome after temporal lobe of AEDs in patients with AD, suggesting no dif- excisions was not signifi cantly different in ference in clinical effi cacy between phenobarbi- patients older than 50 years compared to a sam- tal, levetiracetam, and lamotrigine but minor side ple consisting of patients younger than 50. In effects for levetiracetam [ 95 ] . Levetiracetam has fact, even a subset of patients more than 60 years been demonstrated to be safe in the treatment of old (n = 11) had an outcome similar to the older patients with partial or generalized SE [ 96 ] . younger group. Although surgical and neuro- Use of phenobarbital and phenytoin is advised logical complications were infrequent, they against in older adults, in part due to risk of were signifi cantly higher in the >50 years group. sedation and falls (for a combination of reasons, In addition, the >50 group was more likely to epilepsy doubles the risk of fractures), but phenytoin show signifi cant decline when assessed about remains commonly prescribed in this age group, 12 months after surgery on an index of atten- in part because it is relatively inexpensive and its tion, and the >60 years old group was especially properties are well known [ 12, 14, 18, 19, 22, 23, vulnerable to decline in verbal memory, even 32, 44, 97 ] . though 91% of them underwent a right-sided It should be noted that the cutoff of age 65 to surgery. A report from Germany [ 42 ] concluded designate older age is arbitrary, with no particu- that, although there is modestly increased risk lar biological signi fi cance, because the gradual of complications and neuropsychological health changes associated with aging manifest decline, epilepsy surgery is effective in older themselves at different times in different people. TLE patients. Another report that reviewed Thus, older adults are “not a single cohort” [ 14, results from seven patients who underwent tem- 45, 79 ] . In addition to chronological age, a poral resection after age 60 also concluded that patient’s biological age, based on a physician’s surgery in this group generally is safe and effec- clinical judgment, is an important factor when tive [98 ] . Similarly, based on studies of patients medication choices are made [ 14, 19 ] . with a mean age in the early to mid-50s, other Attempting to minimize AED side effects while authors concluded that neither chronological also controlling seizures is a delicate balance age nor duration of epilepsy should necessarily [22, 33, 35, 39 ] . exclude patients from consideration for epilepsy surgery [100, 102] . While recognizing that the risk of any operative procedure is higher in Epilepsy Surgery elderly patients and that there may be obstacles to surgery for some, these authors emphasized Surgery is a potentially curative treatment for the potential benefi ts of surgery in the context of disabling, medically refractory epilepsy, and in possible medication intolerance, persisting sei- TLE in particular, it is the standard of care in zures, and corresponding physical injuries, loss selected patients [ 98, 99] . There have been few of independence, cognitive decline, and psychi- studies of epilepsy surgery in older adults, and atric disorders in the absence of surgery. More no consensus exists on an upper age limit for research is needed about cognitive outcome and epilepsy surgery candidates [ 100 ] . But the over- quality of life (QOL) after epilepsy surgery in all fi ndings from a small series of studies of epi- older adults. 432 B.D. Bell and A.R. Giovagnoli

population may be more complex than on younger Cognition, Behavior, and Quality groups because health and perceptions of life suc- of Life cess have different defi nitions that are dependent on the modifi ed perspectives, aims, and physio- Quality of Life and Mood logical ability associated with aging. In the general population, the main determinants of On generic measures of health-related QOL, successful aging include absence of disability, scores for both physical and mental health status arthritis and diabetes, and being a nonsmoker and, tend to be lower in epilepsy patients than in the to a lesser extent, social interaction, physical general population, particularly for those with activity, and absence of cognitive impairment and uncontrolled seizures. The few studies of elderly depression [ 110 ] . The impact of epilepsy on QOL epilepsy patients suggest they also have in older adults may depend on a combination of signifi cantly lower QOL compared to the gen- such determinants, as well as on the subjective eral population [ 93, 103 ] . On epilepsy-speci fi c perception of aging and personal resources. The QOL measures [ 35, 104 ] , elderly patients with subjective perception of epilepsy, stigma, loneli- epilepsy generally do not experience poorer ness, low self-esteem, poor mastery, and disease- QOL compared to younger patients, but QOL related distress and, on the other side, life can suffer in those with new-onset epilepsy, fulfi llment and coping abilities interact in the especially those diagnosed after retirement [ 103, individual patient, explaining 20Ð35% of the vari- 104] . As just one example of the potential long- ance of QOL [ 111] . Spiritual aspects may also reaching impact of the illness, veterans with epi- contribute to determine overall well-being, irre- lepsy were about 1.5 times more likely than spective of age [ 109 ] . Improving the factors that those without to report getting no regular exer- enhance QOL in the non-epileptic elderly (e.g., cise which, among other things, may lead to physical exercise, calorie restriction, cognitive decreased muscle mass, falls, hip fractures, and and social stimulation, and psychological sup- frailty [103 ] . port) also would be expected to combat the delete- Young and old epilepsy patients share many of rious effects of epilepsy in older adults [112 ] . the same QOL concerns [91 ] , but the impact of an Depression is common in older epilepsy epilepsy diagnosis on QOL is potentially different patients and is associated with poor subjective in older adults. For example, it may lead to prema- QOL [113 ] . Suicide risk is elevated in people ture admission to a nursing home or other long- with epilepsy and in older adults [114, 115 ] , term care facility [19, 61 ] , and the diagnosis of occurring more frequently in patients with epilepsy in the context of existing age-related phys- chronic long-lasting epilepsy and medical and ical and cognitive changes may lead to a debilitat- psychiatric comorbidities. Other disabling men- ing sense of loss of control or a fear of losing one’s tal health symptoms also are common among mind [20, 32, 105 ] . Also, some senior citizens may people with epilepsy [ 116 ] . More research is be distressed by their own recall of a time when needed to understand QOL issues and the causes there were limited treatments for epilepsy, people and consequences of depression and other psy- did not understand why seizures occurred and were chiatric disorders in geriatric epilepsy [12 ] . afraid of them, and families sometimes sent people with seizures to institutions or kept them isolated from others [106Ð 108 ] . Different epilepsy-speci fi c Studies of Aging and Cognitive QOL measures have not been compared in an Functioning in Epilepsy Patients elderly population [29 ] . It may prove useful to develop a QOL instrument specifi cally for older In young adults with epilepsy, memory and adults and their caregivers [29, 93 ] . word- fi nding dif fi culties are predominant [117 ] . A few studies show that age is not always a These complaints also are common with normal signifi cant predictor for QOL in patients with epi- aging of course, and so they are likely to be fre- lepsy [ 109 ] . The impact of epilepsy on the aged quent among older epilepsy patients. The latter 26 Epilepsy and Aging 433 are more likely to be concerned about the pos- focal brain lesions, aims to produce a functional sibility that they are developing dementia com- map of impaired and preserved functions, high- pared to younger patients. At the group level, lighting the interactions between weaknesses and older people with partial epilepsy show a variety strengths and contributing to determination of the of cognitive impairments as compared to healthy type and severity of brain damage. Other aims are subjects matched for gender, age, and education clinical monitoring, in particular the follow-up of [38, 40, 41, 118 ] . For example, abstraction, AED changes and surgery, and the determination divided attention, word fl uency, and episodic of baseline cognitive and emotional status. The memory were impaired in this group, although neuropsychological approach to presurgical between-group differences generally were not assessment is evolving in the face of advances in large [40, 41] . In one study, results remained neuroimaging [122 ] . Aspects of the therapeutic stable over a 3-year period [ 38 ] , although there assessment model can be applicable in geriatric was failure to benefi t from a testÐretest effect. neuropsychology, including the tenets of address- Early age of onset of epilepsy, a known etiology, ing the patient’s presenting concerns and the and a high number of years with seizures, num- potentially threatening nature of the assessment, ber of years taking medications, number of treating the patient as a collaborator, and providing medications taken, and lifetime number of gen- feedback relevant to the individual’s questions eralized tonicÐclonic seizures are factors that and everyday functioning and circumstances have been associated with poorer neuropsycho- [ 123, 124 ] . logical functioning in the general population of Neuropsychological data refl ect a combination patients with epilepsy [35 ] . Other factors asso- of fi xed factors, such as neuropathology and its ciated with cognition are brain lesion, genetic localization, disease course factors, including abnormalities, seizure frequency, type of sei- history of recent SE or epilepsy surgery, and zure, SE, and surgery [ 119 ] . potentially remediable factors, such as medication Although variables such as age of onset and effects, fatigue, and mood [ 122, 123 ] . When duration of illness are associated with manifesta- cognitive status is in question, neuropsycholo- tion of cognitive de fi cits [40 ] , recent cross- gists can help determine a patient’s ability to sectional studies suggest that cognitive defi cits understand the rationale for medications, written characteristic of early-onset TLE are established instructions about the regimen, use of dosing early in life and tend to remain relatively stable trays, and the potential need for close involve- with aging [120, 121 ] . In older patients with par- ment of a family member and interaction with a tial epilepsy, AED polytherapy so far appears to multidisciplinary health-care team. The treatment be the strongest determinant of cognitive perfor- goal for an epilepsy patient is to achieve seizure mance, regardless of whether seizures are con- freedom with minimal AED side effects and the trolled or refractory [ 40, 41 ] , with effects on least possible decrease in QOL. Since no ideal initiation, shifting, attention, and memory. Older AED exists [ 19, 26, 61 ] , interdisciplinary efforts epilepsy patients on AED polytherapy were can strive for maximization of QOL. impaired compared to patients with amnesic MCI, Health-care professionals and epilepsy advo- whereas those on AED monotherapy showed cacy groups have worked together to publish comparable de fi cits to the MCI group [118 ] . See specifi c recommendations concerning driving Table 26.5 for a summary of the results of studies applicable to people with epilepsy [125 ] , yet for- of cognition in older adults with epilepsy. mal driving restrictions vary widely across different states and countries [126 ] . Neuropsychologists may play a role in advising about driving restric- Framework for Neuropsychological tions related to aging and epilepsy. In particular, Assessment neuropsychologists can provide information about a patient’s awareness of cognitive impairments and The neuropsychological approach to epilepsy, risks for driving, and about the status of the main often assumed as a model to test patients with cognitive resources that are important to complex 434 B.D. Bell and A.R. Giovagnoli ] 95 ] ] ] ] 41 118 38 40 Martin et al. [ [ Martin et al. Grif fi th et al. [ Piazzini et al. [ [ Piazzini et al. Grif fi th et al. [ [ Cumbo and Ligori AED polytherapy more impaired than pts AED polytherapy on monotherapy healthy controls. Epilepsy pts on AED more impaired than MCI pts polytherapy Epilepsy pts impaired on all tests, with the cits in those on AED polytherapy fi de worst 3 years stable pattern over was levetiracetam At 1-year follow-up, associated with seizure decrease and attention, short-term memory, improved lamotrigine with mild uency; fl and verbal decline; and phenobarbital with cognitive signi fi cant worsening Rey Complex Figure Complex Rey Mattis Dementia Rating Scale Epilepsy pts impaired on all tests. Pts Wechsler Memory Scale-III Wechsler Logical Memory subtest Attentional Matrices, Trail Making Tests Memory Scale-III Wechsler Logical Memory subtest Dementia Rating Scale Logical Memory subtest Mini-Mental State Examination Epilepsy pts impaired on all tests, with Alzheimer’s Disease Assessment-Cognitive Memory, learning Memory, Language test, words Paired Short story, functioning test test, Token Fluency Verbal Cognitive Cognitive domain investigated Neuropsychological tests Findings Reference Immediate and long-term memory attention memory functioning Overall cognitive functioning Results of neuropsychological studies of older patients with epilepsy Results of neuropsychological studies older patients with epilepsy patients 40 Healthy older controls 25 Epilepsy pts Abstraction CPM Raven cognitive Overall Study sample 26 Epilepsy pts abilities cognitive Overall Dementia Rating Scale Epilepsy pts impaired with respect to Table 26.5 68 Controls Pts 26 MCI pts 26 Healthy older controls 40 Epilepsy pts ability Lexical test Fluency and divided CFL Word Selective 27 Healthy older controls 17 Epilepsy pts 17 Older controls Immediate and long-term 95 pts with epilepsy and AD treated or with phenobarbital, levetiracetam lamotrigine cognitive Overall Memory Scale-III Wechsler 26 Epilepsy and Aging 435 driving behavior (e.g., visuospatial functions) Table 26.6 NINDS Epilepsy Common Data Element [127 ] . This baseline information may be helpful Project: Recommended neuropsychological test battery [128 ] during other examinations relevant to fi tness to drive, including structured assessment of driving General IQ estimation American National Adult performance (e.g., driving simulation test). Reading Test (AmNART) Formal IQ WAIS-IV, a WAIS-IV short Exclusion of cognitive decline requires at least form, or WASI two examinations, usually separated by a mini- Verbal memory Rey Auditory Verbal mum of 12 months. Especially at advanced ages, Learning Test variability in cognitive reserve may lead to quite Naming Boston Naming Test different individual trajectories of cognitive Phonemic fl uency Controlled Oral Word change. Cognitive reserve, as a product of intelli- Association (aka FAS) gence level, education, lifestyle, social stimula- Semantic fl uency Animal fl uency tion, personal experiences, and motivation, can Set shifting Trail Making Tests A and B modify or buffer the impact of aging and epilepsy Simple attention span WAIS-IV Digit Span Processing speed WAIS-IV PSI (see on cognitive functions. It is a common experience WAIS-IV above) that older patients affected by similar brain pathol- Motor speed Grooved Pegboard ogy may be heterogeneous at the physical, mental, Optional or potential tests and behavioral levels. Cognitive functions may Hypothesis testing Wisconsin Card Sorting refl ect previous neural and functional reorganiza- Test short form (WCST-64) tions, resulting in selectively impaired or pre- Visual memory Brief Visuospatial Memory served function irrespective of epilepsy. This Test-Revised (BVMT-R) underlines the importance of obtaining a com- WAIS-IV Wechsler Adult Intelligence Scale-IV, WASI prehensive neuropsychological profi le in older Wechsler Abbreviated Scale of Intelligence, PSI Processing Speed Index patients with epilepsy and assessing in detail different cognitive abilities. Mental control, episodic memory, the inhibition of interference, set shifting, lexical-semantic competence, constructive praxis, the neuropsychology subcommittee of the NINDS and social cognition may show different trajecto- Epilepsy Common Data Element (CDE) Project ries. The understanding of social situations, in very recently published a recommended test bat- particular, might be relatively preserved with tery for adult epilepsy patients that could be respect to memory and executive functions. A adopted for older adults (see Table 26.6 ) [128, neuropsychological battery sensitive to epilepsy- 129 ] . The subcommittee recommended that when and aging-related variables should assess multiple WAIS-IV or WASI short forms are used, the domains, but the battery should be cognizant of Vocabulary and Block Design tests should be fatigability and fl uctuating compliance. The tests administered, at a minimum. The entire battery, should not be redundant or excessively time- depending on whether an IQ short form or the consuming, preferably divided into 30Ð40 min optional tests are used, should take from 2 to sections. In addition to the necessary psychometric 3.5 h [ 129] . The CDE recommendations empha- properties, the tests ideally should have alterna- size that the tests do not have to constitute a “ fi xed tive forms for serial assessment and be sensitive at battery.” Alternative or novel measures can be the lowest levels of performance, allowing for included to maintain continuity within an exist- detection of small changes. ing program or to advance the fi eld [ 129, 130 ] . As just a few examples, additions might include measures of planning, theory of mind, semantic Test Battery knowledge, and visual perception. The battery listed here does not include psychiatric measures, There is no consensus neuropsychological test but the Epilepsy CDE also does provide a list of battery for older patients with epilepsy. However, recommended psychiatric scales [129 ] . 436 B.D. Bell and A.R. Giovagnoli

Memory Self-Report fi ll the pillbox once per week. A visiting nurse also may enhance AED adherence. Decades ago, a review of the extant self-report memory questionnaire literature led to the conclusion that it is “prudent to employ memory Case Report questionnaires with caution” [ 131 ] . This advice continues to hold true, because there is no close A 77-year-old, right-handed, married woman correlation between self-reported memory ability (FC) with primary schooling reported long-lasting and objective test results across patient groups mental and physical fatigue and recurrent depres- [132 ] . Presurgical adult TLE patients, the most sion. Since age 71, FC experienced CPS that were consistently studied epilepsy group, most often incompletely controlled by carbamazepine. Her overestimate their degree of memory impairment seizures were characterized by sudden gastric distress, [130 ] . Complaints of recent memory dysfunction nausea, and loss of consciousness in the absence of may be associated with a number of factors, falls or motor symptoms; sometimes she including a stable chronic defi cit, increased appeared disoriented or mildly confused for seizure activity, medication side effects, mood, or almost 1 h. After the onset of her seizure disorder, a combination of these factors [34 ] , with depres- FC also complained of naming dif fi culties and sion and anxiety playing a central role in self- autobiographical, immediate, and spatial memory perception of memory [ 39, 132 ] . Thus, it is failures. Some of the memory failures were char- possible that, in some older patients with epi- acterized by sudden interruption of the process- lepsy, identi fi cation of mood problems during a ing or learning of new information (e.g., taking neuropsychological evaluation may lead to both note of a phone call). Minor problems concerned effective psychiatric/psychological treatment and motor planning, with slowing and abnormal reassurance that a feared dementia is not present. sequencing and execution of fi ne actions such as With the patient’s consent, information acquired sewing. Past medical history included undefi ned from family members may help determine the digestive and bowel problems, anemia, chronic severity of the problem in everyday life. When hypokalemia, hypothyroidism and hypocalcemia memory impairment is identifi ed, external mem- with secondary hypoparathyroidism following ory aids, such as a calendar and a personal digital surgical resection of a thyroid adenoma, and assistant (PDA), can be recommended. benefi cial treatment of some of these conditions with thyroxin, calcium, and potassium. Family history was negative. Information for Patients and Family At neurological examination, FC was oriented in time and space, depressed but cooperative; her Guides that may be helpful for patients and fami- behavior was sometimes reactive, with theatrical lies include those published on-line by the manifestations or repeated demands for help. Epilepsy Foundation, The Epilepsy Project, and Speech was fl uent and communicative, and com- Epilepsy Action [ 133Ð 135 ] . For additional prehension was fully preserved. Immediate mem- sources of information, see Loring, Hermann, ory and autobiographical memory were clinically and Cohen [ 136 ] . As noted above, the term epi- impaired. No other cognitive, motor, sensorial, lepsy may have unfortunate connotations and balance, or cranial nerve defects were observed. stigma associated with it for some older patients, The seizures, as well as some sudden memory and so it may be best to avoid the term in those failures, were strongly indicative of epilepsy, cases [11 ] . Family members and caregivers can while cognitive decline, in the light of medical be taught about the signs of AED toxicity to help history, suggested a vascular or secondary meta- prevent falls and other consequences [ 13 ] . A bolic encephalopathy, although a degenerative 7-day pillbox aids adherence to AEDs and some disease had to be excluded. Brain CT showed patients may bene fi t from having a family member cortical atrophy in the posterior parietal and 26 Epilepsy and Aging 437 occipital brain areas and small vascular lacunae although many adult patients with celiac disease in the deep white matter. Positron emission CT may be asymptomatic or have only non-intestinal showed normal brain perfusion. EEG documented symptoms. Recent reports have described differ- left temporal slow waves and spikes. Carotid ent neurological complications of celiac disease, Doppler sonography showed mild acceleration of such as ataxia, peripheral neuropathy, and epi- the blood fl ow at the origin of the internal lepsy. Prevalence of celiac disease is increased carotids. among patients with epilepsy of unknown etiol- The fi rst neuropsychological assessment, at ogy, and humoral immune mechanisms may age 77, showed impaired working memory, ver- explain the neurological complications [137 ] . bal and visuospatial long-term memory, word This case suggests a link between gluten sensitivity fl uency on phonemic and semantic cues, word- and epilepsy. Thus, it is worthwhile to investigate list learning, and constructive praxis, with spared celiac disease in any elderly patient with partial short-term memory span, set shifting, and abstract epilepsy of unknown origin, even in the absence reasoning. A year later, neuropsychological test- of digestive symptoms. FC’s cognitive decline ing revealed a similar qualitative pattern, with was in great part reversible, with the cognitive worsening of visuoperceptual and praxis abilities. changes identifi ed by serial neuropsychological At this time, due to the persistence of medical assessment. After speci fi c dietary restrictions, she symptoms, especially anemia, asthenia, and reached an age-appropriate level of functioning bowel problems, and drug-resistant seizures, she and did not lose her autonomy. The fi ndings from underwent blood testing for antigliadin antibod- the cognitive evaluations excluded degenerative ies that was indicative of gluten intolerance. or vascular dementia, supporting a diagnosis of Biopsy specimens from the small bowel showed normal cognitive aging. villous atrophy and crypt hyperplasia, indicating celiac disease alterations. After a 6-month gluten-free diet, she reported weight loss and Clinical Pearls signi fi cant improvement of physical strength and mental concentration. Moreover, seizures disap- ¥ The neuropsychologist should explain to the peared. Neuropsychological follow-up, at age 80, patient the nature of neuropsychological showed long-term memory and word fl uency assessment in the context of a multidisciplinary de fi cits but improvement of visuospatial abilities, approach. constructive praxis, and divided attention. The ¥ Older patients may be reluctant to acknowl- neurological and neuropsychological picture was edge problems they view as “psychological” unchanged at the age 82 follow-up. or may not be aware of seizure symptoms or This is a rare case of treatable epilepsy-related their signi fi cance. cognitive impairment in an older adult. The ¥ Include spouse or other collateral source in the patient was affected by late-onset seizures and interview to acquire additional information cognitive decline associated with celiac disease. about seizure type(s) and frequency, patient’s Seizures were reversed after dietary restrictions. level of everyday cognitive functioning, etc. At the clinical level, it is worth noting that the ¥ Determine when the most recent seizure seizures were characterized by longer compro- occurred and get detailed information about mise of consciousness compared to typical recent medication changes, adherence, and young-adult seizures and that sudden memory any known side effects. failures, quite different from the other everyday ¥ Take into account comorbid conditions and dif fi culties reported by the patient, may have risks for cognitive impairment, including been the result of TEA. In regard to diagnosis, AEDs and other medications, head trauma, this case underlines the importance of consider- alcohol use, family history of dementia, etc. ing the medical symptoms and comorbidities that ¥ Administer a test battery appropriate to age may raise the suspicion of unexpected etiologies, and stamina; key abilities to assess include 438 B.D. Bell and A.R. Giovagnoli

psychomotor speed, attention, executive func- 14. Leppik IE, Birnbaum AK. Epilepsy in the elderly. tions, and learning (see Table 26.6 ). Make sure Ann N Y Acad Sci. 2010;1184:208Ð24. 15. Ramsay RE, Macias FM, Rowan AJ. Diagnosing to assess for depression, anxiety, suicidality, epilepsy in the elderly. In: Ramsay RE (ed. in Chief), and quality of life. Cloyd JC, Kelly KM, Leppik IE, Perucca E (editors). ¥ Remember that driving restriction is a prime The neurobiology of epilepsy and aging. New York: quality-of-life concern. Elsevier; 2007. p. 129Ð151. 16. Hauser WA. Epidemiology of seizures and epilepsy ¥ Both the patient and spouse may bene fi t from in the elderly. In: Rowan AJ, Ramsay RE, editors. psychosocial support. Seizures and epilepsy in the elderly. Newton, MA: Butterworth-Heinemann; 1997. p. 7Ð18. 17. Leppik IE. Introduction to the International Geriatric References Epilepsy Symposium (IGES). Epilepsy Res. 2006;68 Suppl 1:1Ð4. 1. Commission on Classi fi cation and Terminology of 18. Baker GA, Jacoby A, Buck D, Brooks J, Potts P, the International League Against Epilepsy. Proposal Chadwick DW. The quality of life of older people for revised classifi cation of epilepsies and epileptic with epilepsy: fi ndings from a UK community study. syndromes. Epilepsia. 1981;30:389Ð99. Seizure. 2001;10:92Ð9. 2. Commission on Classi fi cation and Terminology of 19. Brodie MJ, Kwan P. Epilepsy in elderly people. Br the International League Against Epilepsy. Proposal Med J. 2005;331:1317Ð22. for revised clinical and electroencephalographic 20. DeToledo JC. Changing presentation of seizures classifi cation of epileptic seizures. Epilepsia. 1989; with aging: clinical and etiological factors. 22:489Ð501. Gerontology. 1999;45:329Ð35. 3. Commission on Epidemiology and Prognosis, 21. Pugh MJ, Knoefel JE, Mortensen EM, Amuan ME, International League Against Epilepsy. Guidelines Berlowitz DR, Van Cott AC. New-onset epilepsy for epidemiological studies on epilepsy. Epilepsia. risk factors in older veterans. J Am Geriatr Soc. 1993;34:592Ð6. 2009;57:237Ð42. 4. Berg AT, Berkovic SF, Brodie MJ, et al. Revised ter- 22. Ramsay RE, Rowan AJ, Pryor FM. Special consider- minology and concepts for organization of seizures ations in treating the elderly patient with epilepsy. and epilepsies: report of the ILAE Commission on Neurology. 2004;62 Suppl 2:24Ð9. Classifi cation and Terminology, 2005Ð2009. 23. Sheorajpanday R, De Deyn PP. Epileptic fi ts and epi- Epilepsia. 2010;51:676Ð85. lepsy in the elderly: general refl ections, specifi c 5. Beghi E, Carpio A, Forsgren L, et al. Recommendation issues and therapeutic implications. Clin Neurol for a de fi nition of acute symptomatic seizure. Neurosurg. 2007;109:727Ð43. Epilepsia. 2010;51:671Ð5. 24. Tallis R, Hall G, Craig I, Dean A. How common are 6. WHO. World Health Organization: epilepsy: epide- epileptic seizures in old age? Age Ageing. miology, aetiology, and prognosis (WHO Fact 1991;20:442Ð8. Sheet). Geneva: World Health Organization; 2001. 25. Tebartz van Elst L, Baker G, Kerr M. The psychoso- 7. Banerjee PN, Filippi D, Hauser WA. The descriptive cial impact of epilepsy in older people. Epilepsy epidemiology of epilepsy—a review. Epilepsy Res. Behav. 2009;15 Suppl 1:17Ð9. 2009;85:31Ð45. 26. Waterhouse E, Towne A. Seizures in the elderly: 8. Lavados J, Germain L, Morales A, Campero M, nuances in presentation and treatment. Cleve Clin J Lavados P. A descriptive study of epilepsy in the dis- Med. 2005;72 Suppl 3:26Ð37. trict of El Salvador, Chile, 1984Ð1988. Acta Neurol 27. Hermann BP, Seidenberg M, Sager M, Carlsson C, Scand. 1992;85:249Ð56. Gidal B, Rutecki P, Asthana S. Growing old with 9. Birbeck GL, Kalichi EM. Epilepsy prevalence in epilepsy: the neglected issue of cognitive and brain rural Zambia: a door-to-door survey. Trop Med Int health in aging and elder persons with chronic epi- Health. 2004;9:92Ð5. lepsy. Epilepsia. 2008;49:731Ð40. 10. Wallace H, Shorvon S, Tallis R. Age-speci fi c inci- 28. Leppik IE, Kelly KM, deToledo-Morrell L, Patrylo dence and prevalence rates of treated epilepsy in an PR, DeLorenzo RJ, Mathern GW, White HS. Basic unselected population of 2 052 922 and age-speci fi c research in epilepsy and aging. Epilepsy Res. fertility rates of women with epilepsy. Lancet. 2006;68 Suppl 1:21Ð37. 1998;352:1970Ð3. 29. Martin RC, Vogtle L, Gilliam F, Faught E. Health- 11. Brodie MJ, Elder AT, Kwan P. Epilepsy in later life. related quality of life in senior adults with epilepsy: Lancet Neurol. 2009;8:1019Ð30. what we know from randomized clinical trials and 12. Cloyd J, Hauser W, Towne A, et al. Epidemiological suggestions for future research. Epilepsy Behav. and medical aspects of epilepsy in the elderly. 2003;4:626Ð34. Epilepsy Res. 2006;68:39Ð48. 30. Loring DW. History of neuropsychology through 13. Jacobson MP. Epilepsy in aging populations. Curr epilepsy eyes. Arch Clin Neuropsychol. 2010; Treat Options Neurol. 2002;4:19Ð30. 25:259Ð73. 26 Epilepsy and Aging 439

31. Novelly R. The debt of neuropsychology to the epi- ders after cerebral infarction. Neurology. 1996;46: lepsies. Am Psychol. 1992;47:1126Ð9. 350Ð5. 32. Snyder PJ, McConnell HW. Neuropsychological 50. De Reuck J. Management of stroke-related seizures. aspects of epilepsy in the elderly. In: Nussbaum PD, Acta Neurol Belg. 2009;109:271Ð6. editor. Handbook of neuropsychology and aging. 51. Larner AJ. Epileptic seizures in AD patients. New York: Plenum; 1997. p. 271Ð9. Neuromolecular Med. 2010;12:71Ð7. 33. Aldenkamp AP, Baker GA, Meador KJ. The neurop- 52. Mendez MF, Catanzaro P, Doss RC, Arguello R, sychology of epilepsy: what are the factors involved? Frey 2nd WH. Seizures in Alzheimer’s disease: clin- Epilepsy Behav. 2004;5 Suppl 1:1Ð2. icopathologic study. J Geriatr Psychiatry Neurol. 34. Baker GA, Goldstein LH. The dos and don’ts of neu- 1994;7:230Ð3. ropsychological assessment in epilepsy. Epilepsy 53. Scarmeas N, Honig LS, Choi H, et al. Seizures in Behav. 2004;5 Suppl 1:77Ð80. Alzheimer’s disease: Who, when, and how com- 35. Dodrill CB, Matthews CG. The role of neuropsy- mon? Arch Neurol. 2009;66:992Ð7. chology in the assessment and treatment of persons 54. Caramelli P, Castro LH. Dementia associated with with epilepsy. Am Psychol. 1992;47:1139Ð42. epilepsy. Int Psychogeriatr. 2005;17 Suppl 36. Hayashi PJ, O’Connor M. Neuropsychological 1:195Ð206. assessment and application to temporal lobe epi- 55. McCarron M, Gill M, McCallion P, Begley C. Health lepsy. In: Schachter SC, Shomer DL, editors. The co-morbidities in ageing persons with Down syn- comprehensive evaluation and treatment of epi- drome and Alzheimer’s dementia. J Intellect Disabil lepsy: a practical guide. New York: Elsevier; 1997. Res. 2005;49:560Ð6. p. 111Ð30. 56. Palop JJ, Mucke L. Epilepsy and cognitive impair- 37. Zeman A, Butler C. Transient epileptic amnesia. ment in Alzheimer disease. Arch Neurol. 2009;66: Curr Opin Neurol. 2010;23:610Ð6. 435Ð40. 38. Grif fi th HR, Martin RC, Bambara JK, Faught E, 57. Armon C, Shin C, Miller P, et al. Reversible parkin- Vogtle LK, Marson DC. Cognitive functioning over sonism and cognitive impairment with chronic val- three years in community dwelling older adults with proate use. Neurology. 1996;47:626Ð35. chronic partial epilepsy. Epilepsy Res. 2007;74:91Ð6. 58. Roks G, Korf ES, van der Flier WM, Scheltens P, 39. Hermann BP, Meador KJ, Gaillard WD, Cramer JA. Stamm PJ. The use of EEG in the diagnosis of Cognition across the lifespan: antiepileptic drugs, dementia with Lewy bodies. J Neurol Neurosurg epilepsy, or both? Epilepsy Behav. 2010;17:1Ð5. Psychiatry. 2008;79:377Ð80. 40. Martin RC, Grif fi th HR, Faught E, Gilliam F, Mackey 59. Dupont S, Verny M, Harston S, et al. Seizures in the M, Vogtle L. Cognitive functioning in community elderly: development and validation of a diagnostic dwelling older adults with chronic partial epilepsy. algorithm. Epilepsy Res. 2010;89:339Ð48. Epilepsia. 2005;46:298Ð303. 60. Sperfeld AD, Collatz MB, Baier H, et al. FTDP-17: 41. Piazzini A, Canevini MP, Turner K, Chifari R, an early-onset phenotype with parkinsonism and Canger R. Elderly people and epilepsy: cognitive epileptic seizures caused by a novel mutation. Ann function. Epilepsia. 2006;47 Suppl 5:82Ð4. Neurol. 1999;46:708Ð15. 42. Grivas A, Schramm J, Kral T, et al. Surgical treat- 61. Brodie MJ, Stephen LJ. Outcomes in elderly patients ment for refractory temporal lobe epilepsy in the with newly diagnosed and treated epilepsy. In: elderly: seizure outcome and neuropsychological Ramsay RE (ed. in Chief), Cloyd JC, Kelly KM, sequels compared with a younger cohort. Epilepsia. Leppik IE, Perucca E (editors). The neurobiology of 2006;47:1364Ð72. epilepsy and aging. New York: Elsevier; 2007. p. 43. Scheuer ML, Cohen J. Seizures and epilepsy in the 253Ð263. elderly. Neurol Clin. 1993;11:787Ð804. 62. Kellinghaus C, Loddenkemper T, Dinner DS, 44. Ruggles KH, Haessly SM, Berg RL. Prospective Lachhwani D, Luders HO. Seizure semiology in the study of seizures in the elderly in the Marshfi eld elderly: a video analysis. Epilepsia. 2004;45:263Ð7. Epidemiologic Study Area (MESA). Epilepsia. 63. Ito M, Echizenya N, Nemoto D, Kase M. A case 2001;42:1594Ð9. series of epilepsy-derived memory impairment 45. Leppik IE. Epilepsy in the elderly. Epilepsia. 2006;47 resembling Alzheimer disease. Alzheimer Dis Assoc Suppl 1:65Ð70. Disord. 2009;23:406Ð9. 46. Burn J, Dennis M, Bamford J, et al. Epileptic sei- 64. Van Cott AC. Epilepsy and EEG in the elderly. zures after a fi rst stroke: the Oxfordshire community Epilepsia. 2002;43 Suppl 3:94Ð102. stroke project. Br Med J. 1997;315:1182Ð7. 65. Seidenberg M, Pulsipher DT, Hermann B. 47. Ferro JM, Pinto F. Poststroke epilepsy: epidemiol- Association of epilepsy and comorbid conditions. ogy, pathophysiology, and management. Drugs Future Neurol. 2009;4:663Ð8. Aging. 2004;21:639Ð53. 66. Bladin CF. Seizures in the elderly. Neurology. 48. Myint PK, Staufenberg EFA, Sabanathan K. Post- 1994;44: 194Ð5. stroke seizure and post-stroke epilepsy. Postgrad 67. Jetter GM, Cavazos JE. Epilepsy in the elderly. Med. 2006;82:568Ð72. Semin Neurol. 2008;28:336Ð41. 49. So EL, Annegers JF, Hauser WA, O’Brien PC, 68. O’Donovan CA, Lancman ME, Luders HO. New- Whisnant JP. Population-based study of seizure disor- onset mesial temporal lobe epilepsy in a 90-year-old: 440 B.D. Bell and A.R. Giovagnoli

clinical and EEG features. Epilepsy Behav. patients with psychogenic nonepileptic seizures. J 2004;5:1021Ð3. Clin Exp Neuropsychol. 2011;33:335Ð43. 69. Tinuper P, Provini F, Marini C, et al. Partial epilepsy 86. Ramsay RE, Pryor F. Epilepsy in the elderly. of long duration: changing semiology with age. Neurology. 2000;55 Suppl 1:9Ð14. Epilepsia. 1996;37:162Ð4. 87. Hogh P, Smith SJ, Scahill RI, et al. Epilepsy present- 70. Gallassi R. Epileptic amnesic syndrome: an update ing as AD: neuroimaging, electroclinical features, and further considerations. Epilepsia. 2006;47 Suppl and response to treatment. Neurology. 2002;58: 2:103Ð5. 298Ð301. 71. Kapur N. Transient epileptic amnesia: a clinical 88. Drury I, Selwa LM, Schuh LA, et al. Value of inpa- update and a reformulation. J Neurol Neurosurg tient diagnostic CCTV-EEG monitoring in the Psychiatry. 1993;56:1184Ð90. elderly. Epilepsia. 1999;40:1100Ð2. 72. Mendes MHF. Transient epileptic amnesia: an under- 89. Noe KH, Drazkowski JF. Safety of long-term video- diagnosed phenomenon? Three more cases. Seizure. electroencephalographic monitoring for evaluation 2002;11:238Ð42. of epilepsy. Mayo Clin Proc. 2009;84:495Ð500. 73. Muhlert N, Milton F, Butler CR, Kapur N, Zeman 90. Veran O, Kahane P, Thomas P, Hamelin S, Sabourdy AZ. Accelerated forgetting of real-life events in C, Vercueil L. De novo epileptic confusion in the Transient Epileptic Amnesia. Neuropsychologia. elderly: a 1-year prospective study. Epilepsia. 2010;51: 2010;48:3235Ð44. 1030Ð5. 74. Theodore WH. The postictal state: effects of age and 91. Martin RC, Vogtle L, Gilliam F, Faught E. What are underlying brain dysfunction. Epilepsy Behav. the concerns of older adults living with epilepsy? 2010;19:118Ð20. Epilepsy Behav. 2005;7:297Ð300. 75. Towne AR. Epidemiology and outcomes of status 92. Ettinger AB, Baker GA. Best clinical and research epilepticus in the elderly. In: Ramsay RE (ed. in practice in epilepsy of older people: focus on Chief), Cloyd JC, Kelly KM, Leppik IE, Perucca E antiepileptic drug adherence. Epilepsy Behav. (editors). The neurobiology of epilepsy and aging. 2009;15 Suppl 1:60Ð3. New York: Elsevier; 2007. p. 111Ð127. 93. Laccheo I, Ablah E, Heinrichs R, et al. Assessment 76. Gastaut H. Classi fi cation of status epilepticus. Adv of quality of life among the elderly with epilepsy. Neurol. 1983;34:15Ð35. Epilepsy Behav. 2008;12:257Ð61. 77. Coeytaux A, Jallon P, Galobardes B, et al. Incidence 94. Glauser T, Ben-Menachem E, Bourgeois B, et al. of status epilepticus in French-speaking Switzerland: ILAE treatment guidelines: evidence-based analysis (EPISTAR). Neurology. 2000;55:693Ð7. of antiepileptic drug effi cacy and effectiveness as ini- 78. Logroscino G, Hesdorffer DC, Cascino G, et al. tial monotherapy for epileptic seizures and syn- Mortality after a fi rst episode of status epilepticus in dromes. Epilepsia. 2006;47:1094Ð120. the United States and Europe. Epilepsia. 95. Cumbo E, Ligori LD. Levetiracetam, lamotrigine, 2005;46:46Ð8. and phenobarbital in patients with epileptic seizures 79. Leppik IE. Epilepsy in the elderly: scope of the prob- and Alzheimer’s disease. Epilepsy Behav. 2010;17: lem. In: Ramsay RE (ed. in Chief), Cloyd JC, Kelly 461Ð6. KM, Leppik IE, Perucca E (editors). The neurobiol- 96. Fattouch J, Di Bonaventura C, Casciato S, et al. ogy of epilepsy and aging. New York: Elsevier; Intravenous levetiracetam as fi rst-line treatment of 2007. p. 1Ð14. status epilepticus in the elderly. Acta Neurol Scand. 80. McBride AE, Shih TT, Hirsch LJ. Video-EEG moni- 2010;121:418Ð21. toring in the elderly: a review of 94 patients. 97. Pugh MJ, Van Cott AC, Cramer JA, Knoefel JE, Epilepsia. 2002;43:165Ð9. Amuan ME, Tabares J, Ramsay RE, Berlowitz DR, 81. Kawai M, Hrachovy RA, Franklin PJ, Foreman PJ. et al. Trends in antiepileptic drug prescribing for Video-EEG monitoring in a geriatric veteran popula- older patients with new-onset epilepsy: 2000Ð2004. tion. J Clin Neurophysiol. 2007;24:429Ð32. Neurology. 2008;70:2171Ð8. 82. Drane DL, Coady EL, Williamson DJ, Miller JW, 98. Acosta I, Vale F, Tatum IV WO. Epilepsy surgery Benbadis S. Neuropsychology of psychogenic non- after age 60. Epilepsy Behav. 2008;12:324Ð5. epileptic seizures. In: Schoenberg MR, Scott JG, 99. Wiebe S, Blume WT, Girvin JP, Eliasziw M. editors. The little black book of neuropsychology: a Effectiveness and Ef fi ciency of Epilepsy Surgery for syndrome-based approach. New York: Springer; Temporal Lobe Epilepsy Study Group. A random- 2011. p. 521Ð50. ized, controlled trial of surgery for temporal-lobe 83. Duncan R, Oto M, Martin E, Pelosi A. Late onset epilepsy. N Engl J Med. 2001;345:311Ð8. psychogenic nonepileptic attacks. Neurology. 100. Costello DJ, Shields DC, Cash SS, Eskandar EN, 2006;66:1644Ð7. Cosgrove GR, Cole AJ. Consideration of epilepsy 84. Binder LM, Salinsky MC. Psychogenic nonepileptic surgery in adults should be independent of age. Clin seizures. Neuropsychol Rev. 2007;17:405Ð12. Neurol Neurosurg. 2009;111:240Ð5. 85. Locke DE, Thomas ML. Initial development of 101. Cascino GD, Sharbrough FW, Hirschorn KA, Marsh Minnesota Multiphasic Personality Inventory-2- WR. Surgery for focal epilepsy in the older patient. Restructured Form (MMPI-2-RF) scales to identify Neurology. 1991;41:1415Ð7. 26 Epilepsy and Aging 441

102. Murphy M, Smith PD, Wood M, et al. Surgery for amnestic mild cognitive impairment. Epilepsy temporal lobe epilepsy associated with mesial tem- Behav. 2006;8:161Ð8. poral sclerosis in the older patient: a long-term fol- 119. Meador KJ. Cognitive outcomes and predictive fac- low-up. Epilepsia. 2010;51:1024Ð9. tors in epilepsy. Neurology. 2002;58 Suppl 5:21Ð6. 103. Pugh MJ, Berlowitz DR, Kazis L. The impact of epi- 120. Helmstaedter C, Elger CE. Chronic temporal lobe lepsy on older veterans. In: Ramsay RE (ed. in epilepsy: a neurodevelopmental or progressively Chief), Cloyd JC, Kelly KM, Leppik IE, Perucca E dementing disease? Brain. 2009;132:2822Ð30. (editors). The neurobiology of epilepsy and aging. 121. Baxendale S, Heaney D, Thompson PJ, et al. New York: Elsevier; 2007. p. 221Ð233 Cognitive consequences of childhood-onset tempo- 104. Baker GA, Smith DF, Dewey M, Jacoby A, Chadwick ral lobe epilepsy across the adult lifespan. Neurology. DW. The initial development of a health-related 2010;75:705Ð11. quality of life model as an outcome measure in epi- 122. Baxendale S, Thompson P. Beyond localization: the lepsy. Epilepsy Res. 1993;16:65Ð81. role of traditional neuropsychological tests in an age 105. Morrison JH, Hof PR. Life and death of neurons in of imaging. Epilepsia. 2010;51:2225Ð30. the aging cerebral cortex. In: Ramsay RE (ed. in 123. Jamora CW, Ruff RM, Connor BB. Geriatric neu- Chief), Cloyd JC, Kelly KM, Leppik IE, Perucca E ropsychology: implications for front line clinicians. (editors). The neurobiology of epilepsy and aging. NeuroRehabilitation. 2008;23:381Ð94. New York: Elsevier; 2007. p. 41Ð57 124. Potter GG, Attix DK. An integrated model for geri- 106. de Boer HM. Epilepsy stigma: moving from a global atric neuropsychological assessment. In: Attix DK, problem to global solutions. Seizure. 2010;19: 630Ð6. Welsh-Bohmer KA, editors. Geriatric neuropsychol- 107. Kobau R, DiIorio CA, Anderson LA, Price PH. ogy: assessment and intervention. New York: Further validation and reliability testing of the Guilford; 2006. p. 5Ð26. Attitudes and Beliefs about Living with Epilepsy 125. American Academy of Neurology, American Epilepsy (ABLE) components of the CDC Epilepsy Program Society and Epilepsy Society, Epilepsy Foundation of Instrument on Stigma. Epilepsy Behav. 2006; America. Consensus statement, sample statutory provi- 8:552Ð9. sions and model regulations regarding driver licensing 108. www.epilepsyfoundation.org/living/seniors . and epilepsy. Epilepsia. 1994;35:696Ð705. 109. Giovagnoli AR, Meneses RF, da Silva AM. The con- 126. Drazkowski J. An overview of epilepsy and driving. tribution of spirituality to quality of life in focal epi- Epilepsia. 2007;48 Suppl 9:10Ð2. lepsy. Epilepsy Behav. 2006;9:133Ð9. 127. Reger MA, Welsh RK, Watson GS, et al. The rela- 110. Depp CA, Jeste DV. De fi nitions and predictors of tionship between neuropsychological functioning successful aging: a comprehensive review of larger and driving ability in dementia: a meta-analysis. quantitative studies. Am J Geriatr Psychiatry. Neuropsychology. 2004;18:85Ð93. 2006;14:6Ð20. 128. Loring DW, Lowenstein DH, Barbaro NM, et al. 111. Suurmeijer TP, Reuvekamp MF, Aldenkamp BP. Common data elements in epilepsy research: devel- Social functioning, psychological functioning, and opment and implementation of the NINDS epilepsy quality of life in epilepsy. Epilepsia. 2001;42:1160Ð8. CDE project. Epilepsia. 2011;52(6):1186Ð91. 112. Vahia IV, Depp CA, Palmer BW, et al. Correlates of 129. http://www.commondataelements.ninds.nih.gov/ spirituality in older women. Aging Ment Health. Epilepsy.aspx . 2010;4:1Ð6. 130. Loring DW. Material, modality, or method? 113. Hermann BP, Seidenberg M, Bell B. Psychiatric Manageable modernization of measurement. comorbidity in chronic epilepsy: identifi cation, con- Epilepsia. 2010;51:2364Ð5. sequences, and treatment of major depression. 131. Herrmann DJ. Know thy memory: the use of ques- Epilepsia. 2000;41 Suppl 2:31Ð41. tionnaires to assess and study memory. Psychol Bull. 114. Kramer G. Broadening the perspective: treating the 1982;92:434Ð52. whole patient. Epilepsia. 2003;44 Suppl 5:16Ð22. 132. Hall K, Isaac CL, Harris P. Memory complaints in 115. Jones JE, Hermann BP, Barry JJ, Gilliam FG, Kanner epilepsy: an accurate refl ection of memory impair- AM, Meador KJ. Rates and risk factors for suicide, ment or an indicator of poor adjustment? A review of suicidal ideation, and suicide attempts in chronic the literature. Clin Psychol Rev. 2009;29:354Ð67. epilepsy. Epilepsy Behav. 2003;4 Suppl 3:31Ð8. 133. www.epilepsyfoundation.org . 116. Butterbaugh G, Rose M, Thomson J, et al. Mental 134. www.epilepsy.com . health symptoms in partial epilepsy. Arch Clin 135. www.epilepsy.org.uk . Neuropsychol. 2005;20:647Ð54. 136. Loring DW, Hermann BP, Cohen MJ. 117. Giovagnoli AR. Characteristics of verbal semantic Neuropsychology advocacy and epilepsy. Clin impairment in left hemisphere epilepsy. Neuropsychol. 2010;24:417Ð28. Neuropsychology. 2005;19:501Ð8. 137. Peltola M, Kaukinen K, Dastidar P, et al. Hippocampal 118. Grif fi th HR, Martin RC, Bambara JK, Marson DC, sclerosis in refractory temporal lobe epilepsy is Faught E. Older adults with epilepsy demonstrate associated with gluten sensitivity. J Neurol Neurosurg cognitive impairments compared with patients with Psychiatry. 2009;80:626Ð30. Neuropsychological Assessment of Older Adults with a History 2 7 of Cancer

Mariana E. Witgert and Jeffrey S. Wefel

Abstract Older adults are at increased risk for developing cancer. Given the aging population, the incidence of cancer is predicted to rise and, as a result, cancer is likely to become an even greater public health concern. Anticancer therapies can have potential untoward impacts on cognitive functioning, which is of particular concern for aging individuals that are already at increased risk for cognitive decline. This chapter reviews the potential cognitive side effects varies of cancer therapies and presents the most common considerations for differential diagnosis of memory complaints in this population. Instructive case examples are provided along with clinical pearls for the neuropsychologist working with older adults in an oncology setting.

Keywords Neuropsychological assessment ¥ Cancer ¥ Cognition ¥ Older adults

Adults over the age of 65 have a 9.6 times greater predicts a rapid rise in the number of individuals risk of cancer diagnosis and 17.4 times greater in the United States who are over the age of 65. risk of cancer-related mortality [ 1 ] . In fact, it is In 2010, it was estimated that there were 40.2 estimated that 54.2% of cancer incidence and million people aged 65 or older; this number is 69.5% of cancer-related mortality occur in indi- projected to rise to 88.5 million by the year 2050 viduals aged 65 or older. The US Census Bureau [2 ] . As a result, cancer is likely to become an even greater public health concern. Signiﬁ cant advances have been made in multimodal drug therapy and have resulted in increased success in M. E. Witgert , Ph.D. () ¥ J. S. Wefel, Ph.D. the management of many cancers. However, Section of Neuropsychology, Department since many anticancer therapies are not highly of Neuro-Oncology , University of Texas M.D. Anderson speciﬁ c, healthy tissues are also placed at risk. Cancer Center , 1515 Holcombe Blvd, Unit 431 , Houston , This can have potential untoward impacts on cog- TX 77030-4009 , USA e-mail: [email protected] ; nitive functioning, which may be of particular [email protected] importance for an aging population whose

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 443 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_27, © Springer Science+Business Media, LLC 2013 444 M.E. Witgert and J.S. Wefel members are at increased risk for cognitive Treatment-Related Cognitive decline and toxicities related to cancer therapies. Impairment

Cancer-Related Cognitive Impairment In addition to the potential for cognitive impairment related to cancer itself, cancer therapies, including surgery, radiation, chemotherapy, In order to determine whether or not cancer immunotherapy, and hormonal therapy, may have therapies impact cognitive functioning, one must an untoward impact on cognitive functioning. fi rst understand the presence and pattern of cognitive symptoms prior to the initiation of treatment. Patients with brain tumors may present Surgery with a variety of cognitive complaints as tumors destroy, crowd, and in fi ltrate brain tissue; the Undergoing surgery and associated exposure to nature and severity of cognitive impairments anesthesia may carry differential risk for older vary in association with lesion location and patients, who appear to be more vulnerable to lesion momentum, or the rate at which tumors developing postoperative cognitive dysfunction, grow. Cancer-related cognitive dysfunction is or POCD, affecting memory, attention and con- not limited to central nervous system (CNS) can- centration, and speed of processing [ 9 ] . We are cers. Several studies have demonstrated cancer- not aware of any data to suggest that the surgical related cognitive dysfunction in non-CNS resection of non-CNS cancers carries any greater cancers as well. For example, cognitive dysfunc- risk than other non-CNS surgeries. However, in tion in at least a subgroup of women with breast patients with brain tumors, surgery may result in cancer has been demonstrated prior to initiation damage to normal tissue that surrounds the tumor. of chemotherapy, with estimates ranging from This can engender relatively focal cognitive 11% to 35% of patients [ 3Ð 6 ] . The fi rst of these impairments or more diffuse impairments sec- studies revealed particularly frequent diffi culties ondary to the disconnection of subcortical (18Ð25%) on measures assessing learning and networks. memory [ 3] . Pretreatment cognitive dysfunction has also been found in other patient populations, including acute myelogenous leukemia (AML) Radiation and myelodysplastic syndrome (MDS), with pretreatment impairments in learning and mem- It is well known that radiation to the brain may be ory (41Ð44%), cognitive processing speed (28%), associated with the development of neuropsycho- aspects of executive dysfunction (29%), and logical dysfunction both during and after treat- upper extremity fi ne motor dexterity (37%) [ 7 ] . ment. The acute phase (during treatment) is Patients with small cell lung cancer have also characterized by transient symptoms of head- been shown to exhibit pretreatment cognitive ache, fatigue, fever, and nausea, as well as exac- impairments. Meyers et al. [ 8] demonstrated that erbation of preexisting neurologic defi cits. Early 70Ð80% of patients with small cell lung cancer delayed toxicity typically develops 2Ð5 months exhibited memory defi cits, 38% had defi cits in after completion of radiotherapy and has been executive functions, and 33% showed impaired associated with declines in information process- motor coordination before treatment was initi- ing speed, attention, learning ef fi ciency and ated. Without a clear understanding of the pre- memory retrieval, executive functioning, and fi ne treatment cognitive status, impairments in motor dexterity; these symptoms may resolve cognition that are observed posttreatment could spontaneously. Late-delayed toxicity can occur be erroneously attributed to a specifi c treatment, months to years after completion of radiation when in fact they might have been associated therapy and includes progressive dementia, with the cancer itself. 27 Neuropsychological Assessment of Older Adults with a History of Cancer 445 personality changes, and leukoencephalopathy; chemotherapy [ 21] , which may be of particular unlike acute and early delayed effects, late- concern for older individuals who are already at delayed toxicity tends to be irreversible [ 10 ] . increased risk for cognitive decline secondary to Numerous risk factors for developing radiation- noncancer-related factors [21 ] . induced cognitive dysfunction and necrosis have Cognitive and emotional dysfunction associ- been identi fi ed and include age over 60 years, ated with hematopoietic stem cell transplant greater than 2 Gy dose per fraction, higher total (HSCT) has also been reported by a number of dose, greater total volume of brain irradiated, investigators and is thought to result from the hyperfractionated schedules, shorter overall treat- intense treatment regimen utilizing high-dose ment time, concomitant or subsequent treatment chemotherapy and total-body irradiation during with chemotherapy, and the presence of comorbid pre-transplant conditioning [22, 23 ] . Studies in vascular risk factors [ 11, 12 ] . Current practice this group of patients are limited by small sample utilizes lower doses of radiation in an attempt to size and cross-sectional designs; however, the reduce exposure of the surrounding healthy brain available prospective neuropsychological assess- tissue. Continued advances in treatment modali- ment data suggest a decline in executive func- ties (i.e., intensity modulated radiation therapy, tions [ 23 ] and memory [24 ] following HSCT. whole brain radiation with hippocampal sparing, and proton therapy) should further improve the therapeutic ratio and limit incidental brain irra- Biological Response Modifi ers diation, thereby minimizing associated neurobehavioral complications. The risks and benefi ts of Biological response modifi ers (BRMs; also focal versus whole brain radiation are still being known as immunotherapies) are aimed at modi- debated, but it has been shown that patients with fying the immune response of cancer patients in 1Ð3 newly diagnosed brain metastases treated hopes of yielding a therapeutic effect [25 ] . Such with stereotactic radiosurgery plus whole brain agents include a wide variety of treatments, radiation were at increased risk of signi fi cant including cytokines, vaccines, monoclonal anti- declines in learning and memory at 4 months bodies, thymic factors, and colony-stimulating after treatment compared to those treated with factors [26 ] . In normal, healthy controls, a single stereotactic radiosurgery alone [13 ] . The most dose of only 1.5 million international units of the profound effects of radiation treatment may not cytokine interferon alpha (IFN-alpha) worsened be evident for several years posttreatment. reaction time at 6 and 10 h after injection. When Therefore, careful monitoring of cognitive func- used as a treatment for cancers such as chronic tion in patients over time remains necessary. myelogenous leukemia and melanoma, IFN- alpha is delivered at much higher doses for longer periods of time. Posttreatment cognitive impair- Chemotherapy ments have been documented on measures of memory, psychomotor speed, and executive func- The majority of research regarding chemotherapy- tioning, especially when used in combination related side effects has been conducted in patients with chemotherapy [ 27, 28 ] . In addition, IFN- with breast cancer; cognitive dysfunction has most alpha has been associated with depression [ 29 ] frequently been observed in learning and memory, and the so-called dysphoric mania, characterized attention, executive function, and processing by extreme irritability or agitation that is often speed, with estimates of dysfunction ranging from accompanied by poor insight and does not 13% to 70% [ 4, 5, 14Ð 20 ] . Posttreatment follow- respond to treatment with antidepressants [30 ] . up has revealed that a subset of these women fails Although antidepressants may be used prophy- to achieve complete recovery [20 ] . More recent lactically for symptom prevention/reduction in studies have also raised concern for ongoing, some patients, pretreatment screening in combi- progressive cognitive decline after completion of nation with close serial monitoring of a patient’s 446 M.E. Witgert and J.S. Wefel mood may help avoid unnecessary medications consolidation processes [36 ] . These impairments and potential side effects [30, 31 ] . typically manifest in complaints of diffi culty with short term memory, such as forgetting the details of recent conversations and events as well as mis- Hormonal Therapies placing possessions. They also frequently describe problems with sustained attention, organization, Estrogen and testosterone have been found to and multitasking. impact cognitive functioning [32, 33 ] , and treatments affecting these hormones are commonly used in the care of breast and prostate cancer patients. Cancer in Older Adults Studies in breast cancer have investigated both selective estrogen receptor modulators (SERMs) Prognosis appears to worsen with age for some such as tamoxifen (TAM) and aromatase inhibi- cancers such as acute myeloid leukemia and non- tors such as anastrozole or exemestane. Patients Hodgkin’s lymphoma. In contrast, older age is receiving TAM, anastrozole, or a combination associated with more favorable tumor biology in of those therapies performed more poorly than breast cancers. In non-small cell lung cancer noncancer controls on measures of memory and (NSCLC), research has found no impact or a processing speed [ 23 ] . One year of treatment favorable impact of age on prognosis. It appears with TAM was associated with declines in that overall, prognosis is impacted more by char- memory and executive functioning, whereas no acteristics of the tumor than by age [ 37 ] . Despite such decline was observed in patients treated this, older adults are generally less likely to be with exemestane [34 ] . included in clinical trials, despite an equal will- In prostate cancer, LHRH agonists such as ingness to participate in trials when offered, and leuprolide and goserelin have been found to be this appears to potentially be due to age bias and associated with alterations in visuospatial pro- toxicity concerns [ 38 ] . Indeed, older adults are cessing, including visual memory, and executive more likely to have comorbid conditions which functioning, with contradictory fi ndings with may make them more vulnerable to treatment- regard to verbal memory performance [33 ] . While related toxicity [ 39] . Age is associated with group analyses of mean change often fail to dem- reduced renal function and bone marrow reserves, onstrate a statistically signifi cant effect, reliable as well as increased anemia, which could change index based analyses have demonstrated infl uence the way chemotherapies are tolerated cognitive decline in up to 50% of men treated [37 ] As a result of comorbid conditions and with an LHRH agonist [35 ] . greater toxicities, older patients are less likely to receive optimal doses of chemotherapy [40, 41 ] . Although concerns regarding increased risk of toxicity should not be dismissed, it has been dem- Cognitive Profi le Associated with onstrated that older adults do benefi t from cancer Cancer Therapy treatment. In a recent study, patients aged 70 years or older with newly diagnosed glioblastoma and The cognitive de fi cits associated with brain tumors a poor performance status treated with chemo- are often specifi c to lesion location; however, the therapy (temozolomide) alone were found to pattern of treatment-related cognitive decline have an acceptable toxicity pro fi le and increased tends to be suggestive of frontal-subcortical dys- survival as compared to supportive care, and an function. This pattern includes impairments in improvement in functional status was observed in executive functioning, speed of processing, and 30% of cases [ 42 ] . Studies using a combination speeded motor coordination, as well as of chemotherapy (temozolomide) and radiation inef fi ciencies in learning and memory retrieval in therapy have also revealed a survival benefi t and the context of relatively well-preserved memory acceptable rates of toxicity in adults over the age 27 Neuropsychological Assessment of Older Adults with a History of Cancer 447 of 65 [ 43, 44] . This suggests that more studies studies investigating cognition in cancer patients should consider inclusion of older adults. that were identifi ed in a recent literature review It has been suggested that evaluation of comorbid included patients whose mean or median age was conditions is a more appropriate surrogate for life 65 or above; of these, 27% utilized the MMSE as expectancy than chronological age and should be a measure of cognitive status [46 ] . taken into consideration over and above age when Data available from the limited number of stud- making treatment decisions for older adults [ 39 ] . ies that have investigated the presence and pattern The European Organization for Research and of cancer and cancer treatment-related cognitive Treatment of Cancer (EORTC) elderly task force symptoms in older adults suggest that, similar to recommends design of specifi c trials for older younger adults, a subset of older adult cancer patients, with separate trials for those patients con- patients exhibits cognitive impairment prior to the sidered fi t, vulnerable, and frail. The task force also initiation of treatment. For example, in older men advocates for inclusion of geriatric assessment in diagnosed with prostate cancer, 45% scored ³ 1.5 clinical trials, such as the Comprehensive Geriatric standard deviations below the normative mean on Assessment (CGA), which evaluates functional, at least two neuropsychological tests prior to nutritional, and mental status, as well as the pres- beginning androgen ablation therapy [47 ] . ence of comorbid conditions, use of associated Posttreatment cognitive changes have also been pharmacologic interventions, and the individual’s documented in older adults. In one of the few pro- level of social support. In addition, the task force spective studies focusing on chemotherapy-related suggested consideration of “elderly-specifi c” out- cognitive dysfunction in older adults, patients aged comes, such as functional independence, time to 65Ð84 with a diagnosis of breast cancer underwent progression, or a combination of effi cacy and tox- neuropsychological and geriatric assessment prior icity, as well as close monitoring and early inter- to the initiation of chemotherapy and 6 months vention for toxicities to which older adults are more after treatment. Consistent with research per- vulnerable, including myelotoxicity, anemia, formed in younger women, results revealed a sub- mucositis, diarrhea, and dehydration [ 37 ] . set of patients who demonstrated posttreatment cognitive decline, most often in the domains of memory, psychomotor speed, and attention [ 6 ] . Cognition in Older Adults with a A more recent study found that breast cancer History of Cancer patients in the older age group (60Ð70) performed more poorly on a measure of processing speed While the above data regarding the ability of than younger patients or healthy controls [48 ] . older adults to tolerate and benefi t from cancer Hormonal therapies also appear to impact therapies is promising, it is noted that those stud- older adults in a manner similar to that observed ies did not include formal measures of cognitive in younger adults. Older women ( ³65) treated functioning. Few studies have investigated the with TAM were found to perform signifi cantly impact of cancer and cancer therapies on cogni- worse than healthy controls on measures of tion in older adults, despite the higher incidence memory and information processing speed [ 34 ] . of cancer diagnosis and potential increased risk In older men treated with LHRH agonists for of treatment-related morbidity in that population. prostate cancer, patients who scored in the aver- The majority of studies investigating the impact age range or above on cognitive tests at baseline of chemotherapy on cognition in patients with displayed improvements in visuospatial plan- breast cancer have been performed in younger ning and phonemic fl uency posttreatment; those women, despite the fact that the majority of breast who performed below expectation at baseline cancers occur in women over the age of 65 and displayed no signifi cant change in cognition. It aging is the number one risk factor for breast can- was hypothesized that this lack of improvement cer [45 ] . This tendency to focus on younger adults (presumably due to practice effects) may in and is prevalent across cancer types; only 17% of of itself be representative of impairment [ 47 ] . 448 M.E. Witgert and J.S. Wefel

at least 6Ð12 months following radiation [ 54 ] . Cancer and Dementia Severe dementia requiring full-time caregiving was documented in 10% of anaplastic glioma It has been suggested that there may be a link patients treated with accelerated radiotherapy between cancer and the development of demen- followed by chemotherapy [ 55 ] . tia, particularly Alzheimer’s disease (AD). This concern was raised in a retrospective study of Swedish twin pairs discordant for cancer his- Neuropsychological Assessment of tory, which reported that twins with a history of Older Adults with a History of Cancer cancer were more likely to be classifi ed as cognitively impaired based on a telephone mental Occasionally, older adults are referred for neu- status screening measure [ 49 ] . However, as was ropsychological evaluation prior to undergoing highlighted in an editorial response to that cancer treatment to help with decision making study, screening measures are inadequate to regarding appropriate therapies. Most commonly, make such a conclusion. Further, there was no patients are referred during or after their cancer statistically signifi cant difference in the rate of treatment with complaints of memory loss. Some clinician-determined dementia between twins of the most common considerations for differen- with and without a history of cancer [ 50 ] . tial diagnosis are listed in Table 27.1 ; in addition Results of a more recent study indicate that in to the untoward impact of cancer and cancer White older adults, AD is actually associated treatments or metastatic disease, alternative etio- with a reduced risk of cancer and that a history logical considerations include those seen in older of cancer is associated with a reduced risk of adults without a history of cancer, such as neuro- AD [51 ] . It was suggested by another investiga- degenerative dementias, potentially reversible tor that this fi nding might re fl ect underdiagno- metabolic or electrolyte imbalances, and cogni- sis of cancer in AD patients [ 52 ] ; however, the tive change secondary to mood disturbance. same study that found a reduced risk of cancer Baseline evaluations of neuropsychological in AD patients found no association between functioning allow for the identifi cation of even cancer and vascular dementia, and the authors subtle treatment-related neurotoxicities; such point out that underdiagnosis, if present, would information can prevent misclassifi cation of be just as likely to exist in this patient group as patients who do experience clinically and func- in AD patients [ 51 ] . A longitudinal study tionally meaningful declines in cognitive func- confi rmed a slower rate of cancer development tion but continue to perform within normal limits in individuals with a preexisting diagnosis of AD; the authors hypothesize that this may re fl ect a protective relationship between the two Table 27.1 Common etiologies for memory loss in older conditions or that they may share a common adult patients with a history of cancer biological mechanism which affects the vulner- Cancer- and treatment-related toxicity ability of cells to apoptosis, which is excessive Brain metastases in AD and may be insuffi cient in cancer [ 53 ] . It Dementia including is noted that these studies included cancers of Cerebrovascular disease all types; patients with cancer requiring radiation Alzheimer’s disease to the brain should be considered separately, as Lewy body dementia they are at an increased risk of treatment-related Frontotemporal dementia dementia. As noted above, in patients who Potentially reversible conditions including have been treated with whole brain radiation B12 de fi ciency (WBRT), late effects of treatment are of concern, Thyroid abnormalities and progressive dementia secondary to WBRT Electrolyte abnormalities is more likely to emerge in patients who survive Complications of mood disturbance and fatigue 27 Neuropsychological Assessment of Older Adults with a History of Cancer 449 relative to normative standards. For example, in a perceived prior to initiation of treatment and are prospective, longitudinal study, Wefel et al. [ 20 ] exacerbated during treatment. found that classifying posttreatment cognitive Appropriate neuropsychological assessment performance as impaired using a conventional of patients with cancer includes careful selection classifi cation criterion (e.g., 1.5 SDs below the of reliable and valid measures that are sensitive to normative mean), without consideration of their subtle changes in functioning and are robust to pretreatment baseline level of performance, practice effects [36 ] . In this patient population, resulted in false-negative classi fi cation errors there is often a heavy emphasis on tests assessing approximately 50% of the time. While baseline frontal-subcortical network functioning. Addi- cognitive evaluation is critical for research, it is tional test selection may vary in association with rarely available as a point of comparison for cli- cancer diagnosis; for example, tests of visu- nicians, who are most often asked to address ospatial functioning are likely less sensitive to referral questions in the absence of baseline data treatment-related cognitive decline in women and in the aftermath of cancer and cancer treat- with breast cancer, but may be critical in the ment. Thus, as with any evaluation, one must assessment of treatment-related cognitive decline conduct a thorough interview investigating the in men with prostate cancer. Similarly, test selec- premorbid level of functioning, including infor- tion for patients with brain tumors may vary mation regarding educational and occupational somewhat depending on lesion location. attainment and any developmentally-based weak- In addition to the above considerations, a thor- nesses, as well as the use of neuropsychological ough neuropsychological examination includes tests to estimate premorbid functioning. an assessment of fatigue and affective distress, Information regarding medical comorbidities which can have an untoward impact on cognitive and the type of cancer treatment received should performance, particularly with regard to aspects also be obtained during the clinical interview, and of attention and memory. It is important to note can be of particular importance when the obtained that in cancer patients, self-report of cognitive cognitive pro fi le and clinical correlates, such as complaints has been shown to correlate more imaging studies, may be ambiguous. For example, strongly with fatigue and mood disturbance than a patient’s cognitive performance may reveal a pat- with objective evidence of cognitive dysfunction, tern suggestive of frontal-subcortical dysfunction, as assessed by standardized neuropsychological and imaging studies might reveal white matter tests [56 ] . Thus, a thorough assessment may be changes, which could be secondary to vascular dis- needed to elucidate whether perceived diffi culties ease or may re fl ect leukoencephalopathy second- are secondary to cancer- and treatment-related ary to treatment with certain cancer treatments such cognitive dysfunction and/or affective distress as methotrexate. Knowledge regarding the pres- and fatigue. ence or absence of risk factors for cerebrovascular disease and the type of cancer therapy utilized may therefore elucidate the underlying etiology of Case Examples observed cognitive impairments. The clinician should also determine the onset and course of cog- Ms. A, Ms. B, and Ms. C are college-educated nitive symptoms, and how that timeline relates to women in their mid-70s who have a history of cancer diagnosis and treatment. In the most straight- breast cancer and were treated with standard dose forward case, patients and their family members adjuvant chemotherapy including fl uorouracil, are likely to describe cognitive diffi culties that had Adriamycin, and cyclophosphamide. All three onset during treatment or became noticeable shortly women presented with similar complaints, namely thereafter, when the patient was presented with problems with recent memory characterized by increased cognitive challenges. These dif fi culties dif fi culty remembering recent conversations, for- are often described as nonprogressive. Greater getting to pay bills, and diffi culty with medica- challenges arise when cognitive problems are tion management. Ms. C and her family members 450 M.E. Witgert and J.S. Wefel also described word-fi nding diffi culty. As a result recent onset and, per her family’s report, had of these complaints, the women were referred for been gradually progressive. This was worrisome evaluation of their cognitive functioning in an for a neurodegenerative process. The patient effort to determine whether cognitive symptoms was therefore referred to neurology for a further refl ected the impact of cancer and associated diagnostic work-up. treatment or whether there was concern for an additional neurodegenerative process. Neuropsychological evaluation of Ms. A Preventing Cognitive Sequelae revealed a pattern consistent with frontal-subcor- of Cancer and Cancer Therapy tical dysfunction and characterized by mild impairments in memory retrieval (in the context Risk factors for treatment-related cognitive dys- of intact memory consolidation processes), work- function (i.e., high dose, agent, and schedule of ing memory, and bilateral fi ne motor dexterity. administration) can be adjusted to reduce neuro- The latter impairments were believed to refl ect toxicity while maintaining adequate disease con- her peripheral neuropathy, which is commonly trol [ 57, 58] . Pharmacologic interventions targeted associated with the chemotherapies she received. at specifi c underlying mechanisms of some neu- The observed pattern of performance, and the rotoxic side effects have also been investigated; it fact that her reported functional dif fi culties had remains unclear whether these interventions are onset during her chemotherapy and developed differentially effective for older versus younger simultaneously with her peripheral neuropathy, is patients. Psychostimulant medications have been consistent with the untoward impact of her breast shown to be effective in addressing fatigue and cancer and cancer treatment. cognitive dysfunction in cancer patients. A com- Ms. B’s cognitive profi le was very similar to monly used psychostimulant is methylphenidate, that of Ms. A’s; however, in Ms. B’s case, the eti- which has been found to be benefi cial in reducing ology of her cognitive impairments is less clear, fatigue in non-CNS cancer patients [ 59Ð 61] . In as her medical history was also notable for numer- patients with primary brain tumors, methylpheni- ous cerebrovascular risk factors, including hyper- date has been effective in combating cognitive tension, hypercholesterolemia, and a previous symptoms associated with treatment-related fron- transient ischemic attack. Thus, it is possible that tal-subcortical dysfunction, such that patients the observed cognitive impairments result from demonstrated signifi cant improvements in mem- cerebrovascular disease, her cancer and chemo- ory, psychomotor speed, visual-motor function, therapy, or from a combined effect of vascular executive function, and fi ne motor speed [ 62 ] . burden and treatment effect. Patients with cardiovascular diseases may not be Finally, Ms. C’s neuropsychological evalua- ideal candidates for this medication, as stimulants tion revealed moderate to severe impairments in have been associated with increased blood pres- learning and memory, with little to no bene fi t sure and elevated heart rate. As with patients of all from the provision of retrieval cues. In addition, ages, medical comorbidities must be taken into she evidenced disorientation, dysnomia, and account when considering the appropriateness of impairments in processing speed and visuocon- this and other pharmacological interventions. struction. Basic attention span and reasoning Other medications that have been used in oncol- skills remained relatively preserved. The sever- ogy populations include moda fi nil to alleviate ity and pattern of the observed diffi culties fatigue and donepezil to combat diffi culties with exceeded that which might be expected second- cancer-related fatigue, attention, and memory ary to breast cancer and associated treatment [63 ] . The use of high-dose vitamin E has been alone; in addition, it was noted that while her shown to be bene fi cial in patients with nasopha- cancer diagnosis and treatment were quite ryngeal carcinoma who had imaging evidence of remote, her cognitive diffi culties had more unilateral or bilateral temporal lobe necrosis, such 27 Neuropsychological Assessment of Older Adults with a History of Cancer 451 that patients who were treated with vitamin E specialists, was found to improve community demonstrated greater improvement on measures independence and employment outcomes in brain of learning, memory, and cognitive fl exibility than tumor patients at a signi fi cantly lower cost and nontreated controls [64 ] . shorter treatment length than was typical of survi- Animal studies have identi fi ed additional vors of traumatic brain injury who took part in the potential pharmacologic interventions. For exam- same program [72 ] . Training in the use of compen- ple, the severe memory impairment observed in satory strategies and attention retraining has also rats treated with chemotherapy was fully prevented shown promise in addressing both cognitive by supplementation with an antioxidant, N -acetyl complaints and mental fatigue [73 ] . Compensatory cysteine [65 ] . Similarly, administration of the tools might include external memory aids such as peroxisomal proliferator-activated receptor-g memory notebooks, user-programmable paging agonist pioglitazone prevented memory distur- systems, and medication reminder systems to bance associated with whole brain irradiation in assist neurologically impaired patients compen- rats [66 ] . Radiation-induced memory loss was also sate for dif fi culties with forgetfulness. Older attenuated via transplantation of human embry- adults, particularly those with multiple comorbidi- onic stem cells into the rat hippocampus [67 ] . ties, may require adjustments to their environment In addition to making adjustments to primary and increased support to make certain that demands treatments and using pharmacological inter- do not exceed capacity while maintaining safety ventions to combat cognitive ineffi ciencies and and ensuring treatment compliance. fatigue, goal-focused compensatory interventions and behavioral strategies may be useful in minimizing the impact of neurobehavioral symptoms Summary on daily life in patients with cancer. Physical exercise has been linked to improvements in at Older adults are at increased risk for developing least some aspects of cognitive functioning in cancer, thus the incidence of cancer is predicted patients with mild cognitive impairment and to increase with an aging population [ 1 , 2 ] . Alzheimer’s disease [68, 69 ] and has been associ- Despite the possibility of treatment-related ated with increased patient self-reported quality cognitive declines for some patients, these treat- of life, including cognitive functioning, in cancer ments remain a critical component in the man- patients [70 ] . Animal studies provide support for agement and eradication of many cancers. Thus, exercise as a protective factor against cancer the potential side effects of these therapies must treatment-related cognitive side effects; daily be considered in the context of the overall health running after WBRT prevented declines in spatial benefi t they provide. Continued research into the memory in mice [ 71] . Further studies are needed mechanisms of treatment-related cognitive dys- with regard to physical activity as an intervention function may afford opportunities for the devel- against cognitive dysfunction in human cancer opment of neuroprotective therapies, effective patients. adjuvant supportive pharmacotherapies, or Knowledge gained from traditional rehabilita- modi fi cation of primary treatments. Advances in tion disciplines treating survivors of traumatic behavioral interventions will help minimize the brain injury or stroke has yielded important infor- impact of cancer and cancer therapy on cognitive mation regarding evidenced-based compensatory function, mood, quality of life, and functional strategies that may be applicable to patients with abilities. It appears that older adults can benefi t cancer-related cognitive dysfunction. Such multi- from cancer treatments; as with younger adults, disciplinary therapeutic interventions, provided by medical comorbidities, cognitive status, and a team of psychologists, speech/language pathol- social support are important clinical consider- ogists, occupational therapists, and vocational ations. To date, older adults have often been 452 M.E. Witgert and J.S. Wefel excluded from studies investigating the impact of treatment-related cognitive decline in maxi- cancer and cancer therapies on cognitive func- mizing their daily functioning. tioning, and more research is needed to determine whether older adults are differentially affected. References

Clinical Pearls 1. Altekruse SF, et al., editors. SEER Cancer Statistics Review, 1975Ð2007. Bethesda, MD: N.C. Institute; 2010. ¥ Cognitive changes can result from CNS and 2. Vincent GK, Velkoff VA. The next four decades, the non-CNS cancers, even prior to the initiation older population in the United States: 2010 to 2050. of treatment. Current Population Reports. Washington, DC: U.S.C. Bureau; 2010. p. P25Ð1138. ¥ Treatment-related cognitive changes may 3. Wefel JS, et al. ‘Chemobrain’ in breast carcinoma? result from surgical intervention, radiation, A prologue. Cancer. 2004;101(3):466Ð75. chemotherapy, immunotherapy, and hormonal 4. Hermelink K, et al. Cognitive function during neoad- therapy. juvant chemotherapy for breast cancer: results of a prospective, multicenter, longitudinal study. Cancer. ¥ Treatment-related cognitive declines most 2007;109(9):1905Ð13. often occur during or immediately after sur- 5. Schagen SB, et al. Change in cognitive function after gery, chemotherapy, and hormonal therapy. In chemotherapy: a prospective longitudinal study in contrast, late-onset cognitive decline can breast cancer patients. J Natl Cancer Inst. 2006;98(23): 1742Ð5. occur, and is more likely to be progressive, 6. Hurria A, et al. Cognitive function of older patients after treatment with radiation. receiving adjuvant chemotherapy for breast cancer: a ¥ The neuropsychological pro fi le of treatment- pilot prospective longitudinal study. J Am Geriatr related cognitive decline often suggests fron- Soc. 2006;54(6):925Ð31. 7. Meyers CA, Albitar M, Estey E. Cognitive impair- tal-subcortical dysfunction. ment, fatigue, and cytokine levels in patients with ¥ Screening measures such as the MMSE are acute myelogenous leukemia or myelodysplastic syn- insuf fi cient to detect the subtle cognitive drome. Cancer. 2005;104(4):788Ð93. changes often associated with cancer and can- 8. Meyers CA, Byrne KS, Komaki R. Cognitive de fi cits in patients with small cell lung cancer before and after cer treatment. chemotherapy. Lung Cancer. 1995;12(3):231Ð5. ¥ Neuropsychological assessment should 9. Newman S, et al. Postoperative cognitive dysfunction include measures that are sensitive to frontal- after noncardiac surgery: a systematic review. subcortical network dysfunction; test selection Anesthesiology. 2007;106(3):572Ð90. 10. Sheline GE, Wara WM, Smith V. Therapeutic irradia- may vary depending on cancer type and tion and brain injury. Int J Radiat Oncol Biol Phys. location. 1980;6(9):1215Ð28. ¥ Older adults have additional risk of cognitive 11. Crossen JR, et al. Neurobehavioral sequelae of cranial impairment, as age independently increases irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol. 1994;12(3):627Ð42. risk and they are also more likely to have 12. Lee AW, et al. Factors affecting risk of symptomatic comorbid conditions that may have an untow- temporal lobe necrosis: signi fi cance of fractional dose ard effect on cognition. and treatment time. Int J Radiat Oncol Biol Phys. ¥ Older adults with a history of cancer do not 2002;53(1):75Ð85. 13. Chang EL, et al. Neurocognition in patients with brain appear to be at increased risk for the develop- metastases treated with radiosurgery or radiosurgery ment of Alzheimer’s disease, though AD and plus whole-brain irradiation: a randomised controlled cancer can exist as comorbid conditions. trial. Lancet Oncol. 2009;10(11):1037Ð44. ¥ Few pharmacologic interventions for cancer 14. Ahles TA, et al. Neuropsychologic impact of standard-dose systemic chemotherapy in long-term treatment-related cognitive impairment have survivors of breast cancer and lymphoma. J Clin been identi fi ed to date. The use of compensa- Oncol. 2002;20(2):485Ð93. tory strategies is often the most effective inter- 15. Brezden CB, et al. Cognitive function in breast cancer vention to assist individuals with cancer patients receiving adjuvant chemotherapy. J Clin Oncol. 2000;18(14):2695Ð701. 27 Neuropsychological Assessment of Older Adults with a History of Cancer 453

16. Schagen SB, et al. Late effects of adjuvant chemo- 33. Nelson CJ, et al. Cognitive effects of hormone therapy therapy on cognitive function: a follow-up study in in men with prostate cancer: a review. Cancer. breast cancer patients. Ann Oncol. 2002;13(9): 2008;113(5):1097Ð106. 1387Ð97. 34. Schilder CM, et al. Effects of tamoxifen and exemes- 17. Schagen SB, et al. Cognitive de fi cits after postopera- tane on cognitive functioning of postmenopausal tive adjuvant chemotherapy for breast carcinoma. patients with breast cancer: results from the neuropsy- Cancer. 1999;85(3):640Ð50. chological side study of the tamoxifen and exemes- 18. Hurria A, et al. A prospective, longitudinal study of tane adjuvant multinational trial. J Clin Oncol. the functional status and quality of life of older 2010;28(8):1294Ð300. patients with breast cancer receiving adjuvant chemo- 35. Green HJ, et al. Altered cognitive function in men therapy. J Am Geriatr Soc. 2006;54(7):1119Ð24. treated for prostate cancer with luteinizing hormone- 19. van Dam FS, et al. Impairment of cognitive function releasing hormone analogues and cyproterone acetate: in women receiving adjuvant treatment for high-risk a randomized controlled trial. BJU Int. 2002;90(4): breast cancer: high-dose versus standard-dose chemo- 427Ð32. therapy. J Natl Cancer Inst. 1998;90(3):210Ð8. 36. Wefel JS, Kayl AE, Meyers CA. Neuropsychological 20. Wefel JS, et al. The cognitive sequelae of standard- dysfunction associated with cancer and cancer thera- dose adjuvant chemotherapy in women with breast pies: a conceptual review of an emerging target. Br J carcinoma: results of a prospective, randomized, lon- Cancer. 2004;90(9):1691Ð6. gitudinal trial. Cancer. 2004;100(11):2292Ð9. 37. Pallis AG, et al. EORTC elderly task force position 21. Wefel JS, et al. Acute and late onset cognitive dys- paper: approach to the older cancer patient. Eur J function associated with chemotherapy in women Cancer. 2010;46(9):1502Ð13. with breast cancer. Cancer. 2010;116(14):3348Ð56. 38. Kemeny MM, et al. Barriers to clinical trial participa- 22. Syrjala KL, et al. Neuropsychologic changes from tion by older women with breast cancer. J Clin Oncol. before transplantation to 1 year in patients receiving 2003;21(12):2268Ð75. myeloablative allogeneic hematopoietic cell trans- 39. Taylor WC, Muss HB. Adjuvant chemotherapy of plant. Blood. 2004;104(10):3386Ð92. breast cancer in the older patient. Oncology (Williston 23. Ahles TA, et al. Psychologic and neuropsychologic Park). 2010;24(7):608Ð13. impact of autologous bone marrow transplantation. 40. Given B, Given CW. Older adults and cancer treat- J Clin Oncol. 1996;14(5):1457Ð62. ment. Cancer. 2008;113(12 Suppl):3505Ð11. 24. Friedman MA, et al. Course of cognitive decline in 41. Pal SK, Hurria A. Impact of age, sex, and comorbidity hematopoietic stem cell transplantation: a within-sub- on cancer therapy and disease progression. J Clin jects design. Arch Clin Neuropsychol. 2009;24(7): Oncol. 2010;28(26):4086Ð93. 689Ð98. 42. Gállego Pérez-Larraya J. A phase II trial of temozolo- 25. National Cancer Institute. Biological therapy. mide in elderly patients with glioblastoma and poor Treatments that use your immune system to fi ght can- performance status (KPS < 70): preliminary results of cer (NIH Publication No. 03-5406). 2003. the ANOCEF “TAG” trial. Neuro Oncol. 2010;12 26. Clark JW. Biological response modi fi ers. Cancer Suppl 4:iv76. Chemother Biol Response Modif. 1996;16:239Ð73. 43. Stummer W, et al. Favorable outcome in the elderly 27. Scheibel RS, et al. Cognitive dysfunction and depres- cohort treated by concomitant temozolomide sion during treatment with interferon-alpha and che- radiochemotherapy in a multicentric phase II safety motherapy. J Neuropsychiatry Clin Neurosci. study of 5-ALA. J Neurooncol. 2011;103(2):361Ð70. 2004;16(2):185Ð91. 44. Gerstein J, et al. Postoperative radiotherapy and 28. Bender CM, et al. Cognitive function and quality of concomitant temozolomide for elderly patients with life in interferon therapy for melanoma. Clin Nurs glioblastoma. Radiother Oncol. 2010;97(3):382Ð6. Res. 2000;9(3):352Ð63. 45. Hurria A, Lachs M. Is cognitive dysfunction a compli- 29. Capuron L, et al. Baseline mood and psychosocial cation of adjuvant chemotherapy in the older patient characteristics of patients developing depressive with breast cancer? Breast Cancer Res Treat. symptoms during interleukin-2 and/or interferon- 2007;103(3):259Ð68. alpha cancer therapy. Brain Behav Immun. 2004;18(3): 46. Bial AK, Schilsky RL, Sachs GA. Evaluation of cog- 205Ð13. nition in cancer patients: special focus on the elderly. 30. Valentine AD, et al. Mood and cognitive side effects Crit Rev Oncol Hematol. 2006;60(3):242Ð55. of interferon-alpha therapy. Semin Oncol. 1998;25(1 47. Mohile SG, et al. Cognitive effects of androgen Suppl 1):39Ð47. deprivation therapy in an older cohort of men with 31. Valentine AD, Meyers CA. Neurobehavioral effects prostate cancer. Crit Rev Oncol Hematol. 2010;75(2): of interferon therapy. Curr Psychiatry Rep. 2005;7(5): 152Ð9. 391Ð5. 48. Ahles TA, et al. Longitudinal assessment of cognitive 32. Maki PM, Sundermann E. Hormone therapy and cog- changes associated with adjuvant treatment for breast nitive function. Hum Reprod Update. 2009;15(6): cancer: impact of age and cognitive reserve. J Clin 667Ð81. Oncol. 2010;28(29):4434Ð40. 454 M.E. Witgert and J.S. Wefel

49. He fl in LH, et al. Cancer as a risk factor for long-term 63. Shaw EG, et al. Phase II study of donepezil in irradi- cognitive de fi cits and dementia. J Natl Cancer Inst. ated brain tumor patients: effect on cognitive function, 2005;97(11):854Ð6. mood, and quality of life. J Clin Oncol. 2006;24(9): 50. Wefel JS, Meyers CA. Cancer as a risk factor for 1415Ð20. dementia: a house built on shifting sand. J Natl Cancer 64. Chan AS, et al. Phase II study of alpha-tocopherol Inst. 2005;97(11):788Ð9. in improving the cognitive function of patients with 51. Roe CM, et al. Cancer linked to Alzheimer disease but temporal lobe radionecrosis. Cancer. 2004; not vascular dementia. Neurology. 2010;74(2): 106Ð12. 100(2):398Ð404. 52. Burke WJ. Cancer linked to Alzheimer disease but not 65. Konat GW, et al. Cognitive dysfunction induced by vascular dementia. Neurology. 2010;75(13):1216. chronic administration of common cancer chemo- author reply 1216. therapeutics in rats. Metab Brain Dis. 2008;23(3): 53. Roe CM, et al. Alzheimer disease and cancer. 325Ð33. Neurology. 2005;64(5):895Ð8. 66. Zhao W, et al. Administration of the peroxisomal 54. DeAngelis LM, Delattre JY, Posner JB. Radiation- proliferator-activated receptor gamma agonist piogli- induced dementia in patients cured of brain metastases. tazone during fractionated brain irradiation prevents Neurology. 1989;39(6):789Ð96. radiation-induced cognitive impairment. Int J Radiat 55. Levin VA, et al. Phase II study of accelerated fraction- Oncol Biol Phys. 2007;67(1):6Ð9. ation radiation therapy with carboplatin followed by 67. Acharya MM, et al. Rescue of radiation-induced PCV chemotherapy for the treatment of anaplastic cognitive impairment through cranial transplantation gliomas. Int J Radiat Oncol Biol Phys. 2002;53(1):58Ð66. of human embryonic stem cells. Proc Natl Acad Sci 56. Castellon SA, et al. Neurocognitive performance in USA. 2009;106(45):19150Ð5. breast cancer survivors exposed to adjuvant chemo- 68. Baker LD, et al. Effects of aerobic exercise on mild therapy and tamoxifen. J Clin Exp Neuropsychol. cognitive impairment: a controlled trial. Arch Neurol. 2004;26(7):955Ð69. 2010;67(1):71Ð9. 57. Keime-Guibert F, Napolitano M, Delattre JY. 69. Yaguez L, et al. The effects on cognitive functions of Neurological complications of radiotherapy and che- a movement-based intervention in patients with motherapy. J Neurol. 1998;245(11):695Ð708. Alzheimer’s type dementia: a pilot study. Int J Geriatr 58. Valentine AD. Managing the neuropsychiatric adverse Psychiatry. 2010;26(2):173Ð81. effects of interferon treatment. BioDrugs. 1999;11(4): 70. Korstjens I, et al. Quality of life of cancer survivors 229Ð37. after physical and psychosocial rehabilitation. Eur J 59. Bruera E, et al. Patient-controlled methylphenidate Cancer Prev. 2006;15(6):541Ð7. for the management of fatigue in patients with 71. Wong-Goodrich SJ, et al. Voluntary running prevents advanced cancer: a preliminary report. J Clin Oncol. progressive memory decline and increases adult 2003;21(23):4439Ð43. hippocampal neurogenesis and growth factor expres- 60. Bruera E, et al. Patient-controlled methylphenidate for sion after whole-brain irradiation. Cancer Res. 2010; cancer fatigue: a double-blind, randomized, placebo- 70(22):9329Ð38. controlled trial. J Clin Oncol. 2006;24(13):2073Ð8. 72. Sherer M, Meyers CA, Bergloff P. Ef fi cacy of post- 61. Sarhill N, et al. Methylphenidate for fatigue in acute brain injury rehabilitation for patients with advanced cancer: a prospective open-label pilot study. primary malignant brain tumors. Cancer. 1997;80(2): Am J Hosp Palliat Care. 2001;18(3):187Ð92. 250Ð7. 62. Meyers CA, et al. Methylphenidate therapy improves 73. Gehring K, et al. Cognitive rehabilitation in patients cognition, mood, and function of brain tumor patients. with gliomas: a randomized, controlled trial. J Clin J Clin Oncol. 1998;16(7):2522Ð7. Oncol. 2009;27(22):3712Ð22. Evaluating Cognition in Patients with Chronic Obstructive Pulmonary 2 8 Disease

Elizabeth Kozora and Karin F. Hoth

Abstract In this chapter, we focus on the neuropsychological evaluation of patients with chronic obstructive pulmonary disease (COPD), a common adult pulmonary disorder characterized by restrictive airfl ow and respiratory distress. First, we will review the epidemiology and diagnostic criteria of COPD and of the most common medical comorbidities. Next, we will review the literature of cognition in patients with COPD and identify the most consistent neuropsychological defi cits in the population. Multi- disciplinary rehabilitation is commonly prescribed for COPD patients. We will discuss the role of the neuropsychologist within the team. Finally, to more clearly illustrate the neuropsychological evaluation in patients with COPD, we will discuss a fi ctional case from our center with details regarding frequent referral questions, special considerations for the clinical interview, selection of cognitive tests, interpretation of tests, and fi nal recommendations for the patient and/or the interdisciplinary rehabilitation team.

Keywords Pulmonary disease ¥ COPD ¥ Air ﬂ ow limitation ¥ Hypoxia

Chronic obstructive pulmonary disease (COPD) is a chronic progressive pulmonary disease with signi fi cant physical, cognitive, and psychological sequelae. There are several types of restrictive lung diseases (e.g., COPD, emphysema), and E. Kozora , Ph.D. () ¥ K. F. Hoth , Ph.D. although conditions vary across individuals, they Division of Psychosocial Medicine, Department of are all related to air fl ow limitation. COPD is a Medicine , National Jewish Health, 1400 Jackson St., Room M107G , Denver , CO 80206 , USA preventable/treatable disease; however, the “pulmonary” component, characterized by airfl ow Departments of Psychiatry and Neurology , University of Colorado Denver , Aurora , CO , USA limitation, is not fully reversible. The air fl ow lim- e-mail: [email protected] ; [email protected] itation is usually progressive and associated with

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 455 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_28, © Springer Science+Business Media, LLC 2013 456 E. Kozora and K.F. Hoth an abnormal in fl ammatory response in the lung in COPD have also been inversely related to to noxious particles and gases [ 1 ] . COPD is socioeconomic status [ 2 ] . currently recognized as the fourth leading cause of death in the United States, accounting for more than 120,000 deaths annually, and is predicted to Classi fi cation of Severity of COPD be the third leading cause of death by 2020. Although mortality in men appears to be peaking The current gold standard for classifying COPD in the USA, for women, mortality continues to severity and monitoring progression is the Global rise and may exceed that among men [ 2 ] . In addi- Initiative for Chronic Obstructive Lung Disease tion, COPD progresses with age and is more (GOLD) classifi cation system (2008), where the prevalent in older populations. In the USA, 15% criteria rely on measures of airfl ow limitation from of the total population aged 55Ð64 will have at spirometry to stratify COPD into four stages (see least moderate COPD, which increases to over Table 28.1 ). Spirometry measures the amount and 25% for those older than 75 [3 ] . rate of air a patient breathes in and out over a period COPD is clinically heterogeneous and can of time. The GOLD classi fi cation criteria are based result from several etiologies with the primary on spirometry results obtained after administration being cigarette smoke. Cigarette smoking has of an inhaled bronchodilator, such as albuterol. been clearly established as the most important Testing before and after a bronchodilator mini- risk factor, with approximately 10Ð15% of mizes variability in how the test is administered smokers developing COPD. Notably, smokers and provides some information about the potential lose lung function in a dose-dependent matter responsiveness of the airways to medication. As and a majority of smokers will have reduced can been seen in Table 28.1, the major difference lung function as they age [ 1 ] . Eighty percent of across COPD stages is decreasing FEV1 , which individuals who have COPD, and 80% who die refl ects the volume of air that can be forced out in from COPD, are smokers [ 2 ] . Other risk factors the 1 s after taking a deep breath. are estimated to contribute between 27% and The functional impact of COPD on any indi- 60% of overall COPD mortality [4 ] . Several vidual patient is due not only to degree of air fl ow distinct mechanisms and genetic factors may limitation, but also to symptom severity (e.g., alter individual responses. Factors that may shortness of breath, exercise intolerance). Airfl ow contribute to accelerated loss of lung function limitation and symptom severity are associated, include occupational exposures (i.e., farming or but do not have a one to one relationship. The work in dusty occupations), environmental air authors of the GOLD criteria acknowledge this pollution (increased particulates), and indoor and suggest that COPD stage should be thought air exposure (smoke from use of biomass fuels), but there are also likely genetic determinants Table 28.1 COPD GOLD stage classi fi cation such as mutations in the serine proteinase inhibitor alpha -protease inhibitor. Other factors GOLD stage Spirometric classi fi cation based 1 on post-bronchodilator FEV include early life events such as maternal smoking 1 I Mild FEV 1 /FVC < 0.7 and low birth weight, asthma, and mucus hyper- FEV ³ 80% predicted secretion [ 1 ] . Although male gender predomi- 1 II Moderate FEV1 /FVC < 0.7 nance in COPD has been reported, it is primarily 50% £ FEV1 < 80% predicted related to exposure to cigarettes and other toxins, III Severe FEV1 /FVC < 0.7 30% £ FEV < 50% predicted and it has been suggested that COPD is equally 1 IV Very severe FEV /FVC < 0.7 prevalent among genders [4 ] . Women do appear 1 FEV < 30% predicted or to have different comorbidities with lower prev- 1 FEV 1 < 50% plus chronic alence of ischemic heart disease but higher respiratory failure prevalence of congestive heart failure, osteopo- FEV 1 forced expiratory volume in 1 s, FVC forced vital rosis, and diabetes [ 5 ] . Morbidity and mortality capacity 28 Evaluating Cognition in Patients with Chronic Obstructive Pulmonary Disease 457 of as a general indication as to the initial approach empty). The patient must take a deep breath and to management. The GOLD statement does, blow into a mouthpiece attached to a spirometer. however, provide general descriptors of typical A computerized sensor within the spirometer cal- presentation of patients at each stage. In stage I culates and graphs the results, typically presented “mild COPD,” chronic chough and sputum pro- as volume vs. time. Of particular importance for duction may be present, but not always. At this COPD diagnosis and monitoring is the volume stage, the individual is usually aware that his or forced out within the fi rst second (forced expira- her lung function is abnormal. In stage II “mod- tory volume in 1 s, FEV1) and total volume of air erate COPD,” shortness of breath typically devel- forced out of the lungs (forced vital capacity, ops on exertion, and cough and sputum production FVC). sometimes are also present. This is the stage at which patients typically seek medical attention because of chronic respiratory symptoms or an Alpha-1 Antitrypsin Screening exacerbation of their disease. In stage III “severe COPD,” greater shortness of breath, reduced Alpha-1 antitrypsin de fi ciency (a -1) is a genetic exercise capacity, fatigue, and repeated exacerba- disorder that can cause liver disease and early- tions that almost always have an impact on onset emphysema. a -1 antitrypsin is a protein patient’s quality of life may be present. In stage primarily produced in the liver and released into IV “very severe COPD,” respiratory failure may the blood stream that protects the lungs against lead to effects on the heart such as cor pulmonale damage from things like infections and smoke. In (right side heart failure). At this stage, quality of addition to treatments that may be used in COPD life is appreciably impaired, and exacerbations in general (e.g., bronchodilators, corticosteroids), may be life threatening. The most common causes some individuals with a -1 antitrypsin de fi ciency of death in COPD are from cardiovascular com- may be candidates for a -1 augmentation plications, lung cancer, and in patients with very therapy. advanced COPD, respiratory failure.

Exercise Capacity Common Medical Diagnostic Tests Exercise capacity is an important component of Diagnosis of COPD by a physician involves a the evaluation of COPD patients, given that limi- thorough medical history, physical examination, tations in exercise capacity have a signiﬁ cant spirometry, and a chest X-ray with additional impact on day to day functioning. Several differ- measures ordered depending upon the clinical ent exercise measures are available including situation. In the following section, additional treadmill or cycle testing, the 6-min walk test, or information about common medical tests a neu- shuttle walk testing. Assessment of exercise ropsychologist may encounter when reviewing capacity is most often conducted in the context of the medical record of a patient with COPD will pulmonary rehabilitation or physical therapy be reviewed. evaluation.

Spirometry Dyspnea

As mentioned above, spirometry is needed to Given that a patient’s degree of pulmonary dis- make a certain diagnosis of COPD. The test mea- ease does not directly correlate with disability, it sures the volume of air exhaled during a maximal is often helpful to obtain a subjective rating from the forced expiratory maneuver (i.e., blowing out as hard patient on the impact of their shortness of breath. and fast as possible until lungs feel absolutely A commonly used measure of breathlessness in 458 E. Kozora and K.F. Hoth

COPD is the Modifi ed Medical Research Council COPD is also associated with an increased rate (MRC) dyspnea scale [ 6 ] . The scale is a fi ve-item of psychological symptoms, particularly anxiety questionnaire on which patients rate their own and depression. In a comprehensive review of 81 disability from dyspnea, with grade 1 indicating studies, Hynninen et al. [17 ] reported that the preva- the least impact from breathlessness (i.e., only lence of psychiatric disorders ranged from 30% to breathless with strenuous exercise) and grade 5 58%. Depression and anxiety appear to be the most indicating the most severe impact (i.e., too breath- commonly observed psychological problems in less to leave the house or breathless when dress- COPD [ 17Ð 21 ] . The prevalence of depression has ing/undressing). been estimated between 10% and 79.1% [ 17, 22Ð Additional tests that are often ordered for 24 ] . Some of the discrepancies in estimates may patients with COPD include arterial blood gas relate to the method of assessing depression. For measurement, sleep study, cardiology evaluation, example, prior studies with higher levels of depres- occupational medicine, and health and behavior sion have tended to use self-report questionnaires assessment with a psychologist or psychiatrist. rather than a clinically derived diagnosis of major depression [ 25, 26] . Eiser and colleagues [ 27 ] screened a large group of COPD patients with mod- Common Medical Comorbidities of COPD erate to severe COPD using screening questionnaires followed with a psychiatric interview. They COPD has traditionally been understood as a report prevalence rates of depression of 35% using disease of the lungs characterized by chronic the questionnaire and 21% by clinical interview. airfl ow obstruction; however, the importance of This is consistent with another study that diagnosed extrapulmonary effects of COPD has become depression in COPD utilizing a structured psychi- increasingly recognized over the past decade atric clinical interview and reported that 23% of [7Ð 9 ] . COPD has systemic effects that can have the COPD patients had major depression [ 28 ] . an important impact on the patient’s health The prevalence of depression in older adults in the including cachexia, skeletal muscle wasting, general population has been estimated between 8% osteoporosis, anemia, cardiovascular disease, and 20%; thus, studies to date clearly indicate higher and depression. The consequences of systemic depression rates in patients with COPD [29 ] . in fl ammation on other organ systems have been The symptoms of anxiety, depression, and one major area of focus in understanding extra- dyspnea are not mutually exclusive. Whereas pulmonary changes in COPD [ 10 ] . dyspnea is a characteristic feature of panic Cardiovascular disease is one of the most attacks, feelings of panic and anxiety are also a prevalent comorbidities in COPD [ 11Ð 14 ] . COPD frequent manifestation of pulmonary disease. In is associated with a 2Ð3-fold increase in the risk COPD, approximately one third of patients meet of ischemic heart disease, stroke, and sudden clinical criteria for an anxiety disorder, with panic death [14 ] . In fact, more patients with COPD are disorder being the most common. Approximately hospitalized and die from cardiovascular causes one fourth of patients meet criteria for panic dis- than respiratory causes [ 15 ] . Although smoking order, which is 10 times the rate in the general is a risk factor for both COPD and cardiovascular population [ 19] . Symptoms of depression and disease, the association between airfl ow obstruc- anxiety are important to consider as they may tion (e.g., FEV1 ) and cardiovascular disease exists contribute to cognitive impairment in COPD, in even after adjusting for risk factors that are addition to their impact on quality of life. common to both conditions including age, sex, smoking history, cholesterol, and socioeconomic class, suggesting that there is a direct underlying Neuropsychological Studies in COPD relationship [13 ] . Additional medical comorbidities of COPD typically include anemia and osteo- Multiple studies using standardized tests have porosis [16 ] . identi fi ed neuropsychological de fi cits in patients 28 Evaluating Cognition in Patients with Chronic Obstructive Pulmonary Disease 459 with COPD [ 30Ð 36] . The pattern and extent of COPD group on all measures except verbal cognitive dysfunction reported in COPD varies fl uency. Neuroimaging studies have reported across patients and appears to be associated with hypoperfusion in frontal and association areas in disease severity. In COPD patients with moderate COPD [ 39, 42 ] . In contrast to AD or another to severe hypoxemia, de fi cits have been reported neurodegenerative process, there may be some in simple motor movement and overall strength, improvement in cognition in patients with COPD, perceptual-motor integration, abstract reasoning, particularly memory gains following oxygen or attention to auditory stimuli, learning and mem- multidisciplinary rehabilitation. Therefore, repeat ory, and language skills [ 31, 33Ð 35, 37Ð 39 ] . neuropsychological assessment 6Ð12 months fol- Some studies in COPD patients have suggested lowing treatment, as well as consultation from that even mild hypoxemia may be associated with neurology and neuroradiology, may be useful in a impairment in higher cerebral functioning. complete workup in COPD patients with severe Prigatano, et al. [ 33 ] studied 100 mildly hypox- memory disorders. emic COPD patients (mean age = 61.5, mean

PaO2 = 66.3) and reported de ﬁ cits in this group compared to controls in abstract reasoning and Interdisciplinary Treatment of COPD attention to auditory stimuli. Grant et al. [ 31 ] combined data from a number of sites of a multi- Comprehensive rehabilitation programs for treat- center NIH trial and reported that mildly hypox- ment of COPD include a wide range of assessment emic COPD patients (mean age = 61.6, mean procedures and educational programs, instruction

PaO2 = 67.8) performed signifi cantly lower than on respiration, psychosocial support, and exercise controls on a global index of cognitive function- training with the goal of restoring patients to the ing. Twenty-seven percent of COPD patients with highest level of independent function [43 ] . There mild hypoxemia showed global de fi cits as com- is evidence that suggests that comprehensive mul- pared to 61% of patients with severe hypoxemia. tidisciplinary rehabilitation programs can also The mildly hypoxemic group performed improve cognitive functioning and psychological signifi cantly below matched controls on mea- status in emphysema/COPD patients [25, 43Ð 45 ] . sures of associate learning, immediate recall of Studies from our group have suggested improved verbal and nonverbal material, logical analysis verbal memory and visuomotor sequencing in and reasoning, sustained visual attention, and patients with lung volume reduction surgery com- fi ne motor coordination. Liesker et al. [ 40 ] also pared to rehabilitation at 6-month follow-up using reported that 30 COPD patients with mild hypox- a comprehensive battery [ 46 ] . In a later study with emia showed decline in visuomotor speed and a much larger sample, there were no differences attention compared to 20 health controls. In a between the two groups on a visuomotor sequenc- large review of COPD studies with and without ing task over a 3-year period [ 47 ] . Notably, the hypoxemia, the correlations between cognitive fi rst study utilized a comprehensive battery, and functions and degree of hypoxemia were less the second study included only the measure of impressive and thought to be inconsistent [16 ] . visuomotor sequencing. Due to the age of the COPD population, the potential for other central nervous system (CNS) disorders, including a progressive neurodegener- Role of Neuropsychologist ative disorder such as Alzheimer’s disease (AD), should be considered in differential diagnosis. At hospitals such as ours (National Jewish Health We compared 32 mildly hypoxic COPD patients (NJH) in Denver, CO), the role of the neuropsy- to 32 subjects with mild Alzheimer’s disease chologist in the pulmonary assessment and reha- (AD) and 32 healthy controls matched on age, bilitation process is well established and integral education, and gender [41 ] . Results indicated that to the program. Physicians board-certi fi ed in pul- the mild AD group performed worse than the monology are directly responsible for assessment, 460 E. Kozora and K.F. Hoth diagnosis, treatment, and evaluation. In addition, after their initial appointment with a patient. board-certi fi ed physicians in cardiology, allergy Intake documents also track patient/family con- and immunology, otolaryngology, orthopedics, and cerns regarding memory and mental abilities, and other medical specialties are available to evaluate a some COPD patients are fl agged prior to their variety of comorbid medical disorders in the COPD visit for brief cognitive evaluations. All referrals patients. Physical therapists and exercise physiolo- essentially request information regarding (1) the gists formulate the plan to help individuals reach presence, degree, and domains of cognitive their maximal physical function, and occupational impairment; (2) etiological factors (i.e., is cogni- therapists teach effi cient coordinated activities for tive dysfunction related primarily to COPD or daily living skills specifi cally designed to limit other factors such as other CNS changes such as breathlessness. The team also includes a respiratory a progressive dementia); (3) what is the role of therapist to assist in diagnostic procedures, a patient depression and anxiety in the cognitive dysfunc- education coordinator to develop and maintain edu- tion; (4) what impact do the cognitive skills have cational materials, a pharmacist to assist staff and on the day to day life of the patient (i.e., patients patients with medication issues and a dietitian to ability to live independently given cognitive provide assessment and recommendations for nutri- impairment); and (5) is the patient able to under- tional care. A behavioral health clinician (including stand and carry out medical treatment regimens. clinical psychologists and social workers) is avail- The neuropsychologist might address poten- able for all patients for consultation and interven- tial problems with medication adherence (i.e., tion to address adjustment to illness, adherence whether the patient has adequate compensatory concerns, other behavioral factors impacting ill- strategies), dif fi culties related to use of inhaler or ness, and mental health issues impacting medical use of oxygen, and the patient’s capacity to care management. In addition, there is access to a smok- for themselves following surgery/major medical ing cessation counselor to assist with behavioral intervention. and pharmacological interventions of tobacco cessation and a psychiatrist for patients who need medical and or pharmacological intervention to Clinical Interview treat possible psychiatric comorbid conditions. The neuropsychologists on the team evaluate pat- When conducting a clinical neuropsychological ients who are experiencing cognitive diffi culties, interview with patients with COPD, there are such as defi cits in memory or attention, and work several unique issues to consider in addition to closely with the team to recognize defi cits and gathering the typical background/medical history help adapt treatment plans to the specifi c patient’s information that would be obtained during any cognitive strengths and weaknesses. In contrast to neuropsychological evaluation. First, for patients the behavioral health clinician specifi cally evalu- on oxygen, it is helpful to discuss at the begin- ating health behaviors, coping styles, depression, ning of the appointment how much oxygen they and emotional factors, the neuropsychologist’s require to last through the assessment. It is far role in our clinic is speci fi cally devoted to cogni- better to determine ahead of time that more oxy- tive functioning and to any continued consultation gen is required than to run out midway through for neurology, neuroradiology, etc. Specifi c referral testing. Acute drops in oxygen saturation and questions will be reviewed below. associated symptoms like fatigue might impact test results causing them to poorly refl ect the patient’s typical status. If oximetry is available in Common Neuropsychological Referral your clinical setting, it can be helpful to obtain a

Questions resting measure of SaO2 to determine if the patient is hypoxemic on the day of testing. Asking The referrals for neuropsychological assessment about perceived shortness of breath and level of in our facility are typically initiated by the pul- fatigue on the day of testing is also helpful to monologist or the behavioral health clinician understand if the day is typical for the patient. 28 Evaluating Cognition in Patients with Chronic Obstructive Pulmonary Disease 461

Depending upon one’s clinical setting, it may tasks due to physical vs. cognitive symptoms is be helpful to provide additional explanation of clearly important for diagnosing cognitive impair- the multidisciplinary model of care, specifi cally ment and may require some additional prompting the role of neuropsychology in treating patients in this population. with COPD (e.g., some common roles are As a part of any neuropsychological interview, described in the referral question section above). information about past history that may impact Patients with COPD may be referred by pulmo- brain function is obtained. In COPD, patients are nary or primary care physicians who are con- more likely than the general population to have cerned about the patient’s cognition, while the had past environmental exposure to toxins/chem- patient is primarily focused on respiratory icals, as this is one risk factor for subsequently symptoms like shortness of breath and has not developing COPD. Furthermore, since smoking raised his or her own concerns about cognition. is the top risk factor for COPD and nicotine use Explaining the neuropsychological evaluation and use of other substances are common, it is in the context of improving quality of life and important to ask about potential substance use. daily functioning and understanding cognitive There is surprisingly little information regarding strengths and weaknesses to assist the medical actual rates of substance abuse in COPD, as the team in working with the patient can be helpful few articles published to date on alcohol use in in alleviating hesitance a patient may feel about COPD have primarily examined the impact of seeing a neuropsychologist. alcohol use on pulmonary symptoms [ 48 ] . During the interview, it is helpful to ask if Nonetheless, in our clinic, we have observed that patients and their family members have noticed concerns about alcohol use are common enough fl uctuations in the patient’s perceived cognitive in patients referred for neuropsychological test- function in association with changes in respira- ing to have incorporated expanded substance use tory status. Patients might experience fl uctuations questions as an area of focus in the interview. in cognitive status depending upon their physical activity level, symptoms of COPD, on or off oxygen, or after taking medications. Many patients Neuropsychological Testing with COPD experience exacerbations of their symptoms that require outpatient treatment with The neuropsychological test battery used in our steroids or hospitalization. Anecdotally, patients COPD population emphasizes domains of pro- with COPD and their families often describe cessing speed and attention, learning and memory worsening cognition following hospitalization, for verbal and nonverbal material, executive func- as can be the case with any ICU or hospital stay, tions, and visuoconstructive and visuomotor although the reasons for this in COPD speci fi cally skills. Intellectual testing or estimated IQ testing have not been explored in the research literature. are also frequently assessed. Various language Understanding potential fl uctuations in cognitive skills and academic abilities (i.e., math, spelling, symptoms can help with determining the degree reading comprehension) might also be consid- to which cognitive symptoms are attributable to ered in relation to the referral question and con- pulmonary disease and making recommendations cerns about comprehension of oral and written about how patients can plan the timing of engag- information and role in day to day activities (i.e., ing in demanding cognitive tasks. understanding written instructions and forms, Due to the impact that physical symptoms of paying their own bills, etc.). As with most evalu- COPD have on activities of daily living, it is nec- ations, considerations for test selection include essary to spend some time clarifying with the the age and education of the patient, the overall patient how their cognitive symptoms impact health and expected stamina of the patient, and daily tasks. Patients tend to report about activities the referral question. We also recommend that that they can and cannot do and are less likely to patient’s with prescribed oxygen have suffi cient think about what aspect of the task is dif fi cult for oxygen available in their tanks upon the start of them. The distinction between limitations in daily the appointment. In our facility, backup oxygen is 462 E. Kozora and K.F. Hoth available if necessary but may require special records indicate that Ms. Smith has a history of arrangements in some outpatient facilities. tobacco abuse, COPD GOLD stage II, and high In our clinic, there may also be differences in blood pressure. She smoked an average of one testing based on availability of the patient. In-state pack of cigarettes from age 18Ð60, but has not patients with complex referral question (i.e., smoked in 9 years. The patient had no history of COPD vs. progressive dementia vs. depression) head injury, other neurological illness, learning are typically scheduled for more in-depth evalua- disability, substance abuse, psychological tions whereas out-of-state patients scheduled to diffi culties, or hearing/visual problems. Ms. be in our clinic for 1Ð2 weeks are more likely to Smith graduated from high school with average get a brief neuropsychological battery designed grades and later obtained training and was speci fi cally for our COPD clinic (see case exam- certifi ed as a home nursing aid. She worked full ple below). Interpretation of tests utilizing nor- time for 30 years and had been retired for 10 years mative data adjusting for age, education, gender, at the time of her evaluation. Medications and ethnicity is always considered. In our clinical included ipratropium-albuterol nebulizer four setting, the neuropsychological test results for the times per day, lisinoprin 10 mg per day, metro- COPD clinic are available within 24 h and pre- prolol 200 mg per day, oxazepam 60 mg per day, sented at the weekly team meeting in order to oxygen 2.5 L as needed, Spiriva 18 mcg per day, incorporate fi ndings into day-to-day care and and Ventolin 108 mcg every 4Ð6 h. provide specifi c recommendations (i.e., neurol- No unusual behaviors were noted during the ogy, neuroradiology) for patients who require evaluation, and the patient was fully ambulatory additional evaluation of the CNS. and taking oxygen. Her SaO2 level at the beginning of the session was 93. She did not appear to have any dif fi culty understanding test instruc- Case Example of Neuropsychological tions, and her effort appeared within normal lim- Screening in COPD its. She completed the brief measure of psychological functioning (Hospital Anxiety and As an example, we will review a neuropsycho- Depression Scale, [49 ] ), and she endorsed mild logical evaluation performed on a female patient symptoms of depression. participating in the COPD assessment and Impairment levels for the patient’s neurop- rehabilitation program at National Jewish Health sychological tests scores (based on normative in Denver, CO. Ms. Smith is a 69-year-old data adjusting for age, education, and when Caucasian, right-handed female who was referred possible gender and ethnicity) are shown in by her pulmonologist for our brief out-of-state Table 28.2 . Overall, her neuropsychological NP battery due to concerns regarding cognitive test results indicate mild to moderate cognitive dysfunction identifi ed in her intake forms and by dysfunction. Based on her educational and work the pulmonologist during his or her on-site intake. history, as well as her estimated premorbid IQ, Ms. Smith reported some dif fi culty with her these scores likely represent a decline from memory during our interview. Family members average premorbid functioning. As noted in present during the interview indicated that she Table 28.2 , Ms. Smith was moderately impaired frequently forgets appointments, is slow to complete in her learning and severely impaired in her tasks, and may not be taking her medications cor- memory for verbal information and mildly rectly. They also reported that she has dif fi culty impaired for visually presented material. Her understanding complex information. Regarding recognition for verbal and visual information the onset of her memory concerns, Ms. Smith and following a delay was intact. She was impaired her family indicated that her memory dif fi culty in her drawing of a clock to command with began approximately 5 years ago with noticeable diffi culty noted in terms of spacing of numbers worsening following both of her hospitalizations and ability to set hands to the required time. for COPD exacerbations in the past year. Medical There was some evidence of mild to moderate 28 Evaluating Cognition in Patients with Chronic Obstructive Pulmonary Disease 463

Table 28.2 Brief neuropsychological battery for COPD assessment: case example Function Measure Performance range Intellectual functioning Oral reading/estimated premorbid IQ WTARa Average Attention and processing speed Attention to numeric sequences WAIS-IVb digit span Mildly impaired Visual scanning and tracking speed Trailmaking Testc Form A Average Nonverbal attention and learning WAIS-IV coding Average Executive functioning and problem solving Sequencing ef fi ciency Trailmaking Test Form B Mildly to moderately impaired Verbal abstract reasoning WAIS-IV similarities Average Nonverbal reasoning WAIS-IV matrix reasoning Average Learning and memory Verbal list acquisition HVLT-Rd total trials 1Ð3 Mildly to moderately impaired Verbal list free recall HVLT-R delayed recall Severely impaired Verbal list recognition HVLT-R recognition Average Nonverbal acquisition BVMT-Re total trials 1Ð3 Mildly impaired Nonverbal recall BVMT-R delayed recall Mildly impaired Nonverbal recognition BVMT-R recognition Average Language functioning Naming to confrontation BNT—Short Formf Below average Verbal fl uency COWATg Mildly impaired Semantic fl uency Animal naming Mildly to moderately impaired Visuospatial functioning Visuoconstruction WAIS-IV block design Average Drawing to command Clockh drawing Moderately impaired Drawing to copy Clock copy Average a WTAR = Wechsler Test of Adult Reading [50 ] b WAIS-IV = Wechsler Adult Intelligence Scale—Fourth Edition [50 ] c Trailmaking Test [51 ] d HVLT-R = Hopkins Verbal Learning Test—Revised [52 ] e BVMT-R = Brief Visuospatial Memory Test—Revised [53 ] f BNT = Boston Naming Test—Short Form [54 ] g COWAT = Controlled Oral Word Association Test [55 ] h Clock Drawing Test [26, 56 ] sequencing diffi culty (Trails B); however, basic episodes of hypoxemia. In addition, there was reasoning was intact. We would not expect her some evidence of a minor mood disturbance; to have signifi cant diffi culty with medical deci- however, it is not likely the primary cause of sion making with careful discussion. She had her cognitive diffi culties. Due to the severity of mild diffi culty with auditory attention. Her her memory problems, further evaluation with a naming ability was generally within normal neurologist was highly recommended to further limits, but she was slow in her verbal fl uency to evaluate any other changes in the central ner- letter and semantic cues. We concluded that her vous system and assess the potential for revers- memory defi cits are likely to interfere with ible disorders. Repeat testing following any aspects of her day-to-day function and some substantial medical or multidisciplinary treat- assistance and review of safety in her current ment may also be useful in identifying living arrangement would be useful. The etiol- signifi cant changes (improvement or decline) ogy of her defi cits is most likely related to her over time. She was diagnosed with cognitive medical history including COPD and prior disorder NOS from the DSM-IV nosology. 464 E. Kozora and K.F. Hoth

Recommendations provided to the patient, her suffi cient oxygen is available in his or her family, and the rehabilitation team fi rst addressed tanks to last throughout the exam. her poor verbal learning and memory and the ¥ Query about exposure to environmental toxins importance of using compensation techniques. as well as smoking and substance use/history. Given their concerns regarding medication use, it ¥ It is common for patients with COPD and their was recommended she use a carefully constructed families to describe worsening cognition fol- checklist or a pill box for medication types and lowing hospitalization, as can be the case with dosages by the hour. Use of a schedule or appoint- any ICU or hospital stay, yet this has not been ment book was also recommended for day-to-day systematically studied. activities. The patient’s relative strengths were in ¥ Moderate to severe neuropsychological visual learning and memory (mildly impaired defi cits may suggest the need for additional vs. moderately to severely impaired); therefore, neurologic workup (i.e., neurologic exam, some techniques to capitalize on this were dis- neuroimaging) to assess other CNS cussed with her and the rehabilitation team. comorbidities. Instead of verbally communicating instructions ¥ Repeat neuropsychological testing following for new activities, it was recommended that she medical therapy (i.e., oxygen or medication learn by watching and using visual cues. For changes) or comprehensive rehabilitation may example, instead of describing a new activity, be useful in documenting change over time and such as getting on a treadmill to exercise, demon- to assess any potential for other CNS disorders. strate the activity and have her practice several ¥ Identi fi cation of cognitive strengths and weak- times. In addition, keeping written notes avail- nesses in COPD patients can be utilized to able for new procedures might be useful. As with propose compensation techniques for day-to- other patients with COPD, visuomotor skills day activities and for a rehabilitation team to were slightly impaired, and additional time to work effectively with the patient. complete tasks involving motor function should be considered. As noted by her family, she was a little slow to generate words, and this is likely References related to her COPD, as this is a common fi nding in the literature. It is not likely to interfere dra- 1. Shapiro SD, Reilly JJ, Rennard SI. Chronic bronchitis matically with her day-to-day life but having and emphysema. In: Mason RJ, editor. Murray and Nadel’s textbok of respiratory medicine. 5th ed. additional time to express herself may be more Philadelphia: WB Saunders; 2010. comfortable for the patient. 2. Mannino DM, Homa DM, Akinbami LJ, Ford ES, et al. Chronic obstructive pulmonary disease surveillance—United States, 1971–2000. MMWR Surveill Summ. 2002;51(6):1Ð16. Clinical Pearls 3. Stockley RA, Mannino D, Barnes PJ. Burden and pathogenesis of chronic obstructive pulmonary dis- ¥ Patients with COPD demonstrate cognitive ease. Proc Am Thorac Soc. 2009;6(6):524Ð6. impairment that worsens with severity of 4. Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet. COPD and the presence of hypoxemia. 2007;370(9589):765Ð73. ¥ Cognitive areas that are most commonly 5. Almagro P, Lopez Garcia F, Cabrera F, Montero L, impaired include aspects of verbal learning and et al. Comorbidity and gender-related differences in memory, visuomotor speed, and verbal fl uency. patients hospitalized for COPD. The ECCO study. Respir Med. 2010;104(2):253Ð9. ¥ Identi fi cation of cognitive dysfunction in 6. Fletcher CM, Elmes PC, Fairbairn AS, Wood CH. The COPD patients may be mediated by a number signi fi cance of respiratory symptoms and the diagno- of comorbidities, including cardiovascular sis of chronic bronchitis in a working population. Br disease, depression, and anxiety. Med J. 1959;2(5147):257Ð66. 7. Agusti A, Thomas A. Neff lecture. Chronic obstruc- ¥ Determine at the onset of the appointment if the tive pulmonary disease: a systemic disease. Proc Am patient is prescribed oxygen therapy and whether Thorac Soc. 2006;3(6):478Ð81. 28 Evaluating Cognition in Patients with Chronic Obstructive Pulmonary Disease 465

8. Agusti A. Systemic effects of chronic obstructive 25. Agle DP, Baum GL, Chester EH, Wendt M. pulmonary disease: what we know and what we Multidiscipline treatment of chronic pulmonary don’t know (but should). Proc Am Thorac Soc. insuffi ciency. 1. Psychologic aspects of rehabilitation. 2007;4(7):522Ð5. Psychosom Med. 1973;35(1):41Ð9. 9. Celli BR, MacNee W. Standards for the diagnosis and 26. Goodglass H, Kaplan E. The assessment of aphasia treatment of patients with COPD: a summary of the and related disorders. Philadelphia: Lea and Febiger; ATS/ERS position paper. Eur Respir J. 2004;23(6): 1983. 932Ð46. 27. Eiser N, Harte R, Spiros K, Phillips C, et al. Effect of 10. Gan WQ, Man SF, Senthilselvan A, Sin DD. Association treating depression on quality-of-life and exercise tol- between chronic obstructive pulmonary disease and erance in severe COPD. COPD. 2005;2(2):233Ð41. systemic infl ammation: a systematic review and a 28. Kunik ME, Roundy K, Veazey C, Souchek J, et al. meta-analysis. Thorax. 2004;59(7):574Ð80. Surprisingly high prevalence of anxiety and depres- 11. Boussuges A, Rossi P, Gouitaa M, Nussbaum E. sion in chronic breathing disorders. Chest. 2005;127(4): Alterations in the peripheral circulation in COPD 1205Ð11. patients. Clin Physiol Funct Imaging. 2007;27(5): 29. Unutzer J, Patrick DL, Simon G, Grembowski D, 284Ð90. et al. Depressive symptoms and the cost of health ser- 12. Han MK, McLaughlin VV, Criner GJ, Martinez FJ. vices in HMO patients aged 65 years and older. A Pulmonary diseases and the heart. Circulation. 4-year prospective study. JAMA. 1997;277(20): 2007;116(25):2992Ð3005. 1618Ð23. 13. Maclay JD, McAllister DA, Macnee W. Cardiovascular 30. Fix AJ, Golden CJ, Daughton D, Kass I, et al. risk in chronic obstructive pulmonary disease. Neuropsychological defi cits among patients with Respirology. 2007;12(5):634Ð41. chronic obstructive pulmonary disease. Int J Neurosci. 14. Mills NL, Miller JJ, Anand A, Robinson SD, et al. 1982;16(2):99Ð105. Increased arterial stiffness in patients with chronic 31. Grant I, Heaton RK, McSweeny AJ, Adams KM, obstructive pulmonary disease: a mechanism for et al. Neuropsychologic fi ndings in hypoxemic chronic increased cardiovascular risk. Thorax. 2008;63(4): obstructive pulmonary disease. Arch Intern Med. 306Ð11. 1982;142(8):1470Ð6. 15. Anthonisen NR, Connett JE, Enright PL, Manfreda J. 32. Krop HD, Block AJ, Cohen E. Neuropsychologic Hospitalizations and mortality in the Lung Health effects of continuous oxygen therapy in COPD. Chest. Study. Am J Respir Crit Care Med. 2002;166(3): 1973;64(3):317Ð22. 333Ð9. 33. Prigatano GP, Parsons O, Wright E, Levin DC, et al. 16. Dodd JW, Getov SV, Jones PW. Cognitive function in Neuropsychological test performance in mildly hypox- COPD. Eur Respir J. 2010;35(4):913Ð22. emic patients with chronic obstructive pulmonary 17. Hynninen KM, Breitve MH, Wiborg AB, Pallesen S, disease. J Consult Clin Psychol. 1983;51(1):108Ð16. et al. Psychological characteristics of patients with 34. Incalzi RA, Gemma A, Marra C, Muzzolon R, et al. chronic obstructive pulmonary disease: a review. J Chronic obstructive pulmonary disease. An original Psychosom Res. 2005;59(6):429Ð43. model of cognitive decline. Am Rev Respir Dis. 18. Agle DP, Baum GL. Psychological aspects of chronic 1993;148(2):418Ð24. obstructive pulmonary disease. Med Clin North Am. 35. Stuss DT, Peterkin I, Guzman DA, Guzman C, et al. 1977;61(4):749Ð58. Chronic obstructive pulmonary disease: effects of 19. Norwood R. Prevalence and impact of depression in hypoxia on neurological and neuropsychological mea- chronic obstructive pulmonary disease patients. Curr sures. J Clin Exp Neuropsychol. 1997;19(4):515Ð24. Opin Pulm Med. 2006;12(2):113Ð7. 36. Ozge C, Ozge A, Unal O. Cognitive and functional 20. Wamboldt FS. Anxiety and depression in COPD: a deterioration in patients with severe COPD. Behav call (and need) for further research. COPD. Neurol. 2006;17(2):121Ð30. 2005;2(2):199Ð201. 37. Krop HD, Block AJ, Cohen E. Neuropsychological 21. Weaver TE, Narsavage GL. Physiological and psy- effects of continuous oxygen therapy in chronic obstruc- chological variables related to functional status in tive pulmonary disease. Chest. 1977;64:317Ð22. chronic obstructive pulmonary disease. Nurs Res. 38. Grant I, Prigatano GP, Heaton RK, McSweeny AJ, 1992;41(5):286Ð91. et al. Progressive neuropsychologic impairment and 22. Gift AG, McCrone SH. Depression in patients with hypoxemia. Relationship in chronic obstructive pul- COPD. Heart Lung. 1993;22(4):289Ð97. monary disease. Arch Gen Psychiatry. 1987;44(11): 23. van Ede L, Yzermans CJ, Brouwer HJ. Prevalence of 999Ð1006. depression in patients with chronic obstructive pul- 39. Antonelli Incalzi R, Marra C, Giordano A, Calcagni monary disease: a systematic review. Thorax. ML, et al. Cognitive impairment in chronic obstruc- 1999;54(8):688Ð92. tive pulmonary disease—a neuropsychological and 24. Aydin IO, Ulusahin A. Depression, anxiety comorbid- spect study. J Neurol. 2003;250(3):325Ð32. ity, and disability in tuberculosis and chronic obstruc- 40. Liesker JJ, Postma DS, Beukema RJ, ten Hacken NH, tive pulmonary disease patients: applicability of et al. Cognitive performance in patients with COPD. GHQ-12. Gen Hosp Psychiatry. 2001;23(2):77Ð83. Respir Med. 2004;98(4):351Ð6. 466 E. Kozora and K.F. Hoth

41. Kozora E, Filley CM, Julian LJ, Cullum CM. Cognitive following medical therapy. J Cardiopulm Rehabil functioning in patients with chronic obstructive pul- Prev. 2010;30(4):251Ð9. monary disease and mild hypoxemia compared with 48. Greene CC, Bradley KA, Bryson CL, Blough DK, patients with mild Alzheimer disease and normal et al. The association between alcohol consumption controls. Neuropsychiatry Neuropsychol Behav and risk of COPD exacerbation in a veteran popula- Neurol. 1999;12(3):178Ð83. tion. Chest. 2008;134(4):761Ð7. 42. Ortapamuk H, Naldoken S. Brain perfusion abnor- 49. Zigmond AS, Snaith RP. The hospital anxiety and depres- malities in chronic obstructive pulmonary disease: sion scale. Acta Psychiatr Scand. 1983;67(6):361Ð70. comparison with cognitive impairment. Ann Nucl 50. Wechsler D. Wechsler adult intelligence scale— Med. 2006;20(2):99Ð106. Fourth edition. San Antonio, TX: Pearson Education, 43. Toshima MT, Kaplan RM, Ries AL. Experimental Inc.; 2008. evaluation of rehabilitation in chronic obstructive 51. Reitan RM, Wolfson D. The Halstead-Reitan neurop- pulmonary disease: short-term effects on exercise sychology test battery. Tucson: Neuropsychological endurance and health status. Health Psychol. Press; 1988. 1990;9(3):237Ð52. 52. Brandt J, Benedict RH. Hopkins Verbal Learning 44. Emery CF, Leatherman NE, Burker EJ, MacIntyre Test—Revised. Lultz, FL: Psychological Assessment NR. Psychological outcomes of a pulmonary rehabili- Resources, Inc.; 1991. tation program. Chest. 1991;100(3):613Ð7. 53. Benedict RH. Brief Visuospatial Memory Test— 45. Kozora E, Tran ZV, Make B. Neurobehavioral Revised. Lutz, FL: Psychological Assessment improvement after brief rehabilitation in patients with Resources, Inc.; 1997. chronic obstructive pulmonary disease. J Cardiopulm 54. Fastenau PS, Denburg NL, Mauer BA. Parallel short Rehabil. 2002;22(6):426Ð30. forms for the Boston Naming Test: psychometric 46. Kozora E, Emery CF, Ellison MC, Wamboldt FS, properties and norms for older adults. J Clin Exp et al. Improved neurobehavioral functioning in Neuropsychol. 1998;20(6):828Ð34. emphysema patients following lung volume reduction 55. Borkowski JG, Benton AL, Spreen O. Word ﬂ uency surgery compared with medical therapy. Chest. and brain damage. Neuropsychologia. 1967;5:135Ð40. 2005;128(4):2653Ð63. 56. Kozora E, Cullum CM. Qualitative features of clock 47. Kozora E, Emery CF, Zhang L, Make B. Improved drawings in normal aging and Alzheimer’s disease. neurobehavioral functioning in emphysema patients Assessment. 1994;1(2):179Ð88. Hepatic Encephalopathy 2 9 Robin C. Hilsabeck and Amy L. Webb

Abstract Hepatic encephalopathy (HE) is a metabolically-induced, usually reversible neuropsychiatric syndrome that results in signiﬁ cant morbidity and mortality. The incidence is unknown, but it is estimated that most individuals with cirrhosis develop some degree of HE, and advanced age is a risk factor. Cognitive, behavioral, and motor dysfunction are the characteristic features, although the pattern and severity differ among grades. Neuropsychologists are most likely to encounter HE in the context of liver transplant evaluations. The current chapter reviews the classiﬁ cation and pathogenesis of HE, diagnosis and treatment considerations, and also provides a clinical case example and reviews practical issues that will arise for neuropsychologists involved in the care of patietns with HE.

Keywords Minimal hepatic encephalopathy • Portosystemic encephalopathy • End-stage liver disease • Chronic liver disease • Cirrhosis • Neuropsychological • Neuroimaging • Neurophysiological

R. C. Hilsabeck , Ph.D., ABPP () A. L. Webb , M.D. Psychology Service, South Texas Veterans Health Care Psychology Service, South Texas Veterans Health Care System , 7400 Merton Minter Blvd. , San Antonio , TX System , 7400 Merton Minter Blvd. , San Antonio , TX 78229 , USA 78229 , USA Department of Psychiatry , University of Texas Health Hepatology Clinic, South Texas Veterans Health Care Science Center at San Antonio , San Antonio , TX , USA System , San Antonio , TX , USA Department of Psychiatry , University of California, Department of Medicine , University of Texas Health San Diego , San Diego , CA , USA Science Center at San Antonio , San Antonio , TX , USA e-mail: [email protected] e-mail: [email protected]

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 467 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_29, © Springer Science+Business Media, LLC 2013 468 R.C. Hilsabeck and A.L. Webb

Hepatic encephalopathy (HE), also referred to as Table 29.1 Nomenclature of hepatic encephalopathy (HE) portosystemic encephalopathy (PSE), is a meta- Type of HE Subcategory of HE bolically induced, usually reversible neuropsy- A—associated with Episodic—onset of delirium chiatric syndrome resulting from failure of the acute liver failure (without evidence of preexisting liver to perform its detoxifying function. HE is dementia) that may develop spontaneously or after a precipitat- usually associated with acute and/or chronic liver ing event and may be recurrent dysfunction but can also be due to portosystemic (i.e., occur more than once within shunts that divert portal blood into circulation a year) before removal of toxins by the liver. In its mild- B—associated with Persistent—continuing cognitive est form, HE manifests as subtle cognitive or portal–systemic impairment that interferes with bypass without social and/or occupational motor dif fi culties that may not be detectable upon intrinsic liver functioning that may be mild clinical exam alone. HE is one of the most seri- disease (grade 1) or severe (grades 2–4) ous complications of liver dysfunction and is a or recur soon after treatment is feature of fulminant hepatic failure. In its most discontinued severe form, HE results in coma and death. C—associated with Minimal—continuing cognitive cirrhosis impairment without obvious Between one-third and one half of hospitaliza- and portal mental status changes (grade 0) tions of patients with cirrhosis are due to HE, and hypertension or that may negatively affect daily the frequency of hospitalization for HE has portal–systemic activities (e.g., driving)—for- doubled over the past decade, with average shunts merly referred to as “subclinical” hospital stays between 5 and 7 days [ 1 , 2 ] . HE is a marker of poor prognosis [ 3], resulting in on severity of HE. Importantly, use of the term death in over 75% of patients within 3 years of “subclinical” HE was discouraged due to con- their fi rst episode [ 4] . In patients with acute liver cern that it trivialized the clinical signifi cance failure, prognosis is even grimmer, with only of a condition with detrimental effects on ability about half surviving hospitalization [ 5 ] . Although to perform complex tasks like driving [ 8– 13 ] , rare, acute liver failure is the most frequent indi- and health-related quality of life (HRQOL) cation for emergency liver transplantation in [14– 17 ] , and outcome [18– 23 ] . most countries [6 ] . Severity of HE is graded on a scale from 0 to 4, where 0 represents a normal clinical examination and 4 is coma. Grade 0 is also known as Classi fi cation and Grading of HE “minimal HE,” and grades 1–4 are considered “overt HE.” The most widely used method of In 1998, a working party was convened at the 11th grading HE is the West Haven Criteria (WHC) World Congress of Gastroenterology to standard- [ 24, 25] , which is determined by clinical exami- ize the defi nition and classifi cation of HE in an nation and based on the subjective evaluation of effort to bring consistency to the literature for the clinician (see Table 29.2 ). This method has more precise study, particularly in clinical trials. been criticized for lack of sensitivity to detect Nomenclature for type and subcategories of HE subtle brain dysfunction [ 26 ] . Neuropsychological was proposed and is shown in Table 29.1 [ 7 ] . or neurophysiological measures are recom- The type of HE is based on underlying liver mended to identify less severe stages of HE [ 7, dysfunction. Type A is associated with a cute 27 ] . It is important to remember that although liver dysfunction, type B with portosystemic specifi c criteria have been determined to be char- b ypass in the absence of liver disease, and type acteristic of each grade, clear distinctions between C with liver c irrhosis, which is the most common. grades sometimes cannot be made, and patients The subcategories of episodic, persistent, and may fl uctuate from grade to grade within minutes minimal are based partly on course and partly or hours, further clouding the clinical picture. 29 Hepatic Encephalopathy 469

Table 29.2 West Haven criteria for grading hepatic source of blood fl ow to the liver. A healthy liver encephalopathy (HE) would quickly convert ammonia into urea, which Grade Characteristics would then be excreted primarily by the kidneys. 0 No abnormalities In the presence of liver dysfunction, ammonia is 1 Trivial lack of awareness synthesized more slowly into urea or not at all, Euphoria or anxiety allowing ammonia to accumulate in the blood Shortened attention span Impairment of addition or subtraction stream. Healthy muscle tissue metabolizes 2 Lethargy or apathy ammonia in this manner, but individuals with Disorientation for time cirrhosis are impaired due to muscle wasting, Obvious personality change physician recommendations for low-protein Inappropriate behavior “liver failure” diets, and an increased catabolic 3 Somnolence or semi-stupor Responsive to stimuli state (i.e., when the body is breaking down tis- Confused, gross disorientation sue). Certain medications (e.g., benzodiazepines) Bizarre behavior sensitize the central nervous system (CNS) to 4 Coma ammonia, even at normal levels. Natural benzodiazepines may also be important since a benzo- Although the true incidence of HE is unknown, diazepine antagonist (e.g., fl umazenil) brie fl y it is estimated that most, if not all, individuals improves the clinical course of some patients with cirrhosis eventually develop some degree of who were not administered pharmaceutical doses HE, and advanced age is a risk factor [ 28 ] . Overt of benzodiazepines [ 39 ] . HE is estimated to affect about 10% of patients When pathologic ammonia is allowed to with well-compensated cirrhosis (i.e., no serious reach the brain, astrocytes provide the primary complications) and about 40% of patients with means to eliminate it through the synthesis of decompensated cirrhosis, [ 29, 30 ] and is consid- glutamine [35 ] . Glutamine is produced by add- ered the “hallmark” of acute liver failure [31 ] . ing one molecule of ammonia to glutamate, Rates of minimal HE are more diffi cult to deter- which is an amino acid present in over 90% of mine since it may be missed on clinical examina- neurons where it acts as an excitatory neu- tion, but it has been estimated to be present in rotransmitter. As glutamine accumulates, its 50–80% of cirrhotic patients when appropriately osmotic effect causes the astrocyte to take in sensitive methods are used for identifi cation water, resulting in brain edema and increased [32– 34 ] . intracranial pressure (ICP). Thus, HE is hypothesized to occur when astrocytes are unable to maintain osmotic equilibrium in response to the Pathogenesis ammonia-induced increase in glutamine. On autopsy, astrocytes of patients with chronic The exact mechanisms underlying HE are com- liver disease show morphologic features char- plex and still largely unknown, but ammonia acteristic of Alzheimer type II astrocytosis neurotoxicity plays a major role [ 35– 38 ] . A pri- (e.g., pale, enlarged, and frequently paired mary reason ammonia may build up in the blood nuclei, prominent nucleole, proliferation of stream is disruption of the urea cycle. Urea is a cytoplasmic organelles) [ 35 ] . nitrogen-containing waste product of protein Another by-product of the ammonia- metabolism. When protein is metabolized, induced increase in glutamine that may con- deamination (break down) of amino acids pro- tribute to the pathogenesis of HE is oxidative duces ammonia. In addition to protein metabo- stress [ 40– 42 ] , which results when reactive lism, intestinal bacteria produce ammonia which oxygen species (ROS) such as free radicals is then absorbed into the portal system, the major and peroxides cannot be removed ef fi ciently, 470 R.C. Hilsabeck and A.L. Webb causing signi fi cant damage to cell structures Table 29.3 Common precipitating factors of hepatic and even cell death. Ammonia has been shown encephalopathy (HE) to generate ROS when added to astrocyte cul- Electrolyte imbalance tures [ 43, 44 ] , and glutamine increases free Hyponatremia—abnormally low levels of sodium in radical production [45 ] . Ammonia also induces the blood oxidative and nitrosative stress in mitochon- Hypokalemia—abnormally low levels of potassium in the blood dria after being carried in and released by glu- Metabolic alkalosis—pH or acidity of tissue is tamine [ 46– 48 ] . elevated above normal levels Other neurotransmitter systems also are Increased nitrogen load affected by ammonia both directly and indirectly Gastrointestinal bleeding through alteration of transmitter synthesis and Excess dietary protein recirculation [ 35, 49 ] . Altered serotonergic and Azotemia—abnormally high levels of nitrogen-con- dopaminergic transmission has been described taining compounds (e.g., urea) in the blood [50– 52 ] , as has activation of glutamatergic Constipation NMDA receptors and modulation of g -aminobu- Central nervous system-acting drugs (especially narcotics, tranquilizers, and sedatives) tyric acid (GABA) receptors by elevated levels Infection (particularly bacterial peritonitis, urinary of neurosteroids and endogenous benzodiaz- tract, skin, or pulmonary) epines [ 53, 54 ] . Overstimulation of excitatory Surgery NMDA receptors by ammonia has been shown Dehydration to induce neuromodulation, neurodegeneration, Urinary obstruction and neuronal apoptosis [ 53 ] . Renal failure In fl ammatory mediators, such as pro- Transjugular intrahepatic portosystemic shunt (TIPS), in fl ammatory cytokines like tumor necrosis particularly in patients aged 60 and older factor-alpha (TNF-a ), interleukin-(IL)-1, and Superimposed liver injury from acute hepatitis, drug-induced liver injury, etc. IL-6, whether produced in the brain as a result Hepatocellular carcinoma of edema and/or ICP or in the periphery in Terminal liver disease response to infection, also have been implicated in the pathogenesis of HE [ 40, 42, 55 ] . This hypothesis is supported by a more rapid progression to severe HE in the presence of infec- load, medications, infection, and/or a host of tion in patients with acute liver failure [ 56, 57 ] , other factors (see Table 29.3 ). Once HE and any as well as astrocyte swelling induced by precipitating factors are identifi ed and treated, cytokine exposure in cell cultures [ 58 ] . patients usually return to baseline functioning within a few days (i.e., episodic HE). In cases of persistent HE, which is less common, the Clinical Presentation patient’s mental status continues to fl uctuate for more than 4 weeks without returning to base- Cognitive, behavioral, and motor dysfunction line and this is an indication for liver transplan- are the characteristic features of HE, although tation [60 ] . the pattern and severity differ among grades. The most severe grade of HE, grade 4, is the Patients with overt HE display changes in men- easiest to recognize, as patients are usually in a tal status over the course of hours or days con- coma. Although patients may respond to pain, sistent with the diagnostic criteria for delirium there often is no response to voice or gentle phys- detailed in the Diagnostic and Statistical Manual ical prodding and no spontaneous speech. Patients of Mental Disorders, Fourth Edition—Text may open their eyes, but this is not done on com- Revision (DSM-IV-TR) [ 59 ] . Overt HE can mand or in conjunction with any purposeful develop spontaneously, but is often precipitated behavior. Decerebrate or decorticate posturing by electrolyte imbalances, increased nitrogen may be seen, even without sternal pressure [ 61 ] 29 Hepatic Encephalopathy 471 and may be a sign of raised ICP. Increased ICP is more than usual or have reversal in their sleep– associated with poor outcome, including high wake cycle, so they sleep more during the day rates of mortality, if not controlled [62 ] . and need medication to sleep at night. These Hallmarks of grade 3 are somnolence and con- patients often can perform simple arithmetic but fusion, including disorientation to place [ 63 ] . have trouble with multiplication or division. Patients in grade 3 are dif fi cult to rouse and keep Handwriting may be small and diffi cult to read. awake and may not orient to the clinician. Once Similar to patients in grade 2, memory for recent awakened, they have trouble paying attention and events is impaired. Motor abnormalities are participating in conversation. They may act similar to those displayed by patients in grade strangely and laugh inappropriately, display para- 2, as well, although dysarthria, tremor, and noia, or become easily agitated. Motor fi ndings hyperre fl exia are the most common in grade 1 may include clonus (i.e., rapid involuntary mus- [63, 64] . It is important to remember, however, cle contraction and relaxation after forced exten- that motor abnormalities in overt HE can be tran- sion or stretching), Babinski’s sign (i.e., toes sient and do not always align with a particular splay out instead of curve inward when sole of grade of HE. The possible exception to this is foot is rubbed with a blunt instrument), or nystag- asterixis, which, when present, is usually an indi- mus (i.e., rapid involuntary eye movements that cator of grade 2 [60 ] . are usually side to side but can be up and down). As noted above, patients with minimal HE, or In grade 2, patients are often lethargic but easy grade 0, usually display no obvious abnormali- to arouse and engage in conversation. Their ties on clinical exam. However, they sometimes movements and thinking are slow. Their speech exhibit subtle motor dysfunction, with motor tends to be slow and monotonous and also may akinesia (i.e., diffi culty initiating motor move- be soft and dysarthric. They typically are aware ments), tremor, and rigidity being most common of their location (i.e., setting and city) but usually [ 65] . They or their family members may com- are not oriented to time (i.e., month or day of the plain of cognitive problems, disturbances in week). Although most can obey simple commands sleep, appetite, and sexuality, and reduced and recognize common objects, they typically effi ciency in performing work and home activi- cannot perform simple addition and subtraction ties. Ability to perform basic activities of daily and have trouble remembering recent events. living, such as bathing and dressing, are often Cranial nerves are usually intact, but patients in not affected. Cognitive testing displays a fron- grade 2 may display either decreased or increased tal–subcortical pattern of defi cits, with impair- tone and/or deep tendon refl exes, reduced speed ments most often seen in psychomotor speed, or clumsiness of rapid alternating movements, attention/concentration, visuospatial/construc- ataxia, tremor, and/or asterixis (i.e., “ fl apping” of tional skills, and executive functions [66– 68 ] . the wrist when arms are held straight out with Poor performances on measures of learning and wrists fl exed and fi ngers outstretched and widely memory may be found but usually are secondary separated). Patients too lethargic to lift their arms to attentional and visuospatial/perceptual can be instructed to grasp the examiner’s hands dif fi culties rather than de fi cits in memory per se or extend the tongue since sustained movement [ 69, 70 ] . Intellectual functioning and language in patients with asterixis oscillates between tense abilities typically are preserved. and relaxed (i.e., never constant) [34 ] . They may have fetor hepaticus, a uniquely pungent, sweet odor of the breath. Differential Diagnosis Patients in grade 1 HE are usually alert and typically oriented to place and generally to time. Because the symptoms of HE are not specifi c, it They may sometimes appear lethargic, but they should be considered only in patients with known more often report that they are tired, and their or suspected liver disease or other portosystemic sleep–wake cycle is off. They may be sleeping shunts. The clinician must additionally rule out 472 R.C. Hilsabeck and A.L. Webb

Table 29.4 Hepatic encephalopathy differential diagnosis fecal nitrogen excretion. It is usually administered Intracranial bleeding orally, but in the more severe grades of HE or Subdural hematoma in patients with ascites (i.e., fl uid retention in Intracranial hemorrhage the abdominal cavity) or peritonitis (i.e., Metabolic encephalopathies caused by infl ammation of visceral or abdominal lining), Uremia administration via retention enema is preferred Sepsis [34, 60 ] . Hypoglycemia In spite of its long-standing and widespread Hypoxia use, the effi cacy of lactulose has been questioned Ketoacidosis [74 ] , and patients are often noncompliant due to Hypercapnea unpleasant side effects, such as increased intesti- Thyroid dysfunction nal gas, abdominal distention and cramping, and Cerebral edema diarrhea [60 ] . Therefore, alternative treatments Ischemic brain disease for HE are a topic of intense study [ 75 ] . Ischemic stroke Transient ischemic attack Nonabsorbable antibiotics, such as neomycin and Central nervous system abscess, encephalitis, or vancomycin, have been suggested with the goal meningitis of reducing bacteria-producing ammonia in the Central nervous system neoplasm gut. However, their effi cacy has not been well Wilson’s disease established, and prolonged use can result in Substance-induced intoxication or withdrawal signifi cant adverse effects (e.g., inner ear and/or Postictal state kidney problems, bacterial resistance, or fungal colonization). A recent and more promising alternative or adjunct to lactulose is rifaximin, a other causes of mental status change with neuro- semisynthetic derivative of rifamycin, which has logical symptoms, including intracranial bleeding, been shown to reduce the number and length of metabolic abnormalities, ischemic brain disease, hospitalizations for HE [ 76, 77 ] . Because of the CNS infection or neoplasm, Wilson’s disease, expense of rifaximin, it has been recommended substance-induced delirium, and postictal state only for patients who are lactulose refractory or (see Table 29.4 ). Seizures and focal neurological intolerant [1, 78 ] . signs, such as hemiparesis and hemiplegia, are Due to the lack of effective treatments for HE, uncommon [71 ] and may suggest another etiology. prevention is the goal [7, 34 ] , particularly given If HE does not resolve within 72 h of treatment, evidence of increased severity of cognitive another cause of encephalopathy or unresolved impairment with each additional episode of overt precipitating factor should be considered. HE [ 79] . Along with diligent management of underlying liver disease and its complications, close monitoring of dietary protein intake is rec- Treatment ommended in patients with a history of HE, as large amounts of protein can increase plasma Given the primary role of ammonia neurotoxicity ammonia levels and possibly precipitate HE in the pathogenesis of HE, management strate- while too little protein correlates with mortality gies focus on reduction and/or elimination of and development of complications [ 80, 81 ] . ammonia, in addition to treatment of precipitat- Findings on dietary supplementation with ing factors, when identifi ed [ 72, 73 ] . The most branched-chain amino acids have been mixed, commonly administered treatment for HE is with some studies showing positive effects on lactulose, which is a nonabsorbable disaccharide cognitive functioning [ 82, 83 ] , particularly in that remains undigested until it reaches the colon. patients with persistent HE [ 84 ] , and prolonged It reduces plasma ammonia levels by inhibiting event-free survival [ 85] , and others showing ammonia production of bacteria and increasing no effect at all [ 86 ] . Liver transplantation is 29 Hepatic Encephalopathy 473 indicated for patients with recurrent episodic or portosystemic shunt and exclude other potential persisting HE due to increased mortality rates [87 ] , causes of encephalopathy. Early identi fi cation of with extracorporeal albumin dialysis serving as a HE is crucial as delays in diagnosis may result in potential bridge to liver transplantation [88, 89 ] . death. A thorough review of possible precipitating factors also is critical so that appropriate treatment can be initiated promptly. For inpatients Clinical Evaluation with HE, examination of mental status should be performed at least 2–3 times a day [34 ] . Although the core manifestations of HE have In determining grade of HE, the WHC been recognized and agreed upon for years, a (Table 29.2 ) can be employed quickly and easily “gold standard” for the diagnosis of HE remains and provides a useful “ballpark” of the patient’s elusive. Defi nition and classifi cation of even the clinical status [27 ] . In more severe grades of HE, basic behavioral and motor alterations needs fur- the Glasgow Coma Scale (GCS) [90 ] may be a ther re fi nement to distinguish among grades of useful adjunct, supplying additional information HE, particularly the less severe grades. Therefore, about ocular and motor responses and thus allow- diagnosis must be based on multiple approaches, ing for wider separation among patients in grades including clinical examination, laboratory 3 and 4 [ 63 ] . In less severe grades, and particularly fi ndings, neuroimaging, neurophysiological mea- in minimal HE, neurocognitive tests and neuro- sures, and neuropsychological assessment. physiological measures are recommended [7 ] . Because some of the items in the WHC are not operationally defi ned and do not correspond well to Clinical Examination the progression of HE, Ortiz and colleagues [ 91 ] developed the Clinical Hepatic Encephalopathy The clinical interview and physical and neuro- Staging Scale (CHESS). The CHESS consists of logical exams are the mainstays for assessing HE. nine manifestations of HE that can be easily The clinician must ensure a history of known or recognized and categorized into dichotomous suspected liver disease or the presence of a groups (see Table 29.5 ) and was designed to

Table 29.5 Clinical Hepatic Encephalopathy Staging Scale (CHESS) 1. Does the patient know which month he/she is in (i.e., January, February)? 0. Yes 1. No, or he/she does not talk 2. Does the patient know which day of the week he/she is in (i.e., Thursday, Friday, Sunday…)? 0. Yes 1. No, or he/she does not talk 3. Can he/she count backwards from 10 to 1 without making mistakes or stopping? 0. Yes 1. No, or he/she does not talk 4. If asked to do so, does he/she raise his/her arms? 0. Yes 1. No 5. Does he/she understand what you are saying to him/her? (based on the answers to questions 1–4) 0. Yes 1. No, or he/she does not talk 6. Is the patient awake and alert? 0. Yes 1. No, he/she is sleepy or fast asleep 7. Is the patient fast asleep, and is it dif fi cult to wake him/her up? 0. Yes 1. No 8. Can he/she talk? 0. Yes 1. He/she does not talk 9. Can he/she talk correctly? In other words, can you understand everything he/she says, and he/she doesn’t stammer? 0. Yes 1. No, he/she does not talk or does not talk correctly 474 R.C. Hilsabeck and A.L. Webb provide a means to monitor the severity of HE. presence of cerebral edema, particularly in acute The CHESS provides a score from 0 (low) to 9 liver failure. Because clinical symptoms of (high), which refl ects the severity of HE, not the increased ICP (e.g., hypertension, bradycardia) grade. Factor analysis supported two factors may not be present, ICP monitoring devices may corresponding to “mild” and “severe” HE, which be helpful to identify cerebral edema early and is consistent with recent proposals to classify prevent herniation until liver transplantation can HE into more clinically meaningful categories of be performed [ 96 ] . Typical neuroimaging fi ndings “low-” (grades 1 and 2) or “high-grade” (grades 3 in HE include hyperintensities in the globus and 4) rather than trying to make fi ne-grained dif- pallidus on magnetic resonance imaging (MRI) ferentiations among grades 0–4. Like the WHC, T1-weighted images (see Fig. 29.1 ), elevated the CHESS should be augmented with the GCS glutamine/glutamate peaks and decreased myo- for more severe HE and with neurocognitive and/ inositol and choline signals on proton magnetic or neurophysiological measures for less severe resonance spectroscopy (1 H MRS), and white grades. matter abnormalities on MRI fast fl uid-attenuated A modifi ed version of the WHC, the Hepatic inversion recovery sequences (FLAIR) and Encephalopathy Scoring Algorithm (HESA), was diffusion-weighted images (DWI) [97 ] . In cirrhotic developed by Hassanein and colleagues [ 64 ] in patients with minimal HE, T2 hyperintensities an attempt to improve its objectivity and sensitiv- along the corticospinal tract (see Fig. 29.2 ) are ity. The HESA combines the clinical exam with suggestive of mild edema [98, 99 ] and have been neuropsychological tests to determine HE grade, found to relate to abnormalities in central motor relying heavily on subjective clinical evaluation pathways that resolve (as do some cognitive in the more severe grades where neuropsycho- dif fi culties) after liver transplantation [100 ] . In logical testing is not possible and more heavily patients with HE due to portosystemic shunt and on objective testing in the less severe grades no liver disease, MRI can be especially helpful as where dysfunction may not be as evident on clin- dietary manganese that is not cleared by the liver ical exam (see Table 29.6 ). Initial fi ndings con fi rm accumulates in the basal ganglia and is detected increased sensitivity and accuracy of the HESA as hyperintensities on T1-weighted images when compared to the WHC in grading HE [64 ] . exam may have found mild Parkinson-like movement changes only [94 ] .

Laboratory Findings Neurophysiological Measures Blood ammonia levels are often elevated in patients with overt HE but do not always corre- Advantages of neurophysiological measures are late with HE grade [ 92, 93 ] . However, signi fi cantly that they are not in fl uenced by demographic vari- elevated blood ammonia levels (>150–200 m mol/l) ables, such as gender, education, or cultural back- in a comatose patient without a history of recent ground, and they are easy to administer by staff seizures are strongly suggestive of HE [60 ] . It without extensive training. Electroencephalogram is important to perform the assay within 30 min (EEG) has been used to diagnose HE since the of drawing blood, or levels may be arti fi cially 1950s [101 ] . However, because fi ndings are not in fl ated [94 ] . specifi c to HE, EEG and other neurophysiological measures are most useful in the comatose patient [102 ] , when the diagnosis is uncertain (i.e., focal Neuroimaging neurological signs or seizure activity is present or the patient has “normal” mental status) or when The primary role of neuroimaging in evaluation evidence of worsening HE is needed [ 103 ] . The of HE is to rule out other possible etiologies of most common EEG fi ndings in HE are slowed neurobehavioral changes [ 95 ] and to establish the mean dominant frequencies, and in minimal HE, Table 29.6 Hepatic Encephalopathy Scoring Algorithm (HESA)

Fig. 29.1 Hyperintensities in the globus pallidus second- failure and parkinsonism. Observe the bilateral and sym- ary to hepatic encephalopathy. Transverse T1-weighted metric high T1 signal-intensity change involving the glo- MR images of the brain in a patient with chronic liver bus pallidus and the anterior midbrain 476 R.C. Hilsabeck and A.L. Webb

Fig. 29.2 Hyperintensities in the corticospinal tract sec- nal intensity along the corticospinal tract in both cerebral ondary to hepatic encephalopathy. ( a ) Transverse hemispheres. (b ) This signal-intensity abnormality almost T2-weighted fast FLAIR images obtained in a patient completely reverses on a follow-up study obtained few with liver cirrhosis during an episode of hepatic enceph- months later, when the patient showed no signs of overt alopathy. Observe the symmetric areas of increased sig- hepatic encephalopathy you may see relatively slowed activity within the Neuropsychological Assessment d (delta) and q (theta) frequency bands [104 ] . In patients with minimal HE, changes in EEG have Neuropsychologists are most likely to encounter been shown to be predictive of developing overt HE in the context of liver transplant evaluations. HE and thus may have prognostic utility [ 23 ] . Pre-transplant evaluations usually are conducted EEG has been criticized for use in detecting HE on an outpatient basis, but occasionally they because it measures cortical rather than subcor- must be performed while the patient is hospital- tical activity, which is where most of the pathology ized and awaiting transplantation. Of course, the in HE is hypothesized to exist. possibility of HE, particularly minimal HE, must Other neurophysiological measures that have always be considered in patients with cirrhosis, been used to identify HE include evoked poten- regardless of reason for referral or inpatient tials (EPs) and critical fl icker frequency (CFF). versus outpatient status. Neuropsychologists EPs, the latency between presentation and detec- also are called upon to assess for HE in the con- tion of a stimulus, may be slightly delayed in text of clinical trials for management of HE and patients with minimal HE, shown most often when insertion of a transjugular intrahepatic using P300 oddball paradigms [ 22, 105– 107 ] , but portosystemic shunt (TIPS) for management of fi ndings are not speci fi c and often confounded by portal hypertension is planned [ 112 ] . Onset or alcohol use or diabetes, which also delay EPs, worsening of HE is common after placement of and are frequently found in patients with cirrho- TIPS, occurring in 35–55% of patients within sis [108 ] . In CFF, the patient is asked to press a the fi rst year [ 113 ] . Baseline assessment and button when a steady light has changed into a subsequent monitoring is important for identify- fl icker and when a fl ickering light has become a ing and treating HE before it escalates and the steady, fused light. Patients with minimal and patient’s status becomes critical, particularly in lower grades of HE have shown reduced ability the fi rst 3 months, since 90% of post-TIPS HE to detect the light fl ickering or fusing [109– 111 ] . 29 Hepatic Encephalopathy 477 occurs in this time frame [113, 114] . The level of As with any patient referred for neuropsycho- neuropsychological assessment will depend on logical assessment, ruling out other possible the severity of HE, with more comprehensive causes of cognitive impairment, including stroke, testing reserved for those with grades 0 or 1. It seizure disorder, traumatic brain injury, or other often is dif fi cult for patients with grades 2 and 3 neuromedical condition, is necessary. Gathering to participate reliably for more than 10–15 min. information about psychiatric and substance use Fatigue is also frequently a factor, even in histories, academic and social functioning, and patients with no or minimal HE, so full day family medical history also is important for dif- evaluations are not routinely employed. ferential diagnosis. Information from a collateral source is helpful when assessing patients with minimal HE due to the possibility of poor insight Clinical Interview and/or awareness [ 115 ] and essential when assessing patients with overt HE who often can- Changes in cognitive and motor functioning not report reliably. secondary to minimal HE are often subtle and result in cognitive inef fi ciencies rather than frank impairment, but still signifi cantly affect daily Test Selection functioning, including ability to work and drive. With regard to driving, patients with minimal HE Selection of measures will depend on the setting report more traffi c violations and motor vehicle (inpatient vs. outpatient), severity of HE, and rea- accidents than those without cognitive dysfunc- son for evaluation (e.g., pre-transplant, monitor- tion [11– 13 ] . Common cognitive complaints ing of HE in clinical trials or following TIPS). In include trouble paying attention, concentrating, the case of pre-transplant outpatient evaluations, remembering, and completing tasks. Aphasia, most patients are either unimpaired or have mini- signi fi cant memory problems such as repeating mal HE, so comprehensive neuropsychological stories or forgetting recent events even when evaluation is appropriate. Assessment of current reminded, and lateralized motor problems (i.e., intellectual and/or estimated premorbid function- weakness or motor abnormality on one side only) ing, language, visuospatial/constructional skills, are uncommon and usually indicate another etiol- attention and processing speed, executive func- ogy. Patients often have diffi culty pinpointing tioning, learning and memory, emotional status, when the symptoms began, but usually indicate and HRQOL is recommended. Because one of that they are not worsening signi fi cantly over the purposes of the pre-transplant evaluation is to time. Report of gradual cognitive decline over rule out neurodegenerative diseases, such as time in the absence of recurrent episodic HE is Alzheimer’s disease, it is important to include suggestive of possible neurodegenerative disease tests that can distinguish cortical from subcorti- process, psychological factors, or medical condi- cal patterns of de fi cits. A couple of studies have tions other than minimal HE contributing to found support for the utility of the Repeatable cognitive complaints. Battery for the Assessment of Neuropsycho- Additional complaints often include fatigue logical Status (RBANS) [116 ] in pre-transplant and changes in appetite, sleep, energy, and activity evaluations [ 117, 118 ] , with one study con fi rming levels. Patients with minimal HE report reduced the expected subcortical pattern of defi cits using HRQOL, such as limited social interactions and the Randolph Cortical-Subcortical Deviation recreational pastimes and dif fi culties managing Score detailed in the RBANS manual [ 118 ] . home and work duties [ 14– 17 ] . Although the When pre-transplant evaluations must be con- patient may endorse affective symptoms, it is ducted on an inpatient basis and the patient can important to establish that these changes do not tolerate more detailed assessment (i.e., is at occur in conjunction with increasingly depressed grade 2 HE or less), the RBANS may be a good or anxious mood. choice since it taps multiple cognitive domains, 478 R.C. Hilsabeck and A.L. Webb can be administered in less than 30 min, and is of the goals of the HESA [ 64 ] , which allows one to easy to transport. measure changes in HE severity across all grades With regard to emotional status, brief self- and is now required in Federal Drug Administration report measures rather than longer measures of (FDA)-sponsored studies. Although more valida- psychopathology (e.g., Minnesota Multiphasic tion of the HESA is needed, particularly in the Personality Inventory—2) [ 119 ] are used to mini- lower grades, it is a viable option for clinical trials, mize fatigue. Of course, if there are concerns as the neuropsychological measures administered about signifi cant psychopathology, particularly are well known and widely used with modifi cations in the context of pre-transplant evaluation, use of to ensure feasibility of administration and scoring a more comprehensive measure of psychological in the inpatient setting while maintaining sensitiv- functioning may be warranted. For HRQOL, ity for detecting impairment. the Medical Outcomes Study Short Form (SF-36) When the goal is to identify the presence of [ 120] is commonly used and enables comparisons minimal HE outside the context of pre-transplant to other chronic diseases, but disease specifi c evaluation or clinical trials, such as when con- measures also are available, including the Chronic ducting evaluations pre- and post-TIPS insertion Liver Disease Questionnaire [121 ] , the National or for monitoring risk of developing overt HE Institute of Diabetes and Digestive and Kidney during clinic visits, a comprehensive battery may Disease (NIDDK)—Quality Assessment [122 ] , not be necessary or appropriate. The consensus and Liver Disease Quality of Life Instrument statement generated by the 1998 working group [123 ] . Recently, a measure of HRQOL for use mentioned previously [7 ] recommended at least speci fi cally with minimal HE patients showed two of the following four measures be used to promising initial validity [ 124 ] . Table 29.7 dis- assess for minimal HE: Parts A and B of the Trail plays a sample outpatient pre-transplant battery Making Test (TMT) [ 125 ] (also known as the and suggested modi fi cations for inpatient status. Number Connection Test), block design test, and When monitoring HE in the course of clinical digit symbol test. Also recommended was the trials, you want to select measures that can be Psychometric Hepatic Encephalopathy Score completed by patients with more severe HE but (PHES) [ 126 ] , which has been validated in sev- also are sensitive enough to detect subtle changes eral languages across several countries, including in cognition in the less severe grades. This was one Germany, Italy, and Spain [ 127 ] . The PHES is a composite score based on demographic-adjusted z-scores from Parts A and B of the TMT, digit Table 29.7 Sample neuropsychological battery for symbol, line tracing, and serial dotting (see Fig. 2 pre-transplant evaluation in Chap. 23 for a picture of the latter two mea- Wechsler Test of Adult Reading [137 ] sures). Scores £ −4 are considered to refl ect mini- Repeatable Battery for the Assessment of mal HE. Neuropsychological Status [116 ] The PHES, along with the RBANS, also was Trail Making Test [125 ] recommended recently by a group of experts Stroop Color and Word Test [138 ] convened by the International Society for Hepatic Boston Naming Test [139 ] Encephalopathy and Nitrogen Metabolism Controlled Oral Word Association Test [140 ] (ISHEN) for use in patients at risk for developing Animal Naming [140 ] Wisconsin Card Sorting Test—64-Card Version [141 ] minimal HE [ 128] . One limitation of the PHES Finger Tapping Test [125 ] for use in the United States is that line tracing Grooved Pegboard [142 ] and serial dotting have not yet been normed in Beck Depression Inventory-II [143 ] the United States. A limitation of the RBANS is Beck Anxiety Inventory [144] that it has not been systematically studied as a Chronic Liver Disease Questionnaire [121 ] method for detecting or monitoring HE [ 129 ] . Note: For inpatient evaluations, suggest administration of Computerized cognitive measures are another the fi rst three tests only method beginning to be used, with the Inhibitory 29 Hepatic Encephalopathy 479

Control Task (ICT), a computerized variant of the standard deviations below the normative mean, continuous performance test, showing good ini- and he evidenced a mild tremor while perform- tial validity [ 130– 132] , including ability to pre- ing tasks. He exhibited signifi cant diffi culty dict future car crashes and traf fi c violations [13 ] . copying this version of the RCF, which was modifi ed to be more simplistic than the original fi gure. Even after having viewed the fi gure three Case Example: Characterization times, his learning score (i.e., raw score = 5) of Overt and Minimal HE [133 ] revealed that he did not encode much additional information beyond that encoded on the initial Following is a case example of a 46-year-old (copy) trial (i.e., raw score = 3.5). Moreover, he non-Hispanic White man with end-stage liver forgot half of the details of the fi gure after a disease (ESLD) secondary to hepatitis C virus 20-min delay. On a measure of selective attention, and alcoholic hepatitis. Mr. J graduated from Digit Cancellation, he required a long time to high school and worked primarily as a machinist complete the task and made a signifi cant num- until he became disabled from ESLD. He was ber of errors (both omission and commission). being followed in a hepatology clinic at a univer- He was able to complete the TMT, albeit very sity hospital and agreed to participant in a research slowly, and he made several cognitive-switching study examining quality of life in persons with errors on Part B. On the SDMT, he performed chronic liver disease. As part of this research pro- very slowly and made a few errors. His cogni- tocol, a brief neurocognitive battery consisting of tive and motor fi ndings during this episode of a modifi ed version of the Rey Complex Figure overt HE are typical of those seen in patients Test (RCF) [ 134 ] , Digit Cancellation (DC) [ 134 ] , with grade 1 HE [ 136 ] . Trail Making Test (TMT), and the written version A couple of months later, after his episode of of the Symbol Digit Modalities Test (SDMT) overt HE had resolved, Mr. J’s performance on [135 ] was administered during a routine clinic this brief battery was signi fi cantly improved. His visit. Mr. J completed this battery on three occa- action tremor was gone, and his test scores were sions: once during an episode of overt HE judged essentially within normal limits, except for SDMT, to be grade 1, once during minimal HE, and once which was approximately 1.5 standard deviations 5 months post-transplant. His raw scores on these below the normative mean. Five months post- measures at each of the three time points are pre- transplant, Mr. J exhibited continued improve- sented in Table 29.8 . ment, particularly on measures relying on Cognitive performance on all measures during executive function (i.e., RCF learning, TMT Mr. J’s episode of overt HE was more than three Part B, and SDMT). Although some of these

Table 29.8 Mr. J’s cognitive test performances over time Pre-transplant Pre-transplant 7 months 5 months Post-transplant Grade 1 HE Grade 0 (Minimal) HE 5 months Modi fi ed RCF copy 3.5 20 19 Modi fi ed RCF learning 5 16 19 Modi fi ed RCF% forgotten 50.0 6.3 5.6 DC total time (s) 278 225 200 DC total errors 31 9 9 TMT-A (s) 85 40 34 TMT-B (s) >300 110 60 SDMT 18 31 44 Note: RCF Rey Complex Figure, DC Digit Cancellation, TMT Trail Making Test, SDMT Symbol Digit Modalities Test (written version) 480 R.C. Hilsabeck and A.L. Webb improvements may have been due to practice • In patients with minimal HE, a frontal–subcortical effects, others were too signi fi cant to be attributed pattern of de fi cits and cognitive inef fi ciencies to practice effects alone. The contrast between are characteristic; aphasia, signifi cant forgetting test performances during minimal HE and post- such as that seen in Alzheimer’s disease, and transplant suggests that although Mr. J generally lateralized de fi cits suggest another etiology. performed within normal limits on all but one task • Traf fi c violations and motor vehicle accidents (i.e., SDMT) pre-transplant, he was still perform- are more common in cirrhotic patients with ing below his baseline. The pattern of fi ndings minimal HE than those without, so careful also is consistent with the literature showing com- inquiry about driving is needed, and physician promised frontal–subcortical circuits. recommendation for the patient to stop driving may be advised.

Clinical Pearls References • HE is associated with impaired abilities to perform complex tasks (e.g., driving), reduced 1. Leevy C, Phillips J. Hospitalizations during the use of HRQOL, and poor outcome, including death. rifaximin versus lactulose for the treatment of hepatic encephalopathy. Dig Dis Sci. 2007;52:737–41. • Severity of HE is usually graded on a scale 2. Poordad FF. Review article: the burden of hepatic enceph- from 0 (minimal) to 4 (coma), and sometimes alopathy. Aliment Pharmacol Ther. 2007;25(S1):3–9. distinctions among grades are dif fi cult to 3. Stewart C, Malinchoc M, Kim W, Kamath PS. Hepatic determine due to fl uctuations in a patient’s sta- encephalopathy as a predictor of survival in patients with end stage liver disease. Liver Transpl. tus or limitations in the methods available for 2007;13:1366–71. grading HE. 4. Bustamante J, Rimola A, Ventura PJ, Navasa M, Ciera • Overt HE typically requires hospitalization I, Reggiardo V, et al. Prognostic signifi cance of and quick identi fi cation and treatment of pre- hepatic encephalopathy in patients with cirrhosis. J Hepatol. 1999;30:890–5. cipitating events to prevent continued deterio- 5. Bernuau J, Durand F. Early prediction of encephal- ration and death. opathy in hospitalized patients with severe acute liver • Blood ammonia levels may not correspond to disease: the narrow window of opportunity for trans- clinical severity of HE and have little clinical plant-free survival. J Hepatol. 2009;51:977–80. 6. Bernal W, Auzinger G, Dhawan A, Wendon J. Acute signi fi cance if serially followed. liver failure. Lancet. 2010;376:190–201. • Minimal HE is present in 50–80% of cirrhotic 7. Ferenci P, Lockwood A, Mullen K, Tarter R, patients and usually undetected unless tested Weissenborn K, Blei AT. Hepatic encephalopathy— with neuropsychological or neurophysiologi- de fi nition, nomenclature, diagnosis, and quanti fi cation: fi nal report of the working party at the 11th World cal measures. Congresses of Gastroenterology, Vienna, 1998. • Although HE should be high on the list of Hepatology. 2002;35:716–21. diagnostic possibilities in delirious patients 8. Schomerus H, Hamster W, Blunck H, Reinhard U, with cirrhosis, other causes of mental status Mayer K, Dolle W. Latent portasystemic encephalopathy. I. Nature of cerebral functional defects and their effect change, such as alcohol withdrawal, occult on fi tness to drive. Dig Dis Sci. 1981;26:622–30. gastrointestinal bleed, infection, and dehydra- 9. Watanabe A, Tuchida T, Yata Y, Kuwabara Y. tion, must be ruled out since they are also Evaluation of neuropsychological function in patients common in patients with cirrhosis. with liver cirrhosis with special reference to their driving ability. Metab Brain Dis. 1995;10:239–48. • In patients with worsening of HE but no 10. Wein C, Koch H, Popp B, Oehler G, Schauder P. clear precipitating factor, check for noncom- Minimal hepatic encephalopathy impairs fi tness to pliance with lactulose or other HE treatments drive. Hepatology. 2004;39:739–45. since patients sometimes are not compliant 11. Bajaj JS, Hafeezullah M, Hoffmann RG, Saeian K. Minimal hepatic encephalopathy: a vehicle for acci- due to unpleasant drug side effects or poor dents and traffi c violations. Am J Gastroenterol. memory. 2007;102:1903–9. 29 Hepatic Encephalopathy 481

12. Bajaj JS, Hafeezullah M, Hoffmann RG, Varma RR, systemic encephalopathy. A controlled, double-blind Franco J, Binion DG, et al. Navigation skill impairment: clinical trial. Am J Dig Dis. 1978;23:398–406. dimension of the driving dif fi culties in minimal hepatic 26. Citro V, Milan G, Tripodi FS, Gennari A, Sorrentino encephalopathy. Hepatology. 2008;47:596–604. P, Gallotta G, et al. Mental status impairment in 13. Bajaj JS, Saeian K, Schubert CM, Hafeezullah M, Franco patients with West Haven grade zero hepatic enceph- J, Varma RR, et al. Minimal hepatic encephalopathy is alopathy: the role of HCV infection. J Gastroenterol. associated with motor vehicle crashes: the reality beyond 2007;42:79–82. the driving test. Hepatology. 2009;50:1175–83. 27. Dhiman RK, Saraswat VA, Sharma BK, Sarin SK, 14. Groeneweg M, Quero JC, De Bruijn I, Hartmann IJ, Chawla YK, Butterworth R, et al. Minimal hepatic Essink-bot ML, Hop WC, et al. Subclinical hepatic encephalopathy: consensus statement of a working encephalopathy impairs daily functioning. Hepatology. party of the Indian Association for Study of the Liver. 1998;28:45–9. J Gastroenterol Hepatol. 2010;25:1029–41. 15. Schomerus H, Hamster W. Quality of life in cirrhotics 28. Riggio O, Angeloni S, Salvatori FM, De Santis A, with minimal hepatic encephalopathy. Metab Brain Cerini F. Incidence, natural history, and risk factors of Dis. 2001;16:37–41. hepatic encephalopathy after transjugular intrahepatic 16. Arguedas MR, DeLawrence TG, McGuire BM. portosystemic shunt with polytetra fl uoroethylene- In fl uence of hepatic encephalopathy on health-related covered stent grafts. Am J Gastroenterol. 2008;103: quality of life in patients with cirrhosis. Dig Dis Sci. 2738–46. 2003;48:1622–6. 29. D’Amico G, Morabito A, Pagliaro L, Marubini E. 17. Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma Survival and prognostic indicators in compensated and A, Agarwal R. Lactulose improves cognitive func- decompensated cirrhosis. Dig Dis Sci. 1986;31:468–75. tions and health-related quality of life in patients with 30. Ginés P, Quintero E, Arroyo V, Teres J, Bruguera M, cirrhosis who have minimal hepatic encephalopathy. Rimola A, et al. Compensated cirrhosis: natural history Hepatology. 2007;45:549–59. and prognostic factors. Hepatology. 1987;7:122–8. 18. Amodio P, Del Piccolo F, Marchetti P, Angeli P, 31. O’Grady JG, Schalm SW, Williams R. Acute liver fail- Iemmolo R, Caregaro L, et al. Clinical features and ure: rede fi ning the syndromes. Lancet. 1993;342:273–5. survival of cirrhotic patients with subclinical cogni- 32. Kim WR, Brown RS, Terrault NA, El-Serag H. Burden tive alterations detected by the number connection of liver disease in the United State: Summary of a test and computerized psychometric tests. Hepatology. workshop. Hepatology. 2002;36:227–42. 1999;29:1662–7. 33. Cash WJ, McConville P, McDermott E, McCormick 19. Amodio P, Del Piccolo F, Petteno E, Mapelli D, Angeli PA, Callender ME, McDougall NI. Current concepts P, Iemmolo R, et al. Prevalence and prognostic value in the assessment and treatment of hepatic encephal- of quantifi ed electroencephalogram (EEG) alterations opathy. Q J Med. 2010;103:9–16. in cirrhotic patients. J Hepatol. 2001;35:37–45. 34. Bajaj JS. Review article: the modern management of 20. Das A, Dhiman RK, Saraswat VA, Verma M, Naik hepatic encephalopathy. Aliment Pharmacol Ther. SR. Prevalence and natural history of subclinical 2010;31:537–47. hepatic encephalopathy in cirrhosis. J Gastroenterol 35. Butterworth RF. Effects of hyperammonaemia on brain Hepatol. 2001;16:531–5. function. J Inherit Metab Dis. 1998;21(S1):6–20. 21. Romero-Gomez M, Boza F, Garcia-Valdecasas MS, 36. Shawcross DL, Jalan R. The pathophysiologic basis of García E, Aguilar-Reina J. Subclinical hepatic encephal- hepatic encephalopathy: central role for ammonia and opathy predicts the development of overt hepatic infl ammation. Cell Mol Life Sci. 2005;62:2295–304. encephalopathy. Am J Gastroenterol. 2001;96:2718–23. 37. Cordoba J, Minguez B. Hepatic encephalopathy. 22. Saxena N, Bhatia M, Joshi YK, Garg PK, Tandon RK. Semin Liver Dis. 2008;28:70–80. Auditory P300 event-related potentials and number con- 38. Bjerring PN, Eefsen M, Hansen BA, Larsen FS. The nection test for evaluation of subclinical hepatic enceph- brain in acute liver failure. A tortuous path from alopathy in patients with cirrhosis of the liver: a follow-up hyperammonemia to cerebral edema. Metab Brain study. J Gastroenterol Hepatol. 2001;16:322–7. Dis. 2009;24:5–14. 23. Saxena N, Bhatia M, Joshi YK, Garg PK, Dwivedi 39. Barbaro G, Di Lorenzo G, Soldinui N, Giancaspro SN, Tandon RK. Electrophysiological and neuropsy- G, Bellomo G, Belloni G, et al. Flumazenil for chological tests for the diagnosis of subclinical hepatic hepatic encephalopathy grade III and IVa in patients encephalopathy and prediction of overt encephalopathy. with cirrhosis: an Italian multicentre double-blind, Liver. 2002;22:190–7. placebo-controlled, cross-over study. Hepatology. 24. Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, 1998;28:374–8. Maddrey WC, Seeff L, et al. Comparison of lactulose 40. Haussinger D, Schliess F. Pathogenetic mechanisms and neomycin in the treatment of chronic portal-systemic of hepatic encephalopathy. Gut. 2008;57:1156–65. encephalopathy. Gastroenterology. 1977;72:573–83. 41. Butterworth RF. Thiamine de fi ciency-related brain 25. Atterbury CE, Maddrey WC, Conn HO. Neomycin- dysfunction in chronic liver failure. Metab Brain Dis. sorbitol and lactulose in the treatment of acute portal- 2009;24:189–96. 482 R.C. Hilsabeck and A.L. Webb

42. Seyan AS, Hughes RD, Shawcross DL. Changing face 59. American Psychiatric Association. Diagnostic and of hepatic encephalopathy: role of in fl ammation and oxi- statistical manual of mental disorders. 4 (text revi- dative stress. World J Gastroenterol. 2010;16:3347–57. sion)th ed. Washington, DC: American Psychiatric 43. Master S, Gottstein J, Blei AT. Cerebral blood fl ow and Association; 2000. the development of ammonia-induced brain edema in 60. Munoz SJ. Hepatic encephalopathy. Med Clin North rats after portacaval anastomosis. Hepatology. 1999;30: Am. 2008;92:795–812. 876–80. 61. Wehbe E, Saad D, Delgado F, Ta H, Antoun SA. 44. Kosenko E, Venediktova N, Kaminsky Y, Montoliu C, Reversible hepatic decerebration: a case report and Felipo V. Sources of oxygen radicals in brain in acute review of the literature. Eur J Gastroenterol Hepatol. ammonia intoxication in vivo. Brain Res. 2010;22:759–60. 2003;981:193–200. 62. Mukherjee KK, Chhabra R, Khosla VK. Raised 45. Norenberg MD. Oxidative and nitrosative stress in intracranial pressure in hepatic encephalopathy. Indian ammonia neurotoxicity. Hepatology. 2003;37:245–8. J Gastroenterol. 2003;22(S2):62–565. 46. Rama Rao KV, Jayakumar AR, Norenberg MD. 63. Hassanein T, Blei AT, Perry W, Hilsabeck R, Stange J, Role of oxidative stress in the ammonia-induced Larsen FS, et al. Performance of the Hepatic mitochondrial permeability transition in cultured Encephalopathy Scoring Algorithm in a clinical trial astrocytes. Neurochem Int. 2005;47:31–8. of patients with cirrhosis and severe hepatic encephal- 47. Albrecht J, Norenberg MD. Glutamine: a Trojan horse in opathy. Am J Gastroenterol. 2009;104:1392–400. ammonia neurotoxicity. Hepatology. 2006;44: 788–94. 64. Hassanein TI, Hilsabeck RC, Perry W. Introduction to 48. Bjerring PN, Hauerberg J, Frederiksen HJ, Jorgensen the Hepatic Encephalopathy Scoring Algorithm L, Hansen BA, Tofteng F, et al. Cerebral glutamine (HESA). Dig Dis Sci. 2008;53:529–38. concentration and lactate-pyruvate ratio in patients 65. Jover R, Company L, Gutierrez A, Zapater P, Perez- with acute liver failure. Neurocrit Care. 2008;9:3–7. Serra J, Girona E, et al. Minimal hepatic encephalopa- 49. Butterworth RF. Hepatic encephalopathy: a neuropsy- thy and extrapyramidal signs in patients with cirrhosis. chiatric disorder involving multiple neurotransmitter Am J Gastroenterol. 2003;98:1599–604. systems. Curr Opin Neurol. 2000;13:721–7. 66. McCrea M, Cordoba J, Vessey G, Blei AT, Randolph 50. Lozeva V, Montgomery JA, Tuomisto L, Rocheleau C. Neuropsychological characterization and detection B, Pannunzio M, Huet PM, et al. Increased brain sero- of subclinical hepatic encephalopathy. Arch Neurol. tonin turnover correlates with the degree of shunting 1996;53:758–63. and hyperammonemia in rats following variable por- 67. Weissenborn K, Ennen JC, Schomerus H, Ruckert N, tal vein stenosis. J Hepatol. 2004;40:742–8. Hecker H. Neuropsychological characterization of 51. Lozeva-Thomas V. Serotonin brain circuits with a hepatic encephalopathy. J Hepatol. 2001;34:768–73. focus on hepatic encephalopathy. Metab Brain Dis. 68. Mooney S, Hassanein TI, Hilsabeck RC, Ziegler EA, 2004;19:413–20. Carlson MD, Maron LM, et al. Utility of the Repeatable 52. Pidoplichko VI, Dani JA. Acid-sensitive ionic channels Battery for the Assessment of Neuropsychological in midbrain dopamine neurons are sensitive to ammo- Status (RBANS) in patients with end stage liver dis- nium, which may contribute to hyperammonemia dam- ease awaiting liver transplant. Arch Clin Neuropsychol. age. Proc Natl Acad Sci USA. 2006;103:11376–80. 2007;22:175–86. 53. Albrecht J, Bender AS, Norenberg MD. Potassium- 69. Weissenborn K, Heidenreich S, Giewekemeyer K, stimulated GABA release is a chloride-dependent but Ruckert N, Hecker H. Memory function in early sodium- and calcium-independent process in cultured hepatic encephalopathy. J Hepatol. 2003;39:320–5. astrocytes. Acta Neurobiol Exp (Wars). 1998;58:169–75. 70. Ortiz M, Cordoba J, Jacas C, Flavia M, Esteban R, 54. Ahboucha S, Butterworth RF. Pathophysiology of hepatic Guardia J. Neuropsychological abnormalities in cir- encephalopathy: a new look at GABA from the molecular rhosis include learning impairment. J Hepatol. standpoint. Metab Brain Dis. 2004;19:331–43. 2006;44:104–10. 55. Odeh M. Pathogenesis of hepatic encephalopathy: the 71. Cadranel JF, Lebietz E, De Martino V, Bernard B, El tumor necrosis factor-a theory. Eur J Clin Invest. Koury S, Tourbah A, et al. Focal neurological signs 2007;37:291–304. in hepatic encephalopathy in cirrhotic patients: 56. Rolando N, Wade J, Davalos M, Wendon J, Philpott- underestimated entity? Am J Gastroenterol. 2001;96: Howard J, Williams R. The systemic infl ammatory 515–8. response syndrome in acute liver failure. Hepatology. 72. Morgan MY, Blei A, Grungreiff K, Jalan R, Kircheis 2000;32:734–9. G, Marchesini G, et al. The treatment of hepatic 57. Vaquero J, Polson J, Chung C, Helenowski I, Schiodt encephalopathy. Metab Brain Dis. 2007;22:389–405. FV, Reisch J, et al. Infection and the progression of 73. Phongsamran PV, Kim JM, Abbott JC, Rosenblatt A. hepatic encephalopathy in acute liver failure. Pharmacotherapy for hepatic encephalopathy. Drugs. Gastroenterology. 2003;125:755–64. 2010;70:1131–48. 58. Haussinger D, Schliess F. Astrocyte swelling and pro- 74. Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable tein tyrosine nitration in hepatic encephalopathy. disaccharides for hepatic encephalopathy: systematic Neurochem Int. 2005;47:64–70. review of randomised trials. Br Med J. 2004;328:1046. 29 Hepatic Encephalopathy 483

75. Mullen KD, Amodio P, Morgan MY. Therapeutic 91. Ortiz M, Cordoba J, Dovals E, Jacas D, Pujadas F, studies in hepatic encephalopathy. Metab Brain Dis. Esteban R, et al. Development of a clinical hepatic 2007;22:407–23. encephalopathy staging scale. Aliment Pharmacol 76. Neff GW, Kemmer N, Zacharias V, Kaiser T, Duncan Ther. 2007;26:859–67. C, McHenry R, et al. Analysis of hospitalizations 92. Bass NM. Review article: the current pharmacologi- comparing rifaximin versus lactulose in the manage- cal therapies for hepatic encephalopathy. Aliment ment of hepatic encephalopathy. Transplant Proc. Pharmacol Ther. 2007;25(S1):23–31. 2006;38:3552–5. 93. Sotil EU, Gottstein J, Ayala E, Randolph C, Blei AT. 77. Huang E, Esrailian E, Spiegel BMR. The cost effec- Impact of preoperative overt hepatic encephalopathy tiveness and budget impact of competing therapies in on neurocognitive function after liver transplanta- hepatic encephalopathy—a decision analysis. Aliment tion. Liver Transpl. 2009;15:184–92. Pharmacol Ther. 2007;26:1147–61. 94. Eroglu Y, Byrne WJ. Hepatic encephalopathy. Emerg 78. Maclayton DO, Eaton-Maxwell A. Rifaximin for Med Clin North Am. 2009;27:401–14. treatment of hepatic encephalopathy. Gastroenterology. 95. Mullen K. Review of the fi nal report of the 1998 2009;43:77–84. Working Party on defi nition, nomenclature and diag- 79. Bajaj JS, Schubert CM, Heuman DM, Wade JB, nosis of hepatic encephalopathy. Aliment Pharmacol Gibson DP, Topaz A, et al. Persistence of cognitive Ther. 2007;25(S1):11–6. impairment after resolution of overt hepatic encephal- 96. Jalan R. Pathophysiological basis of therapy of opathy. Gastroenterology. 2010;138:2332–40. raised intracranial pressure in acute liver failure. 80. Kondrup J, Muller MJ. Energy and protein require- Neurochem Int. 2005;47:78–83. ments of patients with chronic liver disease. J Hepatol. 97. Rovira A, Alonso J, Cordoba J. MR Imaging fi ndings 1997;27:239–47. in hepatic encephalopathy. Am J Neuroradiol. 81. Merli M, Riggio O. Dietary and nutritional indica- 2008;29:1612–21. tions in hepatic encephalopathy. Metab Brain Dis. 98. Cordoba J, Alonso J, Rovira A, Jacas C, Sanpedro F, 2009;24:211–21. Castells L, et al. The development of low-grade cere- 82. Egberts EH, Schomerus H, Hamster W, Jurgens P. bral edema in cirrhosis is supported by the evolution Branched chain amino acids in the treatment of latent of 1 H-magnetic resonance abnormalities after liver portosystemic encephalopathy. A double-blind placebo- transplantation. J Hepatol. 2001;35:598–604. controlled cross-over study. Gastroenterology. 1985;88: 99. Rovira A, Cordoba J, Sanpedro F, Grive E, Rovira- 887–95. Gols A, Alonso J. Normalization of T2 signal abnor- 83. Plauth M, Egberts EH, Hamster W. Long-term malities in hemispheric white matter with liver treatment of latent portosystemic encephalopathy transplant. Neurology. 2002;59:335–41. with branched-chain amino acids: a double-blind 100. Cordoba J, Raguer N, Flavia M, Vargas V, Jacas C, placebo-controlled crossover study. J Hepatol. 1993; Alonso J, et al. T2 hyperintensity along the cortico- 17:308–14. spinal tract in cirrhosis relates to functional abnor- 84. Marchesini G, Dioguardi FS, Bianchi GP. The Italian malities. Hepatology. 2003;38:1026–33. multicenter study group. Long-term oral branched- 101. Foley JM, Watson CW, Adams RD. Signi fi cance of chain amino acids in advanced cirrhosis: a double- the electroencephalographic changes in hepatic blind casein-controlled trial. J Hepatol. 1990;11: coma. Trans Am Neurol Assoc. 1950;75:161–5. 92–101. 102. Guerit JM, Amantini A, Amodio P, Andersen KV, 85. Muto Y, Sato S, Watanabe A. Effects of oral branched- Butler S, de Weerd A, et al. Consensus on the use of chain amino acid granules on event-free survival in neurophysiological tests in the intensive care unit patients with liver cirrhosis. Clin Gastroenterol (ICU): electroencephalogram (EEG), evoked poten- Hepatol. 2005;3:705–13. tials (EP), and electroneuromyography (ENMG). 86. Schulz GJ, Campos ACL, Coelho JCU. The role of Clin Neurophysiol. 2009;39:71–83. nutrition in hepatic encephalopathy. Curr Opin Clin 103. Guerit JM, Amantini A, Fischer C, Kaplan PW, Nutr Metab Care. 2008;11: 275–80; Carithers R. Liver Mecarelli O, Schnitzler A, et al. Neurophysiological transplantation. American Association for the Study investigations of hepatic encephalopathy: ISHEN of Liver Diseases. Liver Transpl. 2000; 6:122–35. practice guidelines. Liver Int. 2009;29:789–96. 87. Cordoba J, Minguez B. Hepatic Encephalopathy. 104. Amodio P, Marchetti P, Del Piccolo F, de Sem Liver Dis. 2008;28:70–80. Tourtchaninoff M, Varghese P, Zuliani C, et al. 88. Stange J, Mitzner SR, Klammt S, et al. Liver support Spectral versus visual EEG analysis in mild by extracorporeal blood puri fi cation: a clinical obser- hepatic encephalopathy. Clin Neurophysiol. 1999; vation. Liver Transpl. 2000;6:603–13. 110:1334–44. 89. Stadlbauer V, Wright AK, Jalan R. Role of arti fi cial 105. W eissenborn K, Scholz M, Hinrichs H, Wiltfang J, liver support in hepatic encephalopathy. Metab Brain Schmidt FW, Kunkel H. Neurophysiological assess- Dis. 2009;24:15–26. ment of early hepatic encephalopathy. Electroencephalogr 90. Teasdale G, Jennett B. Assessment of coma and Clin Neurophysiol. 1990;75:289–95. impaired consciousness. A practical scale. Lancet. 106. Kugler CF, Lotterer E, Petter J, Wensing G, 1974;2:81–4. Taghavy A, Hahn EG, et al. Visual event-related 484 R.C. Hilsabeck and A.L. Webb

P300 potentials in early portosystemic encephal- to measure health related quality of life in patients opathy. Gastroenterology. 1992;103:302–10. with chronic liver disease. Gut. 1999;45:295–300. 107. Kugler CF, Petter J, Taghavy A, Lotterer E, Wensing G, 122. Kim WR, Lindor KD, Malinchoc M, Petz JL, Hahn EG, et al. Dynamics of cognitive brain dysfunc- Jorgensen R, Dickson ER. Reliability and validity of tion in patients with cirrhotic liver disease: an event- the NIDDK-QA instrument in the assessment of related P300 potential perspective. Electroencephalogr quality of life in ambulatory patients with cholestatic Clin Neurophysiol. 1994;91:33–41. liver disease. Hepatology. 2000;32:924–9. 108. Amodio P, Montagnese S, Gatta A, Morgan MY. 123. Gralnek IM, Hays RD, Kilbourne A, Rosen HR, Characteristics of minimal hepatic encephalopathy. Keeffe EB, Artinian L, et al. Development and eval- Metab Brain Dis. 2004;19:253–67. uation of the liver disease quality of life instrument 109. Kircheis G, Wettstein M, Timmermann L, Schnitzler in persons with advanced, chronic liver disease- A, Haussinger D. Critical fl icker frequency for the LDQOL1.0. Am J Gastroenterol. 2000;95: quanti fi cation of low-grade hepatic encephalopathy. 3552–65. Hepatology. 2002;35:357–66. 124. Zhou Y, Chen S, Jiang L, Guo C, Shen Z, Huang P, 110. Romero-Gomez M, Cordoba J, Jover R, del Olmo et al. Development and evaluation of the quality of JA, Ramirez M, Rey R, et al. Value of the critical life instrument in chronic liver disease patients with fl icker frequency in patients with minimal hepatic minimal hepatic encephalopathy. J Gastroenterol encephalopathy. Hepatology. 2007;45:879–85. Hepatol. 2008;24:408–15. 111. Sharma P, Sharma BC, Puri V, Sarin SK. Critical 125. Reitan RM, Wolfson D. The Halstead-Reitan fl icker frequency: diagnostic tool for minimal hepatic neuropsychological test battery: theory and clinical encephalopathy. J Hepatol. 2007;47:67–73. interpretation. 2nd ed. Tuscon, AZ: Neuropsychology 112. O’Carroll RE. Neuropsychological aspects of liver Press; 1993. disease and its treatment. Neurochem Res. 2008;33: 126. Weissenborn K, Heidenreich S, Ennen J, Ruckert N, 683–90. Hecker H. Attention defi cits in minimal hepatic 113. Colombato L. The role of transjugular intrahe- encephalopathy. Metab Brain Dis. 2001;16:13–9. patic portosystemic shunt (TIPS) in the manage- 127. Amodio P, Campagna F, Olianas S, Iannizzi P, ment of portal hypertension. J Clin Gastroenterol. Mapelli D, Penzo M, et al. Detection of minimal 2007;41(S3):344–51. hepatic encephalopathy: normalization and optimi- 114. Montagnese S, Schiff S, Catta A, Riggio O, Morgan zation of the Psychometric Hepatic Encephalopathy MY, Amodio P. Hepatic encephalopathy: you should Score. A neuropsychological and quantifi ed EEG only comment on what you have actually measured. study. J Hepatol. 2008;49:346–53. J Gastroenterol. 2010;45:342–3. 128. Randolph C, Weissenborn K, Hilsabeck R, Kato A, 115. Bajaj JS, Saeian K, Hafeezullah M, Hoffmann RG, Kharbanda P, Li Y, et al. Neuropsychological assess- Hammeke TA. Patients with minimal hepatic enceph- ment of hepatic encephalopathy: International alopathy have poor insight into their driving skills. Society on Hepatic Encephalopathy and Nitrogen Clin Gastroenterol Hepatol. 2008;61:1135–9. Metabolism (ISHEN) practice guidelines. Liver Int. 116. Randolph C. Repeatable Battery for the Assessment 2009;29:629–35. of Neuropsychological Status manual. San Antonio, 129. Bajaj JS. Current and future diagnosis of hepatic TX: The Psychological Corporation; 1998. encephalopathy. Metab Brain Dis. 2010;25:107–10. 117. Sorrell JH, Zolnikov BJ, Sharma A, Jinnai I. 130. Bajaj JS, Saeian K, Verber MD, Hischke D, Cognitive impairment in people diagnosed with end- Hoffmann RG, Franco J, et al. Inhibitory control test stage liver disease evaluated for liver transplantation. is a simple method to diagnose minimal hepatic Psychiatry Clin Neurosci. 2006;60:174–81. encephalopathy and predict development of overt 118. Mooney S, Hasssanein TI, Hilsabeck RC, Ziegler hepatic encephalopathy. Am J Gastroenterol. 2007; EA, Carlson M, Maron LM, et al. Utility of the 102:754–60. Repeatable Battery for the Assessment of 131. Bajaj JS, Hafeezullah M, Franco J, Varma RR, Neuropsychological Status (RBANS) in patients Hoffmann RG, Knox JF, et al. Inhibitory control test with end-stage liver disease awaiting liver transplant. for the diagnosis of minimal hepatic encephalopathy. Arch Clin Neuropsychol. 2007;22:175–86. Gastroenterology. 2008;135:1591–600. 119. Butcher JN, Dahlstrom WG, Graham JR, Tellegen 132. Amodio P, Ridola L, Schiff S, Montagnese S, A, Kaemmer B. MMPI-2 (Minnesota Multiphasic Pasquale C, Nardelli S, et al. Improving the inhibitory Personality Inventory-2): manual for administration control task to detect minimal hepatic encephalopa- and scoring. Minneapolis: University of Minnesota thy. Gastroenterology. 2010;139:510–8. Press; 1989. 133. Ziegler EA, Hilsabeck RC, Carlson MD, Hassanein 120. Ware JE, Sherbourne CD. The MOS 36-item short- TI, Perry W. Resolution of cognitive impairment form health survey (SF-36). Conceptual framework after liver transplantation: a case study [abstract]. and item selection. Med Care. 1992;30:473–83. Arch Clin Neuropsychol. 2001;16:738. 121. Younossi ZM, Guyatt G, Kiwi M, Boparai N, King 134. Franklin GM, Heaton RK, Nelson LM, Filley CM, D. Development of a disease speci fi c questionnaire Seibert C. Correlation of neuropsychological and 29 Hepatic Encephalopathy 485

MRI ﬁ ndings in chronic/progressive multiple sclero- 140. Benton AL. Development of a multilingual aphasia sis. Neurology. 1988;38:1826–9. battery: progress and problems. J Neurol Sci. 135. Smith A. Symbol Digit Modalities Test (SDMT): 1969;9:39–48. manual (revised). Los Angeles, CA: Western 141. Kongs SK, Thompson LL, Iverson GL, Heaton RK. Psychological Services; 1982. Wisconsin Card Sorting Test-64 Card Version. 136. Mattarozzi K, Campi C, Guarino M, Stracciari A. Lutz, FL: Psychological Assessment Resources; Distinguishing between clinical and minimal hepatic 2000. encephalopathy on the basis of speci ﬁ c cognitive 142. Matthews CG, Klove H. Instruction manual for the impairment. Metab Brain Dis. 2005;20:243–9. Adult Neuropsychology Test Battery. Madison, 137. Wechsler D. Wechsler Test of Adult Reading. San WI: University of Wisconsin Medical School; Antonio, TX: The Psychological Corporation; 2001. 1964. 138. Golden CJ, Freshwater SM. Stroop color and word 143. Beck AT, Steer RA, Brown G. Beck Depression test: revised examiner’s manual. Wood Dale, IL: Inventory-II Manual. San Antonio, TX: Psychological Stoelting Co.; 2002. Corporation; 1996. 139. Kaplan EF, Goodglass H, Weintraub S. The Boston 144. Beck AT, Steer RA. Beck Anxiety Inventory: manual. Naming Test. 2nd ed. Philadelphia: Lippincott San Antonio, TX: The Psychological Corporation; Williams & Wilkins; 1983. 1990. Late-Onset Schizophrenia 3 0 Tracy D. Vannorsdall and David J. Schretlen

Abstract Given that psychotic symptoms are relatively common in the older adults and can accompany a variety of conditions, correctly identifying the etiology of psychosis in older patients is essential for developing the most effective treatment plan. Here we focus on the identi ﬁ cation and management of late-onset schizophrenia and schizophrenia-like psychosis.

Keywords Psychosis ¥ Schizophrenia ¥ Late-onset schizophrenia ¥ Very-late-onset schizophrenia-like psychosis ¥ Geriatrics ¥ Older adults ¥ Assessment ¥ Cognition

Symptoms of psychosis, including delusions, hallucinations, loosening of associations, and thought disorder, are prevalent in geriatric populations. In a Swedish community sample of 347 nondemented adults who were 85 years old at T. D. Vannorsdall , Ph.D., ABPP () study entry, 10.1% were found to have at least Department of Psychiatry and Behavioral Sciences , one psychotic-type symptom. The most common Johns Hopkins University School of Medicine , of these were hallucinations (6.9%), paranoid 600 North Wolfe Street, Meyer 218 , Baltimore , ideation (6.9%), and delusions (5.5%) [ 1 ] . Earlier MD 21287-7218 , USA e-mail: [email protected] studies reported that psychosis was present in more than 25% of older patients admitted to inpa- D. J. Schretlen , Ph.D., ABPP Department of Psychiatry and Behavioral Sciences , tient geropsychiatric units [ 2 ] and more than 33% Johns Hopkins University School of Medicine , 600 of older adults admitted to a hospital for psychi- North Wolfe Street, Meyer 218 , Baltimore , atric treatment for the ﬁ rst time [3 ] . Psychosis MD 21287-7218 , USA can occur in a variety of conditions and disorders Russell H. Morgan Department of Radiology and of late life with etiologies including acute condi- Radiological Science , Johns Hopkins University tions such as delirium, or the effects of substance School of Medicine , 600 North Wolfe Street, Meyer 218 , Baltimore , MD 21287-7218 , USA use or withdrawal. Alternatively, psychotic e-mail: [email protected] symptoms may arise from chronic degenerative

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 487 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_30, © Springer Science+Business Media, LLC 2013 488 T.D. Vannorsdall and D.J. Schretlen conditions such as moderate to severe Alzheimer’s reference onset of all schizophrenia-like symp- disease or Lewy body dementia. Finally, a variety toms and delusional disorders with onset after of late-life psychiatric illnesses including delu- age 55 or 60 [6, 7 ] . sional disorder, mood disorder with psychotic Late paraphrenia was included as a diagnosis features, bipolar disorder, and both early- and in ICD-9, and in ICD-10, the term was included late-onset schizophrenia (LOS) can also be as a part of the diagnosis of delusional disorder. accompanied by prominent psychotic features. Despite the lack of data to support an age cutoff, in the DSM-III, schizophrenia was defi ned as having an onset before age 45, thus re fl ecting History and Terminology the “praecox” view of Kraepelin with typical disease onset in late adolescence and early Most individuals with schizophrenia develop adulthood. As evidence that schizophrenia can symptoms of psychosis in late adolescence or emerge after age 44 accumulated, the age cutoff early adulthood. As a result, our understanding of was eliminated and replaced with a late-onset thought disorders primarily stems from these specifi er in the DSM-III-R. Subsequent revi- early-onset patients. However, it has long been sions removed the late-onset specifi er, and the recognized that such symptoms can emerge for most recent edition (DSM-IV-TR) simply notes the fi rst time later in life. Unfortunately, late-life that an onset after age 45 is both possible and psychosis has historically been inconsistently associated with certain characteristics including described, imprecisely defi ned, and understud- female preponderance, better premorbid func- ied. Manfred Bleuler, who fi rst brought attention tioning, more paranoid delusions and hallucina- to the study of late-life psychosis, crystallized tions, and less disorganization and negative these dif fi culties with an often-cited quote [4, 5 ] : symptoms than are characteristic of early-onset schizophrenia. One can hardly deal with late onset schizophrenic An International Late-Onset Schizophrenia pictures without being reminded again and again Group met in 1998 in order to encourage greater how right Kraepelin was when he called the science of psychoses of old age ‘the darkest area of consistency in the recognition, classifi cation, and psychiatry’. Indeed, today as in earlier times the treatment of late-life schizophrenia. Although ground seems to shake under our feet, and our there were still no data to justify specifi c age cut basic psychiatric terms seem to lose their meaning, points for diagnostic classi fi cation, it was felt that when one grapples with late onset schizophrenias (p. 259). some delineation of age groups was necessary in order to stimulate further research in this area. In In fact, the rigorous study of late-onset psy- the resulting consensus statement [ 8 ] , it was con- chotic symptoms started with M. Bleuler who, in cluded that there was suf fi cient evidence to jus- 1943, observed that 15% of the schizophrenia tify the adoption of two illness classifi cations: patients he examined had an onset of symptoms LOS and very-late-onset schizophrenia-like psy- after 40 years of age and another 4% developed chosis (VLOSLP). The former was conceptual- symptoms after age 60 [5 ] . Noting that nearly ized as a subtype of schizophrenia with an onset half of his late-onset cases evidenced symptoms occurring after age 40 years. VLOSLP was that were consistent with those seen in the early- defi ned as having an onset after age 60 and onset schizophrenia, Bleuler coined the term applies when the symptoms cannot be attributed “late-onset schizophrenia” to refl ect a disorder to an affective disorder or a progressive structural with an onset of schizophrenia-like symptoms brain abnormality. It was so named in order to occurring at age 40 years or later. However, this refl ect the relative diagnostic uncertainty that classifi cation did not immediately take hold in arises when attempting to identify a primary psy- the USA or Great Britain. Rather, the term “late chotic disorder at an age in which the risk for paraphrenia” was more commonly used to dementia-related psychoses begins to rise. 30 Late-Onset Schizophrenia 489

with each 5-year increase in age [ 15 ] . Further, Epidemiology while most individuals with LOS or VLOSLP fi rst develop symptoms in their 50s, 60s, and 70s, Despite the fi ndings and age cutoffs recom- Cervantes, Rabins, and Slavney [16 ] reported a mended by the consensus conference statement, woman who, after detailed examination, was the terms LOS and VLOSLP have yet to be uni- found to have developed LOS at the age of 100. formly adopted and the ages used to defi ne “late- Thus, it appears that LOS/VLOSLP can develop onset” still vary across studies. Not surprisingly, at any age in late adulthood. gaining an accurate estimate of the incidence of LOS and VLOSLP has proven diffi cult. The issue is further complicated by the fact that many stud- Clinical Features ies assessing the epidemiology of schizophrenia do not include older adults, and those that do The symptom of schizophrenia, regardless of the make varying levels of effort to exclude individu- age of onset, can include the positive symptoms als whose psychotic symptoms might be due to of delusions, hallucinations, and disorganized such causes as dementias or delirium. speech and behavior, along with negative symp- The available evidence suggests that the 1-year toms such as affective fl attening, alogia, and avo- prevalence rate of schizophrenia, irrespective of lition. According to DSM criteria, in order to age of onset, in people ages 45Ð64 is 0.6% [9 ] . justify the diagnosis of schizophrenia, these The proportion of individuals with schizophrenia symptoms must disrupt a person’s ability to func- whose symptoms emerge after age 40 (i.e., LOS) tion in major life roles, not be accompanied by is estimated to be 23.5%, with only 3% develop- prominent mood symptoms, and not be due to ing symptoms after age 60 (i.e., VLOSLP) [ 10 ] . substance use. Numerous similarities have been The community prevalence estimates for those noted between the clinical presentation of LOS/ age 65 and older range from 0.1 to 0.5% [11Ð 13 ] , VLOSLP and early-onset schizophrenia. In fact, and the incidence of VLOSLP is estimated to be they are often described as being more similar in the range of 17Ð24 per 100,000 [ 14 ] . Greater than different, particularly with respect to their age tends to confer greater risk for the disorder, positive symptom presentation [ 8 ] . On the other as data from fi rst admission reports for patients hand, evidence suggests that early- and late-onset age 60 and above indicate the annual incidence of cases are not identical conditions in terms of their schizophrenia-like psychosis increases by 11% clinical phenomenology (see Table 30.1 ).

Table 30.1 Comparison of patient characteristics by age of onset Very-late-onset Characteristic Early-onset schizophrenia Late-onset schizophrenia schizophrenia-like psychosis Age <40 41Ð59 60+ Sex differences M > W W > M W > M Negative symptoms Prominent Less prominent Uncommon Positive symptoms Prominent Prominent Prominent Thought disorder Prominent Uncommon Uncommon Partition delusion Uncommon Less common Common Family history of Common Less common Uncommon schizophrenia Early-life maladjustment Common Less severe Uncommon Cognitive decline over time Absent Uncommon Uncommon Ef ﬁ cacious antipsychotic dose Greater Lower Lower Adopted from Reeves and Brister [63 ] and Palmer and colleagues [21 ] 490 T.D. Vannorsdall and D.J. Schretlen

Late-Onset Schizophrenia delusions (i.e., the belief that people, objects, or radiation can pass through what would normally There are a number of relative, and sometimes constitute a barrier to such passage) [17, 19 ] . subtle, differences in symptom presentation that Such delusions frequently involve the belief that differentiate early- and late-onset schizophrenia. people or animals invade one’s residence at night. One of the most notable and reliably reported dif- For example, we had one patient with VLOSLP ferences is the relative paucity of classic negative who was convinced that the light on a distant symptoms such as affective fl attening or blunting power line actually was a device being used to in persons with LOS [ 17Ð 19 ] . Almeida and col- monitor her behavior at home. It has also been leagues [20 ] found that only 8.5% of participants reported that some Schneiderian fi rst-rank symp- in their cohort evinced negative symptoms, and toms, such as delusions of control and thought those that did appeared only mildly affected. In insertion, thought withdrawal, or thought broad- contrast, more recent investigations of large num- casting, are far more likely to occur in LOS than bers of well-characterized subjects suggests that in dementia-related psychosis [23 ] . while those with LOS experience relatively fewer negative symptoms than those with early onset of the disease, individuals with LOS still show Very-Late-Onset Schizophrenia-Like greater negative symptoms than age-matched Psychosis healthy controls [21 ] . Individuals with LOS are also markedly less Relatively few studies have focused on the pre- likely to experience formal thought disorder (e.g., sentation of patients who develop psychoses for loosening associations, circumstantiality, etc.) the fi rst time in very late life and whose symp- than those who develop schizophrenia in adoles- toms meet criteria for VLOSLP. Nonetheless, cence or early adulthood [ 17, 19 ] . For example, available evidence does suggest some unique and Pearlson and colleagues [ 17 ] looked at individu- identifying symptoms in these patients. For als who had an onset of symptoms after age 45 example, there is a high prevalence of sensory and found that formal thought disorder was pres- de fi cits including a notable preponderance of ent in only 5.6% of cases. In contrast, thought conduction deafness [ 7, 24 ] and social isolation disorder was present in 51.9% of young adults in those with VLOSLP [7 ] . with early-onset schizophrenia and in 54.5% of Perhaps even more so than in LOS, formal older early-onset cases. Pearlson et al. also found thought disorder and negative symptoms are that the overall occurrence of formal thought dis- extremely rare in those with onset at age 60 or order decreased as age of onset increased, such later [4, 20, 25 ] . Nevertheless, most, if not all, that individuals with the latest onset (i.e., positive symptoms of early-onset schizophrenia VLOSLP) showed markedly lower rates of disor- can also appear in those with VLOSLP. Helping dered thinking. to differentiate VLOSLP from psychotic symp- With respect to positive symptoms, patients toms arising due to other etiologies are the parti- with LOS are more likely to report visual, tactile, tion delusions that occur in up to 70% of VLOSLP and olfactory hallucinations than are those with cases [17, 26, 27 ] but are less common in early- early-onset schizophrenia [ 17, 22 ] , Alzheimer- onset schizophrenia. The nature and pattern of type dementia with psychosis, or major depres- positive symptoms of schizophrenia seen in sion [23 ] . When auditory hallucinations are VLOSLP also tends to be rather unlike the psy- present in LOS, they are more likely to consist of chotic symptoms seen in the so-called organic a third-person, running commentary and accusa- psychoses of aging such as Alzheimer’s disease tory or abusive content [ 19 ] . The content of the and Lewy body dementia. A more characteristic delusions in early- and late-onset schizophrenia delusion of patients with Alzheimer-type demen- may also differ, with LOS patients being more tia is that others are stealing personal effects that likely to experience persecutory and partition the patient actually has misplaced or hidden and 30 Late-Onset Schizophrenia 491 forgotten. That is, unlike dementing conditions Gender wherein delusions and hallucinations tend to be less organized and persistent, the psychotic symp- Perhaps the most consistent risk factor for the toms of VLOSLP tend to be more organized, development of schizophrenia or psychotic symp- fully formed, and stable features of the condition. toms in late life is gender. Unlike early-onset As is discussed below, also unlike psychoses in schizophrenia in which there is a male predomi- dementia, the psychotic symptoms of VLOSLP nance, considerable evidence indicates that a dis- are not invariably associated with a decline in proportionate number of individuals diagnosed cognition over time. with LOS and VLOSLP are female [ 13, 20, 25, 26, When considering the positive symptoms of 30] . In one early study of gender differences in schizophrenia evident in VLOSLP, there is a high schizophrenia onset across the lifespan, Castle and prevalence of visual hallucinations [ 19, 25, 28 ] . Murray [13 ] found a male to female ratio of 1.56:1 Multimodal hallucinations are also quite com- in the 16Ð25-year age group. The ratio was roughly mon in this group. In a well-characterized cohort equal among those with onset around age 30. of persons with VLOSLP from south London, However, for those whose psychosis emerged for Howard [4 ] found visual hallucinations in 40% of the fi rst time between 66 and 75 years of age, the the sample, with 32% experiencing these as well- male to female ratio declined to just 0.38:1.0. formed visual hallucinations. Further, approxi- Further, this difference appears to persist even after mately 20% had what were described as Charles accounting for gender differences in social role Bonnet-type complex recurrent visual hallucina- expectations and care-seeking behavior [31, 32 ] . tions (sometimes described as “Charles Bonnet syndrome plus” [ 29 ] ). Also common, reported in 59.4% of the sample, were visual misinterpreta- Age tions and misidenti fi cations. In comparison to the prominent visual distur- Age also appears to be a risk factor, particularly bances, auditory hallucinations were even more for developing VLOSLP. The risk of developing common in the London cohort, as 70% of those schizophrenia is highest in adolescence and early with VLOSLP were noted to have nonverbal adulthood. It declines during mid-adulthood but auditory hallucinations. Another sizable propor- then increases again after age 60, at which time tion of participants (49.5%) endorsed auditory very LOS-like psychoses occur with increasing hallucinations consisting of third-person voices frequency. VLOSLP has been found to occur in 10 or voices speaking directly to the patient. individuals per 100,000 adults in the 60Ð65 age Hallucinations in other modalities were common bracket. Thereafter, the rates rise steadily to 25 per as well, with 30Ð32% reporting olfactory, gusta- 100,000 among adults aged 90 and above [15 ] . tory, or tactile hallucinations with delusional elaboration. Finally, equally notable were the high rates of delusions of persecution (84.2%) Premorbid Functioning and reference (76.3%) seen in VLOSLP. Although some studies suggest poor childhood adjustment in both early- and late-onset schizo- Risk Factors and Associated Features phrenia [33 ] , many investigations have found notable differences in rates of successful social A number of studies have examined risk factors and role functioning between early- and late- for the development of LOS and VLOSLP includ- onset cases. Generally, individuals who develop ing gender, age, premorbid functioning, family psychosis late in life tend to have better premor- history of schizophrenia and dementia, APOE bid educational attainment, greater occupational genotype, pharmacological treatment response, success, and less impaired psychosocial function- and brain morphometry. ing than is seen in early-onset schizophrenia 492 T.D. Vannorsdall and D.J. Schretlen

[18, 34, 35] . For example, in one study [ 13 ] , half indicates that LOS and VLOSLP often respond of those with early-onset schizophrenia were well to antipsychotic medications. Further, effec- judged to have poor premorbid work adjustment as tive treatment can often be reached at doses that compared to only 15% of the LOS group. are a fraction of those used for early-onset cases. Similarly, while 43% of early-onset subjects were Based on open-label observations, Howard [ 8 ] rated as showing poor premorbid social adjustment, found that LOS can often be effectively managed only 22% of those with LOS were rated as such. on antipsychotic doses that are approximately Rates of marriage were also twice as high among 40% as high as that needed for younger patients. LOS compared to early-onset cases (66% vs. 33%). Similarly, Barak [ 35 ] reported that 71.4% of indi- While later onset of schizophrenia and psycho- viduals with VLOSLP reached a favorable sis may be associated with better psychosocial response to an atypical antipsychotic (risperi- functioning and perhaps a less severe form of the done) as compared to just 57.1% of older patients disease, evidence suggests that those who do with early-onset schizophrenia. As in all popula- develop schizophrenia/VLOSLP in late life are tions, antipsychotic side effects can include seda- more likely to have a history of mild premorbid tion, anticholinergic effects, extrapyramidal schizoid or paranoid personality traits that do not effects, weight gain/diabetes, hyperglycemia, tar- meet criteria for a personality disorder [7, 17, 18 ] . dive dyskinesia, and neuroleptic malignant Further, evidence suggests that while their psy- syndrome. chosocial defi cits are not as severe as those with early-onset schizophrenia, they still have greater rates of general psychopathology and functional Neuroanatomy disability than healthy normal controls [ 30 ] . Neuroanatomic investigations of individuals with schizophrenia have generally failed to detect Family History major changes that differentiate LOS cases from early-onset schizophrenia. Anatomic brain Family studies of LOS and VLOSLP tend to be imaging studies of individuals with LOS have small and have methodological shortcomings. There found increased ventricle-to-brain ratios in LOS/ is some evidence that those with LOS may have VLOSLP compared to matched healthy controls higher rates of schizophrenia among relatives than [35, 39, 40 ] . Semiquantitative analyses of brain unaffected individuals [34 ] . However, studies also MRI scans have demonstrated larger thalamic have found lower rates of schizophrenia among rela- volume in LOS compared to early-onset schizo- tives of those with late- compared to early-onset phrenia [ 41] and smaller third ventricle volumes schizophrenia [17, 36 ] . There does not appear to be compared to age-matched controls [ 42 ] . Focal an increased rate of schizophrenia among relatives changes, such as reduced volumes of the left of patients with VLOSLP [ 21 ] , nor does there appear temporal lobe and superior temporal gyrus, are to be an increased prevalence of family history of also similar to those found in early-onset cases Alzheimer’s disease, vascular dementia, Lewy body [40, 43] . With respect to white matter abnormali- dementia, or APOE e 4 alleles in LOS or VLOSLP ties, some early studies reported that large sub- [37 ] . Consistent with this, LOS patients do not show cortical white matter hyperintensities were the hallmark neuropathological indicators associated common in LOS [ 44 ] . However, subsequent stud- with neurodegenerative dementias on autopsy [ 38 ] . ies that carefully controlled for organic cerebral disorders failed to replicate these earlier fi ndings among late-onset cases [ 35, 45, 46 ] . More recent Pharmacological Treatment Response diffusion tensor imaging fi ndings also failed to fi nd signi fi cant differences in fractional anisot- Although there tends to be a lack of well- ropy or mean diffusivity between those with controlled, double-blind trials, and overreliance VLOSLP and age-matched unaffected adults, on case reports or series, available evidence arguing further against structural white matter 30 Late-Onset Schizophrenia 493 abnormalities as a potential etiology for psychotic of crystallized verbal abilities and working symptoms late in life [47 ] . memory as assessed by Wechsler subtests (Wechsler Information, Vocabulary, Similarities, and Arithmetic subtests). However, the LOS Cognitive Profi le and Course patients showed less severe impairment than early-onset cases on tests of processing speed Contrary to Kraepelin’s notion that schizophrenia (Digit Symbol), visuoconstruction (Block involves a progressive “dementia praecox,” there Design), executive functioning (WCST perse- is now compelling evidence that early-onset verative responses), and verbal memory as schizophrenia is a neurodevelopmental disorder assessed by CVLT long-delay free recall (when that rarely involves progressive dementia. While adjusted for Trial 5 learning). In addition to the development of schizophrenia in early life showing less severe cognitive defi cits, the LOS certainly is associated with widespread cognitive group performed better than early-onset patients dysfunction, it does not predict worsening cogni- on performance-based measures of functional tive decline in late life relative to age-matched capacities, social skills, and health-related qual- controls [ 48, 49] . Some experts have suggested ity of life. Interestingly, in this sample, patients that the emergence of psychotic symptoms late in with LOS showed less severe positive but life may signal the onset of a neurodegenerative equally severe negative symptoms when com- process [50 ] . Further, given that LOS/VLOSLP pared to early-onset cases. The groups did not arises at a time in which rates of dementia begin differ in severity of depression. to rise, differentiating the cognitive pattern of a Most studies examining the cognitive profi le primary psychiatric disease from the psychoses of schizophrenia emerging in late life have that can accompany dementia is important from a combined patients with LOS and VLOSLP. As treatment planning perspective. a result, less is known about whether there are Persons with early-onset schizophrenia show any unique VLOSLP-related cognitive defi cits. severe and pervasive de fi cits across virtually all Those studies that do address this issue have domains of cognitive functioning. The most found that the cognitive de fi cits associated with pronounced impairments typically appear to VLOSLP are widespread, with no pronounced involve psychomotor speed, verbal memory, and differences in cognition between LOS and attention [51, 52] . Beginning in the mid-1990s, VLOSLP [8 ] . studies began fi nding that both early- and late- Of critical importance is determining whether onset schizophrenia involve cognitive dysfunc- the onset of psychosis late in life signals the pres- tion [18, 48 ] and that early- and late-onset ence or onset of a dementing condition. Available groups tended to perform quite similarly to one evidence suggests that the pattern of cognitive another on cognitive testing. In these early stud- defi cits seen in early- and late-onset schizophre- ies, the primary differences seen between the nia differ from those seen in Alzheimer’s disease, early- and late-onset groups tended to occur on with schizophrenia of any age of onset showing a tests of learning/memory and abstraction/men- pattern of defi cient learning coupled with intact tal fl exibility, with later age of onset being asso- retention [18, 48, 53, 54] . This lies in contrast to ciated with better performance on these tasks. the impairments seen in Alzheimer’s disease, Vahia and colleagues [30 ] recently replicated wherein there are defi cits in both learning and the fi nding that outpatients with both early- and retention skills. late-onset schizophrenia performed more poorly Several longitudinal studies have sought to than healthy controls on most cognitive tests, determine whether LOS/VLOSLP might herald but that those with LOS showed less severe dys- the development of a progressive dementia syn- function on most measures, and these differ- drome, but most of these [49, 55, 56 ] have found a ences in cognitive impairment were accompanied pattern of stable cognition over a period of several by notable functional differences. Their early- years. For example, one longitudinal [ 57 ] study of and late-onset groups were equivalent in terms patients with early- or late-onset schizophrenia, 494 T.D. Vannorsdall and D.J. Schretlen mild Alzheimer’s disease, Alzheimer’s disease with psychotic features, and healthy controls found Assessment that both dementia groups showed steep cognitive declines over a 2-year period whereas both schizo- Given the age of the population in question, when phrenia groups and the normal controls remained a patient presents with symptoms of psychosis cognitively stable over the same interval. However, late in life, the referral question tends to focus on the fi nding of stable cognitive functioning over differentiating between late-life psychosis and a time in LOS is not uniform. A few studies with primary dementing illness. However, psychosis longer follow-up periods have reported that some in late life can stem from several etiologies patients decline over time. For example, Holden including acute conditions such as a delirium, [14 ] conducted a retrospective chart review and degenerative conditions like moderate to severe found that 35% of people with LOS developed dementia, or any of several psychiatric illnesses, dementia within a 3-year follow-up period. Brodaty including delusional disorder, mood disorder and colleagues [50 ] reported that 9 of 19 (47%) with psychotic features, bipolar disorder, and older adults with LOS subjects developed demen- either early- or late-onset schizophrenia (see tia over a period of 5 years, whereas none of the 24 Table 30.2). In light of the differential course and healthy controls developed dementia over the same survival rates for these various etiologies, an period. In a longitudinal study of psychogeriatric accurate diagnostic formulation is crucial to for- clinic patients, Rabins and Lavrisha [ 23 ] examined mulating the most effective treatment plan. the rates of conversion to dementia (as indicated by declines in MMSE of ³ 4 points and ful fi llment of DSM-IV criteria for dementia) in 28 cognitively Clinical Interview and Symptom intact, nondepressed patients with LOS; 48 patients Assessment with depression but not dementia or psychosis; and 47 patients with dementia and psychosis. As described above, the cognitive defi cits of While approximately half the LOS cases devel- LOS/VLOSLP are relatively nonspecifi c and oped dementia by 10-year follow-up, those with usually milder than those seen in older adults LOS were no more likely to develop dementia with early-onset schizophrenia. Thus, evaluation than those with late-life major depression. Further, and proper diagnosis of these patients rely heav- those with dementia plus psychosis had shorter ily on taking a thorough history of the patient’s life expectancies than those with LOS or major premorbid functioning and the nature and course depression alone. of the psychotic symptoms. We have found that a Taken together, cross-sectional and longitu- knowledgeable informant can provide critically dinal studies suggest that while individuals with important data. This is particularly the case if a LOS may perform more poorly than normal patient is experiencing intrusive psychotic symp- controls on tests of learning and memory, they toms at the time of the evaluation. However, the can be differentiated from those with primary dementing conditions by the relative preserva- Table 30.2 Common differential diagnoses tion of retention and recognition skills. Further, Delirium the psychosis of LOS and VLOSLP is not Substance use or withdrawal invariably associated with deteriorating cogni- Alzheimer’s disease, moderate to severe tive abilities, and many patients remain cogni- Lewy body dementia tively stable over time. Given the variability in Delusional disorder cognitive outcomes, a progressive dementia Mood disorder with psychotic features syndrome does not appear to be the underlying Bipolar disorder etiology of LOS/VLOSLP. Schizophrenia (early onset) 30 Late-Onset Schizophrenia 495 absence of an identifi able family member, friend, from others as well. Rather, these individuals are or caregiver who knows the patient well enough often suspicious of the assessment procedures, to provide such input suggests a level of social reticent to disclose personal information, or isolation that is fairly common in LOS patients. unwilling to allow a knowledgeable informant to Determining the duration of symptoms can itself speak to the neuropsychologist or treatment be a challenge given that these patients often lead team. relatively solitary lives. In fact, many such indi- As was outlined above, LOS and VLOSLP are viduals only come to the attention of care provid- associated with common but not pathognomonic ers after a neighbor becomes concerned about clinical features. These include prominent posi- paranoid or other fl oridly psychotic behavior. For tive symptoms, such as auditory hallucinations of example, one of our patients repeatedly and accusatory or abusive voices, visual hallucina- angrily confronted the neighbor that she believed tions, and paranoid, persecutory, or partition was breaking in and stealing money from her delusions. Negative symptoms (i.e., alogia, avoli- home. It was only after repeated unsuccessful tion, and affective blunting) tend to be less prom- attempts to convince the patient otherwise that inent, and formal thought disorder is relatively the neighbor contacted the local police, which rare. In our clinic, we augment our clinical inter- prompted the patient’s admission to our geriatric view with the Scale for the Assessment of psychiatry service. Negative Symptoms (SANS) and Scale for the As LOS and VLOSLP are associated with Assessment of Positive Symptoms (SAPS). These various premorbid characteristics, when taking a semistructured interview/observation rating clinical history, particular attention should be scales [58 ] can help quantify the severity of posi- paid to the individual’s occupational and social tive and negative symptoms. The SANS is a functioning during mid-life. Did the patient 25-item scale with fi ve subscales: affective achieve a reasonable degree of occupational suc- fl attening, alogia, avolition/apathy, anhedonia/ cess by mid-adulthood, or is their work history asociality, and inattention. The SAPS consists of characterized by diffi culty maintaining employ- 35 items and four subscales: hallucinations, delu- ment, “underemployment” (working at jobs for sions, bizarreness, and formal thought disorder. which they are clearly overquali fi ed), or recur- Both scales include a global rating, and symp- rent problems working with others so that they toms are rated as they occurred over the preced- quit jobs or were terminated? Since LOS and ing month. VLOSLP are associated with the presence of mild premorbid schizoid or paranoid personality traits, it can also be helpful to determine whether Differentiating LOS/VLOSLP from Other an individual has a full and socially connected Psychiatric Disorders existence or gravitated toward solitary activities in their adulthood. Similarly, it is helpful to deter- A thorough review of a patient’s clinical and psy- mine whether an individual’s history suggests a chiatric history is essential to diagnosis, as the lack of interest or success in forming romantic symptom presentation and cognitive de fi cits can relationships or a general lack of relationships be similar to other disorders. Affective disorders, that could be characterized as close or warm. It is including bipolar disorder and unipolar depres- helpful to determine if the patient is described as sion, also are common in older adults and can be mistrustful of others, quick to perceive slights or accompanied by frank psychosis. The symptoms threats, or frankly suspicious. Although this is of LOS/VLOSLP do not couple tightly with informative, the paranoia that often characterizes fl uctuations in a patient’s mood. If psychotic LOS/VLOSLP makes it dif fi cult to obtain these symptoms resolve with return to a euthymic state details directly from the patient and sometimes or a patient exhibits mood-congruent psychotic 496 T.D. Vannorsdall and D.J. Schretlen features in manic and depressed states, LOS/ vision screener can be used to screen for prob- VLOSLP should not be diagnosed, and consider- lems with near visual acuity. We fi nd it useful to ation should be given to a diagnosis of depression keep a selection of magnifying reading glasses in with psychotic features or bipolar disorder. In our various strengths for patients with decreased near clinic, we routinely administer the 15-item visual acuity to use during testing. Finally, we Geriatric Depression Scale [ 59 ] . The diagnostic often rely on the Judgment of Line Orientation, validity and reliability of this version are compa- Hooper Visual Organization Test, and Boston rable to those of the original 30-item version [ 60, Naming Test to detect the presence of visual mis- 61 ] , and this appears to be the case for middle- perceptions, which are common in LOS and aged adults as well [62 ] . Finally, although delu- VLOSLP. sions can be a feature of LOS and VLOSLP, they Differentiating the psychosis of late-life differ from a late-life delusional disorder in that schizophrenia from the psychosis that can accom- the latter is characterized by the presence of a pany dementia should include a characterization nonbizarre delusion that occurs in the absence of of the initial symptoms and the temporal course prominent auditory or visual hallucinations. of the condition. Hallucinations and delusions are Further, delusional disorders are often associated rarely an initial symptom of dementia. Rather, in with preserved premorbid personality, intact primary dementia syndromes, early cognitive intelligence, and intact functioning in matters decline is often the fi rst indication of a disorder. that are unrelated to the content of the delusion. These cognitive impairments tend to be at least This contrasts with the symptoms of LOS and moderately severe by the time psychotic symp- VLOSLP in that the delusions may be bizarre, toms emerge in patients with a primary dement- multimodal hallucinations are common, and both ing illness. In contrast, the psychotic symptoms cognitive and functional de fi cits may be present. of LOS and VLOSLP are often the fi rst and most prominent manifestations of these conditions. While cognitive de fi cits often co-occur with the Differentiating LOS/VLOSLP hallucinations and delusions, these defi cits are from Dementia Syndromes usually not severe enough by themselves to bring a patient to clinical attention. Qualitatively, the Psychosis can occur in a variety of dementia syn- hallucinations and delusions of LOS and VLOSLP dromes such Alzheimer’s disease, Lewy body tend to be more organized, elaborate, and stable dementia, Parkinson’s disease, and vascular than those seen in dementia. Finally, while not an dementia. However, there are several means of essential feature of dementing illnesses, it is help- differentiating a primary psychiatric disorder ful to assess whether the patient has experienced from a primary degenerative cognitive disorder in a decline in cognition and if so, over what period an older patient. Because of the high rates of sen- of time. A decline in cognition and functioning sory defi cits in LOS/VLOSLP, we often fi nd it over a period of months to years is often a sign of helpful to begin by evaluating the patient’s audi- dementia. The cognitive weaknesses seen in LOS tory and basic visuoperceptual abilities. Hearing and VLOSLP, in contrast, tend to be stable fea- can be informally assessed during the clinical tures of the disorder and generally do not worsen interview by performing basic comprehension over time, particularly when symptoms emerge and repetition tasks or by having the patient close between age 40 and 60 (i.e., LOS). his or her eyes and indicate in which ear they hear When attempting to diagnose an older patient the examiner’s fi ngers rubbing lightly. If auditory with psychosis, it is also important to assess the defi cits are present but mild to moderate, we often presence of other symptoms that are characteristic use a microphone and ampli fi er worn in the ear of particular dementia syndromes, as their pres- during cognitive assessment. More severe defi cits ence decreases the likelihood that the patient has may warrant delaying neuropsychological testing LOS. Both LOS and VLOSLP are associated with until after an audiology consultation. A pocket a broad, generalized pattern of mild cognitive 30 Late-Onset Schizophrenia 497 dysfunction. However, some features are gener- informative in determining whether any strokes, ally not seen in these patients. Apraxia and nam- tumors, or other cerebral abnormalities might ing defi cits are not typical of LOS/VLOSLP, account for the late-onset of psychotic symptoms. whereas they are prominent in Alzheimer’s dis- Finally, given the increased rates of sensory ease. Similarly, in a patient with visual hallucina- de fi cits in patients with LOS/VLOSLP relative to tions, the presence of axial rigidity, disproportionate older patients with affective disorder, early-onset impairment on tests of visual-perceptual or visual- schizophrenia, and age-matched controls [4, 17 ] , constructional ability, and other Parkinsonian fea- recommendations for formal audiology and oph- tures would raise the suspicion for a Lewy body thalmology workups are often helpful to assess dementia and reduce the likelihood of LOS in the the extent to which sensory de fi cits might con- differential diagnosis. Several studies have found tribute to misinterpretations in older patients with that patients with LOS or VLOSLP also be dif- psychosis. See Table 30.2 for common consider- ferentiated from those with dementia by their relations in the differential diagnosis. atively preserved retention of newly acquired information as demonstrated by tests such as the HVLT-R or CVLT-II. Treatment Recommendations

As outlined above, a substantial proportion of Medical Rule Outs patients with LOS/VLOSLP show effective treat- and Recommendations ment response to relatively low-dose neuroleptics. For some patients, such treatment can limit their As with many conditions warranting a clinical experience to a single acute episode. We have found neuropsychological evaluation in older adults, that a geriatric psychiatrist is the most appropriate particular care must be taken to rule out the pres- person to manage a patient’s psychotropic medica- ence of delirium or another organic cause of psy- tions. Further, if sensory impairments are present, chosis when LOS/VLOSLP is in the differential. attempts should be made to remedy these as well as Learning about the course of the patient’s symp- possible, as they might contribute to perceptual toms can be illuminating. Unlike delirium in aberrations. Even if full correction of sensory which hallucinations and delusions appear to wax impairments is not possible, it can be helpful to and wane, the psychotic symptoms of LOS/ educate patients about the potential contribution of VLOSLP tend to be stable and persistent. They hearing or vision impairments to their symptoms rarely show marked fl uctuations over time. We and dif fi culties with everyday functioning. often recommend the patient undergo standard There are also a number of psychosocial laboratory blood studies (e.g., complete blood interventions and recommendations appropriate count, glucose, TSH, electrolytes, BUN, creati- in this population. These include supportive and nine, liver function, B12, folate, RPR, etc.) in cognitive-behavioral therapies. Aguera-Ortiz order to rule out thyroid conditions, infections, and Renese-Prieto [ 4 ] outlined a number of “tips glucose or electrolyte abnormalities, vitamin and tricks” for the psychological management de fi ciencies, and other metabolic abnormalities. of patients with late-life schizophrenia. Even A toxicology screen should be considered, par- though patients may have diffi culty forming an ticularly if there is a suspected history of sub- initial attachment to their treatment providers, stance abuse. Any recent changes in drug use attempts should be made to establish a good should also be considered, as older adults can be therapeutic relationship and a supportive atmo- particularly vulnerable to drug withdrawal. sphere. It is not necessary to agree with a Similarly, it can be helpful to review the patient’s patient’s delusional system, but rather to be medication history to assess for the potential empathic and understanding. Listening to psy- effects of anticholinergic medications and chotic complaints in a nonjudgmental manner adverse drug interactions. Brain imaging can be may lessen the likelihood that they will act on 498 T.D. Vannorsdall and D.J. Schretlen their agitation (e.g., by confronting neighbors). It can also help address a patient’s social isola- References tion, especially if it leads to entry into a larger social sphere. More generally, we have found it 1. Ostling S, Skoog I. Psychotic symptoms and paranoid important to educate family members and care- ideation in a nondemented population-based sample of the very old. Arch Gen Psychiatry. 2002;59(1): givers and to help create a network of persons 53Ð9. (e.g., family members, friends, neighbors, 2. Champagne LL, et al. Psychosis in geropsychiatric church members) who can help ensure a patient’s inpatients with and without dementia. Int J Geriatr ongoing safety. In some instances, the establish- Psychiatry. 1996;11(6):523Ð7. 3. Burke WJ, Roccaforte WH, Wengel SP. Characteristics ment of a conservatorship or guardianship may of elderly patients admitted for the fi rst time to a psy- be in the patient’s best interest. chiatric facility. J Geriatr Psychiatry Neurol. 1988;1(3):159Ð62. 4. Howard R, Rabins PV, Castle DJ. Late onset schizophrenia. Philadelphia: Wrightson Biomedical; 1999. Clinical Pearls p. 278. 5. Bleuler M. Die spatschizophrenen Krankheitsbilder. ¥ LOS/VLOSLP is associated with female gen- Fortschr Neurol Psychiatr. 1943;15:259Ð90. der, increased age, premorbid schizoid or par- 6. Roth M, Morrissey JD. Problems in the diagnosis and classifi cation of mental disorder in old age; with a anoid personality traits, poor premorbid social study of case material. J Ment Sci. 1952;98(410): and occupational functioning, social isolation, 66Ð80. and sensory de fi cits. 7. Kay DW, Roth M. Environmental and hereditary ¥ Symptoms tend to consist primarily of pos- factors in the schizophrenias of age (“late paraphrenia”) and their bearing on the general problem itive symptoms such as auditory or visual of causation in schizophrenia. J Ment Sci. 1961; hallucinations or paranoid delusions. 107:649Ð86. Partition delusions are particularly com- 8. Howard R, et al. Late-onset schizophrenia and very- mon and are fairly unique to LOS/VLOSLP. late-onset schizophrenia-like psychosis: an international consensus. The International Late-Onset Schizophrenia There is also often a notable lack of nega- Group. Am J Psychiatry. 2000;157(2): 172Ð8. tive symptoms and formal thought 9. Keith SJ, Regier AM, Rae DS. Schizophrenic disor- disorder. ders. In: Robins LN, Regier DA, editors. Psychiatric ¥ Similar to early-onset schizophrenia, LOS/ disorders in America: the epidemiologic catchment area study. New York: Free Press; 1991. p. 449. VLOSLP is associated with a generalized, 10. Harris MJ, Jeste DV. Late-onset schizophrenia: an nonspeci fi c pattern of cognitive dysfunction. overview. Schizophr Bull. 1988;14(1):39Ð55. However, the cognitive impairment tends to be 11. Copeland JR, et al. Alzheimer’s disease, other demen- less severe than early-onset schizophrenia. It tias, depression and pseudodementia: prevalence, incidence and three-year outcome in Liverpool. Br J differs from that seen in patients with demen- Psychiatry. 1992;161:230Ð9. tia with psychosis by virtue of the relative 12. Copeland JR, et al. Schizophrenia and delusional disor- sparing of memory abilities and the absence of der in older age: community prevalence, incidence, cortical features and extrapyramidal signs. comorbidity, and outcome. Schizophr Bull. 1998;24(1):153Ð61. LOS and VLOSLP are primarily nondement- 13. Castle DJ, Murray RM. The epidemiology of late-onset ing disorders. schizophrenia. Schizophr Bull. 1993;19(4):691Ð700. ¥ When an older patient presents with psychotic 14. Holden NL. Late paraphrenia or the paraphrenias? symptoms, it is important to fi rst rule out A descriptive study with a 10-year follow-up. Br J Psychiatry. 1987;150:635Ð9. delirium, identifi able medical etiologies, and 15. van Os J, et al. Increasing age is a risk factor for psy- the effects of medications or toxins, as well as chosis in the elderly. Soc Psychiatry Psychiatr prominent mood symptoms. Epidemiol. 1995;30(4):161Ð4. ¥ Treatment, both psychosocial and pharmaco- 16. Cervantes AN, Rabins PV, Slavney PR. Onset of schizophrenia at age 100. Psychosomatics. 2006;47(4):356Ð9. logical, can be successful in helping affected 17. Pearlson GD, et al. A chart review study of late-onset individuals maintain maximal functional inde- and early-onset schizophrenia. Am J Psychiatry. pendence and remain safe. 1989;146(12):1568Ð74. 30 Late-Onset Schizophrenia 499

18. Jeste DV, et al. Clinical and neuropsychological char- 36. Howard RJ, et al. A controlled family study of late- acteristics of patients with late-onset schizophrenia. onset non-affective psychosis (late paraphrenia). Br J Am J Psychiatry. 1995;152(5):722Ð30. Psychiatry. 1997;170:511Ð4. 19. Howard R, et al. A comparative study of 470 cases of 37. Howard R, et al. Apolipoprotein e genotype and late early-onset and late-onset schizophrenia. Br J paraphrenia. Int J Geriatr Psychiatry. 1995;10(2): Psychiatry. 1993;163:352Ð7. 147Ð50. 20. Almeida OP, et al. Psychotic states arising in late life 38. Purohit DP, et al. Alzheimer disease and related neuro- (late paraphrenia) psychopathology and nosology. Br degenerative diseases in elderly patients with schizo- J Psychiatry. 1995;166(2):205Ð14. phrenia: a postmortem neuropathologic study of 100 21. Palmer BW, McClure FS, Jeste DV. Schizophrenia in cases. Arch Gen Psychiatry. 1998;55(3):205Ð11. late life: fi ndings challenge traditional concepts. Harv 39. Jeste DV, et al. Relationship of neuropsychological Rev Psychiatry. 2001;9(2):51Ð8. and MRI measures to age of onset of schizophrenia. 22. Huber G, Gross G, Schuttler R. Late schizophrenia Acta Psychiatr Scand. 1998;98(2):156Ð64. (author’s transl). Arch Psychiatr Nervenkr. 40. Pearlson GD, et al. Quantitative D2 dopamine recep- 1975;221(1):53Ð66. tor PET and structural MRI changes in late-onset 23. Rabins PV, Lavrisha M. Long-term follow-up and schizophrenia. Schizophr Bull. 1993;19(4):783Ð95. phenomenologic differences distinguish among late- 41. Corey-Bloom J, et al. Quantitative magnetic reso- onset schizophrenia, late-life depression, and progres- nance imaging of the brain in late-life schizophrenia. sive dementia. Am J Geriatr Psychiatry. 2003;11(6): Am J Psychiatry. 1995;152(3):447Ð9. 589Ð94. 42. Rabins PV, et al. MRI fi ndings differentiate between 24. Cooper AF. Deafness and psychiatric illness. Br late-onset schizophrenia and late-life mood disorder. J Psychiatry. 1976;129:216Ð26. Int J Geriatr Psychiatry. 2000;15(10):954Ð60. 25. Howard R, Almeida O, Levy R. Phenomenology, 43. Howard R, et al. Magnetic resonance imaging volu- demography and diagnosis in late paraphrenia. metric measurements of the superior temporal gyrus, Psychol Med. 1994;24(2):397Ð410. hippocampus, parahippocampal gyrus, frontal and 26. Herbert ME, Jacobson S. Late paraphrenia. Br temporal lobes in late paraphrenia. Psychol Med. J Psychiatry. 1967;113(498):461Ð9. 1995;25(3):495Ð503. 27. Howard R, et al. Permeable walls, fl oors, ceilings and 44. Tonkonogy JM, Geller JL. Late-onset paranoid psy- doors. Partition delusions in late paraphrenia. Int chosis as a distinct clinicopathologic entity: magnetic J Geriatr Psychiatry. 1992;7(10):719Ð24. resonance imaging data in elderly patients with para- 28. Rabins P, Pauker S, Thomas J. Can schizophrenia noid psychosis of late onset and schizophrenia of begin after age 44? Compr Psychiatry. 1984;25(3): early onset. Neuropsychiatry Neuropsychol Behav 290Ð3. Neurol. 1999;12(4):230Ð5. 29. Howard R, Levy R. Charles Bonnet syndrome plus: 45. Howard R, et al. White matter signal hyperintensities complex visual hallucinations of Charles Bonnet syn- in the brains of patients with late paraphrenia and the drome type in late paraphrenia. Int J Geriatr Psychiatry. normal, community-living elderly. Biol Psychiatry. 1994;9(5):399Ð404. 1995;38(2):86Ð91. 30. Vahia IV, et al. Is late-onset schizophrenia a subtype 46. Symonds LL, et al. Lack of clinically signi fi cant gross of schizophrenia? Acta Psychiatr Scand. structural abnormalities in MRIs of older patients with 2010;122(5):414Ð26. schizophrenia and related psychoses. J Neuropsychiatry 31. Angermeyer MC, Kuhn L. Gender differences in age Clin Neurosci. 1997;9(2):251Ð8. at onset of schizophrenia. An overview. Eur Arch 47. Jones DK, et al. A diffusion tensor magnetic reso- Psychiatry Neurol Sci. 1988;237(6):351Ð64. nance imaging study of frontal cortex connections in 32. Hambrecht M, et al. Transnational stability of gender very-late-onset schizophrenia-like psychosis. Am differences in schizophrenia? An analysis based on J Geriatr Psychiatry. 2005;13(12):1092Ð9. the WHO study on determinants of outcome of severe 48. Heaton R, et al. Neuropsychological de fi cits in schizo- mental disorders. Eur Arch Psychiatry Clin Neurosci. phrenics. Relationship to age, chronicity, and demen- 1992;242(1):6Ð12. tia. Arch Gen Psychiatry. 1994;51(6):469Ð76. 33. Lohr JB, et al. Minor physical anomalies in older 49. Heaton RK, et al. Stability and course of neuropsy- patients with late-onset schizophrenia, early- chological defi cits in schizophrenia. Arch Gen onset schizophrenia, depression, and Alzheimer’s Psychiatry. 2001;58(1):24Ð32. disease. Am J Geriatr Psychiatry. 1997; 50. Brodaty H, et al. Long-term outcome of late-onset 5(4):318Ð23. schizophrenia: 5-year follow-up study. Br J Psychiatry. 34. Castle DJ, et al. Schizophrenia with onset at the 2003;183:213Ð9. extremes of adult life. Int J Geriatr Psychiatry. 51. Schretlen DJ, et al. Neuropsychological functioning 1997;12(7):712Ð7. in bipolar disorder and schizophrenia. Biol Psychiatry. 35. Barak Y, et al. Very late-onset schizophrenia-like psy- 2007;62(2):179Ð86. chosis: clinical and imaging characteristics in com- 52. Heinrichs RW, Zakzanis KK. Neurocognitive de fi cit parison with elderly patients with schizophrenia. in schizophrenia: a quantitative review of the evi- J Nerv Ment Dis. 2002;190(11):733Ð6. dence. Neuropsychology. 1998;12(3):426Ð45. 500 T.D. Vannorsdall and D.J. Schretlen

53. Miller BL, et al. Brain lesions and cognitive function 59. Sheikh JI, Yesavage JA. Geriatric Depression Scale in late-life psychosis. Br J Psychiatry. 1991;158: (GDS): recent evidence and development of a shorter 76Ð82. version. Clin Gerontologist. 1986;5(1Ð2):165Ð73. 54. Almeida OP, et al. Cognitive features of psychotic 60. Almeida OP, Almeida SA. Short versions of the geri- states arising in late life (late paraphrenia). Psychol atric depression scale: a study of their validity for the Med. 1995;25(4):685Ð98. diagnosis of a major depressive episode according to 55. Laks J, et al. Absence of dementia in late-onset ICD-10 and DSM-IV. Int J Geriatr Psychiatry. schizophrenia: a one year follow-up of a Brazilian 1999;14(10):858Ð65. case series. Arq Neuropsiquiatr. 2006;64(4):946Ð9. 61. Mitchell AJ, et al. Which version of the geriatric 56. Rajji TK, Mulsant BH. Nature and course of cognitive depression scale is most useful in medical function in late-life schizophrenia: a systematic settings and nursing homes? Diagnostic validity review. Schizophr Res. 2008;102(1Ð3):122Ð40. meta-analysis. Am J Geriatr Psychiatry. 2010;18(12): 57. Palmer BW, et al. Are late-onset schizophrenia spec- 1066Ð77. trum disorders neurodegenerative conditions? Annual 62. Fieldstone SC, et al. Validation of the 15-item rates of change on two dementia measures. Geriatric Depression Scale for clinical use with young J Neuropsychiatry Clin Neurosci. 2003;15(1):45Ð52. and middle-aged adults. J Int Neuropsychol Soc. 58. Andreasen NC, et al. Correlational studies of the Scale 2010;16(S1):41. for the Assessment of Negative Symptoms and the Scale 63. Reeves RR, Brister JC. Psychosis in late life: emerg- for the Assessment of Positive Symptoms: an overview ing issues. J Psychosoc Nurs Ment Health Serv. and update. Psychopathology. 1995;28(1):7Ð17. 2008;46(11):45Ð52. Capacity Evaluations in Older Adults: Neuropsychological 3 1 Perspectives

Joel E. Morgan and Bernice A. Marcopulos

Abstract Aging necessarily brings with it changes in one’s functional abilities, and this often occurs in the setting of declining cognition. Changes in mental capacities may be subtle, even almost imperceptible, or they may be so glaringly apparent that no one can deny their presence. Older adults with cognitive decline are clearly vulnerable, and this places them at greater risk for abuse and exploitation. Neuropsychologists are becomingly increasingly called upon to consult about such mental capacities in the elderly, to provide opinions to families and courts of law regarding one’s abilities to care for themselves as well as make decisions about their health care, ﬁ nances and other important matters. In this chapter we discuss the role of the neuropsychologist in such capacity evaluations and provide an assessment framework for professionals who may be new to this interesting aspect of practice.

Keywords Elderly decision-making capacity ¥ Competency ¥ Guardianship ¥ Financial ¥ Health care ¥ Individual freedom

Few would disagree that older adults are among the most vulnerable members of society. Scientiﬁ c J. E. Morgan , Ph.D. () Department of Neurology and Neurosciences , research and technological advances over the last UMDNJ—New Jersey Medical School , half-century have led to improvements in medi- Madison , NJ 07940 , USA cine and health-care delivery, resulting in greater e-mail: [email protected] numbers of the older adults living to advanced B. A. Marcopulos, Ph.D. years. For many, late life typically brings age- Department of Graduate Psychology , James Madison related changes in health that often affect physical University , MSC 7401, 70 Alumnae Drive , Harrisonburg , VA 22807 , USA status, cognitive functions, or emotional and social e-mail: [email protected] adjustment. Consequently, changes in cognition

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 501 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0_31, © Springer Science+Business Media, LLC 2013 502 J.E. Morgan and B.A. Marcopulos and mental status often have signifi cant bearing to form a judgment of incompetency. One must on an individual’s capacity to make informed demonstrate specifi c functional impairment on decisions about important aspects of their life, tasks necessary to meet minimal standards for including their health care, living status, fi nances, that particular capacity as a consequence of the benefi ciaries, and other personal matters [ 1 ] . disorder. Civil competency, similar to compe- While some older individuals are fortunate tency in criminal contexts, refers to a person’s enough to remain cognitively intact well into functional ability to make a particular kind of their 80s or 90s, many are not, and they may decision or to perform a particular kind of task therefore be vulnerable to exploitation by others [ 7] . The context of the decision at issue is critical or unknowingly victimized by their own poor to the determination of competency, not merely judgment and delimited cognitive capacity. the examinee’s mental status. Neuropsychological consultation in forensic In matters involving criminal competency, (legal) contexts is growing at exponential rates questions arise concerning a defendant’s capacity [2 ] where neuropsychologists lend their expertise or ability to proceed to trial (e.g., does he have to a wide range of services to the trier of facts [ 3 ] . the presence of mind to know the principal players Among the various roles pursued by neuropsy- in the court setting, that he is in a court of law, the chologists in forensic contexts is the assessment ability to assist his attorney, etc.), to waive rights, of an individual’s competencies [ 4 ] . In this chap- make a plea, be sentenced, be executed, and the ter, we discuss the issues regarding the assess- like [ 4 ] . Civil competency is similar conceptually, ment of competency in older adults, that is, that most generally expressed by the question: Does aspect of mental ability recognized in law as the person have the competency, the mental suf fi cient for the making of decisions [5 ] , such as capacity, to make a certain decision (i.e., to consent for giving informed consent to one’s health care, to health-care treatment, to care for oneself and the making of a will (i.e., “testamentary capac- one’s property, to control their own fi nances, to ity”), and the management of one’s fi nances [ 6 ] , make a will, etc.). Both criminal and civil compe- among others. We will discuss the general prin- tency questions entail the mental status of the ciples of law as they pertain to such issues of individual—that is, does one have the ability, these capacities, the common disorders affecting the capacity; that is, is one competent ? older adults that may impede cognition and deci- Ingrained within the American psyche and sional capacity, and suggest appropriate assess- refl ected throughout the American jurisprudence ment methodologies and assessment instruments system is the concept that people have the right in a variety of such competency evaluations. Case to self-determination. Self-determination extends to examples from the authors’ practices are utilized individuals with mental disorders as well, except to illustrate these issues and methods. when signifi cant harm to others results from their actions or if they are considered incompetent to make the particular decision in question. Thus, The Legal Perspective the right to self-determination “is not absolute” [7 ] . The precise meaning of competence may dif- Capacity refers to mental capacity, or mental fer depending on the specifi c question and the ability, that is, competency. The concept may be context; there is no single legal criterion that expressed by the question, “Does this person applies to all questions of civil competency [8 ] . have the requisite mental abilities to perform this Jurisdictional differences or subtleties in statutes speci fi c task?” From the legal vantage point, the must also be considered, and the reader is cau- presence of a mental disorder or disability does tioned to be familiar with individual state laws. not necessarily equate with or imply an inability Neuropsychological assessment should take to perform a given task, that is, incompetency. into account not only the cognitive status of the Although necessary, the presence of a disorder or examinee but the nature of the capacity issue or disease affecting cognition is insuffi cient by itself question with which the examinee is expected to 31 Capacity Evaluations in Older Adults: Neuropsychological Perspectives 503 comprehend and act on in a reasonable, rational, [10 ] , have proposed conceptual models for the and informed manner. As the reader will see in assessment of capacity. The current chapter later sections of this chapter, the mere presence discusses some of these methodologies, but the of cognitive impairment, psychiatric disorder, or interested reader is referred to these sources for mental status abnormality by itself is insuffi cient greater details concerning those models. to declare someone incompetent. In a similar Guardianship is a legal determination where vein, an individual may be considered competent the state delegates authority over a person’s estate for a particular task or decision but not for (property) or decisional capacity (for instance another. Therefore, the legal standard of compe- fi nancial management or health care) to another tency may be said to vary as a function of the individual. Decisions regarding guardianship issue or question at hand, and the neuropsycho- typically emanate from family after concern logical assessment of competence must consider arises about the elder person’s decisional abili- general cognitive functions as well as case- ties, often after an “incident” occurs that raises specifi c abilities. Because of their expertise in such concerns. Depending on the jurisdiction, general clinical skills, knowledge of the effects of guardianship may be speci fi c to a particular issue, aging and disease on cognition and behavior, and such as in the management of one’s fi nances or in their diagnostic acumen, neuropsychologists are making decisions regarding one’s health care. well suited for such evaluations [ 9 ] . Formal psy- Conversely, some jurisdictions provide for more chometric assessment is just one of two prongs of general as opposed to speci fi c guardianship. necessary assessment methodology; the other In matters concerning the management of prong of assessment requires detailed question- one’s fi nances, the neuropsychologist examiner ing of the examinee relative to his understand- will need to probe into the examinee’s fi nancial ing of the issues and decisions involved, their background, monetary expenditures, and other ramifi cations, potential effects on self and perti- related matters that are typically thought of as nent others, reasoning behind one’s choice, and quite personal. As the subject of such legal deter- in all, a comprehensive assessment of the minations, the elder will of course be required to examinee’s judgment. Thus, even though a disclose such information, traditional privacy neuropsychologist might fi nd defi cits in those concerns notwithstanding. Assessment of cognitive abilities that are most salient for a fi nancial capacity necessarily entails addressing particular capacity evaluation, this does not mean abilities and judgments beyond those ordinarily the respondent lacks capacity. The speci fi c tasks assessed in a neuropsychological evaluation, such must be directly assessed. as knowledge of one’s assets and liabilities, The neuropsychologist may be consulted to income, expenses, savings, math skills involving evaluate persons in a number of different types of money, and knowledge of reasonable costs of civil competencies. The ABAÐAPA Working goods and services. Older adults are particularly Group on the Assessment of Capacity in Older prone to exploitation by unscrupulous individu- Adults prepared a handbook to guide psycholo- als regarding monetary matters. gists evaluating civil capacities of older adults Assessment of one’s judgment regarding which covers six civil capacities: medical con- health-care decisions is multidimensional, as is sent capacity, sexual consent capacity, fi nancial true of all of the capacity decisions in this chap- capacity, testamentary capacity, capacity to drive, ter. Beyond traditional psychometric assessment, and capacity to live independently. The most the examiner will need to probe the examinee’s common of these include the need for guardian- understanding of the health-care issue(s) in ques- ship in making health-care decisions and the tion. Does the elder understand the pros and cons management of one’s fi nances, and testamentary of the decision? Does the elder know what to capacity, that is, the competency to make a will, expect with agreement or disagreement of the among others. Grisso [8 ] , as has the American medical issue? Does the examinee have suffi cient Bar Association [ 11 ] as well as Moye and Braun reasoning capacity to weigh the decision, and its 504 J.E. Morgan and B.A. Marcopulos consequences, to a reasonable extent? Is the elder with norms for older adults and expectations of emotionally prepared to make such a decision, or both normal and pathological cognitive change. will he/she be prepared with treatment? These Contrasted with ARCD, or normal aging, is and other pertinent health-care decisions must be abnormal or malignant cognitive aging, where comprehensively addressed in an assessment. greater cognitive impairment is present (i.e., Testamentary capacity is an issue that most dementia). An “in-between” state has also been typically arises after the will has been prepared. identifi ed, mild cognitive impairment (MCI; That is, questions concerning an individual’s [ 16, 21] ), characterized by the presence of a judgment at the time the will was executed memory complaint, normal activities of daily commonly arise after the will’s execution and living, normal global cognitive functions, and often after the death of the testator (the person abnormal memory functions when compared to preparing the will) [ 7 ] . In the latter instance, age and education norms [ 22 ] . Clinically, MCI postmortem analyses of the testator’s capacity patients manifest memory impairment to a sim- and judgment is required of the neuropsycholo- ilar extent to patients with mild Alzheimer’s gist, a process involving a good deal of research, disease (AD) type, but unlike MCI patients review of documentation, and collateral inter- whose other cognitive functions are relatively views [6, 12] . Executive functions are particu- unimpaired, AD patients show more impair- larly important for testamentary competence ment in other cognitive domains as well [15, [1 ] . Questions concerning the vulnerability 16, 22] . The concept of MCI, however, is not of the testator to undue infl uence necessarily without some controversy. This controversy arise in many of these assessments, as well [ 13 ] , concerns the accuracy and utility of the concept what with the growth of blended families of MCI and essentially whether or not MCI, the and transfer of enormous intergenerational putative “in-between” state, represents an inde- wealth [14 ] . pendent entity thought to be largely nonprogressive or simply represents the earliest stages of AD and progressive decline [ 23, 24 ] . Cognitive and Behavior Change in Conceptual and diagnostic issues aside, the Older Adults major concern relative to the present chapter has to do with the examinee’s cognitive abili- Cognitive change is generally thought to be an ties in the real world, particularly as they relate inevitable part of aging, most commonly affect- to concerns about ability to make informed ing speed of cognitive processing that typically decisions, that is, capacity/competency. affects attention, language, memory, and execu- There are numerous neuropathological pro- tive functions. These changes are referred to as cesses of a neurodegenerative nature that occur in “cognitive aging” and are thought to be normal older adults. Research suggests that nearly 70% and expected [ 15 ] . Researchers characterize the of the dementias seen in older adults are accounted age-related changes in cognition as either for by Alzheimer’s disease (AD), Parkinson’s “benign” or “malignant” [ 16 ] . Benign cognitive disease dementias (PD-D), Lewy body dementia change, or cognitive aging, is sometimes also (LBD), and frontotemporal dementia (FTD) [ 25 ] . referred to as “age-related cognitive decline” Vascular dementia (VaD) and other forms of (ARCD) and is thought to be the hallmark of gen- dementia make up the rest, with VaD thought to erally healthy aging. Contemporary practice indi- be the second most prevalent dementia after AD cates that ARCD is typically used interchangeably [26 ] . Each of these dementias may present some- with normal aging [ 16, 17 ] . Normative studies what differently and have a different course over have determined performance/ability levels for time, but with progression, all usually result in older adults on many neuropsychological instru- severe global impairment [27 ] . These disorders ments [18Ð 20 ] . Neuropsychologists retained in typically impair many aspects of cognitive func- this type of referral context should be familiar tioning, eventually rendering patients incapable 31 Capacity Evaluations in Older Adults: Neuropsychological Perspectives 505 of managing their affairs and providing for nor- spoke little, remained in bed, ate very little, and mal activities of daily living. Depending on the had no living family. She was brought to the severity of their symptoms, these patients may be hospital by her landlord, from whom she rented a unable to form reasonable judgments or make small apartment, paid for with her social security informed decisions. They therefore may be vul- and small teacher’s pension. The landlord became nerable to undue infl uence by others and be in concerned when neighbors reported they had need of guardianship to protect their interests. not seen her come or go in weeks. Upon entering Changes in personality, behavior, and/or social her apartment, the landlord found her in bed, comportment are not uncommon in older adults. unkempt with poor hygiene, in an apartment that These may be the essential features of an emerg- obviously had not been cleaned in some time. ing FTD, exacerbation of chronic psychiatric dis- Concerned about her condition, he brought her to order, behavioral sequelae of cerebral neoplasm the hospital. (e.g., glioma), vascular process (e.g., Binswanger’s On examination, the patient was only margin- disease), delirium, or paraneoplastic syndrome, ally cooperative at fi rst, refusing to be inter- among others. Some alterations in behavior or viewed. After meeting with her briefl y several cognition may be reversible with treatment or times, she became more cooperative and testing static in nature, while others are inexorably pro- was completed. It was clear that her generally gressive. The examining neuropsychologist will normal psychometric test results were not consis- need a complete medical history and recognition tent with de fi ciencies of cognition; she was cer- as to the nature of the disorder, its typical course, tainly not demented. But her mood, behavior, and prognosis. lack of hygiene, and collateral contact with neigh- Some disorders affecting older adults may bors were consistent with severe depressive ill- result in changes of cognition or behavior, but as ness. A psychiatric consult was requested, and previously noted, these changes may not rise to a the patient agreed to a trial of antidepressant level for a determination of de fi nite incompe- medication. With eventual improvements in her tency. In the case of decreased cognition, mild depression, she did agree to the surgery. attention, memory, executive functioning, verbal Interestingly, on interview, she noted, “…looking comprehension, conceptualization, and process- back it really didn’t matter to me about my foot ing, speed decrements may not have a deleterious or my life… I thought I didn’t have much life left effect on one’s capacity to render appropriately anyway… so why bother?” It is worth noting, reasoned decisions regarding fi nances, health however, that in some instances where a mentally care, and so forth [28Ð 32 ] . ill patient refuses life-saving treatment, the examining psychiatrist or hospital administrator may be appointed as a temporary guardian. This is Case Example: Refusing Medical Care most common in cases originating in hospitals or nursing homes when patients refuse to have treat- Although such mild cognitive loss may not ment that physicians recommend, especially life- demonstrably affect decisional capacity, changes saving treatment. Refusal of life-saving treatment in mood, behavior, or personality may render by patients is almost always questioned by their decision making quite impaired. Take for exam- physicians, raising the specter of diminished ple the case of a hospitalized elderly female who mental capacity [33 ] . refused treatment/surgery of her gangrenous foot. This case is illustrative of two important con- Surgeons said that unless amputated, her foot siderations: (1) factors other than cognitive would eventually lead to widespread infection impairment due to neurologic disease (e.g., throughout her body and her death. The physi- dementia) may affect decision-making capacity, cians making the referral for competency to depression in this case, and (2) some conditions refuse medical treatment believed she had demen- that adversely affect judgment are reversible with tia, likely Alzheimer’s. She was uncooperative, treatment (but many are not). 506 J.E. Morgan and B.A. Marcopulos

claiming that his sister’s judgment in fi nancial Case Example: Financial Guardian matters was seriously defi cient. M.W. had not consulted with him, the bookkeeper, her boarder, Do persons with mental retardation necessarily or anyone about the necessity of replacing the lack the capacity to manage their fi nancial affairs? roof and purchasing these expensive items but Most readers would probably agree that the answer had made the decision to do so on her own. She is “not necessarily.” Although the right to self- had apparently not remembered that the roof had determination for persons with intellectual disabil- been replaced 3 years previously at a cost of ity has come under the scrutiny of the law for some $12,000.00 and would be good for at least another time, the central issue and related questions are far 25 years! from resolved [34 ] . The following case presenta- The examination methodology included a tion highlights some of these concerns. review of many records, collateral interviews At the time of the referral, Ms. M.W. was a with M.W.’s brother and bookkeeper, and neu- 73-year-old, single never married, female living ropsychological evaluation. Neuropsychological semi-independently in a home willed to her by assessment was supplemented with many ques- her parents. She had a male boarder who assisted tions concerning money, arithmetic, and related with chores and related matters and a bookkeeper concerns. It hardly needs to be noted, but the who came every 2 weeks to pay bills and handle reader will know that ethically, it matters little such record keeping. She had a long history of what side in a forensic context retains your ser- documented intellectual impairment, having vices, simply call it like it is. attended a private school for the disabled where a Interestingly, M.W.’s IQ (Wechsler) was now StanfordÐBinet test administered at age 14 indi- 58, yet she drove her car around town and main- cated her Full Scale IQ to be 63. M.W. completed tained social activities in her church and bingo club. high school and afterward “helped” in her father’s In fact, she seemed to function quite well within of fi ce but had never had gainful employment. her very predictable and structured lifestyle, that is, She lived at home with her parents and after their with the exception of her judgment and awareness deaths, remained in the house. Her father had of monetary matters. M.W. had little knowledge of arranged for several trust funds for her that paid a her annuity, monies spent, bills, and other obliga- monthly annuity on which she lived. She had an tions, and even worse, she had extremely impaired older brother who was the executor of his par- basic arithmetic skills. In fact, she was observed ents’ estate. He lived out of state but was none- leaving a ten-dollar bill as a tip in a restaurant for a theless in good contact with M.W. and provided lunch that was less than $6.00! appropriate support. Ultimately, M.W. was judged to be “fi nancially M.W. used a credit card for purchases of incompetent” and her brother was awarded clothes, groceries, and other items and provided fi nancial guardianship. The assessment report purchases to the bookkeeper. But M.W. could also was very clear, however, that in the opinion of the write checks, and although she did this very infre- neuropsychologist, none of M.W.’s other inde- quently, concern arose after a number of very pendent activities needed monitoring. large expenditures were noted by the bookkeeper. This case illustrates the fact that sometimes It seemed that M.W. had been exploited by a num- guardianship is appropriate, particularly in a ber of unscrupulous individuals and had paid for a well-documented, circumscribed, and specifi c new roof, appliances, and other high-ticket items domain. The reader will note the importance of when she was approached by a phone call or amending standard neuropsychological assess- “knock on the door.” It is common for older adults ment methodology with appropriate, detailed and the disabled to be exploited in this manner. questions, observations, and interviews. When her brother found out about these Professional tests and psychometric consider- unnecessary expenditures, totaling many thou- ations are obviously important, but so are in vivo sands of dollars, he sought fi nancial guardianship, assessment techniques. 31 Capacity Evaluations in Older Adults: Neuropsychological Perspectives 507

the new will was executed that he did not know Case Example: Dementing Illness what he was doing. In this case, the examinee’s and the Will condition had no doubt worsened since the execution of the will, given the progressive In a case in which one of the authors was involved, nature of PSP. a wealthy, prominent gentleman was sued by his The reader will note that it is not uncommon son-in-law for changing his will and cutting out that competency evaluations present diffi cult his now deceased daughter and her heirs. The man clinical and methodological issues. Sometimes, had progressive supranuclear palsy (PSP) and was providing a scienti fi cally informed, competent quite physically and cognitively impaired. He had examination and forensic opinion is extremely hypophonia, limited visual gaze, impaired swal- challenging. The reader will want to use best neu- lowing, other physical limitations, and was ropsychological practices [ 35 ] , appropriate thought to be demented, thus providing a rationate norms, and collateral interviews, all supple- for the suit. Had the man’s ne’er-do-well son mented with comprehensive and specifi c ques- talked his father out of leaving part of his fortune tioning concerning the examinee’s understanding to his sister’s child after her death? The reader of the issues involved. It is important to remem- may think this scenario is right out of a bad B ber that the presence of cognitive impairment is movie of the 1940s, but it is not fi ctional. insuf fi cient by itself to warrant a determination of In this case, the testator’s condition made incapacity and that ultimately it is one’s clinical assessment almost impossible since he was physi- judgment that must take precedence. cally limited and speech was barely intelligible. Assessment methodology had to utilize as much multiple choice questioning as possible, limiting Clinical Pearls the assessment considerably. In addition to neuropsychologists, both sides of the legal challenge ¥ Just because someone has a diagnosis of called neurologist experts as well. Because of the dementia does not mean that they lack capac- gentleman’s condition, greater retrospective anal- ity, although this greatly increases the likeli- ysis needed to be utilized, as well as interviews hood. Capacity must be assessed by directly with many family members. The essential ques- examining the skills needed to meet the par- tion was, did the gentleman’s condition cause ticular legal standard. cognitive impairment to a suffi cient extent that he ¥ Lacking capacity in one area (such as testa- was vulnerable to the purported undue infl uence mentary) does not automatically render a per- of his son? son incompetent in others (such as medical Expert’s for the testator opined that despite treatment). his medical condition, he was competent to have ¥ Lacking capacity at one point in time does not changed his will, that he was aware of the perti- mean that the person will lack capacity in the nent facts and issues, and that the new will was future, unless the cause for incapacity is due to made free of any outside infl uence. However, a known progressive illness such as ultimately, the man’s condition made it impos- Alzheimer’s disease. Capacity may need to be sible for plaintiff expert (representing the daugh- reassessed in the future. ter’s estate, the granddaughter) to obtain enough ¥ Capacity involves both execution of tasks and reliable and valid information from him to ade- decision making about the issue. quately and competently assess his status at the ¥ Impairment on neuropsychologist tests does time the will was changed. In such instances, not equate to lack of capacity. The clinical the court usually responds in a conservative neuropsychologist needs to augment neurop- fashion, siding with the testator in that plaintiff sychological test results with specifi c task failed to document beyond a reasonable doubt information to make a recommendation that the gentleman was so impaired at the time about capacity. 508 J.E. Morgan and B.A. Marcopulos

15. Smith GE, Bondi MW. Normal aging, mild cognitive References impairment and Alzheimer’s disease. In: Morgan JE, Ricker JH, editors. Textbook of clinical neuropsychology. New York: Psychology Press; 2008; 768Ð780. 1. Marson DC, Huthwaite J, Hebert T. Testamentary 16. Smith G, Rush BK. Normal aging and mild cognitive capacity and undue infl uence in the elderly: a juris- impairment. In: Attix DK, Welsh-Bohmer KA, edi- prudent therapy perspective. Law Psychol Rev. tors. Geriatric neuropsychology: assessment and 2004;28:71Ð96. intervention. New York: Guilford Press; 2006;27Ð55. 2. Kaufmann PM. Cases, controversies, and legal author- 17. Caccappolo-Van Vliet E, Manly J, Tang MX, Marder ity in neuropsychological practice. Clin Neuropsychol. K, Bell K, Stern Y. The neuropsychological pro fi les of 2009;23(4):556 [CE Workshop presented at the 7th mild Alzheimer’s disease and questionable dementia Annual AACN Conference, San Diego, CA.]. as compared to age-related cognitive decline. J Int 3. Greiffenstein MF. Basics of forensic neuropsychol- Neuropsychol Society. 2003;9:720Ð32. ogy. In: Morgan JE, Ricker JH, editors. Textbook of 18. Smith GE, Ivnik RJ, Lucas J. Assessment techniques: clinical neuropsychology. New York: Psychology tests, test batteries, norms and methodological Press; 2008. p. 905Ð41. approaches. In: Morgan JE, Ricker JH, editors. 4. Marcopulos BA, Morgan JE, Denney RL. Textbook of clinical neuropsychology. New York: Neuropsychological evaluation of competency to pro- Psychology Press; 2008;38Ð57. ceed. In: Denney RL, Sullivan JP, editors. Clinical 19. Ivnik RJ, Malec JF, Smith GE, Tangalos EG, Petersen neuropsychology in the criminal forensic setting. New RC, Kokmen E, et al. Mayo’s older American norma- York: Guilford Press; 2008. p. 176Ð203. tive studies: WAIS-R, WMS-R, and AVLT norms for 5. Marson DC. Loss of fi nancial capacity in dementia: ages 56 through 97. Clin Neuropsychol. 1992;6(Suppl): conceptual and empirical approaches. Aging 1Ð104. Neuropsychol Cogn. 2001;8:164Ð81. 20. Heaton R, Grant I, Matthews C. Comprehensive norm 6. Greiffenstein MF. Testamentary competence: ante- s for an expanded Halstead reitan neuropsychological mortem and postmortem neuropsychological analysis. battery: demographic corrections, research fi ndings, Newsletter. 2003;40(21):7Ð36. and clinical applications. Odessa, FL: Psychological 7. Melton GB, Petrila J, Poythress NG, Slobogin C. Assessment Resources, Inc.; 1991. Psychological evaluations for the courts: a handbook 21. Flicker C, Ferris SH, Reisberg B. Mild cognitive for mental health professionals and lawyers. 3rd ed. impairment in the elderly: predictors of dementia. New York: Guilford; 2007. Neurology. 1991;41:1006Ð9. 8. Grisso T. Evaluating competencies: forensic assess- 22. Petersen RC, Smith GE, Waring S, Ivnik RJ, Tangalos ments and instruments. 2nd ed. New York: Springer EG, Kokmen E. Mild cognitive impairment: clinical Science; 2003. characterization and outcome. Arch Neurol. 9. Heilbronner RL, Sweet JJ, Morgan JE, Larrabee GJ, Millis 1999;56:303Ð8. SR. American Academy of Clinical Neuropsychology 23. Andrikopoulos J. Looking into the crystal ball of mild Consensus Conference Statement on the neuropsycho- cognitive impairment: what I see is Alzheimer’s dis- logical assessment of effort, response bias, and malin- ease. In: Morgan JE, Baron IS, Ricker JH, editors. gering. Clin Neuropsychol. 2009;23: 1093Ð129. Casebook of clinical neuropsychology. New York: 10. Moye J, Braun M. Assessment of capacity. In: Oxford University Press; 2011;540Ð559. Lichtenberg PA, editor. Handbook of assessment in 24. Whitehouse P, Brodaty H. Mild cognitive impairment. clinical gerontology. Amsterdam: Elsevier; 2010. p. Lancet. 2006;17:367. 581Ð618. 25. Welsh-Bohmer KA, Warren LH. Neurodegenerative 11. American Bar Association and American Psychological dementias. In: Attix DK, Welsh-Bohmer KA, editors. Association Assessment of Capacity in Older Adults Geriatric neuropsychology: assessment and interven- Project Working Group. Assessment of older adults tion. New York: Guilford Press; 2006;56Ð88. with diminished capacity: a handbook for psycholo- 26. Haaland KA, Swanda RM. Vascular dementia. gists. Washington, DC: American Bar Association and In: Morgan JE, Ricker JH, editors. Textbook of American Psychological Association; 2008. clinical neuropsychology. New York: Psychology 12. Shulman KI, Cohen CA, Hull I. Psychiatric issues in Press; 2008;384Ð91. retrospective challenges of testamentary capacity. Int 27. Lezak MD, Howieson DB, Loring DW. J Geriatr Psychiatry. 2005;20:63Ð9. Neuropsychological assessment. 4th ed. New York: 13. Shulman KI, Cohen CA, Kirsh FC, Hull IA, Champine Oxford; 2004. JD. Assessment of testamentary capacity and vulner- 28. Gurrera RJ, Moye J, Karel MJ, Azar AR, Armesto JC. ability to undue in fl uence. Am J Psychiatry. 2007;164: Cognitive performance predicts treatment decisional 722Ð7. abilities in mild to moderate dementia. Neurology. 14. Moye J, Marson DC. Assessment of decision-making 2006;66:1367Ð72. capacity in older adults: an emerging area of practice 29. Marson DC, Cody HA, Ingram KK, Harrell LE. and research. J Gerontol B Psychol Sci Soc Sci. Neuropsychological predictors of competency in 2007;62:3Ð11. 31 Capacity Evaluations in Older Adults: Neuropsychological Perspectives 509

Alzheimer’s disease using a rational reasons legal Raman R, Marson DC. Cognitive models of medical standard. Arch Neurol. 1995;52:955Ð9. decision-making capacity in patients with mild cogni- 30. Marson DC, Chatterjee A, Ingram KK, Harrell LE. tive impairment. J Int Neuropsychol Soc. 2008;14: Toward a neurologic model of competency: cognitive 297Ð308. predictors of capacity to consent in Alzheimer’s dis- 33. Wettstein RM, Roth LH. The psychiatrist as legal ease using three different legal standards. Neurology. guardian. Am J Psychiatry. 1988;145:600Ð4. 1996;46:666Ð72. 34. Carey A. On the margins of citizenship: intellectual 31. Marson DC, Sawrie SM, McInturff B, Snyder S, disability and civil rights in twentieth century America. Chatterjee A, Stalvey T, et al. Assessing ﬁ nancial Philadelphia, PA: Temple University Press; 2009. capacity in patients with Alzheimer’s disease: a con- 35. American Academy of Clinical Neuropsychology ceptual model and prototype instrument. Arch Neurol. (AACN). American Academy of Clinical 2000;57:877Ð84. Neuropsychology (AACN) practice guidelines for 32. Okonkwo OC, Grif ﬁ th HR, Belue K, Lanza S, neuropsychological assessment and consultation. Clin Zamrini EY, Harrell LE, Brockington JC, Clark D, Neuropsychol. 2007;21:209Ð31. Index

A risk factors , 298 Accelerated long-term forgetting (ALF) , 426 signs and symptoms , 298 Acetylcholinesterase (AChE) , 60, 181–182 symptoms, depression , 308, 309 Activities of daily livings (ADLs) , 6, 7, 246, 247 tPA , 308 Acute myelogenous leukemia (AML) , 444 AD. See Alzheimer’s disease (AD) Acute stroke AD assessment area, treatment effi cacy , 309 aMCI , 278 behavioral assessment clinical diagnosis , 278–279 BDI-FS/BAI , 307 clinical interview feedback , 307 characterized, language disturbance , 274 gyms vs. nursing fl oor , 307 description , 274 multimodal , 307 medial temporal lobe defi cits , 274 occupational, physical, and speech therapist , 307 memory impairment , 274 capacity assessment , 306–307 questions, elucidate cognitive symptoms , 275 cognitive assessment REM , 274 collateral sources , 305 diagnosis cooking/dressing task , 305 beta amyloid (A-beta) , 271 description , 305 cholinesterase inhibitors , 273 medical chart , 305 description , 271 MoCA , 305–306 integrity, specifi c brain systems , 272 neuropsychological test battery , 305 MAP , 271–272 protocol , 305 MRI , 272 test results, medical , 306 neurodegeneration , 272 cognitive impairments , 309 NINCDS–ADRDA , 272 defi nition , 298 PET and FDG , 272 description , 296 DSM-IV criteria , 278 diagnosis ( see Diagnosis, acute stroke) FTD , 279 differential diagnosis , 304 MCI (see Mild cognitive impairment (MCI)) follow-up/recommendations , 307–308 memory incidence , 296–297 advantages , 275 neuropsychology , 296 AVLT and HVLT-R , 276 pathophysiology clinical laboratory , 276 atherosclerosis , 299 description , 275 hemorrhagic , 299 function , 276 ischemic , 298 learning and tests , 276 lacunar , 299 recognition/cued recall , 275 primary intracerebral hemorrhage , 299 SIT and CVLT-II , 276 SAH , 299 neuropsychological poststroke cognitive impairment , 302–304 FDG-PET scans , 278 prevalence , 296 normal aging vs. cerebral dysfunction. , 278 prognosis , 297–298 tests , 277–278 rehabilitation setting , 304 types , 275

L.D. Ravdin and H.L. Katzen (eds.), Handbook on the Neuropsychology of Aging and Dementia, 511 Clinical Handbooks in Neuropsychology, DOI 10.1007/978-1-4614-3106-0, © Springer Science+Business Media, LLC 2013 512 Index

AD assessment (cont.) Anticonvulsants nonmemory functions carbamazepine , 96 executive tests , 277 description , 96 Hooper Visual Organization Test , 277 drugs function , 96 language , 276 phenobarbital , 96 psychomotor speed , 277 Antiepileptic drug (AED) treatment , 429–431 semantic lexicon , 277 Antipsychotics Trail-Making test , 277 AD , 92 visuospatial disturbances and constructional antipsychotics , 92, 93 praxis , 277 aripiprazole , 93 Wisconsin Card Sorting Test , 277 clozapine , 93 ADC/ADPR. See Alzheimer’s Disease Center/ description , 92 Alzheimer’s Disease Patient Registry FDA , 92 (ADC/ADPR) hypnotics and anxiolytics ADLs. See Activities of daily livings (ADLs) anticholinergic activity , 94 Advanced sleep phase syndrome (ASPS) , 83 anxiety , 94 AED. See Antiepileptic drug (AED) benzodiazepines , 94 Age-related cognitive decline (ARCD) , 504 chloral hydrate , 94 Aggression , 66 insomnia , 93 Aging nefazodone , 94 cognitive decline , 12 non-pharmacological , 94 dementia , 12 sleep hygiene , 94 physical effects , 260 Z-drugs , 94 Agitation , 162 zolpidem , 95 Airﬂ ow limitation neuroleptics , 92 functional impact, COPD , 456 olanzapine , 93 restrictive lung diseases , 455 psychotic symptoms , 93 ALF. See Accelerated long-term forgetting (ALF) quetiapine , 93 Alzheimer’s disease (AD) , 26, 34, 409 447 Anti-vertigo and motion sickness agents AChE inhibitor , 182 anticholinergic and antihistaminergic agents , 97 BTW , 140 scopolamine , 97 CDR , 141 Anxiety , 64–65 clinical diagnosis , 13 clinical pearls , 117 cognition-enhancing drugs , 90 diagnosis crash rates , 140 fear , 112 dementia , 140–141, 424 GAD , 113 depression , 264 panic disorder , 113 driving and cognition , 141–142 speciﬁ c phobia , 113 features, depression , 265, 266 epidemiology , 110 neurodegenerative disorders , 51, 259 productive anxiety vs. unnecessary worrying neurologic disorders , 85 delusions , 116 neuropathology , 13 formal measures , 116 pathology , 11 Apnea pathophysiological changes , 51 CPAP , 85 PET scan , 20 CSA , 84 prevention , 186 description , 84 smoking , 177–178 hypopnea index , 84 TCA , 90 OSA , 84 Alzheimer’s Disease Center/Alzheimer’s Disease Patient SDB , 84 Registry (ADC/ADPR) , 244–245 snoring , 85 aMCI. See Amnestic mild cognitive impairment APP. See Amyloid precursor protein (APP) (aMCI) ARCD. See Age-related cognitive decline (ARCD) American Stroke Association , 310 ASPS. See Advanced sleep phase syndrome (ASPS) AML. See Acute myelogenous leukemia (AML) Assessment Amnesia acculturation , 33 psychogenic , 407 interpretation , 221 retrograde , 402 LOS/VLOSLP vs. dementia syndrome spared function , 402 pocket vision screener , 496 Amnestic mild cognitive impairment (aMCI) , 278 Psychosis , 496 Amyloid precursor protein (APP) , 71 visual hallucinations , 497 Index 513

LOS/VLOSLP vs. psychiatric disorders attention/executive functions , bipolar , 495 319–320 GDS , 496 “classic” pattern , 321 medical rule , 497 complex learning and decision making , 320 older adults, diminished capacity , 219 language , 318 performance and patient preparation , 230 memory , 318 preparation , 230–232 patient , 317, 318 primary dementing illness , 494 social behavior and personality , 320 process , 31 visuospatial , 319 screening instruments , 31 Behind-the-wheel exam (BTW) , 137, 145, 147 symptom Benzodiazepines , 94 intrusive psychotic , 494 Berries , 172 SANS , 495 Brain imaging SAPS , 495 age-related changes , 429 unqualiﬁ ed persons , 219 INPH , 389 Auditory verbal learning test (AVLT) , 276 BTW. See Behind-the-wheel exam (BTW) Autoimmune limbic encephalitis , 406 Business issues , 195 AV L T . See Auditory verbal learning test (AVLT)

C B CADASIL. See Cerebral autosomal dominant Babinski’s sign , 470 arteriopathy with subcortical infarcts BAI. See Beck Anxiety Inventory (BAI) leukoencephalopathy (CADASIL) BDI-FS. See Beck Depression Inventory Fast Screen for California verbal learning test—second edition Medical Patients (BDI-FS) (CVLT-II) , 276 BDI-II. See Beck depression inventory-II (BDI-II) Cambridge Examination for Mental Disorders Beck Anxiety Inventory (BAI) , 307 (CAMCOG) , 350 Beck Depression Inventory Fast Screen for Medical Cambridge Semantic Memory Test (CMST) , 409 Patients (BDI-FS) , 307 Canadian Study of Health and Aging (CSHA) , 32 Beck depression inventory-II (BDI-II) , 260–261 Cancer Behavioral variant frontotemporal dementia (bvFTD) androgen ablation therapy , 447 case history and dementia functional evaluation , 325 AD , 447 illness , 324–325 progressive dementia , 448 neuropsychiatric symptom assessment , 325 and therapy, cognitive sequelae neuropsychological test , 325 disease control , 450 social/medical , 325 nasopharyngeal carcinoma , 450 clinical assessment radiation-induced memory loss , 451 behavioral , 323 user-programmable paging systems , 451 change , 321–322 Caregivers , 45, 64, 67, 68, 158–160, 163, 327 cognitive assessment , 322–323 challenges , 154–155 dynamic affect recognition test , 324 involvement , 116–117 emotional/social function , 323 CBD. See Corticobasal degeneration (CBD) family history , 322 CBS. See Corticobasal syndrome (CBS) informant-based measures , 323 CBT. See Cognitive–behavioral therapies (CBT) interview , 321 Central sleep apnea (CSA) , 84 IRI , 323 Cerebral anoxia , 405 neuroimaging , 322 Cerebral autosomal dominant arteriopathy with NPI , 323 subcortical infarcts leukoencephalopathy onset and progression , 321 (CADASIL) , 284 self-monitoring scale , 323 Cerebrospinal fl uid (CSF) , 71 social norms questionnaire , 324 Cerebrovascular disease , 296 clinical pearls , 327 CFA. See Confi rmatory factor analysis (CFA) diagnostic criteria , 314 CFF. See Critical fl icker frequency (CFF) differential diagnosis , 317 CGA. See Comprehensive geriatric assessment earliest signs , 314 (CGA) genetics , 316 CHESS. See Clinical hepatic encephalopathy staging impressions and formulation , 325 scale (CHESS) neuroanatomy and pathology , 316 Cholinesterase inhibitors , 182 neuropsychology Chronic liver disease , 479 514 Index

Chronic obstructive pulmonary disease (COPD) questioning, older adults , 5, 6 alpha-1 antitrypsin screening , 457 Cognitive remediation , 308 cigarette smoking , 456 Cognitive reserve (CR) classifi cation, severity advantages and disadvantages , 16 chronic respiratory symptoms , 457 application GOLD stage classifi cation , 456 diagnostic evaluation , 19 spirometry , 456 imaging tools , 20 sputum production , 457 individual characteristics , 20 exercise capacity , 457 integration , 19 ischemic heart disease , 456 treatment , 20 medical diagnostic tests , 457 awareness , 14 neuropsychological test , 461–464 brain damage stems , 11 progressive pulmonary disease , 455 brain network , 18 spirometry , 457 clinical effects , 14 types, restrictive lung diseases , 455 clinical pearls , 21 Circadian rhythm cumulative life experiences , 16–17 ASPS , 83, 84 dementia data , 12 description , 83 epidemiology , 12 desynchronization , 83 hippocampal integrity , 14 DSPS , 83, 84 immune , 15 treatments , 85 individual characteristics , 16 Cirrhosis intellectual function HE , 467–468 IQ , 17 healthy muscle tissue , 469 single-word reading test , 17 mental status change , 480 structural equation modeling , 17 Clinical assessment, bvFTD leisure activity , 12 behavioral , 323 life exposures , 14 change , 321–322 meta-analysis examining cohort , 12 cognitive assessment , 322–323 neural reserve and compensation , 15 dynamic affect recognition test , 324 neuroimaging , 12 emotional/social function , 323–324 pathology , 13 family history , 322 preliminary evidence , 15–16 informant-based measures , 323 statistical approaches interview , 321 episodic memory , 17 IRI , 323 fl uid characteristic , 18 neuroimaging , 322 residual component, , 18 NPI , 323 verbal recall , 15 onset and progression , 321 Competence in neuropsychology (CCN) model , 27, 29 self-monitoring scale , 323 Competency social norms questionnaire , 324 clinical and methodological issues , 507 Clinical hepatic encephalopathy staging scale older adults , 502 (CHESS) , 473 testamentary capacity , 503 CMST. See Cambridge Semantic Memory Test (CMST) Complementary/alternative interventions Cognition functional relaxation , 129 androgen ablation therapy , 447 health-care , 130 clinicians , 19 mindfulness-based interventions , 129 decline , 496 physical exercise , 129–130 diagnostic evaluation , 19 somatoform symptoms , 128–129 LOS and VLOSLP , 493 yoga , 129 profi le Complex somatic symptom disorder (CSSD) , 123 delusional disorder , 494 Comprehensive geriatric assessment (CGA) , 447 schizophrenia , 493 Confi rmatory factor analysis (CFA) , 32 visuoconstruction , 493 Continuous positive airway pressure (CPAP) , 85 visuospatial planning , 447 COPD. See Chronic obstructive pulmonary disease Cognitive aging theories. See Normal cognitive aging (COPD) Cognitive assessment , 46, 305–306 CoPGTP. See Council of Professional Geropsychology Cognitive–behavioral therapies (CBT) , 128 Training Programs (CoPGTP) Cognitive complaint Corticobasal degeneration (CBD) daily living activities , 6 attention and working memory , 343–344 memory diffi culties , 6 clinical and neurological presentation , 336 Index 515

epidemiology , 335 motor outcome , 367 executive functions , 344 psychosocial changes and quality , 367–368 language , 344 STN , 366 learning and memory , 344 surgery , 366 neuroimaging , 349 Dehydroepiandrosterone (DHEA) , 181, 185 neuropathology , 339 Delayed sleep phase syndrome (DSPS) , 84 neuropsychiatric features , 344 Delay of cognitive decline visuoperceptual and spatial functions , 344 ACTIVE trial , 179 Corticobasal syndrome (CBS) , 352 Alzheimer’s disease prevention , 186 Cost of practice booster training , 179 approved/allowed fee schedules , 202 B vitamins , 169 checklist , 197, 198–202 cardiovascular risk clean claims , 204 AD , 177 CPT codes 96118 and 90806 , 197, 204 diabetes and insulin resistance , 177 different insurer sources, CPT payments , 197, 203 hypertension and hypercholesterolemia , 177 fi nancial report , 195, 196 physical exercise , 178 ICD-9 to ICD-10, questions smoking , 177–178 clearinghouses and payors , 207 vascular disease , 176 management system vendor , 5010, 207–208 chromium , 171–172 management system vendor, ICD-10 , 208 clinical pearls , 186 institutional level , 204 cognitive reserve , 178 issues, Medicare , 206 dementia , 179 Medicare participation depression , 180 NON-PAR , 206 description , 167–168 OPT-OUT , 206 DHA , 173–174 PAR , 205 diet private/institutional , 195 cardiovascular risks , 174 SGR , 204 methodological diffi culties , 175 spreadsheet , 196–197 statistical analyses , 174 X12 4010A1 to 5010 , 207 diet-related items Council of Professional Geropsychology Training alcohol , 175 Programs (CoPGTP) , 222 caffeine , 176 CPAP. See Continuous positive airway pressure (CPAP) garlic , 175 CR. See Cognitive reserve (CR) environmental enrichment , 179 Critical fl icker frequency (CFF) , 475 folate , 170–171 CSA. See Central sleep apnea (CSA) gamma secretase inhibitors , 183–184, 186 CSF. See Cerebrospinal fl uid (CSF) heterogeneity , 168 CSHA. See Canadian Study of Health and Aging hormones (CSHA) acetylcholinesterase inhibitors , 181–182 CSSD. See Complex somatic symptom disorder (CSSD) DHEA , 181 Cultural competence estrogens , 180 awareness and knowledge , 27 hippocampus , 180 ethnic minority patient , 27 HTR , 180 Curcumin , 172–173 memantine , 182–183 CVLT-II. See California verbal learning test—second piracetam , 181 edition (CVLT-II) immune therapy , 183 MCI , 168 multidomain , 179 D neurotransmitter , 169 DC. See Digit cancellation (DC) pathological changes, AD , 168 Deep brain stimulation (DBS) polyphenolic (fl avonoids) clinical considerations and DBS berries , 172 essential tremor , 376 curcumin , 172–173 major depressive disorder , 376–377 phytochemicals , 172 neuropsychologists , 375 prevention , 184–186 obsessive-compulsive disorder , 377 prophylaxis , 168 Tourette’s syndrome , 376 social engagement , 179 GPi , 366–367 temporal lobes , 168 MRI and CT scan , 366 vascular risk factors , 169 neuropsychological outcome vitamin B1 (thiamine) , 169–170 cognitive changes , 367 vitamin B2 (ribofl avin) , 170 516 Index

Delay of cognitive decline (cont.) DHA. See Docosahexaenoic Acid (DHA) vitamin B6 (pyridoxine) , 170 DHEA. See Dehydroepiandrosterone vitamin B12 (cobalamin) , 170 (DHEA) vitamins C and E , 171 Diagnosis, acute stroke Delirium , 66, 90, 92, 94, 470, 471, 494 algorithm , 302 Dementia characterization , 301 defi nition , 168 classifi cation , 301 depression, differential diagnosis description , 300 AD ( see Alzheimer’s disease (AD)) diffusion-weighted MRI , 302 analysis, serial position effects , 265 head CT scans , 301, 302 brain degenerative changes , 262–263 hyperdense image , 302 cognitive and psychiatric symptoms , 261–262 NIHSS , 300 cognitive changes , 263 noncontrast CT , 302 cognitive symptoms , 264 signs and symptoms , 300, 301 disorders , 261 spin density , 302 language and praxis , 265 T1 and T2-weighted images , 302 late-life , 264 Diagnosis, dementia neuroimaging , 263 amyloid beta , 71 older adults ( see Geriatric depression) APP , 71 performance, recognition , 264 biomarkers , 71 phenomenologically and etiologically , 262 cholinesterase inhibitors , 60–61 pseudodementia , 258–259 clinical pearls , 74 recognition component , 264 donepezil , 60 symptom , 258 genetic variants , 72 ethnic minority and non-Hispanic whites , 26 memantine , 61 lewy body , 285 memory defi cits , 70 NPH/cortical , 288 neuriticplaques , 70 screening , 286 nonpharmacological treatments , 62, 63 VaD , 283–284 pharmacological treatments , 60, 61 vascular risk factors , 27 physical and psychological examination VCIND , 282–283 aggression , 66 Dementia with Lewy bodies (DLB) anxiety , 64–65 EEG , 424 comorbid disorders , 62 neuropsychological hallmarks delirium , 66 attention and working memory , 341 delusions , 65 executive functions , 341 depression , 64 language , 341 hallucinations , 65 learning and memory , 341 non-alzheimer , 66–67 neuropsychiatric conditions , 342–343 olanzapine and risperidone , 66 visuoperceptual and spatial functions , 342–343 research participation Parkinson’s disease dementia and dementia altruism , 72 clinical and neurological presentation , 335–336 criteria , 73 epidemiology , 334–335 FDA , 73 neuroimaging , 339–341 rivastigmine , 60 neuropathology , 338–339 social services and planning Depression , 64 attorney , 70 clinical pearls , 117 caregivers , 67 clinician explores , 114 case management , 68 dementia, differential diagnosis (see Dementia) group setting , 67 diagnosis health care proxy , 69 AD , 112 home health aid , 68 adjustment disorder , 111 legal capacity , 70 clinical unipolar , 110 online resources , 68 cognitive defi cits , 111–112 patients families , 67 dysthymia , 111 programs and training , 68 MDD , 110 residential facilities , 69 psychotic , 111 stigma , 59–60 factors , 109 tacrine , 60 grief , 115–116 vitamins, supplements and medical foods vs. normal fl uctuation , 115 axona , 62 suicide , 110, 115 FDA , 62 Index 517

homocysteine , 61 psychological symptoms , 458 omega-3 fatty acids , 62 pulmonary disease , 458 “walking dead” , 60 neuropsychological studies Diagnosis, depression and anxiety AD , 459 accurate , 114–115 cerebral functioning , 459 Bipolar I disorders , 113, 114 cognitive dysfunction , 459 Bipolar II disorders , 114 neuroimaging studies , 459 medical conditions and medications , 114 pulmonary disease , 457 prescription medication , 114 role, neuropsychologist Diagnostic and Statistical Manual (DSM) , 122, 123 maximal physical function , 460 Diffusion-weighted images (DWI) , 475 neuroradiology , 460 Digit cancellation (DC) , 479 pulmonary assessment and rehabilitation Disability , 110, 111, 117, 258 process , 459 Disease management. See Diagnosis, dementia DLB. See Dementia with Lewy bodies (DLB) DLPFC. See Dorsolateral prefrontal cortex (DLPFC) E Docosahexaenoic acid (DHA) , 173–174 Early Alzheimer’s disease , 274 Dorsolateral prefrontal cortex (DLPFC) , 319, 320 ECT. See Electroconvulsive therapy (ECT) Driving evaluation EDS. See Excessive daytime sleepiness (EDS) clinical neuropsychology EEG. See Electro encephalogram (EEG) application , 144 ELD. See External lumbar drainage (ELD) cognitive domains , 144 Elderly decision-making capacity crash rates or BTW , 145 civil competency , 502 illness , 145–146 cognitive and behavior change interventions and recommendations , 148–149 AD , 504 measures , 145 ARCD , 504 multiple abilities , 146 FTD , 504 off-road assessment , 146 LBD , 504 on-road assessment , 146 MCI , 504 risk factors , 146–147 paraneoplastic syndrome , 505 sensitive functional assessment , 147–148 verbal comprehension , 505 cognition cognitive functions , 501 dichotomize performance , 139 dementing illness , 507 older adults , 139 legal perspective predictor , 139 civil competency , 502 simulation , 140 cognitive functions , 503 work strength , 140 mental capacity , 502 considerations neuropsychological assessment , 502–503 aims , 137 neuropsychological evaluation , 503 BTW , 137–138 testamentary capacity , 504 clinical/medical focus , 138 medical care methods , 137 antidepressant medication , 505 performance and outcome , 136 cognitive loss , 505 errors , 138–139 neuropsychological consultation , 502 fast-paced society , 135–136 testamentary capacity , 502 healthy older driver , 138 Electroconvulsive therapy (ECT) , 376 neurological disease Electroencephalogram (EEG) , 475 AD , 140–142 DLB , 424 mild cognitive impairment , 143–144 long-term monitoring , 430 Parkinson’s disease , 142–143 video , 428, 430 pearls , 149 Emotion DSM. See Diagnostic and Statistical Manual (DSM) social function , 323–324 DSPS. See Delayed sleep phase syndrome (DSPS) symptoms (see Emotional symptoms) DWI. See Diffusion-weighted images (DWI) Emotional symptoms Dyspnea depression , 6 arterial blood gas measurement , 458 personality changes , 6 cognitive impairment , 460 Empirically supported treatment , 126, 132 interdisciplinary treatment , 459 End-stage liver disease (ESLD) , 478–479 medical comorbidities Environmental design, cognitive decline anemia and osteoporosis , 458 agitation , 155–156 cardiovascular disease , 458 air conditioning , 155 518 Index

Environmental design, cognitive decline (cont.) Alzheimer’s disease and degenerative bathing and agitation , 162 dementias , 424 caregivers , 155 deﬁ nition , 421–422 clinical pearls , 163–164 older adults , 422–423 cooking , 161 stroke , 423 cues , 160–161 TIA , 423 description , 153 Epilepsy Common Data Element Project , 435 devices and monitoring system , 163 Epilepsy surgery , 431 dressing , 162–163 Episodic and semantic memory disorders eating and nutritional status , 161–162 amnestic syndrome , 401–402 ﬂ uctuation, skills and behaviors , 154 clinical pearls , 414 function and perception , 153, 154 distinction insight , 155 anatomy , 403 losing and searching , 156–157 double dissociation , 403–404 low-stress thresholds , 154 retrograde amnesia , 402–403 memory aides , 156 spared function, amnesia , 402 mobility and falls Episodic memory disorders climbing stairs , 158 anticholinergic medication, effects , 405 dementia , 157–158 autoimmune limbic encephalitis , 406 electric stair lifts , 158–159 cerebral anoxia , 405 fall risk factors , 158 clinical features , 404 monitoring , 156 degenerative disorders , 405 patient’s behavior , 155 dissociative amnesias , 407 toileting , 162 electroconvulsive therapy , 407 transfers etiology , 404 beds , 160 herpes simplex and HSV-6 encephalitis , 405–406 chairs , 160 mild cognitive impairment , 404–405 power struggles , 160 transient global amnesia , 406–407 sit-to-stand , 159 trauma , 406 visual misperceptions and dysfunction vascular disease , 405 depth perception , 157 Wernicke–Korsakoff syndrome , 405 interventions , 157 ESLD. See End-stage liver disease (ESLD) lighting and function , 157 Ethics wandering , 159 dilemma , 218 EORTC. See European Organization for Research and geriatric neuropsychologists , 230 Treatment of Cancer (EORTC) and legal requirements , 221 Epilepsy and aging organizational demands , 229 clinical issues pitfalls , 226 antiepileptic drug treatment , 429–431 principles , 218, 225 brain imaging , 429 Ethnic minority diagnostic challenges , 425–426 bilingual older adults EEG , 428–429 awareness , 34 epilepsy surgery , 431 disadvantages and advantages , 34 non-epileptic paroxysmal syndromes , 427 English and Spanish , 34 psychogenic non-epileptic seizures , 428 factors , 34 status epilepticus , 427 CCN , 27–28 transient epileptic amnesia vs. transient global culture and acculturation amnesia , 426–427 application , 33–34 clinical pearls , 437 Latino patient , 33 cognition, behavior and quality potential contribution , 33–34 and cognitive function , 432–433 English language tests , 32 FC , 436–437 establishing and maintaining rapport , 29 life and mood , 431–432 extensive resources , 28 memory self-report , 435–436 informants , 31 neuropsychological assessment , 433–435 linguistic competence , 28 patients and family, information , 436 non-English language tests test battery , 435 CFA , 32 seizures limitations merit , 33 alcohol and drugs, brain tumor, head trauma SENAS and CSHA , 32 and HIV/AIDS , 424–425 verbal instructions , 32 Index 519

“nuts and bolts” , 29 neuropsychologist (see Geriatrics neuropsychologist) physical space , 28 neuropsychology , 218–222 post-evaluation considerations psychiatry service , 495 feedback session , 35 Geriatrics depression scale (GDS) , 260–261, 496 hypothesis testing , 35 Geriatrics neuropsychologist neuropsychologists , 34–35 assessment instruments , 231 pre-interview , 29 clinical interview , 230 principles , 27 ethical approach , 228 QoE , 29–30 feedback session , 233 qualitative information , 34 multidimensional assessment , 232 screening instruments , 31–32 practice, highest ethical level , 225 sociocultural considerations, Latino patients , 30 stem , 226 sociocultural lens , 29 third-party members and institutions , 228 testing considerations , 31 Glasgow coma scale (GCS) , 473 European Organization for Research and Treatment of Guardianship. See Financial guardian Cancer (EORTC) , 447 GWAS. See Genome-wide association scan (GWAS) Evaluation capacity , 231, 232, 233 self , 219 H Excessive daytime sleepiness (EDS) , 86 Hamilton depression rating scale (HDRS) , 260–261 Experimental therapeutics , 71 Health and human services (HHS) , 207 External lumbar drainage (ELD) , 392 Health care mental capacity , 502 psychometric assessment , 503 F testamentary capacity , 503 FDA. See Food and Drug Administration (FDA) Health maintenance organizations (HMOs) , 194 FDG. See Fluorodeoxyglucose (FDG) Hepatic encephalopathy (HE) Fetal transplantation , 365 Babinski’s sign , 470 Financial guardian behavioral and motor dysfunction , 470 examination methodology , 506 characterization, overt mental retardation , 506 cognitive performance , 479 standard neuropsychological assessment , 506 DC , 479 Fish oil , 186 ESLD , 478–479 Fluorodeoxyglucose (FDG) , 272 frontal–subcortical circuits , 479 FMRI. See Functional magnetic resonance imaging neurocognitive battery , 479 (FMRI) RCF , 479 Food and Drug Administration (FDA) , 73 SDMT , 479 Frontotemporal dementia (FTD) , 67, 279, 424, 504 TMT , 479 bvFTD ( see Behavioral variant frontotemporal classiﬁ cation and grading dementia (bvFTD)) acute liver failure , 469 depression , 261 liver cirrhosis , 468 FTD. See Frontotemporal dementia (FTD) nomenclature , 468 Functional capacity clinical examination ADL , 6, 7 CHESS , 473 functional independence , 7 GCS , 473 Functional magnetic resonance imaging (FMRI) , 241 HESA , 473, 474 physical and neurological exams , 472 cognitive testing , 471 G cranial nerves , 471 GCS. See Glasgow coma scale (GCS) differential diagnosis , 471 GDS. See Geriatrics depression scale (GDS) involuntary eye movements , 470 Gene therapy, PD , 365–366 laboratory ﬁ ndings , 474 Genome-wide association scan (GWAS) , 72 liver dysfunction , 467 Geriatric depression motor abnormalities , 471 BDI-II, HDRS and GDS , 260–261 neuroimaging , 474–475 neuropsychological evaluation , 260 neurophysiological measures psychometric instruments , 260 advantages , 475 symptoms , 260 CFF , 475 Geriatrics EEG , 475 depression scale (GDS) , 496 neuropsychological assessment , 476–478 520 Index

Hepatic encephalopathy (HE) (cont.) ILAE. See International League Against Epilepsy (ILAE) pathogenesis Individual freedom , 502, 503, 504 astrocyte swelling , 469, 470 Inhibitory control task (ICT) , 478 cell cultures , 470 INPH. See Idiopathic normal pressure hydrocephalus ICP , 469 (INPH) neurotransmitter systems , 469 Insomnia , 86 protein metabolism , 469 Instrumental activities of daily living (IADLs) , 251 precipitating factors , 470 International League Against Epilepsy (ILAE) , 422, 430 PSE , 467 Interpersonal reactivity index (IRI) , 323 treatment Intracranial pressure (ICP) ammonia neurotoxicity , 471 brain edema , 469 differential diagnosis , 472 monitoring devices , 475 liver transplantation , 472 pathogenesis, HE , 470 nonabsorbable antibiotics , 472 IRI. See Interpersonal reactivity index (IRI) Wilson’s disease , 471 Hepatic encephalopathy scoring algorithm (HESA) , 473, 474 L Herpes simplex , 405–406 Late-onset schizophrenia (LOS) HESA. See Hepatic encephalopathy scoring algorithm AD/lewy body dementia , 487–488 (HESA) age comparisons , 489 HHS. See Health and human services (HHS) Alzheimer type dementia , 490 HMOs. See Health maintenance organizations (HMOs) assessment Hooper Visual Organization Test (HVOT) , 371 medical rule , 497 Hopkins verbal learning test—revised (HVLT-R) , 276 symptom , 494–495 Hormone replacement therapy (HTR) , 180 VLOSLP vs. dementia syndrome , 496–497 Hormones , 180–181 VLOSLP vs. psychiatric disorders , 495–496 HSV-6 encephalitis , 405–406 auditory hallucinations , 490 HTR. See Hormone replacement therapy (HTR) cognitive profi le , 493–494 HVLT-R. See Hopkins verbal learning test—revised epidemiology , 489 (HVLT-R) prominent mood symptoms , 489 H V O T . See Hooper Visual Organization Test (HVOT) psychosis , 487 Hypertension and hypercholesterolemia , 177 risk factors Hypoxia , 405 age , 491 family , 492 gender , 491 I neuroanatomy , 492–493 IADLs. See Instrumental activities of daily living (IADLs) pharmacological treatment , 492 ICP. See Intracranial pressure (ICP) premorbid functioning , 491–492 ICT. See Inhibitory control task (ICT) Schneiderian fi rst-rank symptoms , 490 Idiopathic normal pressure hydrocephalus (INPH) terminology clinical evaluation , 392 classifi cation , 488 clinical pearls , 398 diagnostic classifi cation , 488 clinical presentation “late paraphrenia” , 488 behavioral/psychiatric symptoms , 387 paranoid delusions and hallucination , 488 cognitive dysfunction , 386–387 “praecox” , 488 gait , 386 treatment , 497–498 urinary symptoms , 386 VLOSLP , 490–491 demographics , 387–388 Lewy body dementia (LBD) , 66, 67, 504 differential diagnosis , 388–389 LOS. See Late-onset schizophrenia (LOS) evidence-based diagnostic criteria possible , 390–391 probable , 389–390 M unlikely , 392 Managed care system , 194 neuropsychological assessment MAP. See Microtubule-associated protein (MAP) family history , 394 MCI. See Mild cognitive impairment (MCI) measurement , 394–396 MDS. See Myelodysplastic syndrome (MDS) pathophysiology , 388 Medical history shunt placement cardiometabolic risk factors , 7 baseline results , 396 patient’s ability , 7 follow-up results , 396–398 self-care , 7 treatment response , 392–393 Medicare. See Neuropsychological care, Medicare patients Index 521

Medicare opt-out issues , 205, 206, 215 Movement disorders, older adults Medications and cognition clinical and neurological presentation laboratory assessment , 90 corticobasal degeneration , 339 neurodegenerative dementia , 90 DLB , 338–339 neuropsychiatric drugs PSP , 337–338 anticonvulsants, 96 clinical pearls , 355 antidepressants , 90–92 dementia , 346 antipsychotics , 92–93 epidemiology anti-vertigo and motion sickness agents , 97 corticobasal degeneration , 339 hypnotics and anxiolytics , 93–95 DLB , 334–335 opiates , 96 progressive supranuclear palsy , 335 Parkinson’s disease , 95–96 neuroimaging, structure and function systemic drugs corticobasal degeneration , 339–340 cardiovascular , 97–98 DLB , 339 cholesterol-lowering drugs , 100 PSP , 340–341 clinical pearls , 100–101 neuropathology corticosteroids and NSAIDs , 99 corticobasal degeneration , 339 H2 blockers and proton-pump inhibitors , 98 DLB , 338–339 urinary antispasmodics , 98–99 PSP , 339 Memantine , 182–183 neuropsychological assessment Memory aides , 156 corticobasal syndrome , 352–353 Microtubule-associated protein (MAP) , 271–272 interview , 348–349 Mild cognitive impairment (MCI) , 31, 61, 424, medical record , 346–348 433, 434, 504 neuropsychiatric symptoms , 352 abnormal cognitive , 51 screening instruments , 349–350 accidental , 52, 54 test , 350–352 Alzheimer’s dementia , 250 neuropsychological hallmarks assessment (see Neuropsychological assessment, corticobasal degeneration , 343–346 MCI) DLB , 341–343 clinicians disclosing , 250 MRI. See Magnetic resonance imaging (MRI) dementia , 44 MSA. See Multiple systems atrophy (MSA) description , 243 MTT. See Multiple trace theory (MTT) diagnosis Multiple systems atrophy (MSA) , 85 aging , 274 Multiple trace theory (MTT) , 403, 404 characterization , 273 Myelodysplastic syndrome (MDS) , 444 criteria , 243–244, 273 types , 273 etiology and prognosis N ADC/ADPR , 244–245 National Institute of Health Stroke Scale (NIHSS) , 297, 300 subtypes , 244 National Institute of Neurological Disorders and Stroke functional abilities , 251 (NINDS) , 298, 435 IADLs , 251 National Institute of Neurologic, Communicative Disorders MegaMemory , 45 and Stroke–AD and Related Disorders memory complains , 252 Association (NINCDS–ADRDA) , 272 neuropsychological evaluation , 251 National Institutes of Health (NIH) , 297 normal cognitive aging (see Normal Neuroanatomy cognitive aging) organic cerebral disorders , 492 older adults, memory complaint, 404 , 405 psychotic symptom , 492–493 pathophysiology and neurodiagnostic , 245 Neuroﬁ brillary tangles (NFTs) , 241 recommendations , 250–251 Neuroimaging revised criteria , 243 bvFTD , 322 subtypes , 244 corticospinal tract, HE , 475, 476 test scores , 251 DWI , 475 Mobility and falls hyperintensities in the globus pallidus , 475 climbing stairs , 158 movement disorders, older adults dementia , 157 corticobasal degeneration , 335 electric stair lifts , 158–159 DLB , 334–335 risk factors , 158 PSP , 335 MoCA. See Montreal cognitive assessment (MoCA) MRI , 475 Monitoring , 156, 163 neurobehavioral changes , 474–475 Montreal cognitive assessment (MoCA) , 286, 306 primary role , 474–475 522 Index

Neurologic disorders RBANS , 477 AD , 85 social functioning , 477 EDS , 86 somatoform Parkinson’s disease (PD) , 85 disorder , 122–123 sleep disorders , 86 symptoms , 121–122, 126 Neurophysiological assessment stroke advantages , 475 behavioral , 307 CFF , 475 capacity , 306–307 EEG , 475 cognitive , 305–306 stages, HE , 468 follow-up/recommendations , 307–308 Neuropsychiatric inventory (NPI) test selection , 477–478 bvFTD patients , 323 TIPS , 476 subscales , 325 TMT , 478 Neuropsychiatric symptom assessment, bvFTD , 325 treatment Neuropsychological assessment , MCI chronic illnesses , 127–128 clinical interview countertransference reactions , 127 ADLs , 246 mental health referral , 127 description , 246 psychic trauma , 126 diagnostic criteria , 246 psychotherapeutic , 126–127 questions, patient’s ability , 246–247 somatizing patients , 126, 127 symptoms, depression , 247 “unseen” factors , 126 vascular risk factors , 247 Neuropsychological assessment, older adults cognitive impairment cancer global screening measure , 248 CGA , 447 sample test battery , 248–249 chronological age , 446 self/family report , 248 EORTC , 447 common neurocognitive defi cits , 249 NSCLC , 446 functional impairment cancer and dementia , 447–448 ADLs , 247 cognition, cancer poorer memory performance , 248 androgen ablation therapy , 447 referrals visuospatial planning , 447 description , 245–246 cognitive impairment differential diagnosis , 246 AML , 444 subtypes, diagnosing , 250 infi ltrate brain tissue , 443–444 Neuropsychological assessment, multiple somatic symptoms MDS , 444 acute rehabilitation , 309, 310 cognitive profi le, cancer therapy , 446 aphasia , 477 competence, compromised functioning , 227 behaviors , 125 distressing and unwelcome results CBT , 128 anticipated risks , 229 chronic liver disease questionnaire , 478 APA ethical standard 3.04 , 229 clinical pearls , 132 cognition and functioning , 229 cognitive function , 125 diagnosis, dementia , 229 common adaptations , 125 dishonor/disgrace , 229 complementary/alternative interventions , 128–130 feedback session , 230 depression , 125 family members, caretakers and third-party systems empirically supported treatments , 132 anxiously , 228 family psychoeducation and therapy , 131 autonomous functioning and dignity , 228 ICT , 478 confl icting agendas and pressure , 228 physical complaints, older patients third parties and APA ethics code , 229 cogniform disorder , 125 transient, fl uctuating/chronic , 229 dementia referrals , 124 feedback session neuropsychologists , 123–124 preparation , 232–233 patient’s ability , 124 recommendations , 233–234 stoic presentation , 124 history, cancer pre-transplant evaluation , 478 etiologies, memory loss , 448 primary care interventions , 131–132 frontal-subcortical dysfunction , 449 psychotropic medications metastatic disease , 448 antidepressants , 130 peripheral neuropathy , 450 medication treatment , 130 incompetent, legal surrogate/guardian meta-analysis , 130 autonomy , 228 Index 523

capacity and time , 228 English language tests and normative data , 32 clinicians answer , 227 establishing and maintaining rapport , 29 harmful interference and care decision , 228 ethical principles , 27 isolation and incapacitated older adult , 228 extensive resources , 28 patient, preparation informants , 31 American Psychological Association linguistic competence , 28 Ethics Code , 226 non-english language tests and normative data , bioethical principles , 226 32–33 notifi cation, purpose and professional service , 226 “nuts and bolts” , 29 potentially distressing , 227 physical space , 28 privacy and confi dentiality , 226–227 post-evaluation , 34–35 pharmacotherapies , 451 pre-interview , 29 preparation QoE , 29 ADLs and IADLs , 232 qualitative information , 34 arthritis and multidimensional , 232 screening instruments , 31–32 bioethical principles and battery test selection , 230 sociocultural considerations, Latino patients , capacity evaluations and cutoff score , 231 30–31 description and diagnostics , 231 “sociocultural lens” , 29 fl uctuating cognitive performance , 232 health disparities , 26 Flynn/cohort effects , 230 Neuropsychological interview global score and subscores , 231 clinical pearls , 8 normative data , 231 complaints recommendations and non-neurological approaches , 4 variables , 232 cognitive symptoms (see Cognitive complaint) sensory and motor limitations , 232 emotional symptoms , 6 test measures/batteries , 231 physical symptoms (see Physical symptoms) prevention, cognitive sequelae , 450–451 demographic information , 4 treatment-related impairment functional capacity , 6–7 biological response modifi ers , 445 medical history , 7 chemotherapy , 445 patient’s presentation , 8 hormonal therapies , 445–446 social history , 7 immunotherapy , 444 Neuropsychological practice. See Older adults radiation , 444–445 Neuropsychological test SERMs , 446 intellectual/IQ testing , 461 surgery , 444 neuroradiology , 462 verbal memory performance , 446 progressive dementia , 462 Neuropsychological care, Medicare patients screening blue cross/blue shield , 194 COPD assessment , 462, 463 business management , 215 hypoxemia , 463 cost of practice (see Cost of practice) neurological illness , 462 description , 194–195 visual learning and memory , 464 HMOs and PPOs , 194 Neuropsychology , VCI level playing fi eld , 194 assessment , 286–288 POS plans , 194 baseline, test results , 290–291 referral form , 209, 210 repeat, evaluation , 291–292 registration form , 209, 211–215 NFTs. See Neurofi brillary tangles (NFTs) responses , 208–209 NIH. See National Institutes of Health (NIH) revenues and expenses , 195 NIHSS. See National Institute of Health Stroke Scale situations and response , 208–209 (NIHSS) waiver of insurance , 209, 214, 215 NINDS. See National Institute of Neurological Disorders Neuropsychological evaluation and Stroke (NINDS) biopsychosocioculture , 26 Non-epileptic paroxysmal syndromes , 427 clinical pearls , 36 Non-small cell lung cancer (NSCLC) , 446 cultural factors , 35 Normal cognitive aging culture and cognitive aging description , 239 dementia , 26–27 individual factors misdiagnosis , 27 description , 242 ethnic minority older adults, considerations higher education , 243 bilingual older adults , 34 physical health status , 242 CCN , 27 interindividual variation , 239–240 culture and acculturation , 33–34 language function , 240 524 Index

Normal cognitive aging (cont.) P older adults , 240 Parkinson Neuropsychometric Dementia Assessment vs. pathological , 240 (PANDA) , 350 poorer effortful/controlled processing , 240 Parkinson’s disease (PD) , 85, 95 processing speed , 240 clinical considerations and DBS (see Deep brain structural brain changes stimulation (DBS)) decreases, white matter density , 240 DBS , 366–367 loss, dopaminergic receptors , 241 dementia (see Movement disorders, older adults) myelin integrity , 240–241 diagnoses NFTs and SPs , 241 50-year-old man , 371–374 PET and fMRI , 241 57-year-old man , 374 volumetric shrinkage , 240 71-year-old woman , 371 theories dopamine level , 364 dedifferentiation and sensory driving and cognition , 142–143 function , 241 driving errors and routine driving ability , 142 processing-speed , 242 Long Island Jewish Health System scaffolding , 242 assessment measures , 370–371 Normal pressure hydrocephalus (NPH) , 285 team and roles , 369–370 North Shore-Long Island Jewish Health System (NSLIJ) , neuropsychological outcome, DBS (see Deep brain 369, 370 stimulation (DBS)) NPH. See Normal pressure hydrocephalus (NPH) neuropsychologists , 368–369 NPI. See Neuropsychiatric inventory (NPI) risk factors, dementia , 335 NSCLC. See Non-small cell lung cancer (NSCLC) treatment NSLIJ. See North Shore-Long Island Jewish Health fetal transplantation , 365 System (NSLIJ) gene therapy , 365–366 Levodopa , 364 surgical treatment , 364–365 O Parkinson’s disease dementia (PDD) Obsessive-compulsive disorder (OCD) , 377 clinical diagnostic criteria , 336 Obstructive sleep apnea (OSA) , 84 older adults (see Movement disorders, older adults) Ofﬁ ce overhead costs , 197, 204, Patients, COPD Older adults. See also Neuropsychological alpha-1 antitrypsin screening , 457 assessment, older adults brain function , 461 age-related changes , 240 classiﬁ cation, severity , 456–457 APA ethics code , 218 dyspnea , 457–460 bilateral activation , 241 exercise capacity , 457 cognitive ability , 243 medical diagnostic tests , 457 cohort effects , 221 neuropsychological test , 461–464 CoPGTP , 222 oxygen saturation , 460 cultural considerations , 221 physical symptoms , 461 description , 217–218 spirometry , 457 early-onset schizophrenia , 494 types, restrictive lung diseases , 455 ethical and legal requirements , 221 PD. See Parkinson’s disease (PD) family and social systems , 220 PDD. See Parkinson’s disease dementia (PDD) frank psychosis , 495 PET. See Positron emission tomography (PET) gist/familiar stimuli , 240 Phosphatidylinositol-binding clathrin assembly protein guidelines and resources , 219 (PICALM) , 72 late adulthood, distinct developmental stage , Physical symptoms 219–220 questioning, older adults , 5 medical status , 220 sensory complaints , 4–5 neuropsychological assessment (see sleep disorders , 5 Neuropsychological assessment, somatic complaints , 4 older adults) tremor and motor , 4 neuropsychological evaluation , 497 PICALM. See Phosphatidylinositol-binding clathrin professional competence , 218–219 assembly protein (PICALM) developing , 221 PIGD. See Postural instability and gait disturbance recommendations, promoting , 221 (PIGD) psychopathology and neuropathology , 220 PMR. See Progressive muscle relaxation (PMR) Opiates , 96 PNES. See Psychogenic non-epileptic seizures (PNES) OSA. See Obstructive sleep apnea (OSA) Point of service (POS) plans , 194 Index 525

Portosystemic encephalopathy (PSE) , 467 Q Positron emission tomography (PET) , 241, 272 Quality of education (QoE) , 29–30 Postural instability and gait disturbance (PIGD) , 334 PPOs. See Preferred provider organizations (PPOs) Practice effects R defi nition , 52 Rapid eye movement (REM) , 66, 80, 274 neurocognitive biomarker , 52 RBANS. See Repeatable battery for the assessment of Practice expenses , 195 neuropsychological status (RBANS) pre-DBS assessment , 372 RBD. See REM behavior disorder (RBD) Predicting reliable change RCF. See Rey complex fi gure test (RCF) actual standard deviation , 49 Recovery bias and error , 47 assessment, cognitive and emotional clinical practice functioning , 310 AD , 51 function , 304 memory defi cit , 52 stroke , 310 neurodegenerative disease , 51 Referral form , 209, 210 predicted retest scores , 52 Registration form , 209, 211–214 test–retest scores , 52, 53 Rehabilitation. See Acute stroke dispersion measures , 48–49 REM. See Rapid eye movement (REM) predictors , 48 REM behavior disorder (RBD) regression models dream mentation , 85 hypothetical patient , 50 synucleinopathies , 85 practice effects , 51 treatment , 85 statistical steps , 50 Repeatable battery for the assessment of trajectory , 51. neuropsychological status (RBANS) , 477 SEE , 49–50 Rey complex fi gure test (RCF) , 479 simple vs. predicted , 47–48 SRB , 49 statistical approach , 47 S test–retest change scores , 48 SAH. See Subarachnoid hemorrhage (SAH) Preferred provider organizations (PPOs) , 194 Scaffolding theory , 242 Processing-speed theory , 242 Schizophrenia Progressive muscle relaxation (PMR) , 83 classifi cation and treatment , 488 Progressive supranuclear palsy (PSP) psychosis , 488 attention and working memory , 344 SD. See Semantic dementia (SD) clinical and neurological presentation , 337–338 SDB. See Sleep-disordered breathing (SDB) epidemiology , 335 SDMT. See Symbol digit modalities test (SDMT) . executive functions , 344–345 SEE. See Standard error of the estimate (SEE) language , 345 Selective estrogen receptor modulators (SERMs) , 446 learning and memory , 345 Selective serotonin reuptake inhibitors (SSRIs) , 64, MRI , 340 326–327, 376 neuroimaging , 339 Semantic dementia (SD) neuropathology , 338–339 defi nition , 405 neuropsychiatric features , 345–346 patients , 408–409 visuoperceptual and spatial functions , 345 Semantic interference test (SIT) , 276 PSE. See Portosystemic encephalopathy (PSE) Semantic memory disorders Pseudodementia Alzheimer’s disease , 409 cognitive symptoms , 258 clinical examination , 410–412 depressed/demented , 259 clinical features , 407–408 description , 258 etiology , 408, 410 DSM , 259 herpes simplex encephalitis , 409–410 reversible dementia , 258 neurodiagnostic considerations , 412–414 PSP. See Progressive supranuclear palsy (PSP) semantic dementia , 408–409 Psychogenic non-epileptic seizures (PNES) , 428 SENAS. See Spanish and English Neuropsychological Psychosis Assessment Scales (SENAS) Alzheimer-type dementia , 490 Senile plaques (SPs) , 241 dementia syndromes , 496 Serial assessments, dementia symptoms , 487 alternate forms , 46–47 Pulmonary disease bias , 46 cognitive symptoms , 461 clinical neuropsychology , 43–44 dyspnea , 458 cognitive change , 54 526 Index

Serial assessments, dementia (cont.) SPs. See Senile plaques (SPs) diagnosis , 44 SRB. See Standardized regression-based error , 46 (SRB) approach neurocognitive biomarker SREDA. See Subclinical rhythmic electrical discharges cognitive change , 54 of adulthood (SREDA) MCI , 52, 54 SSRIs. See Selective serotonin reuptake inhibitors memory training , 54 (SSRIs) practice effects , 52 SSSD. See Simple somatic symptom disorder (SSSD) neuropsychological tests , 45 Standard error of the estimate. (SEE), 49–50 norms Standardized regression-based (SRB) approach , deviations , 45 49, 50 diagnostic approach , 44–45 Status epilepticus , 427 memory disorders , 45 Stroke pearls , 55 AD , 283 reliable change large vessel , 286 basic model , 47–51 risk , 284 clinical practice , 51–52 seizures and epilepsy, older adults , 423 older adults , 47 sites and clinical features , 282 statistical approach , 47 Subarachnoid hemorrhage (SAH) , 299 share , 46 Subclinical rhythmic electrical discharges of adulthood traditional single-point evaluations , 44 (SREDA) , 429 SERMs. See Selective estrogen receptor modulators Subthalamic nucleus (STN) , 364, 366–367 (SERMs) Suicide , 110, 115 SGR. See Sustainable growth rate (SGR) Sustainable growth rate (SGR) , 204 SIADH. See Syndrome of inappropriate antidiuretic SWS. See Slow-wave sleep (SWS) hormone secretion (SIADH) Symbol digit modalities test (SDMT) , 479 Simple somatic symptom disorder (SSSD) , 123 Syndrome of inappropriate antidiuretic hormone Single-word reading test , 17 secretion (SIADH) , 64 SIT. See Semantic interference test (SIT) Sleep and aging apnea , 84–85 T circadian rhythms , 83–84 TCA. See Tricyclic antidepressants (TCA) clinical pearls , 86 TEA. See Transient epileptic amnesia (TEA) insomnia TENS. See Transcutaneous electrical nerve stimulation defi nition , 80 (TENS) perpetuating activity , 82 TIAs. See Transient ischemic attacks (TIAs) precipitating events , 81 Tissue plasminogen activator (tPA) , 308 predisposing characteristics , 81 TMT. See Trail making test (TMT) treatment , 82–83 Tourette’s syndrome , 376 N1 and N2 stages , 80 tPA. See Tissue plasminogen activator (tPA) neurologic disorders , 85–86 Trail making test (TMT) , 479 REM behavior disorder , 85 Transcutaneous electrical nerve stimulation SWS, defi nition , 79 (TENS) , 63 Sleep-disordered breathing (SDB) , 84 Transient epileptic amnesia (TEA) , 426–427 Slow-wave sleep (SWS) , 79 Transient global amnesia (TGA) , 426–427 Social behavior and personality , 320 Transient ischemic attacks (TIAs) , 286, 423 Social history , 7 Trauma , 406 Somatization Treatment, insomnia disorders benzodiazepines , 82 CSSD , 123 CBT-I , 82 DSM-V , 122–123 cognitive therapy , 83 “neurotic” , 122 polysomnograms , 83 rationale , 123 relaxation techniques , 83 SSSD , 123 sleep restriction therapy , 82 symptoms stimulus control therapy , 83 DSM , 122 Tricyclic antidepressants (TCA) “mind–body” disorders , 122 anticholinergic effects , 90–91 neuropsychological assessment , 121 cognitive defi cits or memory impairment , 92 Spanish and English Neuropsychological Assessment mouse model , 92 Scales (SENAS) , 32, 33 scopolamine , 91–92 Index 527

U Vascular cognitive impairment no dementia Urinary symptoms , 285, 386, 389 (VCIND) frontal white matter hyperintensities , 283 MRI lesions , 283 V prodromal stage, VaD , 283 VaD. See Vascular dementia (VaD) risk factors , 283 Vascular cognitive impairment (VCI) types , 282 assessment, neuropsychology Vascular dementia (VaD) ADL , 288 ADDTC and NINDS-AIREN criteria , amnestic pattern, AD , 286 284 communicate, families , 288 depression , 283 MoCA , 286 description , 283 NINDS and Canadian Stroke Harmonization DSM-IV criteria , 284 Network , 287 episodic memory defi cits , 283 protocol , 287 stroke and AD , 283 clinical interview and history Vascular disease , 405 memory failure description , 286 VCI. See Vascular cognitive impairment normal aging , 286 (VCI) solicitation , 286 VCIND. See Vascular cognitive impairment no dementia stepwise vs. progressive decline , 286 (VCIND) TIA , 286 Very-late-onset schizophrenia-like psychosis vessel infarcts , 286 (VLOSLP) description , 282 Alzheimer-type dementia , differential diagnosis , 285 490–491 MRI-defi ned , 285 vs. dementia syndrome , 496–497 neuroimaging corroboration formal thought disorder , 490 cerebrovascular disease , 288 vs. psychiatric disorders , 495–496 extensive vascular disease , 289 visual hallucinations , 491 fi ngerprint , 288 Vitamins FLAIR images, characterization , 288 B6 vitamin (pyridoxine) , 170 radiology and MRI report , 289 B12 vitamin (cobalamin) , 170 3T MRI , 288 B vitamins , 169 neuropsychological evaluation B1 vitamins (thiamine) , 169–170 data , 292 B2 vitamins (ribofl avin) , 170 T2 and FLAIR signal , 292 C and E vitamins , 171 older adults, cognitive diffi culties , 292 folate , 170–171 risk factors , 284–285 VLOSLP. See Very-late-onset schizophrenia-like severe (see Vascular dementia (VaD)) psychosis (VLOSLP) spectrum , 282 stroke sites and clinical features , 282 test results, neuropsychological W baseline and 12-month data , 289 Wandering , 159 cerebrovascular disease , 289 Wernicke–Korsakoff syndrome , 405 TIAs, stroke, and memory loss , 289 Wilson’s disease , 471