Neuropsychological Evaluation of

Neuropsychological Evaluation of Alzheimer s Disease Joanne M. Hamilton, Ph.D. Shiley-Marcos Alzheimer s Disease Research Center Department of Neurosciences University of California, San Diego

Establish importance of neuropsychological evaluation for distinguishing between dementia syndromes Neuropsychological py features of preclinical AD Neuropsychological py detection of early AD Distinction between AD and DLB

The study of brain-behavior behavior relationships The science of neuropsychology has provided clues to understanding which brain areas are involved in specific behaviors Neuropsychological py studies have identified cognitive profiles associated with specific dementia syndromes

A comprehensive assessment of cognitive and behavioral functions using a set of standardized tests t and procedures. Memory Language Executive Functions Attention Visuospatial skills Psychomotor Speed Emotional Functioning

List Learning Tests Paragraph Recall Paired Associates Figure Recall

Auditory attention (Digit Span) Concentration (Cancellation) Visual scanning (Visual Search) Mental Control (Working memory)

Planning Problem Solving (WCST) Judgment Abstract Thought (Similarities) Cognitive Flexibility (Trails B)

Production of language (Fluency) Comprehension of language (BDAE) General knowledge (Vocabulary) Semantic associations (BNT and Category Fluency)

Understanding visual orientation and location in space Understanding spatial relationships between objects Capacity to draw or assemble an object from its component parts

Visuomotor integration Finger-tapping/Grooved pegboard Sequencing

Depression (Beck Depression Inventory-II or Geriatric Depression Scale) Psychotic features (NPI) Alcoholism

Detect cognitive dysfunction and assess its severity Document relative strengths and weaknesses in cognitive functioning Aid in differential diagnosis of various neurological and psychiatric disorders Measure efficacy of treatment for disorders affecting cognition

Latent Phase Diffuse Plaques Malignant Phase Neuritic plaques, tangles, neuron and synapse loss Initiation factors APOE ε4 AD genes Down s syndrome Family history Head trauma Coronary disease Preclinical Phase Promoting factors Age Significant cognitive decline Diagnosis Significant functional decline Death Loss of independence

Mild Cognitive Impairment (MCI) (Peterson 2000) Memory complaint (e.g., decline reported by patient or family) Memory impairment ( > 1.5 SDs below normal on formal test) Normal general cognitive function (e.g. MMSE > 23/30) Minimally i impaired i functional abilities i No major depression

MCI subjects progress to dementia at about 8-15% per year

Question: How does memory yperformance change during the preclinical period of AD? Study: Examine delayed recall performance one year and two years prior to conversion in patients who subsequently developed AD.

Preclinical AD (N=20) Age 74.1 Education 14.9 MMSE 27.6

10 Mean Score Long Delay Recall 50 45 40 35 30 25 20 15 10 5 0-2 -1 0 Years to Conversion 8 6 4 2 0-2 -1 0 Years to Conversion Mean Score Trials 1-5

25 25 20 15 Immediate Mean Score: Delay 20 15 10 5 0-2 -1 0 Years to Conversion 10 5 0-2 -1 0 Years to Conversion Mean Score:

NC n = 11 Conv n = 11 Age 77.3 77.1 Education 16.9 16.9 MMSE -2 years 29.6 28.1 MMSE -1 years 29.6 27.7 MMSE Conv. year 29.1 27.6

Executive Functions: Semantic Knowledge: mwcst (perseverative errors) Letter Fluency (FAS) Trail-Making Making, Part A and Part B Category Fluency (AFV) Boston Naming Test (30 item) Episodic Memory: CVLT Recognition (d ) CVLT Long Delay Free Recall CVLT Long Delay Cued Recall

0.0-0.5-1.0-1.5-2.0-2.5 25 Episodic Memory Executive (+Trails B) Semantic Knowledge -3.0 n-2 n2 n-1 n1 n Year

Compensatory Mechanisms Invoked Mild, relatively stable memory decline in the early preclinical period Episodic Memory Perform mance Plaques and tangles, neuron and synapse losses accruing Severe, rapid memory decline in the late preclinical period -5-4 -3-2 -1 0 1 2 Year Preclinical Phase Clinical Phase

Decrements in episodic memory can precede the onset of AD by several years and may serve as a marker for the imminent onset of dementia There is an orderly, linear decline in episodic memory, semantic memory, and executive functions in preclinical AD in the few years immediately preceding dementia diagnosis These cognitive measures might provide a means of quantifying treatment response in clinical and preclinical AD

Spread of Pathology of Alzheimer s Disease Mild Moderate NIA AD Education and Referral Center Severe

Cognitive Abilities Affected by AD Learning and Memory Executive Functions/Attention Language and Semantic Memory Visuospatial /Constructional Ability

NC AD (N=98) (N=98) Age 71.6 72.0 Education 14.2 14.1 MMSE 29.5 25.5 Salmon et al., 2002

Memory: Logical Memory: Imm./Delay Visual Reproduction: Imm./Delay California Verbal Learning Test Language: Vocabulary Boston Naming Test Category Fluency Visuospatial: Block Design Visual Reproduction Copy Draw and Copy a Clock Executive Function: Modified Wisconsin Card Sort Trail-Making Test Part B Phonemic Fluency (FAS) Attention/Psychomotor Speed: Trail-Making Test Part A Digit Symbol Substitution Test WAIS-R Digit Span Test

0-1 NC AD 0-1 -2-2 -3-3 -4 Trials 1-5 -4 Long Delay Sensitivity: 98% Specificity: 88%

250 NC 200 AD 150 250 200 150 100 100 50 50 0 Part A 0 Part B Sensitivity: 85% Specificity: 83%

50 45 NC 40 AD 35 30 25 20 15 10 5 0 50 45 40 35 30 25 20 15 10 5 0 Letter Fluency Category Fluency Sensitivity: 96% Specificity: 88%

CVLT Trials 1-5 (T-Score) Category Fluency Test 100 100 90 90 The most sensitive cognitive measures for distinguishing i between very mild AD patients and normal elderly were tests of: Se ensitivity (%) 80 70 60 50 Cutpoint: < 36 40 Sensitivity = 95% 30 Specificity = 89% 20 10 0 0 10 20 30 40 50 60 70 80 90 100 Specificity i (%) Trail-Making Test: Part B 100 Se ensitivity (%) 80 70 60 50 Cutpoint: < 38 40 Sensitivity = 96% Specificity = 88% 30 20 10 0 0 10 20 30 40 50 60 70 80 90 100 Specificity it (%) Block Design Test (WISC-R) 100 episodic memory category fluency executive function Se ensitivity (%) 90 80 70 60 50 40 30 20 Cutpoint: > 130 Sensitivity = 85% Specificity = 83% Se ensitivity (%) 90 80 70 60 50 40 30 20 Cutpoint: < 34 Sensitivity = 78% Specificity = 79% 10 10 0 0 10 20 30 40 50 60 70 80 90 100 Specificity it (%) 0 0 10 20 30 40 50 60 70 80 90 100 Specificity it (%)

Memory tests with measure of delayed recall Tests of verbal fluency for items from semantic categories Tests of executive functioning that require ability to switch mental set

Little relative improvement with recognition memory testing in AD Clock drawing/confrontation i naming are more impaired in early AD Category fluency is disproportionately worse than letter fluency in AD Psychomotor slowing may be more pronounced in depression compared to AD

Progressive dementia that interferes with ADL Well-formed visual hallucinations Parkinsonism Waxing and waning attention and alertness Prominent visuospatial deficits and executive dysfunction McKeith et al., 2005

Gilman et al., 2007

DLB n = 50 AD n = 50 NC n = 70 Mean (SD) Mean (SD) Mean (SD) Age (yrs) 74.5 (5.9) 74.4 (5.9) 74.2 (6.0) Education (yrs) 14.3 (3.0) 14.0 (3.2) 13.9 (3.1) Women : Men 20 : 30 21 : 29 43 : 27 MMSE 21.0 (5.1) 21.4 (4.7) 29.2 (0.9) Estimated Duration (yrs) 3.8 (2.6) 4.3 (3.2) NA Test-Death Interval (yrs) 4.5 (3.2) 5.5 (3.3) NA PODS 12.7 (5.0) 12.2 (4.9)

Memory: Logical Memory Immediate Logical Memory Savings Visual Reproduction Immediate Visual Reproduction Savings Language: Vocabulary Boston Naming Test Category Fluency Visuospatial: Block Design Visual Reproduction Copy Copy a Clock Executive Function: Modified Wisconsin Card Sort Categories Achieved Trail-Making Test Part B Phonemic Fluency (FAS) Attention/Psychomotor Speed: Trail-Making Test Part A Grooved Pegboard Right Hand Grooved pegboard Left Hand Digit Symbol Substitution Test

0 Visuospatial Attn/Executive Memory Language ite Z-Score Mea an Compos -1-2 -3-4 -5 DLB AD * *

0 Visuospatial Attn/Executive Memory Language -1 Mea an Composit te Z-Score -2 * * -3-4 -5-6 Mild Dementia (MMSE > 22) DLB AD

0 Visuospatial Attn/Executive Memory Language -1 ite Z-Score Mea an Compos -2-3 * -4-5 -6 Moderate Dementia (MMSE < 22) * DLB AD

DLB AD

DLB n = 24 AD n = 94 Visual Hallucinations 22 % 1 % EPS 26 % 16 % Visuoconstructive ti Impairment 74 % 45 % Vi l H ll i ti P t PPV 83% Visual Hallucination Present: PPV = 83% Visuoconstructive Impairment Absent: NPV = 90%

l Score Mean DRS Total 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 AD DLB Baseline Eval 1 Eval 2

WISC-R Block Design Clock Drawing Test--Copy Me ean DRS Total Score 140 130 120 110 100 90 80 70 60 50 40 High AD 30 High DLB 20 Low AD Low DLB 10 0 140 130 120 110 100 90 80 70 60 50 40 30 20 10 Baseline Eval 1 Eval 2 Baseline Eval 1 Eval 2

Category Fluency Boston Naming Test (30-item) Mean DRS Tota al Score 140 130 120 110 100 90 80 70 60 50 140 130 120 110 100 40 High AD 40 30 High DLB 30 20 Low AD 20 Low DLB 10 10 0 Baseline Eval 1 Eval 2 90 80 70 60 50 Baseline Eval 1 Eval 2

Memory complaints may precede diagnosable AD by two or more years The earliest symptoms of AD are typically memory loss with rapid forgetting Loss of semantic knowledge measured by tests such as confrontation naming and category fluency occurs early in the course Severe early visuospatial dysfunction is suggestive of DLB

May predispose patients for visual hallucinations (Mosimann et al., 2004; Hamilton et al., 2009) Can differentiate DLB from AD with 80% sensitivity and 90% specificity (Ferman et al., 2006) May predict the rate of cognitive decline in DLB patients (Hamilton et al., 2008)

S-VIS M-VIS (n = 36) (n = 22) VH at baseline 40% (14/36) 5% (1/22) VH during follow-up* 60% (12/20) 11% (2/19) Extrapyramidal signs 58% (21/36) 18% (4/22) Braak Stage 2.6±2.1 4.6±1.6 * Four patients were seen only at baseline