Neurobehavioral Assessment

Review Article

Address correspondence to Dr Daniel I. Kaufer, CB 7025, Neurobehavioral 3129 POB, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, Assessment kauferd@neurology.unc.edu. Relationship Disclosure: Daniel I. Kaufer, MD, FAAN Dr Kaufer serves on the board of Alzheimers North Carolina and the scientific advisory council of the Lewy Body ABSTRACT Dementia Association, Inc; served as a symposium director Purpose of Review: This article presents a multidimensional, integrative approach for the American Neuropsychiatric to clinical assessment and management of neurobehavioral disorders. Association’s Annual Meeting; Recent Findings: Behavioral neurology and neuropsychiatry has grown as a subspecialty provides study design support for Johnson & Johnson along with increased recognition of two common brain disorders: dementia and traumatic Services, Inc; and provided brain injury. Alzheimer disease is a highly prevalent dementia and a prototypical mem- independent medical review ory disorder, which has led to a primary focus on cognitive screening and assessment. and deposition for HensonFuerst. By contrast, recent attention concerning possible long-term sequelae of repetitive trau- Unlabeled Use of Products/Investigational matic brain injury has emphasized aberrant behavior (eg, depression, impulsivity, aggres- Use Disclosure: sion). Clinical phenotyping across cognitive and behavioral dimensions, in conjunction Dr Kaufer reports no disclosure. with advancements in structural and functional neuroimaging, brain electrophysiologic * 2015, American Academy techniques, and molecular genetics, is essential to improve diagnostic precision and of Neurology. therapeutic targeting along the spectrum of CNS disorders. Summary: All neurologists benefit from honing their clinical skills in neurobehavioral assessment. A systematic approach to cognitive and behavioral assessment increases differential diagnostic specificity, helps focus appropriate therapeutic interventions, and improves the quality of life for patients and their families. This article highlights practical approaches to neurobehavioral assessment in support of differential diagnosis and therapeutic monitoring in general neurology practice.

Continuum (Minneap Minn) 2015;21(3):597–612.

INTRODUCTION tive biomarker data in dementia, traumatic The seeds of contemporary cognitive brain injury, and other neuropsychiatric and behavioral neurology arose about disorders. In current neurology practice, a half-century ago in the fertile soil of cognitive, functional, and behavioral as- Boston led by Norman Geschwind. This sessment is far from standardized. In a renaissance in behavioral neurology tertiary memory disorder clinical practice advanced work from the middle to late setting, there is much greater diagnostic 19th century, first in aphasiology (Broca yield from obtaining a detailed and com- and Wernicke) and later in dementia (ie, prehensive history than from ordering a Pick and Alzheimer). The necessity of a battery of esoteric tests. Accordingly, this detailed neurologic and neurobehavioral article focuses on the basic elements of a examination accrued from a forced de- comprehensive neurobehavioral assess- pendence on inferential data in the ab- ment that are amenable to general neu- sence of direct visualization of the brain. rology practice settings. Over the last several decades, brain imaging has revolutionized the daily practice HISTORY of neurology and is on the cusp of advanc- The primary focus of clinical neurobe- Supplemental digital content: ing structural, functional, and molecular havioral assessment is a change from a Direct URL citations appear in the printed text and are provided diagnostic tools that will marry clin- previous level of functioning, which in- in the HTML, PDF, and app ver- ical diagnostic assessment with objec- cludes cognitive and functional abilities, sions of this article.

Continuum (Minneap Minn) 2015;21(3):597–612 www.ContinuumJournal.com 597

KEY POINTS 1 h The primary focus of mood, emotional responsiveness, and often compromised. Impaired aware- clinical neurobehavioral social behavior. The clinical history is ness of cognitive deficits is difficult to assessment is a often the most critical data source for a measure clinically but has important im- change from a previous neurobehavioral evaluation and typically plications for a patient’s ability to comply level of functioning, requires an informant who knows the pa- with appropriate restrictions on driving which includes cognitive tient well in order to ensure an accurate or accept supervision for activities such and functional abilities, rendering. Knowing the reason for the as managing finances. Conversely, a pa- mood, emotional evaluation helps determine strategy re- tient may report a greater cognitive symp- responsiveness, and garding how to engage the patient and tom burden than a reliable informant, social behavior. informant. For example, a patient who is with cognitive testing aligning more h A marked discrepancy unaware that he or she is being evaluated with the latter’s assessment. This profile between a patient’s and for a memory problem needs to be inter- is more likely to be associated with a informant’s portrayal of viewed (and debriefed) differently from mood disturbance, anxiety symptoms, clinical cognitive changes one who is concerned about his or her or elevated level of stress. Although the sets the stage for clinical own memory functioning. In the former term ‘‘worried well’’ is sometimes used hypothesis testing case, it is often helpful to speak with the in this context, in certain cases it may be based on the degree of agreement with informant separately or, alternatively, al- appropriate to pursue a more in-depth formal cognitive testing. low the informant an opportunity to neuropsychological evaluation to en- discretely communicate sensitive infor- sure that early signs of a neurocognitive h Impaired awareness of mation. Although informants generally disorder are not being missed. This is cognitive deficits is difficult to measure provide a reliable history, at times their particularly true in highly educated indi- clinically but has frustration and distress may lead to their viduals, where ‘‘normal’’ performance on important implications overstating symptom severity in patients. standard cognitive screening tests may for how challenging In such circumstances it is often produc- be misleading. complying with tive to focus attention on helping them Other historical data may help elab- appropriate restrictions cope with caregiving demands. Rarely, orate a differential diagnosis, including or supervision for informants may have nefarious financial temporal onset and course, hereditary activities, such as driving motives for exaggerating clinical symp- factors, and comorbid medical condi- and managing finances, toms and associated disability in order tions (Table 1-1). A positive family his- can be for the patient. to obtain guardianship. Conversely, pa- tory deserves close attention, particularly tients with either depression or morbid if autosomal dominant inheritance is anxiety may be hypercritical of their self- suspected. Within a given family, a wide perceived cognitive status and exagger- range of phenotypic variability may be ate cognitive changes. seen with autosomal dominant mutations. A marked discrepancy between a pa- For example, an autosomal dominant mu- tient’s and informant’s portrayal of clin- tation on chromosome 9 associated with ical cognitive changes sets the stage for the expansion of a hexanucleotide repeat clinical hypothesis testing based on the (chromosome 9 open reading frame 72 degree of agreement with formal cog- [c9orf72]) is the most common cause nitivetesting.Forexample,ifan of both familial ALS and familial fronto- informant’s report of the patient’s deficits temporal degeneration.2 Affected mem- is supported by cognitive testing and the bers within a family can exhibit clinical deficits reported are greater than the pa- features on a spectrum between these tient’s self-report, it is reasonable to infer two disorders. Sleep disturbances such that the patient has impaired awareness as insomnia, restless leg syndrome, and of his or her deficits. This finding is sug- sleep apnea are common comorbidities gestive of a neurodegenerative disorder in neurobehavioral disorders, and rapid such as Alzheimer disease or traumatic eye movement (REM) behavior disor- brain injury, where deficit awareness is der is a hallmark of synucleinopathies.3

598 www.ContinuumJournal.com June 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS h TABLE 1-1 Diagnostic Elements in the Clinical History Documenting a careful history of head injuries b Initial/Concomitant Symptoms and their associated acute (eg, alteration or Cognitive: Memory, language, visuospatial, executive (eg, judgment) loss of consciousness) Functional: Work, managing finances, driving, shopping, household chores and chronic (eg, Neuropsychiatric: Apathy, depression, anxiety, psychosis, impulsivity, disinhibition headaches, vertigo) Motor: Tremor, rigidity, incoordination, balance difficulty, dysarthria, weakness accompaniments will b Temporal likely play an increasing Onset: Abrupt, subacute, insidious role in understanding complex relationships Course: Static, progressive, fluctuating, improving between mechanical b Traumatic brain injury and Altered consciousness (eg, dazed, confused, groggy, ‘‘saw stars’’) neurodegenerative Loss of consciousness (duration) disorders, such as Amnesia (retrograde/anterograde) frontotemporal Neurologic sequelae (eg, headache, nausea, vertigo, vision change, sleep alteration) degeneration and ALS. b Individual h A hallmark of Age, gender, cultural background neurobehavioral assessment is its Educational level, learning disability, premorbid personality multidimensional and Social circumstances, financial resources, occupational activities integrative nature. b Genetic Family history suggesting autosomal dominant inheritance Familial cases suggesting polymorphism association (eg, apolipoprotein E4 [APOE] in Alzheimer disease) b General Medical conditions (eg, hypothyroidism, vitamin deficiency, peripheral vascular disease) Neurologic conditions (eg, transient ischemic attack, stroke, seizure, head trauma) Sleep disturbances (eg, sleep apnea, insomnia, sleep-associated movement disorder)

A history of mild repetitive traumatic companiments will likely play an increas- brain injury or concussions draws scru- ing role in understanding complex tiny as a risk factor for a later-developing relationships between mechanical brain dementia syndrome: chronic traumatic injury and neurodegenerative disorders, encephalopathy.4 Head injuries associ- such as frontotemporal degeneration ated with falls, automobile or bicycle and ALS. accidents, recreational activities (eg, skiing, sledding), military activities, sports-related CLINICAL ASSESSMENT injuries, and other home- or work-related A hallmark of neurobehavioral assess- accidents may cause or exacerbate neu- ment is its multidimensional and inte- rologic disorders such as headaches or grative nature. Among dementias, the seizures. Documenting a careful history high prevalence of Alzheimer disease and of head injuries and their associated acute its cardinal manifestations of short-term (eg, alteration or loss of consciousness) memory and other cognitive disturbances and chronic (eg, headaches, vertigo) ac- weight clinical assessment heavily toward

Continuum (Minneap Minn) 2015;21(3):597–612 www.ContinuumJournal.com 599

cognitive symptoms. However, recently screening for depression and managing revised diagnostic criteria for Alzheimer neuropsychiatric disturbances. Moreover, disease now recognize noncognitive symp- other AAN quality measures for Parkinson toms such as depression and apathy as disease7 and ALS8 include provisions for primary disease manifestations,5 and other cognitive and psychiatric symptom assess- neuropsychiatric symptoms are often the ment. The former also highlights assessing most prominent changes in disorders sleep-wake disturbances such as REM be- such as dementia with Lewy bodies and havior disorder and daytime somnolence as frontotemporal degeneration. Moreover, common associated clinical manifestations. recent dementia quality measures developed by the American Academy of Neu- Cognitive Assessment rology (AAN) and other stakeholders The examiner can evaluate cognitive symp- highlight a broad range of clinical param- toms both informally through a clinical in- eters that support comprehensive care to terview and objectively by assessment with improve clinical outcomes (Table 1-2).6 neurocognitive testing. The Ascertain De- Among these 10 quality measures, mentia 8 (AD8), an 8-item measure of which are used as part of Physician Qual- informant-reported changes in cognitive ity Reporting System (PQRS) and Mean- functioning, is a well-validated and widely ingful Use (MU) requirements, numbers used historical cognitive screening instru- 2 to 6 under Evaluation and Treatment ment (Supplemental Digital Content 1-1, Strategies emphasize the multidimen- links.lww.com/CONT/A140).9 sional aspects of care. In addition to the The AD8 was derived from semi- standard cognitive assessment, there is structured interviews involving a large also the provision for neuropsychiatric research data set and includes histo- and functional assessments, as well as rical features that were most strongly

TABLE 1-2 Dementia Quality Measures from the American Academy of Neurologya

b Evaluation and Treatment Strategies Measure 1: Staging of Dementia Measure 2: Cognitive Assessment Measure 3: Functional Status Assessment Measure 4: Neuropsychiatric Symptom Assessment Measure 5: Management of Neuropsychiatric Symptoms Measure 6: Screening for Depressive Symptoms b Safety Issues Measure 7: Counseling Regarding Safety Concerns Measure 8: Counseling Regarding Risks of Driving b Patient-Centered Care Strategies Measure 9: Palliative Care Counseling and Advance Care Planning Measure 10: Caregiver Education and Support

a Detailed information on these measures can be found at www.aan.com/uploadedFiles/Website_Library_ Assets/Documents/3.Practice_Management/2.Quality_Improvement/1.Quality_Measures/1.All_ Measures/Dementia%20measure%20set%202014%20transition.pdf.

600 www.ContinuumJournal.com June 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS associated with Alzheimer disease. An in- included to evaluate for depression, h Inquiring about the formant typically completes the screening anxiety, and effort (eg, malingering). patient’s ability to questions, although patients can self- All screening cognitive tests have manage finances 10 report if no informant is available. The limitations and require specific knowl- deserves special AD8 content includes memory, orienta- edge regarding test administration and attention because tion, and other faculties, including exec- scoring in order to be valid. More de- financial capacity is utive, motivation, praxis, and functional tailed and sophisticated cognitive tests often affected early in ability (eg, managing money). A score of generally require more training of the the course of mild 2 or higher (out of 8 total items) on the examiner. A screening test such as the cognitive impairment, AD8 is highly predictive of dementia (sen- Mini-Cog may yield a negative screen Alzheimer disease, sitivity 0.85, specificity 0.86). Inquiring about based on the patient recalling all three and other forms of dementia, and the the patient’s ability to manage finances words, yet indicate a potential problem deserves special attention because fi- potential consequences in a patient with, for example, Parkinson can be devastating. nancial capacity is often affected early in disease, who may have difficulty draw- h the course of mild cognitive impairment ing a clock. When administering cogni- When administering cognitive tests, it is (MCI), Alzheimer disease, and other forms tive tests, it is crucial to document any crucial to document any of dementia, and the potential conse- potential confounds to the validity of the potential confounds to quences of poor financial management test, such as hearing or vision problems, 11 the validity of the test, can be devastating. motor dysfunction, language barrier to such as hearing or Performing cognitive testing in clin- understanding instructions, and psy- vision problems, motor ical practice is a challenge that varies in chological factors such as effort, moti- dysfunction, language proportion to the length and complex- vation, depression, and anxiety. barrier to understanding ity of required testing and available A fundamental limitation regarding clin- instructions, and testing resources. The standard single- ical cognitive testing is that it is generally psychological factors system neurologic examination generally not reimbursable. One exception is to such as effort, motivation, covers level of arousal, attention, orien- administer a battery of cognitive tests and depression, and anxiety. tation, speech, language, recent and remote bill as a separate neurobehavioral status memory, and general fund of knowledge examination (Current Procedural Termi- and is useful only for general screening. nology [CPT] code 96116). This approach These data should also be supplemented by requires a physician or advanced practice observations regarding affect (eg, blunted, practitioner to conduct most of the test- expansive, pseudobulbar), mood state (eg, ing, which may not be feasible in many hypomanic, sad, anxious), motivation clinical practice settings. Another alter- (eg, apathetic, disinhibited), distractibil- native is to have an office staff person ity, fidgetiness, restlessness, persever- supervise testing the subject in a computer- ation, obsessive thinking, paranoid or administered test battery such as CNS psychotic thinking, impulsivity, or other Vital Signs.13 This assessment consists behavioral phenomena noted to be pres- of seven neuropsychological tests that ent. Beyond this, clinical cognitive assess- yieldfivedomainscores:memory,psycho- ment is used for a variety of purposes, motor speed, reaction time, cognitive ranging from screening for possible de- flexibility, and complex attention, with mentia using tests such as the Mini-Cog,12 scaled percentile performance indices to performing a comprehensive neuro- generated automatically. While this ap- psychological evaluation. The latter typ- proach collects data on a battery of tests ically involves several hours of testing with minimal supervision, lack of train- using age- and education-adjusted nor- ing qualifications and clinical diagnostic mative data, yielding a quantitative psy- standards for data interpretation currently chometric assessment. Behavior and limit its utility. Computer-based test mate- psychological rating scales are also often rials offer the prospect of improving

Continuum (Minneap Minn) 2015;21(3):597–612 www.ContinuumJournal.com 601

KEY POINTS h The Montreal Cognitive standardization and scoring of clinical points), reproducing the intersecting Assessment (MoCA) cognitive testing, which, combined with pentagon figure from memory (4 addi- test is a comprehensive the establishment of robust training and tional points), and long-delayed spon- cognitive screening test application criteria, may eventually sup- taneous recall of the three words with with multiple alternate port higher levels of reimbursement. multiple-choice recognition for any that forms and an expanding The prevailing standard for cognitive are not recalled (6 additional points). In normative database. assessment in neurologic practice is to the MMX delayed recall/recognition test, h The MoCA test administer brief cognitive tests such 2 points are given for each word that is represents a distillation as the Mini-Mental State Examination recalled, and for those that are not, 1 point of a neurobehavioral (MMSE) or Montreal Cognitive Assess- is given if correctly identified from among Y status examination ment (MoCA).14 16 The primary aim of three choices. This test may also provide battery and requires such testing is to evaluate cognitive symp- useful qualitative information to help dis- specific training in toms reported to be present in daily criminate Alzheimer disease and amnestic test administration activities, as opposed to screening for MCI from other types of cognitive im- and scoring. cognitive impairment.17 Although the pairment, as these patients also tend to MMSE is the historical gold standard do poorly on multiple-choice recognition for clinical cognitive assessment, it testing. was copyright protected more than The MoCA is a comprehensive cog- 25 years after its initial publication and nitive screening test with multiple alter- now requires payment on a per-use basis nate forms and an expanding normative (www.parinc.com). database (mocatest.org). The MoCA is Although the MMSE is fairly well suited sensitive to detecting cognitive distur- to screening for and tracking Alzheimer bances in Parkinson disease and MCI.19,20 disease over time, it is not particularly Studies in community samples suggest useful for identifying MCI or nonY that it may have lower specificity in less- Alzheimer dementias. However, in de- educated subjects (ie, high false-positive pressed or disinhibited patients, the con- rates), a trade-off to being sensitive to tent of the sentence they compose (eg, early cognitive impairment. A dementia ‘‘I am depressed’’ or ‘‘I love you’’) may, at cutoff score lower than 26 may need to times, provide useful diagnostic data. be used in selected clinical populations.21 An extended 50-point version of the The five-word recall test is more chal- MMSE, the Mini-Mental State Examina- lenging than the three-word test on the tion Extended (MMX), was developed, MMSE and includes qualitative mea- which requires minimal additional time, sures for cued recall and multiple-choice yields standard MMSE scores, and is recognition. The MoCA represents a sensitive to MCI and nonYAlzheimer distillation of a neurobehavioral status dementias (Table 1-3).18 The additional examination battery and requires spe- 20 points of the MMX test are derived cific training in test administration and from a combination of alternate scor- scoring. Untrained examiners commonly ing criteria and some brief additions fail to instruct the test subject to rem- (Table 1-4). Alternate scoring involves ember the five-word list after repeat- scoring the sum of serial 7s subtraction and ing the list over two trials, as this script WORLD backward scores (5 additional is not printed on the test form. This points, 10 points total) and using a 4-point omission invalidates the test as it was scoringschemefortheintersectingpen- designed and may contribute to false- tagon figure (3 additional points, 4 points positive results. total). Additional items include adding The St. Louis University Mental Sta- pen clip or pen holder and watchband tus (SLUMS) examination is a 30-point or watch strap to naming (2 additional cognitive screening test that includes a

602 www.ContinuumJournal.com June 2015

Test Format and Content Comments Mini-Mental State 30-point scale Old standard assessment for Examination (MMSE) Orientation, memory, attention, Alzheimer disease, not sensitive to praxis, language, constructions mild cognitive impairment and nonYAlzheimer disease disorders, withdrawn from public domain Mini-Mental State Examination 50-point scale (MMSE with Yields standard MMSE with little Extended (MMX) an additional 20 points) effort, sensitive to mild cognitive Y Constructions, language, impairment and non Alzheimer verbal/nonverbal memory dementia, MMSE forms are copyright protected, requiring pay per use Montreal Cognitive 30-point scale Sensitive to mild cognitive Y Assessment (MoCA) Memory, constructions, executive, impairment and non Alzheimer visuospatial, language dementia, alternate forms; requires training; may see false-positive results in subjects with less than a college education St. Louis University Mental 30-point scale Word list and paragraph recall, Status (SLUMS) examination Memory attention, language, emphasizes practical cognitive functions, praxis, abstraction, calculations belongs to the public domain, alternative to MMSE five-word memory list and story recall, have similar characteristics to the MoCA as well as fluency, orientation, clock with respect to identifying MCI and de- drawing, and other executive cognitive mentia.23 The SLUMS includes a word- tasks.22 The SLUMS has been shown to based arithmetic problem and paragraph

TABLE 1-4 Mini-Mental State Examination (MMSE) Versus the Mini-Mental State Examination Extended (MMX)

MMSE (30 Points) MMX (50 Points) Added Points Alternate scoring Mental control WORLD backward or serial WORLD backward and serial +5 7s subtraction (5 points) 7s subtraction (10 points) Figure copy 0Y1 Point 0Y4 Pointsa +3 Additions Naming Pen (1 point) Pen clip (holder) (1 point) +2 Watch (1 point) Watchband (strap) (1 point) Figure recall NA 0Y4 pointsa +4 Three-word delayed NA Spontaneous recall (2 points each) +6 recall/recognition Multiple choiceb (1 point each) NA = not applicable. a One point for each pentagon, one point if there is any overlap, one point if the overlap is four-sided. b Used only for words not recalled (eg, carrot [choices: celery/carrot/cabbage], robin [choices: robin/sparrow/bluejay], hammer [choices: wrench/screwdriver/hammer]).

Continuum (Minneap Minn) 2015;21(3):597–612 www.ContinuumJournal.com 603

KEY POINT h recall test that may better reflect real- in frontotemporal degeneration or de- Single-domain cognitive 24,25 tests may be useful as world functioning (ie, ecological validity). mentia with Lewy bodies. For either adjuncts to cognitive Single-domain cognitive tests may be test, unwitting repetitions provide a back- screening or as part of a useful as adjuncts to cognitive screening door view of memory function, and strat- more comprehensive or as part of a more comprehensive egies the patient employs in word neurocognitive evaluation. neurocognitive evaluation. Clinical tests generation may paint a portrait of other of attention, memory, language, higher cognitive functions as well. visuoperceptual, and visuomotor (eg, Short forms of the Boston Naming figure copy) function are generally sen- Test are also useful for aphasia screen- sitive to corroborating reported deficits ing.26,27 Confrontational naming is usu- in these domains. By contrast, executive ally markedly impaired in the semantic dysfunction, which encompasses a wide variant of primary progressive aphasia, array of cognitive/behavioral/motor pro- where errors typically involve semantic cesses such as working memory, plan- relatedness (eg, saying airplane for ning, sequencing, and abstract conceptual helicopter). The Northwestern Nam- thinking, may be more challenging to de- ing Battery is a more recently devel- monstrate. Fluency testing is a combined oped naming assessment that includes language and executive task that involves both verbs and nouns, assesses both asking subjects to name as many items production and comprehension, and from a given class or category as they can has been developed for patients both in 1 minute using stimuli such as animals poststroke and with primary progressive (semantic) or a letter (S or D). Semantic aphasia.28 A brief summary of commonly fluency is often selectively impaired in used single-domain cognitive tests is Alzheimer disease or the semantic shown in Table 1-5. variant of primary progressive aphasia, whereas selective impairment in letter Functional Assessment fluency is more suggestive of frontal The assessment of functional abilities subcortical network dysfunction as seen is indirectly related to specific cognitive

TABLE 1-5 Single-Domain Cognitive Tests

Domain Test Description (approximate normal range) Working memory Digit span forward (7 T 2) Divided attention Digit span backward (6 T 2) Months in reverse order (15Y20 sec) Orientation Time (date, month, season, year) Location (building, floor, city, state) Fluency Category: number of animals named in 1 min (18 T 6) Letter: number of S words named in 1 min (12 T 2) Language (naming) 15-item Boston Naming Test Constructions Copy cube or intersecting pentagons Visuomotor Clock drawing (including drawing the hands as 10 minutes after 11) Executive Trails B (letter-number tracing), age-dependent Verbal memory 3Y5 word list (spontaneous/cued recall)

604 www.ContinuumJournal.com June 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT domains and reflects the collective prac- severity, as opposed to a condition h From a clinical perspective, tical impact of cognitive dysfunction. that is either present or absent. Com- it is useful to think of High-level daily functional abilities (instru- ponents of depression include he- depression as a mental activities of daily living) include donic state (eg, sadness), level of effort/ multidimensional managing finances, shopping, operating motivation, neurovegetative changes syndrome with variable a motor vehicle, and performing house- (eg, sleep/appetite), and comorbidities features and severity, as hold chores. Whether or not cognitive such as anxiety, irritability, and agita- opposed to a condition symptoms are clinically significant un- tion. The Patient Health Questionnaire- that is either present or derscores the categorical distinction be- 9(PHQ-9)(Figure 1-230) and 15-item absent. Components tween dementia and MCI, which can be Geriatric Depression Scale (GDS-15) of depression include ambiguous at times. The Functional Ac- (Figure 1-331) are two of the more hedonic state (eg, sadness), level of tivities Questionnaire (FAQ) is a brief widely used scales for clinically assess- effort/motivation, informant-rated 10-item measure of in- ingdepression.Onerecentstudy neurovegetative changes strumental activities of daily living that showed the GDS-15 to be more sen- (eg, sleep/appetite), is part of the uniform data set for sitive as a depression screen than the and comorbidities such Alzheimer disease research centers PHQ-9 in a cohort of subjects with as anxiety, irritability, 29 32 (Figure 1-1). Basic activities of daily Parkinson disease. and agitation. living such as dressing, bathing, and toi- The Neuropsychiatric Inventory (NPI) leting tend to be preserved early in the developed by Cummings and colleagues33 course of dementing disorders but, over is the gold-standard assessment for neu- time, become important determinants ropsychiatric symptoms in dementia and of overall care needs and disposition. has been widely used as an outcome measure in Alzheimer disease clinical Neuropsychiatric Assessment therapeutic trials. However, as an Neuropsychiatric symptoms overlap with informant-based interview, the test is idiopathic psychiatric disorders in con- not well suited for standard clinical ditions such as depression, anxiety, and practice. A derivative clinical form of psychosis, but differ in that they occur the NPI, the Neuropsychiatric Inventory by definition in the setting of a neurologic Questionnaire (NPI-Q),34 uses a ques- disorder. Other symptoms such as apa- tionnaire format where caregivers rate thy, disinhibition, and agitation typi- 10 behavioral domains, as well as eating cally accompany or are associated with and sleep-related behaviors, in terms neurobehavioral disorders such as de- of symptom severity in the patient mentia and traumatic brain injury. Mood along with associated caregiver distress disturbance may be a primary manifes- (Supplemental Digital Content 1-2, tation of neuropsychiatric disorders and links.lww.com/CONT/A141). The NPI-Q is a common comorbidity of neurologic is also used in multicenter Alzheimer conditions. The term pseudodementia, disease research studies (administered which refers to cognitive dysfunction as an interview to increase data quality) attributed to a mood disturbance, was and includes symptoms that aid in the used historically as a counterpoint to differential diagnosis of frontotemporal ‘‘true’’ dementia (eg, dementia versus degeneration (eg, apathy, disinhibition, pseudodementia). This wayward con- aberrant motor behavior, appetite or struct has given way to recent find- eating changes) and dementia with Lewy ings that depression is an independent bodies (eg, hallucinations, anxiety, and risk factor for dementia. From a clini- sleep disturbances) (Case 1-1).Neuro- cal perspective, it is useful to think psychiatric symptom burden in subjects of depression as a multidimensional with MCI increases the risk of prog- syndrome with variable features and ressing to Alzheimer disease.35

Continuum (Minneap Minn) 2015;21(3):597–612 www.ContinuumJournal.com 605

FIGURE 1-1 Functional Activities Questionnaire. Reprinted with permission from Pfeffer RI, et al, J Gerontol.29 B 1982, Gerontological Society of America. geronj.oxfordjournals.org/ content/37/3/323.short.

606 www.ContinuumJournal.com June 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 1-2 Patient Health Questionnaire-9 (PHQ-9). Reprinted from Kroenke K, et al. J Gen Intern Med.30 link.springer.com/article/10.1046/j.1525-1497.2001.016009606.x.

Continuum (Minneap Minn) 2015;21(3):597–612 www.ContinuumJournal.com 607

FIGURE 1-3 Geriatric Depression Scale: Short Form. Reprinted from Sheikh JI, Yesavage JA, Clin Gerontol.31

608 www.ContinuumJournal.com June 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Case 1-1 A 68-year-old right-handed man developed cognitive, behavioral, and motor changes over a 1- to 2-year period. His past medical history was notable for obstructive sleep apnea that had been diagnosed approximately 15 years earlier, and he had used the continuous positive airway pressure (CPAP) machine regularly since then. However, he reported a history of loud snoring for 25 to 30 years prior to being diagnosed with obstructive sleep apnea. Neuropsychiatric evaluation yielded the diagnoses of bipolar disorder and obsessive-compulsive disorder, which were treated with serial additions of clomipramine, valproic acid, and lamotrigine. Neurologic evaluation revealed gait disturbance and brain MRI showed prominent ventriculomegaly, raising the possibility of normal-pressure hydrocephalus (NPH) (Figure 1-4). However, he showed no response to either a high-volume lumbar puncture or a subsequent 48-hour lumbar drain procedure. Examination revealed the following: a Mini-Mental State Examination (MMSE) score of 25 out of 30 (1 out of 3 recall, 3 out of 5 WORLD, poor pentagon copy), a Mini-Mental State Examination Extended (MMX) score of 38 out of 50, and verbal fluency: animals 17, F-words 7; clock drawing: intact. On the Neuropsychiatric Inventory Questionnaire (NPI-Q) completed by his daughter, the patient reportedly exhibited moderate symptoms of apathy, euphoria, disinhibition, irritability, and appetite changes (craving sweets). Neurologic examination was notable for hypomimia, intact extraocular movements, no dysarthria, stooped posture, decreased left arm swing with ambulation, and reduced stride length. Over the next several months, serial medication changes included discontinuing clomipramine, valproic acid, and lamotrigine and adding sertraline, resulting in significantly improved motor, behavioral, and cognitive symptoms. He exhibited some residual obsessive symptoms, but was able to resume living independently without any appreciable decline for several years.

FIGURE 1-4 Imaging of the patient in Case 1-1. Axial fluid-attenuated inversion recovery (FLAIR) MRI showing minimal frontal and temporal lobe atrophy. There is also subcortical atrophy, characterized by enlarged ventricles.

Comment. This patient was variably diagnosed with a neuropsychiatric disturbance based on prominent changes in behavior and possible NPH based on motor and cognitive signs as well as brain imaging that was suggestive of this disorder. He was duly evaluated for NPH and failed to improve with a lumbar drain. His overall presentation met criteria for behavioral variant frontotemporal degeneration, with congruent MRI findings. However, his motor dysfunction and cognitive symptoms improved dramatically with medication adjustments, suggesting an iatrogenic etiology. The conundrum of this case is why his MRI appeared so abnormal, particularly suggestive of NPH. It is noteworthy that obstructive sleep apnea and NPH may have a shared pathophysiologic substrate, with pressure waves associated with obstructive sleep apnea contributing to loss of ventricular compliance seen in NPH. Moreover, repeated episodes of hypoxia and hypercarbia associated with obstructive sleep apnea may cause oxidative stress that preferentially affects frontal and temporal lobe regions that regulate mood, motivation, and executive functions.36

Continuum (Minneap Minn) 2015;21(3):597–612 www.ContinuumJournal.com 609

FIGURE 1-5 Neurobehavioral screen.

610 www.ContinuumJournal.com June 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT CONCLUSION Alzheimer’s disease: recommendations from the National Institute on AgingYAlzheimer’s h Conducted in parallel, This review has focused on delineating Association workgroups on diagnostic a comprehensive the various elements of a comprehensive guidelines for Alzheimer’s disease. screening history and Y neurobehavioral assessment, including a Alzheimers Dement 2011;7(3):263 269. general cognitive doi:10.1016/j.jalz.2011.03.005. systematic approach to history taking assessment (which can and involving clinical history assessments 6. Odenheimer G, Borson S, Sanders AE, et al. often be administered Quality improvement in neurology: dementia by clinic staff) can that assay cognition, functional abilities, management quality measures. Neurology be accomplished in and behavior. An informant generally 2013;81(17):1545Y1549. doi:10.1212/ provides these data components due to WNL.0b013e3182a956bf. real time prior to, or in conjunction with, the limited reliability of a patient with 7. Cheng EM, Tonn S, Swain-Eng R, et al; physician involvement. impaired memory and insight. The in- American Academy of Neurology Parkinson Disease Measure Development Panel. struments reviewed use a questionnaire Quality improvement in neurology: AAN format that the caregiver can complete Parkinson disease quality measures: report in the waiting room or while the phy- of the Quality Measurement and Reporting sician is performing a cognitive assess- Subcommittee of the American Academy of Neurology. Neurology 2010;75(22): ment on the patient. Conducted in parallel, 2021Y2027. doi:10.1212/WNL. a comprehensive screening history and 0b013e3181ff96dd. general cognitive assessment (which clinic 8. Miller RG, Brooks BR, Swain-Eng RJ, staff can administer) can be accomplished et al. Quality improvement in neurology: in real time prior to, or in conjunction amyotrophic lateral sclerosis quality measures: report of the Quality Measurement with, physician involvement. Although and Reporting Subcommittee of the American this review covers domain-specific screen- Academy of Neurology. Neurology 2013;81(24): ing questionnaires that are widely used 2136Y2140. doi:10.3109/21678421.2013.875706. in research studies, an informal hybrid 9. Galvin JE, Roe CM, Powlishta KK, et al. The form may be adequate to support clini- AD8: a brief informant interview to detect cal care (Figure 1-5). dementia. Neurology 2005;65(4):559Y564. doi:10.1212/01.wnl.0000172958.95282.2a.

10. Galvin JE, Roe CM, Coats MA, Morris JC. REFERENCES Patient’s rating of cognitive ability: using 1. Edmonds EC, Delano-Wood L, Galasko DR, the AD8, a brief informant interview, as a et al; Alzheimer’s Disease Neuroimaging self-rating tool to detect dementia. Arch Initiative. Subjective cognitive complaints Neurol 2007;64(5):725Y730. doi:10.1001/ contribute to misdiagnosis of mild cognitive archneur.64.5.725. impairment. J Int Neuropsychol Soc 11. Triebel KL, Martin R, Griffith HR, et al. 2014;20(8):836Y847. doi:10.1017/ Declining financial capacity in mild cognitive S135561771400068X. impairment: a 1-year longitudinal study. 2. Sha SJ, Takada LT, Rankin KP, et al. Neurology 2009;73(12):928Y934. Frontotemporal dementia due to C9ORF72 doi:10.1212/WNL.0b013e3181b87971. mutations: clinical and imaging features. 12. Borson S, Scanlan J, Brush M, et al. The Neurology 2012;79(10):1002Y1011. mini-cog: a cognitive ‘vital signs’ measure doi:10.1212/WNL.0b013e318268452e. for dementia screening in multi-lingual 3. Boeve BF, Silber MH, Ferman TJ, et al. elderly. Int J Geriatr Psychiatry Clinicopathologic correlations in 172 cases 2000;15(11):1021Y1027. of rapid eye movement sleep behavior disorder with or without a coexisting 13. Gualtieri CT, Johnson LG. Reliability and neurologic disorder. Sleep Med validity of a computerized neurocognitive 2013;14(8):754Y762. doi:10.1016/ test battery, CNS Vital Signs. Arch Clin Y j.sleep.2012.10.015. Neuropsychol 2006;21(7):623 643. doi:10.1016/j.acn.2006.05.007. 4. Jordan BD. The clinical spectrum of sport-related traumatic brain injury. Nat Rev Neurol 2013;9(4): 14. Folstein MF, Folstein SE, McHugh PR. 222Y230. doi:10.1038/nrneurol.2013.33. ‘‘Mini-mental state.’’ A practical method for grading the cognitive state of patients 5. McKhann GM, Knopman DS, Chertkow H, for the clinician. J Psychiatr Res 1975;12(3): et al. The diagnosis of dementia due to 189Y198. doi:10.1016/0022-3956(75)90026-6.

Continuum (Minneap Minn) 2015;21(3):597–612 www.ContinuumJournal.com 611

15. Nasreddine ZS, Phillips NA, Bedirian V, et al. mild cognitive impairment and Alzheimer’s The Montreal Cognitive Assessment, MoCA: disease. Arch Clin Neuropsychol 2013;28(5): a brief screening tool for mild cognitive 400Y410. doi:10.1093/arclin/act039. impairment. J Am Geriatr Soc 2005;53(4): 695Y699. doi:10.1111/j.1532-5415.2005.53221.x. 25. Possin KL, Feigenbaum D, Rankin KP, et al. Dissociable executive functions 16. Cordell CB, Borson S, Boustani M, et al; in behavioral variant frontotemporal Medicare Detection of Cognitive and Alzheimer dementias. Neurology Impairment Workgroup. Alzheimer’s 2013;80(24):2180Y2185. doi:10.1212/ Association recommendations for WNL.0b013e318296e940. operationalizing the detection of cognitive impairment during the Medicare Annual 26. Kaplan E, Goodglass H, Weintraub S. Wellness Visit in a primary care setting. The Boston naming test. Philadelphia, PA: Alzheimers Dement 2013;9(2):141Y150. Lea and Febiger, 1983. doi:10.1016/j.jalz.2012.09.011. 27. del Toro CM, Bislick LP, Comer M, et al. 17. Lin JS, O’Connor E, Rossom RC, et al. Development of a short form of the Boston Screening for cognitive impairment in naming test for individuals with aphasia. older adults: a systematic review for the J Speech Lang Hear Res 2011;54(4):1089Y1100. U.S. Preventive Services Task Force. Ann Intern doi:10.1044/1092-4388(2010/09-0119). Med 2013;159(9):601Y612. doi:10.7326/ 0003-4819-159-9-201311050-00730. 28. Thompson CK, Lukic S, King MC, et al. Verb and noun deficits in stroke-induced 18. Kaufer DI, Williams CS, Braaten AJ, et al. and primary progressive aphasia: the Cognitive screening for dementia and mild Northwestern Naming Battery. Aphasiology cognitive impairment in assisted living: 2012;26(5):632Y655. doi:10.1080/ comparison of 3 tests. J Am Med Dir Assoc 02687038.2012.676852. 2008;9(8):586Y593. doi:10.1016/ j.jamda.2008.05.006. 29. Pfeffer RI, Kurosaki TT, Harrah CH Jr, et al. 19. Hoops S, Nazem S, Siderowf AD, et al. Measurement of functional activities in Validity of the MoCA and MMSE in the older adults in the community. J Gerontol Y detection of MCI and dementia in Parkinson 1982;37(3):323 329. Y disease. Neurology 2009;73(21):1738 1745. 30. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: doi:10.1212/WNL.0b013e3181c34b47. validity of a brief depression severity measure. 20. Chou KL, Lenhart A, Koeppe RA, Bohnen NI. J Gen Intern Med 2001;16(9):606Y613. Abnormal MoCA and normal range MMSE 31. Sheikh JI, Yesavage JA. Geriatric Depression Scale scores in Parkinson disease without dementia: (GDS): recent evidence and development of a cognitive and neurochemical correlates. shorter version. Clin Gerontol 1986;5(1/2):165Y173. Parkinsonism Relat Disord 2014;20(10): 1076Y1080. doi:10.1016/j.parkreldis.2014.07.008. 32. Thompson AW, Liu H, Hays RD, et al. 21. Goldstein FC, Ashley AV, Miller E, et al. Diagnostic accuracy and agreement across Validity of the Montreal cognitive assessment three depression assessment measures for as a screen for mild cognitive impairment Parkinson’s disease. Parkinsonism Relat Y and dementia in African Americans. J Geriatr Disord 2011;17(1):40 45. doi:10.1016/ Psychiatry Neurol 2014;27(3):199Y203. j.parkreldis.2010.10.007. doi:10.1177/0891988714524630. 33. Cummings JL, Mega M, Gray K, et al. The 22. Tariq SH, Tumosa N, Chibnall JT, et al. Neuropsychiatric Inventory: comprehensive Comparison of the Saint Louis University assessment of psychopathology in dementia. mental status examination and the Neurology 1994;44(12):2308Y2314. mini-mental state examination for detecting 34. Kaufer DI, Cummings JL, Ketchel P, et al. dementia and mild neurocognitive Validation of the NPI-Q, a brief clinical form disorderVa pilot study. Am J Geriatr of the Neuropsychiatric Inventory. Psychiatry 2006;14(11):900Y910. J Neuropsychiatry Clin Neurosci doi:10.1097/01.JGP.0000221510.33817.86. 2000;12(2):233Y239. 23. Cummings-Vaughn LA, Chavakula NN, Malmstrom TK, et al. Veterans Affairs 35. Rosenberg PB, Mielke MM, Appleby BS, et al. Saint Louis University Mental Status The association of neuropsychiatric symptoms examination compared with the Montreal in MCI with incident dementia and Alzheimer Cognitive Assessment and the Short Test of disease. Am J Geriatr Psychiatry 2013;21(7): Mental Status. J Am Geriatr Soc 2014;62(7): 685Y695. doi:10.1016/j.jagp.2013.01.006. Y 1341 1346. doi:10.1111/jgs.12874. 36. Hanigan WC, Zallek SN. Headaches, shunts, and 24. Teng E, Leone-Friedman J, Lee GJ, et al. obstructive sleep apnea: report of two cases. Similar verbal fluency patterns in amnestic Neurosurgery 2004;54(3):764Y789.

612 www.ContinuumJournal.com June 2015