Mild Cognitive Impairment Douglas W

Mild Cognitive Normal Impairment (MCI) Mild Cognitive Impairment Douglas W. Scharre, MD Director, Division of Cognitive Neurology Ohio State University Dementia

Dementia Definition • Syndrome of acquired persistent intellectual impairment • Persistent deficits in at least three of the following: Definitions 9 Memory 9 Language 9 Visuospatial 9 Personality or emotional state 9 Cognition • Resulting in impairment in Activities of Daily Living (ADL)

1 Mild Cognitive Impairment MCI Related (MCI) Definition Conditions • Definitions vary - be careful! AAMI: Age-Associated Memory Impairment • Petersen criteria • Non-disease, aging-related decline in – Memory complaint memory – Memory loss on testing greater that 1.5 standard • Diagnostic criteria are ambiguous deviations below normal for age • Complaints of memory loss more related – Other non-memory cognitive domains normal or to affect/personality than test scores mild deficits (language, visuospatial, executive, personality or emotional state) • Prevalence in the elderly varies from 18% up to 38% depending on the study – Mostly normal activities of daily living Barker et al. Br J Psychiatry 1995;167:642-8 Arch Neurol 1999;56:303-8 Hanninen et al. Age and Aging 1996;25:201-5

MCI Related MCI Related Conditions Conditions • Age-Associated Memory Impairment Benign Senescent Forgetfulness or Mild (AAMI) Memory Impairment (MMI) • Memory tests > 2 s.d. below normal age and • Benign Senile Forgetfulness or Mild education matched individuals Memory Impairment (MMI) • Normal non-memory cognitive domains • Amnestic Mild Cognitive Impairment (MCI) • Normal activities of daily living • Multiple Domain Impairment (MDI) • No know disease causing impairments • Single (non-memory) Domain Impairment • Incipient AD may start this way (SDI) • Fairly similar to Petersen’s MCI definition

Kral 1978

2 Amnestic Mild Cognitive Impairment (aMCI) MCI Related • Memory complaint usually corroborated by an Conditions informant Multiple Domain Impairment (MDI) • Objective memory impairment for age - that represents a change in function for the person • Mild impairment in several cognitive domains • Essentially preserved general cognitive function • Normal activities of daily living • Largely intact functional activities • Incipient Alzheimer’s disease often starts like this with deficits in memory, language, and • Not demented visuospatial domains • Vascular dementia and other dementias often • Alzheimer’s disease may start like this but many present this way non-AD conditions present like this also

Petersen J Int Med 2004;256;183-194 Morris et al. Arch Neurol 2001;58:397-405

MCI Classification MCI Related MCI Conditions

Memory Impaired? Yes No Single (non-memory) Domain Impairment (SDI) • Mild impairment in one non-memory cognitive Amnestic MCI Non-Amnestic MCI domain • Normal activities of daily living Memory Impairment Single non-memory cognitive domain Only? impaired? • Frontotemporal dementia and other non- Alzheimer’s dementias often present this way Yes No Yes No

Amnestic MCI Amnestic MCI Non-amnestic MCI Non-amnestic MCI • Most, but not all AD patients start with amnestic Single domain Multiple domain Single domain Multiple Domain memory problems initially

Petersen J Int Med 2004;256;183-194

3 Treatment of Alzheimer’s Disease 5 Early Diagnosis 4 of MCI 3 2 Patients (millions) 1

Prevalence Diagnosed Treated* * Any drug treatment, not limited to acetylcholinesterase inhibitors. Source: Decision Resources, March 2000.

Importance of Early Early Diagnosis: Diagnosis of MCI and Clinical Dementia • Early treatment depends on identification of MCI and prediction of progression to • Plaques and tangles start 20 years before dementia clinical symptoms of AD • First, look for clues of MCI - forgetfulness, • Disease modifying agents are coming word finding, date disorientation, slow • Patients with MCI and early dementia have thinking, impaired judgment, getting impaired insight turned around • Preventing or delaying AD could save • Assess cognition and function with patient billions of dollars and lead to improved and caregiver quality of life for patients and families • Alternative diagnoses ruled out

4 Early Diagnosis of Cognitive Screening: MCI and Dementia MMSE

• 0 (worst) - 30 (best) • Cognitive Screening Tests • Tests orientation, attention, mental control, calculations, delayed memory, • Structural Neuroimaging language, and constructional praxis • Easy to use, available, well known • Functional Neuroimaging • No clueing of memory words

Folstein et al. J Psychiat Res 1975;12:189-98 Feher et al. Arch Neurol 1992;49:87-92

Early Diagnosis: Cognitive Screening: Cognitive Screening MMSE Short Screening Tests • MMSE • Not great for frontal or executive functions • Clock Drawing Test • Sensitivity 78% and specificity 84% for • 7-minute Screen dementia with a cutoff of 26/30 • Montreal Cognitive Assessment (MOCA) • Takes 5 to 10 minutes; needs examiner • Self-Administered Gerocognitive Examination (SAGE) Detailed evaluation if screen positive

• Neuropsychological batteries Folstein et al. J Psychiat Res 1975;12:189-98 Feher et al. Arch Neurol 1992;49:87-92

5 Cognitive Screening: Clock Drawing Test • Various scoring methods • Tests constructional praxis, visuospatial skills, and executive functioning • Easy to use, available, well known • Limited in evaluating other cognitive domains • Sensitivity 83% and specificity 72% for AD • Takes 1 minute; needs no examiner

Shulman et al. Int Geriatr Psychiatry 1986;1:135-40 Cahn et al. Arch Clin Neuropsych 1996;11:529-39

Early Diagnosis: Cognitive Screening

6 Cognitive Screening: Cognitive Screening: Montreal Cognitive Assessment 7 Minute Screen (MOCA) • Special scoring calculator required • Tests orientation, memory, clock drawing, • Tests orientation, memory, clock drawing, constructions, verbal fluency, naming, verbal fluency repetition, attention, abstraction, calculations, executive (trails B) • Not easy to use in primary care office • Not easy to give in primary care office • Low scores very specific for AD • Sensitivity 100% and specificity 87% for • Sensitivity 92% and specificity 96% for AD AD vs normal controls vs normal controls • Takes 7 - 12 minutes; needs examiner • Takes 10-15 minutes; needs examiner

Solomon et al. Arch Neurol 1998;55:349-55 Nasreddine et al. J Am Geriatr Soc 2005;53:695-699

7 Minute Screen

7 Cognitive Screening: SAGE Modified Trails B Self-Administered Review this e xample (this first one is done for you) then go to question 10 below: Draw a line from one circle to another starting at 1 and alternating numbers and letters (1 to Gerocognitive Exam (SAGE) A to 2 to B to 3 to C). A C

• Tests orientation, memory, language, verbal 1 2 fluency, naming, visuospatial/constructional B

praxis, abstraction, calculations, executive Start functioning (trails B), and problem solving 3 10. Do the following: Draw a line from one circle to another starting at 1 and • Self-administered, easy to use; not yet available alternating numbers and letters in order before ending at F (1 to A to 2 to B and so on). nor well known - due out in 2008 1 4 F Start C • Limited memory evaluation; impressive End executive measures 6 A • Sensitivity 88% and specificity 92% for dementia 3 D vs non-dementia B 2 • Takes 15 minutes; needs no examiner E Scharre 2007 5

SAGE Naming Early Diagnosis: Examples Structural Neuroimaging • Volumetric measurement of hippocampus and entorhinal cortex atrophy with MRI is sensitive (95%) but not specific (40%) for AD • Change in MRI hippocampal volume may be predictive over time in both MCI and individuals at genetic risk for AD • 7-Tesla and 8-Tesla MRI being used in AD research

Laakso et al. Neurology 1996;46:678-81 Golomb et al. Neurology 1996;47:810-3 Whitaker et al. Society for Neuroscience 2001

8 Alzheimer’s Disease Early Diagnosis: Neuroimaging Initiative (ADNI) Functional Neuroimaging • To identify serial biomarkers and neuroimaging techniques that are • Single photon emission computed sensitive and change quickly as the subject goes from normal to MCI to AD tomography (SPECT) studies • Academia - Industry Partnership • Positron emission tomography (PET) studies • $60 million for 5 years at about 50 sites • Functional MRI (fMRI) studies • Data available to all researchers

Gray Matter Reductions in AD Using Voxel Based Functional Morphometry Neuroimaging: SPECT • SPECT shows hypoperfusion in bilateral parietal, temporal, and eventually frontal cortex in AD patients • The probability of AD diagnosis was 82% with bilateral temporoparietal hypoperfusion on SPECT and only 19% with a normal SPECT image • SPECT predicted the risk of progression to AD in 83% of questionable AD subjects

Bonte et al. Semin Nucl Med 1990;20:342-52 Holman et al. J Nucl Med 1992;33:181-5 Alexander GE et al., ADNI MRI Core Team, 2007 Johnson et al. Neurology 1998;50:1563-71

9 Functional SPECT in AD Neuroimaging: PET • PET shows hypometabolism in bilateral parietal, temporal, and posterior cingulate cortex in AD subjects and those who are asymptomatic but at increased risk for AD (those with Apo E ε4) • PET predicted 94% of MCI subjects whose disease progressed to dementia during a 3 year period

Minoshima et al. J Nucl Med 1995;36:1238-48 Minoshima et al. Ann Neurol 1997;42:85-94 Small et al. JAMA 1995;273:942-47

SPECT in AD Typical AD PET Scan

Normal Brain AD Brain

Provided courtesy of M. Mega, MD, PhD, Department of Neurology, UCLA School of Medicine.

10 Preliminary FDG PET Comparisons: Regional Hypometabolism in Functional Probable AD (purple) & MCI (blue) Neuroimaging: fMRI • fMRI uses contrast dependent on blood oxygen • Mild cognitively impaired and AD subjects had decreased brain activation during memory tasks after cholinesterase inhibitor treatment • This may represent improved efficiency of neural processing

Smith et al. Neurology 1999;53:1391-96 Bookheimer et al. N Engl J Med 2000;343:450-6 Backman et al. Neurology 1999;52:1861-70 Chen, K, et al., ADNI PET Coordinating Center, 2007 Narayanan et al. Neurology 2007;68(Suppl 1):A10

PET with Pittsburgh Compound B (PIB) • PIB is a hydroxylated benzothiozole PET MCI: tracer Predicting • Attaches to the amyloid beta peptide Progression to • MCI patients have more amyloid than Dementia normals and less that AD patients

Klunk et al. Ann Neurol 2004;55(1)

11 MCI: Predicting MCI: Predicting Dementia Progression Dementia Progression Rates of Dementia Conversion • Older age and lower MMSE scores • Vary from 1% - 25% per year to AD depending on • Disorientation to date the definition used and measurement instruments • Clock drawing impairments • 10% - 12% per year to AD is typical • Lexical processing task and a working • 57% conversion to dementia after 3 years in one memory task correctly identified 85% of study those progressing • 25% do not convert to dementia even with long term follow-up

Chertkow et al. Neurology 2001;56:B46 Chertkow et al. Neurology 2001;56:B46

MCI: Predicting Dementia Progression Summary • MCI definitions vary • ApoE E4 carrier status has been significant in some studies but not others • More study is needed to identify which MCI subjects will progress to dementia or AD • MRI hippocampal volume is intermediate between normal controls and AD but does • Early diagnosis of MCI and AD is mostly not reliably predict conversion done by clinical means; screening should be done • Change in MRI hippocampal volume may • Identification of genetic markers, biomarkers, be predictive over time and neuroimaging markers will be a great boost to early diagnosis Petersen et al. Arch Neurol 1999;56:303-8 Chertkow et al. Neurology 2001;56:B46 Parnetti et al. JAGS 1995;44:133-8

12 Prevalence of MCI Selected Studies • Canadian Study of Health and Aging-17%. Mild Cognitive Graham et al. Lancet 1997 • Cardiovascular Health Study-18%. Lopez et al. Impairment Arch Neurol. 2003 • Indianapolis study of Health and Aging- 12%-23%. Unverzag et al. Neurol 2001 Maria Kataki, MD, PhD • Kuopio Study. Hanninan et al. 5%. Acta Neurol The Ohio State University Scand. 2002 • Leipzig Longitudinal study of aging. 3%-38%. Busse et al. Act Neurol Scand. 2003

Overview Neuroanatomy of Memory • Epidemiology of Mild Cognitive Impairment (MCI) • Neuroanatomy of Memory • Differential Diagnosis of Memory loss • Clinical Progression of MCI • Current management

N Engl J Med 2005; 352;692-9

13 Episodic Memory

• Alzheimer’s Disease • Mild Cognitive Impairment, amnestic type • Encephalitis • Frontal Variant of Frontotemporal Dementia • Korsakoff’s syndrome

N Engl J Med 2005; 352;692-9 N Engl J Med 2005; 352;692-9

Episodic Memory • Transient Global Amnesia • Concussion • Traumatic Brain Injury • Seizure • Hypoxic-Ischemic injury • Cardiopulmonary bypass • Side effects of medication • Space occupying lesions

N Engl J Med 2005; 352;692-9 N Engl J Med 2005; 352;692-9

14 Episodic Memory Procedural Memory • Deficiency of B12 • Parkinson’s Disease • Hypoglycemia • Anxiety • Huntington’s Disease • Temporal lobe surgery • Progressive Supranuclear Palsy • Vascular Dementia • Olivopontocerebellar Degeneration • Multiple Sclerosis • Depression • Normal Pressure hydrocephalus • Obsessive-Compulsive Disorder • Obstructive Sleep Apnea

N Engl J Med 2005; 352;692-9 N Engl J Med 2005; 352;692-9

Semantic Memory Working Memory • Normal Aging • Alzheimer’s Disease • Vascular Dementia • Semantic Dementia • Frontal Variant of Frontotemporal • Traumatic brain injury Dementia • Encephalitis • Alzheimer’s Disease • Dementia with Lewy bodies • Multiple Sclerosis

N Engl J Med 2005; 352;692-9 N Engl J Med 2005; 352;692-9

15 Representative images of the middle frontal cortex and hippocampal sector CA1 from a healthy individual (patient 29), a patient with amnestic mild cognitive impairment (aMCI) (patient 3), and a patient with Working Memory Alzheimer disease (AD) (patient 51) stained with antibodies to beta- amyloid and tau (AT8), respectively (original magnification, x100) • Traumatic Brain Injury • Side effects of Medications • Attention deficit-hyperactivity disorder • Obsessive Compulsive Disorder • Schizophrenia

Petersen, R. C. et al. Arch Neurol 2006;63:665-672.

Working Memory Neuroanatomic Boundaries • Parkinson’s Disease • Huntington’s Disease • Progressive Supranuclear Palsy • Cardiopulmonary bypass • Deficiency of B12

N Engl J Med 2005; 352;692-9 Jack, C. R. et al. Neurology 1999;52:1397

16 Theoretical Progression of a Person Developing Alzheimer's Disease (AD) Heterogeneity of the Term Mild Cognitive Impairment

Petersen, R. C. et al. Arch Neurol 2001;58:1985-1992. Petersen, R. C. et al. Arch Neurol 2001;58:1985-1992.

Comparison of the clinical diagnoses of normal aging, Mean Alzheimer's Disease Assessment Scale-Cognitive mild cognitive impairment (MCI), and Alzheimer's disease Subscale (ADAS-Cog) subscores for controls, patients with (AD), compared with the approximate stages on the rating mild cognitive impairment (MCI), patients with Alzheimer scales, Clinical Dementia Rating (CDR) and Global disease (AD) and global Clinical Dementia Rating (CDR) 0.5, Deterioration Scale (GDS) and patients with AD and global CDR 1.0

Petersen, R. C. et al. Arch Neurol 2001;58:1985-1992. Grundman, M. et al. Arch Neurol 2004;61:59-66.

17 Relative performance among 4 groups: controls, subjects with mild Scatter plots of neuritic plaque counts in ventromedial cognitive impairment (MCI) (Clinical Dementia Rating [CDR] 0.5), and temporal lobe structures of normal control subjects (NRM), patients with Alzheimer disease (AD) (CDR 0.5; CDR 1), on measures of patients with mild cognitive impairment (MCI), and patients global cognitive functioning, Mini-Mental State Examination (MMSE), and with early Alzheimer disease (EAD) in the amygdala (A), full-scale IQ compared with performance on measures of delayed recall entorhinal cortex (B), CA1 (C), and subiculum (D) for verbal materials (Logical Memory II) and nonverbal materials (Visual Reproductions II)

Petersen, R. C. et al. Arch Neurol 1999;56:303-308. Markesbery, W. R. et al. Arch Neurol 2006;63:38-46.

Predicted 7-year paths of change in five different cognitive domains in typical participants with mild cognitive impairment Scatter plots of neurofibrillary tangle counts in ventromedial temporal lobe (dotted line) compared with those without cognitive structures of normal control subjects (NRM), patients with mild cognitive impairment (solid line) impairment (MCI), and patients with early Alzheimer disease (EAD) in the amygdala (A), entorhinal cortex (B), CA1 (C), and subiculum (D)

Bennett, D. A. et al. Neurology 2002;59:198-205 Markesbery, W. R. et al. Arch Neurol 2006;63:38-46.

18 Annual rates of conversion from mild Percentages of persons with no cognitive impairment (NCI), mild cognitive impairment (MCI), and dementia by Braak Stage, modified Consortium to cognitive impairment (MCI) to Establish a Registry for Alzheimer's Disease neuropathologic criteria, and dementia over 48 months National Institute on Aging-Reagan neuropathologic criteria

Copyright restrictions may apply. Petersen, R. C. et al. Arch Neurol 1999;56:303-308. Bennett, D. A. et al. Neurology 2005;64:834-841

Regions of the brain with abnormally low CMRgl in young adult carriers of Frequency of Stages of Alzheimer-Related the APOE {epsilon}4 allele and their relation to brain regions with Lesions in Different Age Categories abnormally low CMRgl in patients with probable AD

19 Cerebral metabolic and cognitive decline in persons at genetic risk Mild Cognitive Impairment for Alzheimer’s disease Clinical Trials • Donepezil Vitamin E 9 769 patients 9 3 years duration 9 Primary outcome AD 9 Progression Rate 16% 9 Result: Partially Positive

Normal Cholinergic Mild Cognitive Impairment Function Clinical Trials • Rivastigmine 9 1018 patients 9 3-4 years duration 9 Primary outcome AD 9 Progression Rate 9% 9 Result: Negative

Acta Neurol Scand Suppl. 1992;139:69-74. Treatment of Mild Cognitive Impairment: Leon Thal. Syllabus AAN 2007

20 Mild Cognitive Impairment Clinical Trials MCI Clinical Trials • Vitamin E and Donepezil in the treatment of • Galantamine Mild Cognitive Impairment. 9 Alzheimer’s Disease cooperative Study Trial 9 2048 patients 9 769 amnestic MCI patients treated with Donepezil 9 2 years duration 10mg po qd, Vit E 2000iu qd or placebo 9 3 year follow up 9 Primary outcome CDR 1 9 Progression to clinical AD 9 Progression Rate 5% 9 Donepezil delays clinical diagnosis of AD for up 9 Result: Negative to 12 months. Treatment effect persisted for 36 months in ApoE 4 carriers.

Petersen et al: New Engl. J M. Vol 352:2379-2388 June 9, 2005 Treatment of Mild Cognitive Impairment: Leon Thal. Syllabus AAN 2007 Number 23: Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment

Efficacy of donepezil in mild Mild Cognitive Impairment cognitive impairment Clinical Trials A randomized placebo-controlled trial • Rofecoxib • 270 patients with MCI 9 1457 patients 9 133 treated with donepezil 10mg po qd and 137 with 9 3-4 years duration placebo 9 Primary outcome AD • Primary efficacy measures of the NYU Paragraph 9 Progression Rate 5% Recall test and the ADCS CGIC-MCI 9 Result: Negative did not show significant treatment effects

S. Salloway, MD MS, S. Ferris, PhD, A. Kluger, PhD, R. Goldman, PhD, T.Griesing, PhD, D. Kumar, MS and S. Richardson, PhD for the Treatment of Mild Cognitive Impairment: Leon Thal. Syllabus AAN 2007 Donepezil "401" Study Group*NEUROLOGY 2004;63:651-657

21 Efficacy of donepezil in mild cognitive impairment A randomized placebo-controlled trial Current Prevention

• Decrease Homocysteine, with Folic acid, B6, B12

• Maintain Physical exercise • More donepezil-treated patients showed • Oral antioxidants improvements in ADAS-cog total scores, • Anti-inflammatory agents in tests of attention and psychomotor speed, and in PGA scores. • Low Cholesterol, low fat diet • Prevention of Hypertension, Vascular disease

S. Salloway, MD MS, S. Ferris, PhD, A. Kluger, PhD, R. Goldman, PhD, T.Griesing, PhD, D. Kumar, MS and S. Richardson, PhD for the Donepezil "401" Study Group*NEUROLOGY 2004;63:651-657 Dekosky: Clinical trial, syllabus AAN 2005

Current Prevention Conclusions • Mild Cognitive impairment represents the • Screening of patients elderly 65 years old by pathology of common degenerative health care providers. illnesses. • Standardized questionnaires assessing • Early diagnosis is appropriate. cognition, function, mood, behaviors • It has a risk of progressing to Alzheimer’s • Early diagnosis and treatment disease and other dementias. 9 Clinical and financial benefit • Can be associated with behavioral features 9 Alleviate patient and caregiver burden • Follow up is recommended. • Prevention.

Fillit. Neurology:65, 6,suppl 3, S5-9