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SCREENING TOOLS FOR MCI (mild cognitive impairment)

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1 SCREENING TOOLS FOR MCI (mild cognitive impairment)
J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral Sciences Stanford University Senior Research Scientist Stanford / VA Aging Clinical Research Stanford University and VA Palo Alto Health Care System International Conference on Alzheimer’s disease July 12, 2010 Slides at: (Dr. Ashford’s lectures)

2 Disclosures for Dr. Ashford
Alzheimer’s Association Member, Northern California Branch Scientific Advisory Board Alzheimer’s Foundation of America Medical Advisory Board member Chair, Memory Screening Advisory Board Journal of Alzheimer’s Disease Clinical Editor Developing a memory test: MemTrax – for computers, internet, audience presentations Partner with HAPPYneuron Consultant for Orasi, Inc. Developing MEG test for AD Share owner in Satoris, Inc. Developing proteomics test for AD Share owner, consultant for Neurotez, Inc Developing Leptin as a treatment for AD

3 Screening Tools for MCI (outline of presentation)
Definition of Mild Cognitive Impairment (MCI) Dementia signs without social impairment Is it “cost-worthy” to screen for MCI? Estimate based on benefits, costs, incidence, sensitivity, specificity Understanding the progression of Alzheimer’s disease Gompertz Hazard Curve in early AD pathological changes, genetics Central concept of change over time – Gompertz Survival Curve Existing cognitive tools for MCI screening MMSE, BAS, MIS, MCIS, episodic memory tests, MemTrax Biomarkers for MCI screening Genetics, CSF, blood, brain scanning, EEG/ERP/MEG Future directions for MCI screening Longitudinal assessment MemTrax – quick, fun games for precise memory measurement

4 Diagnostic Criteria For Dementia Of The Alzheimer Type (DSM-IV, APA, 1994)
Multiple Cognitive Deficits 1. Memory Impairment Especially new learning, a prominent early symptom 2. Other Cognitive Impairment: Aphasia, apraxia, agnosia, or executive dysfunction Deficits sufficiently severe to impair Social/Occupational functioning Course Shows Gradual Onset And Decline Must represent a decline from a previous level of functioning Deficits Are Not Due to: 1. Other CNS Conditions 2. Substance Induced Conditions Do Not Occur Exclusively during Delirium Not Due to Another Psychiatric Disorder

5 Mild Cognitive Impairment Essentially normal functional activities
Cognitive complaint Not normal for age 1/3 AD, 1/3 not, 1/3 both. Not demented Cognitive decline Essentially normal functional activities MCI Memory impaired? Yes Amnestic MCI Non-amnestic MCI Single domain Yes No Single non-memory cognitive domain impaired? Multiple domain Memory impairment only? Amnestic MCI Single domain Yes No Amnestic MCI Multiple domain CP Petersen: J Int Med, 2004 Petersen, Ronald C MN

6 What’s the Difference? Normal Aging
Occasional loss of memory for words and names. Slowed processing speed. Difficulty sustaining attention when faced with competing environmental stimuli. No functional impairment. MCI Memory impairment beyond that expected for age, increasing over last six to 12 months. Other cognitive functions generally unimpaired. Daily function not significantly impaired. Not demented. Source: Dr. Pierre Tariot, University of Rochester Medical Center. “What is on the Horizon for Alzheimer’s Disease Research?“ 6

7 Cognitive Continuum Normal Mild Cognitive Impairment Dementia
CP Added to series , MC Petersen, Ronald C MN

8 Mild Cognitive Impairment
Normal MCI AD 0.5 1 CDR (clinical dementia rating scale) Petersen, Ronald C MN

9 AAMI / MCI/ early AD -- DEMENTIA
ALZHEIMER’S DISEASE COURSE (calculated from the CERAD data set) The best model to fit the progression, both mathematically and biologically, is the Gompertz survival curve (99.7% fit to mean changes over time): S(t) = exp(Ro/alpha *(1- exp (alpha * t))) (Time-Index Scale) AAMI / MCI/ early AD DEMENTIA Ashford et al., 1995

10 Progression Time (years) Presymptomatic MCI Clinical Dementia
CDR 0.5 CDR 1 CDR 2 CDR 3 Neuropsychological/Functional Status Threshold for Clinical Detection Progression AD Pathological Burden Time (years) Adapted from Daffner & Scinto, 2000

11 Is it worth screening for Alzheimer’s disease or MCI?
“If there was treatment for AD, I'd recommend screening, but there is no disease-modifying therapy." Anonymous Alzheimer expert -2008 “All older adults benefit from memory screening because it detects cognitive problems before memory loss is noticeable.” Healthy Aging, 2008; repost, 2010 “Memory Screening: Is it Worth It?”

12 Alzheimer's Disease Is Under-diagnosed
Early AD is subtle, the diagnosis continues to be missed It is easy for family members to avoid the problem and compensate for the patient Physicians tend to miss the initial signs and symptoms Less than half of AD patients are diagnosed Estimates are that 25%–50% of cases remain undiagnosed Diagnoses are missed at all levels of severity: mild, moderate, severe Undiagnosed AD patients often face avoidable social, financial, and medical problems Early diagnosis and appropriate intervention may lessen disease burden Early treatment may substantially improve overall course No definitive laboratory test for diagnosing AD exists Efforts to develop biomarkers, early recognition by brain scan 12

13 Why MCI Screening Is Important to Consider
Cognitive impairment is disruptive to human well- being and psychosocial function Cognitive Impairment is potentially a prodromal condition to dementia and Alzheimer’s disease (AD) Dementia is a very costly condition to individuals and society With the aging of the population, there will be a progressive increase in the proportion of elderly individuals in the world Screening will lead to better care 13

14 No Testing: What happens without screening?
Total Population Risk=P P’ P Do not have AD Have AD No effective intervention Helena Kraemer, 2003

15 Testing: What happens with testing?
Helena Kraemer, 2003 Total Population Specificity = Sp Sensitivity = Se P’ P AD No AD Se Se’ Sp’ Sp Unnecessary intervention OK No effective intervention Effective intervention $ Testing $Testing $ Testing $ Testing $ Intervention $ Intervention Iatrogenic Damage? Clinical Wash Clinical Wash Clinical Gain Major(?) Loss Minor (?) Loss Minor(?) Loss Major(?) Gain Some gain False Positive True Negative False Negative True Positive

16 Factors for Deciding whether a Screening Test is Cost-Effective
Benefit of a true positive screen Benefit of a true negative screen Cost of a false positive screen Cost of a false negative screen Incidence of the disease (in population) Test sensitivity (in population) Test specificity (in population) Test cost

17 $W = Cost–Worthiness Calculation $W > ($B x I x Se) – ($C x (1-I) x (1-Sp)) - $T
BENEFIT $B = benefit of a true positive diagnosis Earlier diagnosis may mean proportionally greater savings Estimate: (100 years – age ) x $1000 Save up to $50,000 (e.g., nursing home cost for 1 year) (after treatment cost deduction at age 50, none at age 100) (cost-savings may vary according to your locale) True negative = real peace of mind (no money) COST $C = cost of a false positive diagnosis $500 for further evaluation (time, stress of suspecting dementia) False negative = false peace of mind (no price) I = incidence (new occurrences each year, by age) Se = sensitivity of test = True positive / I Sp = specificity of test = True negative / (1-I) = (1-False positive/(1-I) $T = cost of test, time to take (Subject, Tester) Kraemer, Evaluating Medical Tests, Sage, 1992

18 Benefits of Early Alzheimer Diagnosis: Social
Undiagnosed AD patients face avoidable problems Social, financial Early education of caregivers How to handle patient (choices, getting started) Advance planning while patient is competent Will, proxy, power of attorney, advance directives Reduce family stress and misunderstanding Caregiver burden, blame, denial Promote safety Driving, compliance, cooking, etc. Patient’s and family’s right to know Especially about genetic risks Promote advocacy For research and treatment development 18

19 Benefits of Early Alzheimer Diagnosis Medical
Early diagnosis and treatment and appropriate intervention may: improve overall course substantially lessen disease burden on caregivers / society Specific treatments now available for dementia (anti-cholinesterases, memantine) Improve cognition Improve function (ADLs) Delay conversion from Mild Cognitive Impairment to AD Slow underlying disease process, the sooner the better Decreased development of behavior problems Delay nursing home placement, possibly over 20 months Delay nursing home placement longer if started earlier

20 Benefits of Early Treatment of Alzheimer’s Disease
Neurophysiological pathways in patients with AD are still viable and are a target for treatment Opportunity to reduce from a higher level: Functional decline Cognitive decline Caregiver burden Need to estimate net benefit monetarily (key factor in determining case for screening) Estimate benefit = (100 years – age ) x $1000 Purpose: To emphasize the point that patients with moderate to severe AD can still benefit from drug treatment Key Points: There are a number of benefits to treating. Based on current data from imaging and other noninvasive studies in patients with AD as well as autopsies of patients with AD, we have recognized that the levels of degeneration in the brain may be substantially less than previously thought (based on studies in the late 1970s and 1980s). Much more cellular content and signaling remain viable late in the disease, which represents an opportunity for intervention. Early treatment and effective therapies for patients with moderate to severe AD may help provide opportunities to slow symptomatic decline in function and cognition, and reduce caregiver burden.

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23 Cost of False-Positive Screen
Referral of normal individual for further testing (more specific testing) Value of individual’s time Cost of additional testing Estimate cost = $500 per false-positive screen This does not and should not include the cost of untoward results of misdiagnosis, medication side-effects, or malpractice – quality management should address these

24 Other Benefits and Costs of Screening
Benefit of true-positive screen = intangible Peace of mind Plan further into future Cost of false-negative screen = wash Delay in diagnosis and treatment No different from current condition

25 INCIDENCE OF MCI (Hazard per year)
Based on estimate of 4 million AD patients with dementia in US in 2000, with an incidence that doubles every 5 years, illness duration of 8 years. Assume average of 5 years from onset of MCI to onset of dementia

26 U(t) = Ro * exp (alpha * t)
The Gompertz survival curve explains 99.7% of male and female mortality Variance between 30 and 95 y/o: U(t) = Ro * exp (alpha * t) (Incidence for a to a + 1 year) JW Ashford, MD PhD, 2003; See: Raber et al., 2004

27 U(t) = Ro * exp (alpha * t)
Using the Gompertz equation to model rate of dementia increase with age: U(t) = Ro * exp (alpha * t)

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29 D(t) = U(t) * S(t) Using Gompertz equations to model probability of
dementia with age: D(t) = U(t) * S(t)

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33 Cache County, probability of incident dementia Circles – females
Squares - males Open – ApoE-e44 Gray – ApoE-e4/x Black – ApoE-ex/x Miech et al., 2002

34 Using a Gompertz survival
curve to model probability of not having dementia with age: S(t) = exp(Ro/alpha *(1- exp (alpha * t)))

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36 Se, Sp

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39 ADNI ADCS FDG-PET MRI hipp CSF-Aβ42 Cognition Amyloid imaging Function
(protein decline) Cognition Amyloid imaging (ligand increase) Function CSF-tau ADNI ADCS

40 Critical Factors for Developing Cost-Effective Screening
Develop benefit of a true positive screen - Need effective disease slowing treatments Define value of genetic testing - Need to recognize central role of APOE genotype Determine sensitivity and specificity of tests - Parameters must apply to population Need to determine cost-worthiness - This must be determined for each test Specific tests must be optimally sequenced - Frequent cognitive screens triggering biomarker tests

41 Need to Develop Better Screening and Early Assessment Tools
Trait factors – determine at 50 y/o to plan screening Genetic vulnerability testing (or family history) Vulnerability factors (education, occupation, head injury, blood pressure) State factors (begin annually at appropriate age) Early recognition (10 early warning signs), ADLs Screening tools (6th vital sign in elderly) Brief clinical screens vs. computerized tests Tests need to assess likely level of function Detecting early change over time Measuring rate, predicting progression Positive diagnostic tests CSF – amyloid levels low (early), tau levels elevated (MCI) Brain scan – PET – f-DG, f-DDNP, f-amyloid ligands (early) Dementia severity tested on “time-index” continuum

42 Alzheimer's Disease Top 10 Warning Signs (not early)
Recent memory changes affecting daily life Challenges in problem solving and planning Difficulty performing familiar tasks Disorientation to time and/or place Difficulty understanding visual images and/or spatial relationships Problems with spoken and written language (eg, paraphasia, agraphia) Misplacing things Poor judgment Withdrawal from activities (eg, social, work) Changes in personality and/or mood Need a Top 10 Early Warning Signs Alzheimer's Association. 10 Signs of Alzheimer's. Available at: Accessed April 20, 2009. 42

43 Challenges With the Mini-Mental State Examination
Mini-Mental State Exam (MMSE) Folstein MF, et al. J Psychiatr Res. 1975;12: Several items do not provide adequate information Adds noise rather than discrimination between demented and nondemented individuals, particularly in early AD, MCI Poor range for measuring change Large standard error of measurement Poor power for assessing medication benefit Inadequate screening tool Too long Better, shorter tests are available Copyright is being enforced (test is not free) Ashford JW. Aging Health. 2008;4: 43

44 Ashford et al., 1989

45 Ashford et al., 1989

46 Mini-Mental State Exam items
MMSE items Mini-Mental State Exam items Neuropsychological Testing (WAIS, WECHSLER) Memory: Short-term, Remote Verbal Function, Fluency Visuo-Spatial Function Attention Executive Function Abstract Thinking Account for Education Account for Prior Dysfunctions

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49 Implications of Item Characteristic Curves for Patient Testing
REMOVE POOR ITEMS, ESPECIALLY THOSE THAT ADD NOISE SELECT ITEMS THAT BETTER PERTAIN TO FOCUS OF STUDY MAXIMIZE INFORMATION OBTAINED PER MINUTE OF TESTING DECREASE VARIABILITY IN TEST IMPROVE ACCURACY, PRECISION DEVELOP BETTER SCREENING TESTS ON-LINE COMPUTATION -

50 Relatively Brief Cognitive and Memory Tests
Name of Test Author Animal Naming in 1 minute Rey Auditory Verbal Learning Test Abbreviated Mental Test Halstead, 1943 Rey, 1958 Hodkinson, 1972 Short Portable Mental Status Questionnaire (SPMSQ) Pfeiffer, 1975 Clifton Assessment Procedures for the Elderly-Cognitive Assessment Scale (CAPE-CAS) Pattie, 1981 Blessed 6-Item Katzman, 1983 Visual memory, category fluency, temporal orientation Eslinger, 1985 Short Test of Mental Status Kokmen, 1987 Delayed Word Recall test (DWR) Knopman, 1989 Memory Impairment Screen Buschke, 1999 Three Words–Three Shapes Weintraub, 2000 General Practitioner Assessment of Cognition (GP-COG) Brodaty, 2002 6-Item Screener Callahan, 2002 Ashford JW. Aging Health. 2008;4: 50

51 Relatively Brief Cognitive and Memory Tests (cont.)
Name of Test Author Efficient Office-Based Assessment of Cognition Karlawish, 2003 Mini-Cog Borson, 2003 Rapid Dementia Screening Test (RDST) Kalbe, 2003 Brief Alzheimer Screen (BAS) Mendiondo, 2003 Short Cognitive Evaluation Battery (SCEB) Robert, 2003 AB Cognitive Screen)(ABCS) Molloy, 2005 Quick & Easy (Q&E) Dash, 2005 Mild Cognitive Impairment Screen (MCIS) Shankle, 2005 Blessed Memory Test/Category Fluency Kilada, 2005 10-Item Free Recall With Serial Position Effect Analysis Tractenberg, 2005 From Ashford, Aging Health. (2008) 4(4): Ashford JW. Aging Health. 2008;4: 51

52 Screening tools tested for MCI
3-word memory +clock draw (MiniCog, Borson) + FAQ (Functional Activity Questions) – Steenland et al., 2008 3-word memory + temporal orientation + “spell WORLD backwards” + category naming – BAS (Brief Alzheimer Screen) – Mendiondo et al., 2003 (only test based on item construct validity) 4-word memory (deep encoding – MIS, Buschke) + Isaacs Set Test (category fluency) – Chogard et al., 2008 5-word memory, 4 sets – Gialaouzidis, 2010 10-word memory with computation (MCIS) – Shankle et al. Internet tools: Test Your Memory – 10 skill assessment – Brown et al., 2010 Computer Self Test – 6 cognitive domains – Canon, Dougherty, 2010 Memtrax – Computer Memory Game – Ashford et al., 2006 Note: word memory is American tradition; name & address memory is English tradition

53 JW Ashford, MD PhD, 2001

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55 Brief Alzheimer Screen (BAS)
Repeat these three words: “apple, table, penny”. So you will remember these words, repeat them again. What is today’s date? D = 1 if within 2 days. Spell the word “WORLD” backwards S = 1 point for each word in correct order “Name as many animals as you can in 30 seconds, GO!” A = number of animals “What were the 3 words I asked you to repeat?” (no prompts) R = 1 point for each word recalled BAS = 3 x R /3 x A x D x S Mendiondo, Ashford, Kryscio, Schmitt., J Alz Dis 5:391, 2003

56 JW Ashford, MD PhD, 2001

57 JW Ashford, MD PhD, 2003

58 Brief Alzheimer Screen (BAS) ROC for Univ. Kentucky ADRC Clinic Cases
Schmitt et al., 2006

59 Spearman Correlations Between Neuropsychological and MRI Volumetric Data
Grey Mat. White Mat. Right Hipp. Left Hippo. Right Ento Left Ento MIS Controls 0.18 0.112 0.185 0.243 –0.085 –0.205 MCI –0.022 –0.213 0.430a 0.378 0.156 0.21 AD –0.100 0.033 0.192 0.23 –0.012 –0.061 FCSRT learning 0.25 0.249 0.048 0.252 –0.214 –0.152 –0.044 –0.243 0.469a 0.383 0.374a 0.424a –0.032 –0.224 –0.091 0.211 –0.074 –0.168 FCSRT delayed 0.161 0.136 0.028 0.233 –0.325 –0.295 –0.010 –0.267 0.554b 0.426a 0.407a –0.126 0.286 0.451a 0.104 0.081 Abbreviations: AD, Alzheimer Disease; ento, entorhinal; hipp., hippocampus; mat., matter FCSRT, Free and Cued Selective Reminding Test; MIS, Memory Impairment Screen; a Significant correlations are flagged with P < .05. b Significant correlations are flagged with P < .001.

60 The MCIS For Clinical Practice & Research
Takes 10 Minutes Accuracy1-4 is: 96-97% for Normal vs. Mild Cognitive Impairment. 99% for Normal vs. Mild Dementia. Improves Signal:Noise Ratio by 100% over standard scoring methods5. 16 culturally unbiased, equivalent wordlists randomly selected without replacement in each patient to minimize test-retest effects5. Available in English, Spanish and Japanese. Adopted in all Medicare regions. 1Shankle et al. PNAS. 2005 2Trenkle et al. J. Alz. Dis 3Cho et al. Jap. J. Exp. Med 4Tabara et al. Hypertension Research 5Shankle et al. Alz. & Dementia, 2009.

61 Developing The Measurement Technology: Memory Patterns
Raw CWL Data Matrix of Recalled and Forgotten Words (eg: ) Correspondence Analysis1 (Multivariate Gaussian-Distributed Optimal Patient & Word Score Vectors) Logistic Regression ROC Curve Analysis Age-Specific Prevalence Classification algorithm & Memory Performance Index (MPI) scaling 1This method explains the maximum possible amount of the raw data’s variance for the class of linear methods. In contrast to FA & PCA, Correspondence analysis accounts for differences due to heterogeneous samples. Optimal Scores Vary By: List Position Exposure Frequency Delay Being Recalled or Not Item Responses Are Usually Scored As 0 or 1: All Items Have Equal Value Word 1 Word 2 Word 3 Word 4 Word 5 Word 6 Word 7 Word 8 Word 9 Word 10 Wordlist Memory Task: 4 Trials 1Kendall & Stuart, The Advanced Theory of Statistics 2Shankle et al. PNAS. 2005

62 Wordlist Development 600 nouns met these criteria
1 million common nouns. Frequency, range, and diversity of usage statistics paralleled CERAD and ADAS-Cog Wordlists 600 nouns met these criteria Constructed 10-word lists that met the following requirements Each word: could be used only once. could only have 1 or 2 syllables has unique letter or sound. has no homonyms or antonyms in list. has low associability with all other list words. Each target list word can be matched on all above criteria with a word in its accompanying distracter list. 16 Wordlists Met All Above Criteria (Subjects Must Be Tested 9 Times Before They See The Same Wordlist Twice)

63 MCIS Performance Summary
Study Comparisons ROC Accuracy Sensitivity Specificity Normal vs. MCI* (3 Validation Studies)1,2,3 96-97% 94-96% 88-100% Normal vs. MCI Due To Alzheimer’s Disease1,2 99% 98% 92% Normal vs. MCI Due To Non-Alzheimer’s Disease1,2 96% 91% 88% Normal vs. Mild Dementia1 Normal vs. Asymptomatic CI (Primary Care Sample)2 93% 86% *The underlying etiologies of the MCI syndrome in the primary care, community and academic samples included Alzheimer’s disease, Lewy Body disease, Parkinson’s disease, Frontal Temporal Lobe dementia, normal pressure hydrocephalus, cerebrovascular disease, alcohol dependence, traumatic brain injury, metabolic disorders, and depressive pseudo-dementia. Psychometric Properties Positive Predictive Value for MCI1,2 86-100% Negative Predictive Value for Normal Aging1,2 96-99% Within-Subject Inter-Rater Reliability: Office Staff vs Neuropsych. (Cronbach alpha)2 0.87 ± 0.07 Validity compared to Clinical Diagnosis (Kappa statistic)2 0.92 ± 0.09 False Negative Rate Based on Long-Term Care Claims After 3 years exposure: N=250,0004 % 1Shankle et al. PNAS: Trenkle et al. J. Alz Dis: 2007. 3Cho et al. Am J. Alz Dis Other Dem Cohen et al. National Underwriter, 2009.

64 Japanese MCIS vs. Biomarkers
Cho et al., 2009

65 Comparing Standard Recall & MCIS Scoring Method (MPI)
Regression of Recall Scores or MCIS Scoring Method (MPI) Score Against Age, Gender, Education, Race, Method of Administration & Wordlist Used1 N=121,481 Applicants for Long-Term Care Insurance: Ages Delayed, Immediate or Total Free Recall R2 = % of variance explained MPI Score R2 = 55.5% of variance explained Effect sizes (Cohen’s d) were as follows: Effect of Race, gender, and wordlist on MPI Score were negligible (<0.02) Effect of Education & phone vs. in-person testing on MPI Score were small ( ) Effect of Age on MPI Score was large (0.68) Effect of all covariates on Free Recall scores was negligible or small (< 0.09) 1Shankle et al. Alz. And Dementia. 5; 2009:

66 Time to Administer Available Short Screening Tests
Top cognitive tests studied for BRIEF SCREENING for MCI Brief Alzheimer Screen 2 – 3 min Mini-cog + FAQ min MIS + Isaacs Set Test 4 – 6 min MCIS min A suitably accurate cognitive test for MCI is not available. Because on variability between individuals, MCI screening requires longitudinal assessment!!

67 Need to Develop More Sensitive and Specific Tools for MCI
Genetic vulnerability testing (trait risk) APOE genotype + age is among the best currently Improve awareness of vulnerability factors, ask the “right questions” of the patient or informant (education, occupation, head injury) Early recognition “10 warning signs” Activities of daily living (ADLs), behavior changes, forgetting Increase suspicion and use available screening tools (while new and better tools/tests are developed) "6th vital sign" in elderly Utilize current diagnostic tests that can best identify probable AD Cerebrospinal fluid: tau levels, amyloid levels Brain scan, PET scan: f-2DG, f-DDNP, f-amyloid-ligands More routine use of mild dementia severity assessments Detect early change over time Measure rate of change, predict progression 67

68 Memory / MCI / Dementia Screening Test
Need test for cognitive screening of patients for early Alzheimer’s disease Test needs to be on multiple platforms Doctor’s offices Best if computerized for rapid, objective assessment Internet-based testing CD-ROM distribution Kiosk administration (eg, drug stores, shopping malls) Test needs to be very brief (~1-minute) Multiple test-forms needed so it can be repeated often (quarterly) Annual screening annually after age 50 years Repeated every 3 months for individuals over 65 years or with concerns/risk factors Variety of versions allow daily testing as an exercise Any change over time needs to be detected The test should be free (or cost very little) 68

69 MEMTRAX - Memory Test (For Dementia Screening, Cognition Assessment)
Test to screen patients for dementia, AD: Subjects are asked to respond to images that are repetitions of previously shown images. Computerized test (computer or web - 3 minutes) KIOSK administration (clinic check-in) Group administration (Power-Point – 6 minutes) On the paper & pencil version, each slide is shown for 5 seconds. The test-taker is ask to fill in the circle next to the number for a repeated slide. After a practice set, the 50-slide test takes 4 minutes and 10 seconds. For the computerized test, each image is shown for 3 seconds, and the subject pushes the space bare to indicate recognition of a repeated picture. Estimate level (based on 2,000 patients, caregivers) >90% very good 80-90% good 70-80% consider mild cognitive impairment <70% dementia

70 MEMTRAX Memory Test 116 subjects – mostly elderly normals, some young, some dementia patients False positive errors (false recognition) – 33(64);6(58);47(27)—4,18,23,34(1);1,2,8(0) - mean – 8.3% (sd-14.5%) errors per item False negative errors (failure to recognize) – 35(33);27(20);5(16)—32(4);24(3);45(3) - second presentation (#15): mean- 10.5% (sd-6.2%) errors per item - third presentation (#10) mean – 5.7% (sd-2.5%) errors per item - second 10 vs. same third 10: 10.5% (sd-3.4%) vs 6.6% (sd-2.5%)

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73 CONCLUSIONS on MEMTRAX
A short, computerized test provides a measure of cognitive function, including memory and attention, on a robust continuum, establishing a baseline of cognitive function and potentially predicting the presence of dementia Computerized version – 2-3 minutes, fun game, provides reaction time measure Paper&Pencil, with PowerPoint slide show, can be given to a large audience Testing for reliability and validity are Classical Test Theory concepts Modern Test Theory examines performance across individual items on a continuum (varied by first repeat vs second repeat, number of slides between first show and first repeat, etc. Analysis for maximum likelihood level of cognition (both recognition and attention), provides information about dementia probability Information about visuo-spatial and language function is available

74 MEMTRAX - Memory Test (to detect AD onset)
New test to screen patients for AD: World-Wide Web – based testing CD-distribution KIOSK administration (grocery stores, drug stores) Determine level of ability / impairment Test takes about 1-minute Test can be repeated often (e.g., weekly, quarterly) Any change over time can be detected Experimental tests at: Social network tests at: Clinical test at:

75 Comprehensive Screening Plan
At age 50 years: initial screen, review risks Review dementia family history – strongly consider APOE genotyping Review of systems, vital signs Brief cognitive evaluation – establish baseline for longitudinal assessment Complete blood count (CBC), B12, cholesterol Begin yearly assessments if high risk At age 55–60 years: follow-up assessments Brief cognitive evaluation using longitudinal measures!! CBC, B12, cholesterol At age 65 years and older: begin annual assessments Brief cognitive evaluation watching longitudinal changes 75

76 Secondary Screen: Specific Testing
More cognitive testing Complete orientation testing Test ability to name animals and vegetables in 1 minute Ask for recall of 10 items after distraction Test praxis Draw clock, cube Talk with a knowledgeable informant Ask questions about activities of daily living Ask questions about depression, sleep 76

77 Potential AD Biomarkers Probably not cost-worthy as screening tests, but may be useful for secondary screening Blood, urine Aβ40? Aβ42? Neuritic threads? Most studies suggest not helpful, may be wrong Protein levels in blood – Leptin, Proteomics Lower Leptin predicts MCI progression to dementia CSF: Aβ40? Aβ42? Others Aβ species? Possibly highly predictive CSF: tau, p-tau Assess active disease progression. EEG/MEG/ERP Neuroimaging Structural (volumetric assessments) Functional (FDG-PET, SPECT) Specific protein imaging (PET)

78 Serum Leptin levels and cognition in the elderly
In elderly, higher serum leptin appears to protect against cognitive decline (5 yr prospective study, 2,871 elders, Holden et al., 2009) Patients with AD have lower serum leptin levels compared to controls, independent of BMI (Power et al., 2001) Data: Satoris, Inc. 20 AD Leptin (ng/ml) 10 MiId Normal Severe Moderate 78 78

79 PROTEOMICS: Expression patterns of Alzheimer disease (AD) signature proteins discriminate between plasma samples from patients with AD and controls. Britshgi & Wyss-Coray, 2009 Correlation networks of Alzheimer disease (AD) signature proteins in plasma of controls without dementia and patients with AD.

80 CSF in Alzheimer’s Disease, both MCI and Dementia patients: Low Aβ and High Tau
Concentration (pg/mL) Tau Sunderland T, et al. JAMA. 2003;289: 80

81 ADNI data, 2008 81

82 ADNI Data – CSF ABeta, total tau
Comparison p-value 33 vs 34 <.0001 33 vs 44 34 vs 44 0.08 Normal vs MCI 0.57 Normal vs Mild AD 0.15 MCI vs Mild AD 0.20 Comparison p-value 33 vs 34 0.07 33 vs 44 0.67 34 vs 44 0.99 Normal vs MCI 0.05 Normal vs Mild AD <.01 MCI vs Mild AD 0.06 82

83 ADNI CSF Data – total tau
Number of participants that provided CSF at baseline Ages +std of participants that provided CSF at baseline APOE genotype Normal MCI Mild AD 33 67 (72%) 82 (44%) 29 (31%) 34 24 (26%) 81 (44%) 42 (45%) 44 2 (2%) 22 (12%) 22 (24%) APOE genotype Normal MCI Mild AD 33 75.8 ± 5.0 75.4 ± 8.4 76.3 ± 8.6 34 75.8 ± 6.0 73.9 ± 6.7 75.6 ± 6.6 44 77.0 ± 1.4 72.2 ± 6.0 69.8 ± 7.0 CSF ABeta levels ± std CSF tau levels ± std APOE genotype Normal MCI Mild AD 33 212.4 ± 48.4 189.1 ± 59.8 168.8 ± 52.3 34 156.0 ± 47.8 148.4 ± 42.4 139.0 ± 27.2 44 126.0 ± 2.8 119.8 ± 23.5 116.2 ± 22.3 APOE genotype Normal MCI Mild AD 33 67.8 ± 26.9 83.6 ± 40.8 123.8 ± 68.6 34 81.8 ± 42.6 122.4 ± 72.7 113.3 ± 42.0 44 71.0 ± 2.8 110.6 ± 45.9 128.9 ± 53.1 83

84 Future directions for MCI screening
Successful treatments for MCI APOE genotyping – routine at 50 y/o Preventive measures based on genetics Longitudinal assessment of memory Computer games to monitor cognition quick, fun, inexpensive Can beta-amloid deposition be controlled by mental, physical exercises, better sleep?


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