Neuropsychological Evaluation of

Transcription

1 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

2 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

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4 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

5 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

6 List Learning Tests Paragraph Recall Paired Associates Figure Recall

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

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

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

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

11 Visuomotor integration Finger-tapping/Grooved pegboard Sequencing

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

13 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

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15 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

16 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

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

18 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.

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

20 10 Mean Score Long Delay Recall Years to Conversion Years to Conversion Mean Score Trials 1-5

21 Immediate Mean Score: Delay Years to Conversion Years to Conversion Mean Score:

22 NC n = 11 Conv n = 11 Age Education MMSE -2 years MMSE -1 years MMSE Conv. year

23 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

24 Episodic Memory Executive (+Trails B) Semantic Knowledge -3.0 n-2 n2 n-1 n1 n Year

25 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 Year Preclinical Phase Clinical Phase

26 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

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

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

30 NC AD (N=98) (N=98) Age Education MMSE Salmon et al., 2002

31 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

32 0-1 NC AD Trials Long Delay Sensitivity: 98% Specificity: 88%

33 250 NC 200 AD Part A 0 Part B Sensitivity: 85% Specificity: 83%

34 50 45 NC 40 AD Letter Fluency Category Fluency Sensitivity: 96% Specificity: 88%

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

37 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

38 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

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40 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

41 Gilman et al., 2007

42 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 : : : 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)

43 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

44 0 Visuospatial Attn/Executive Memory Language ite Z-Score Mea an Compos DLB AD * *

45 0 Visuospatial Attn/Executive Memory Language -1 Mea an Composit te Z-Score -2 * * Mild Dementia (MMSE > 22) DLB AD

46 0 Visuospatial Attn/Executive Memory Language -1 ite Z-Score Mea an Compos -2-3 * Moderate Dementia (MMSE < 22) * DLB AD

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48 DLB AD

49 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%

50 l Score Mean DRS Total AD DLB Baseline Eval 1 Eval 2

51 WISC-R Block Design Clock Drawing Test--Copy Me ean DRS Total Score High AD 30 High DLB 20 Low AD Low DLB Baseline Eval 1 Eval 2 Baseline Eval 1 Eval 2

52 Category Fluency Boston Naming Test (30-item) Mean DRS Tota al Score High AD High DLB Low AD 20 Low DLB Baseline Eval 1 Eval Baseline Eval 1 Eval 2

53 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

54 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)

55 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± ±1.6 * Four patients were seen only at baseline