1. Using computers to conduct mass screening for dementia - practical issues and ethics - April 15, 2011 International Association of Geriatrics and Gerontology J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) of Psychiatry & Behavioral Sciences Stanford University Senior Research Scientist Stanford/VA Aging Clinical Research Center, VA Palo Alto Health Care System Palo Alto, California Slides at: www.medafile.com/IAGG2011.pptwww.medafile.com/IAGG2011.ppt

2. Two issues to be covered Establishing the Cost-Worthiness of dementia screening (ethical issues) Demonstrating a practical dementia screen Slides at: www.medafile.com/IAGG2011.ppt www.medafile.com/IAGG2011.ppt

3. Dementia Definition Multiple Cognitive Deficits: – Memory dysfunction – especially new learning, a prominent early symptom – At least one additional cognitive deficit aphasia, apraxia, agnosia, or executive dysfunction Cognitive Disturbances: – Sufficiently severe to cause impairment of occupational or social functioning and – Must represent a decline from a previous level of functioning

4. AD - Dementia Continuum NormalMCIAD 00.51 CDR (clinical dementia rating scale) 3004153-1

5. AAMI / MCI/ early AD -- DEMENTIA Introducing the time-index model of the course of Alzheimer’s disease Ashford et al., 1995 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))) (calculated from the CERAD data set) (Time-Index Scale)

6. Is it worth screening for memory problems or Alzheimer’s disease? “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.” Anonymous Alzheimer expert -2008 Healthy Aging, 2008; repost, 2010 “Memory Screening: Is it Worth It?” http://healthy-aging.advanceweb.com http://healthy-aging.advanceweb.com/Patient-Resource-Center/Disease- Management-and-Prevention/Memory-Screening-Is-it-Worth-It.aspxhttp://healthy-aging.advanceweb.com/Patient-Resource-Center/Disease- Management-and-Prevention/Memory-Screening-Is-it-Worth-It.aspx

7. 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

8. Why Memory 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 (issue of who is paying for screening, patient care) With the aging of the population, there will be a progressive increase in the proportion of elderly individuals in the world (must consider costs to society) Screening will lead to better care (more cost-effective care)

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

10. Testing: What happens with testing? Total Population No AD AD Unnecessary intervention OK No effective intervention Effective intervention $ Testing$Testing$ Testing $ Testing $ Intervention Iatrogenic Damage?Clinical WashClinical Wash Clinical Gain Major(?) LossMinor (?) LossMinor(?) Loss Major(?) Gain Some gain False PositiveTrue NegativeFalse Negative True Positive PP’ Se Se’ SpSp’ Helena Kraemer, 2003 Specificity = Sp Sensitivity = Se

11. Factors for Deciding whether a Screening Test is Cost-Effective 1)Benefit of a true positive screen 2)Benefit of a true negative screen 3)Cost of a false positive screen 4)Cost of a false negative screen 5)Incidence of the disease (in population) 6)Test sensitivity (in population) 7)Test specificity (in population) 8)Test cost

12. $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

13. 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

14. 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 (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

15. 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

17. - Sharpness of peak relates to increased sensitivity and specificity - Location of peak relates to point in dementia continuum where recognition would be most beneficial – adjusting sensitivity versus specificity More specificMore sensitive

18. 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 issues

19. 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

20. INCIDENCE OF DEMENTIA (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.

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

22. Relative Risk Factors for Alzheimer’s Disease (after age, early onset genotypes) APOE-e4 genotype 1 allele x 4; 2 alleles x 16 Family history of dementia3.5 (2.6 - 4.6) Family history - Downs 2.7 (1.2 - 5.7) Family history - Parkinson’s2.4 (1.0 - 5.8) Obese, large abdomen3.6 Maternal age > 40 years1.7 (1.0 - 2.9) Head trauma (with LOC)1.8 (1.3 - 2.7) History of depression1.8 (1.3 - 2.7) History of hypothyroidism2.3 (1.0 - 5.4) History of severe headache0.7 (0.5 - 1.0) History of “statin” use0.3 NSAID use0.2 (0.05 – 0.83) Use of NSAIDs, ASA, H2-blockers0.09 Roca, 1994; ‘t Veld et al., 2001, Breitner et al., 1998, Wolozin et al., 2000

23. JW Ashford, MD PhD, 2003; See: Raber et al., 2004

24. Zandi et al., JAMA, November 6, 2002—Vol 288, No. 17 p.2127

26. Using the Gompertz equation to model rate of dementia increase with age: U(t) = Ro * exp (alpha * t) JW Ashford, MD PhD, 2003; See: Raber et al., 2004

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

28. JW Ashford, MD PhD, 2000 e4/4 – 2% of pop, 20% of cases e3/4 - 20% of pop, 40% of cases e3/3 - 65% of pop, 35% of cases

29. Se, Sp

30. Varying Benefit:

32. Mini-Mental State Exam items MMSE items

33. The Taxonomy of Long-Term Memory (Squire and Zola, 1996)

34. JW Ashford, MD PhD, 2001

36. 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 + 2/3 x A + 5 x D + 2 x S Mendiondo, Ashford, Kryscio, Schmitt., J Alz Dis 5:391, 2003 www.medafile.com/bas.htm

37. JW Ashford, MD PhD, 2001

38. JW Ashford, MD PhD, 2003

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

40. Need for Mass Screening Alzheimer’s disease, dementia, and memory problems are difficult to detect when they are mild – about 90% missed early – about 25% are still missed late There are important accommodations and interventions that should be made when there are cognitive impairments – (like needing glasses or having driving restrictions if you have vision problems)

41. Recommendations being considered for mandatory Medicare screen (April, 2011) 1)Ask patient and significant other (if available) if memory is a problem 2)Ask patient and significant other (if available) if remembering to take medications is a problem 3)Ask patient to remember 3 unrelated words, and have the patient repeat the 3 items twice 4)Ask patient the date (note if off by more than 2 days) 5)Ask the patient to name as many animals as possible in 1 minute (note concern if number is below 10) 6)Ask the patient to draw a clock (note issues) 7)Ask the patient to recall the 3 items that were repeated (note concern if 2 or 3 items not recalled) 8)Evaluate the clinical responses. If problems noted, consider possible explanations or need for further evaluation

42. There is considerable resistance to implementation of clinical screening 1)Clinicians are concerned that they don’t have time to screen 2)Certain organizations recommend use of warning signs, which have not been studied or ever shown to be effective for recognizing early cases 3)There needs to be a technique for easy recognition of memory problems in an at-risk individual 4)Audience memory screening is available 5)Memory tests are available on the WEB 6)Computerized testing is more effective and efficient

43. Issues for Memory Screening Memory (neuroplasticity) is the fundamental deficit of Alzheimer’s disease Current testing for memory problems is based on having a tester sit in front of a subject for a prolonged period of time and administer unpleasant tests Testing must be – Inexpensive (minimal need for administrator) – Fun (so people will return for frequent testing) – More precise, reliable, and valid To improve sensitivity To improve specificity

44. Audience Screening: CONTINUOUS RECOGNITION TEST Presentation of complex pictures (that are easily remembered normally) are useful for detecting memory difficulties Testing memory using a pictures approach needs standardization for population use Picture memory is less affected by education Picture memory can be tested by computer Audiences can be shown slide presentations

45. Answer Sheet for Memory Screening (back of sheet) Carefully look at each picture. If you see a picture that you have seen before, mark the circle next to the number of the repeat picture. For the main test, you will see 50 pictures. Each picture is numbered. The pictures will stay on the screen for 5 seconds. 25 pictures are new, 25 pictures are repeated.

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96. THE END Please note the number on your answer sheet, then hand it in.

97. 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) False negative errors (failure to recognize) – 35(33);27(20);5(16)—32(4);24(3);45(3)

98. 249 - False Positive Responses for Each Slide, by Slide Number Order (116 subjects voluntarily participating at local informational talks)

99. 242 - False Positive Responses by Slide Number, by Number of Errors (116 subjects voluntarily participating at local informational talks)

100. 249 - False Negative Responses for Each Slide, by Slide Number Order (116 subjects voluntarily participating at local informational talks)

101. 249 - False Negative Responses for Each Slide, by Number of Errors (116 subjects voluntarily participating at local informational talks)

103. Test Performance for 1018 subjects 82 (8%) had perfect scores, 82 (8%) had perfect scores, 230 (23%) made 1 error (98% correct), 230 (23%) made 1 error (98% correct), 700 (69%) made 5 or fewer errors (>90% correct), 700 (69%) made 5 or fewer errors (>90% correct), 132 (13%) made 6 – 10 errors (80 – 88% correct), 132 (13%) made 6 – 10 errors (80 – 88% correct), 186 (18%) made > 10 errors ( 10 errors (<80% correct).-------------------------------------------------------------------- 70 (7%) scored < 80% correct for True Negatives 70 (7%) scored < 80% correct for True Negatives – 19 (6%) males, 51 (8%) females (false positive responses = saying a picture is repeated when not), (false positive responses = saying a picture is repeated when not), 79 (8%) scored < 80% correct for True Positives 79 (8%) scored < 80% correct for True Positives – 25 (7%) males, 54 (8%) females (false negative responses = failure to recognize/recall repeat picture) (false negative responses = failure to recognize/recall repeat picture)

106. The relationship between discriminability (d′) and age on the audience-based continuous recognition test of memory for 868 individuals with all information.

107. The relationship between discriminability performance (d′) and age in 868 individuals on the continuous recognition test of memory.

109. The relationship between discriminability index (d′) and education in 868 individuals on the continuous recognition test of memory. *

110. The relationship between the number of intervening items (between initial and first repeat presentations) and percent correct on those items on the continuous recognition test of memory.

111. The relationship between percent correct and item repetition in 868 individuals on the continuous recognition test of memory.

112. WEB-based Screening On-line Testing Same test paradigm as Audience Screening Testing can be faster – 1-2 minutes for 50 image Many different variations of the test can be given Other aspects of cognition can be tested Test can be repeated several times to decrease variance Test can be taken over time to detect changes Improved anonymity to protect private information

113. 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 2 to 3 minutes Test can be repeated often (e.g., weekly, quarterly) Any change over time can be detected

114. MemTrax WEB Testing Blueberry Study – 12 subjects – no health problems reported – Mean age = 49.3 + 11.7 (range 31-68) – 2 weeks of testing (5 days each week) – 11 different tests – 14 to 18 administrations per subject

121. GenderAged'd' TotBeta Beta Total Memtrax RT Faces RTO-HAP Gender - Age-0.20 - d'0.01-0.14 - d' Total0.26-0.380.88 - Beta0.61-0.430.180.52 - Beta Total0.61-0.530.330.670.98 - Memtrax RT-0.420.29-0.31-0.55-0.67-0.66 - Faces RT-0.230.26-0.59-0.78-0.73-0.740.75 - Offline HAP0.76-0.570.050.320.780.77-0.70-0.47 - Vis-Accom0.55-0.720.010.190.170.28-0.100.160.57 Correlation coefficient with n-2 (9 for 11 subjects) degrees of freedom is: significant at p <.10 level with a value of at least 0.521, p <.05 at 0.602, and p <.01 at 0.735. Correlations significant at the.10,.05 and.01 level are shown in red, blue, and green type respectively. BlueBerry Study – MemTrax – correlation analyses

123. Conclusions The ethical concerns of values and harms must be estimated as costs and benefits Incidence, costs, and test accuracy each play a role in determining whether screening is justified Calculations show that screening for memory problems is justified under specific circumstances, age, and risks Memory can be measured in mass settings using an audience- based system or web administration over the internet The remaining question is whether health systems are prepared to provide the care that will improve the lives of those affected In the future, the incidence is climbing, so the problem may be much worse. Will future treatments be better? Legislation is needed to require training of clinicians to properly diagnose, treat, and manage dementia patients and for mandating appropriate reimbursements of clinicians for their work Screening tests are ready for widespread implementation

124. Screening Tests Available On-Line www.memtrax.com (clinical) www.memtrax.com www.memtrax.net (research) www.memtrax.net www.medafile.com (information) www.medafile.com Slides at: – www.medafile.com/IAGG2011.ppt www.medafile.com/IAGG2011.ppt For further information, contact: – Wes Ashford: washford@medafile.comwashford@medafile.com

125. Future directions for screening Successful prevention of dementia, AD APOE genotyping – routine at birth – Preventive measures based on genetics Can amyloid preprotein dysfunction be controlled by diet, mental stimulation (education), physical exercises, better sleep, drugs, to prevent AD? Longitudinal assessment of memory – To treat dementia when not prevented Computer games to monitor/improve cognition – Quick, fun, inexpensive, user-friendly, repeated