Screening Elderly Clinic Patients for Early Dementia: Psychological Tests, Brain Scans, Genetic Tests, and CSF Biomarke

1. Screening Elderly Clinic Patientsfor Early Dementia:Psychological Tests, Brain Scans, Genetic Tests, and CSF Biomarkers J. Wesson Ashford, M.D., Ph.D. Stanford / VA Alzheimer’s Center VAMC, Palo Alto, California May 16, 2005 Stanford University Medical Center Slides at: www.medafile.com(Dr. Ashford’s lectures)

2. 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

3. Differential Diagnosis: Top Ten (easy mnemonic device: AVDEMENTIA) 1. Alzheimer Disease (pure ~40%, + mixed~70%, ? dLbd) 2. Vascular Disease, MID (5-20%) 3. Drugs, Depression, Delirium 4. Ethanol (5-15%) 5. Medical / Metabolic Systems 6. Endocrine (thyroid, diabetes), Ears, Eyes, Environ. • Neurologic (other primary degenerations, fronto-temporal, - consider diffuse Lewy body dementia, Parkinson component) 8. Tumor, Toxin, Trauma 9. Infection, Idiopathic, Immunologic 10. Amnesia, Autoimmune, Apnea, AAMI Adapted from Yesavage, 1979

4. Alzheimer’s DiseaseversusDementia • 50 - 70% of dementias are due to AD • Probable AD - 30% of cases, 90% neuropath - correct • 20% have other contributing diagnoses • Possible AD - 40% of cases, 70% are AD at neuropath • 40% have other contributing diagnoses • Unlikely AD - 30% of cases, 30% are AD at neuropath • 80% have other contributing diagnoses • Alzheimer’s disease is a pathological condition • Dementia is a clinical condition frequently caused by AD • The AD dementia has some characteristics and some heterogeneity

5. AD Can Be Readily Diagnosed • A diagnosis of Alzheimer’s disease can be made with a high degree of certainty • Using NINCDS-ADRDA criteria, accuracy in autopsy-verified cases is approximately 90% • Diagnosis is a 2-step process: • Detection through screening (test vs. family concern) • Confirmation through patient history and physical, caregiver interview, brain imaging, and appropriate laboratory studies McKhann G et al. Neurology. 1984;34:939-944. Kazee AM et al. Alzheimer Dis Assoc Disord. 1993;7:152-164. Ashford JW et al, Psychiaric Annals, 1996;26:262-268.

6. AD is Under-diagnosed • Early Alzheimer’s disease 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% to 50% of cases remain undiagnosed • Diagnoses are missed at all levels of severity: mild, moderate, severe • No definitive laboratory test for diagnosing AD exists • Efforts to develop biomarkers, early recognition by brain scan Evans DA. Milbank Quarterly. 1990; 68:267-289

7. Reasons to Diagnose Alzheimer’s Disease Early Social / financial • Undiagnosed AD patients often face avoidable social and financial problems • Early education of caregivers of 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 (blame, denial) • Promote safety (driving, compliance, cooking, etc.) • Patient’s and Family’s right to know, especially about genetic risks • Opportunity to reduce caregiver burden • Promote advocacy for research and treatment development

8. Reasons to Diagnose Alzheimer’s Disease Early Medical • Early diagnosis and appropriate intervention may lessen disease burden and early treatment may improve overall course substantially • Neurophysiological pathways in patients with AD are still viable and are a target for treatment • Specific treatments now available (anti-cholinesterases, memantine) • Improve cognition • Improve function (ADLs) • Delay conversion to AD from Mild Cognitive Impairment • 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

9. Benefits of Treatment of AD With Acetylcholinesterase Inhibitors • AChEIs may improve, maintain, or slow the decline of cognitive, behavioral, and functional performance in patients with mild-to-moderate AD • Delay of treatment leads to loss of potential benefit • AChEIs may delay nursing home placement over 20 months, and potentially much more when started early. • AChEIs have demonstrated consistent efficacy and safety in maintaining cognitive function, as measured by ADAS-cog in patients with mild-to-moderate AD for up to 1 year – relative to placebo!! Donepezil1 38 weeks Rivastigmine2 38–42 weeks Galantamine3 52 weeks 1. Rogers SL et al. Eur Neuropsychopharmacol. 2000;10:195-203. 2. Farlow M et al. Eur Neurol. 2000;44:236-241. 3. Raskind MA et al. Neurology. 2000;54:2261-2268.

10. Recent Findings about Donepezil • Petersen et al., 2005: for Mild Cognitive Impairment patients with an E4 allele, conversion to AD in 36 months: • placebo = 76% • donepezil = 23% • Hashimoto et al., 2005: slowing of annual hippocampal atrophy: • APOE4 (1 or 2) • control = 5.6% • donepezil = 4.2% • No APOE4 • control = 4.4% • donepezil = 3.2%

11. BIOPSYCHOSOCIAL SYSTEMS AFFECTED BY ADNEUROPLASTIC MECHANISMS AFFECTED AT ALL LEVELS (Ashford, Mattson, Kumar, 1998; Teter, Ashford, 2002) • SOCIAL SYSTEMS • INSTRUMENTAL ADLs - EARLY • BASIC ADLs - LATE • PSYCHOLOGICAL SYSTEMS • PRIMARY LOSS OF SHORT-TERM MEMORY • LEARNING PROCESSES – CLASSICAL, OPERANT • LATER LOSS OF LEARNED SKILLS • NEURONAL MEMORY SYSTEMS • CORTICAL GLUTAMATERGIC STORAGE • SUBCORTICAL • (acetylcholine, norepinephrine, serotonin) • CELLULAR PLASTIC PROCESSES • APP metabolism – early, broad cortical distribution • TAU hyperphosphorylation – late, focal effect, dementia related

12. NEUROPATHOLOGY OF AD • Senile plaques • beta-amyloid protein (? Primary problem) • Neurofibrillary tangles • hyper-phosphorylated tau (loss of synapses, dementia) • Neurotransmitter losses • Acetylcholine (Ach) – major loss of nicotinic receptors • Norepinephrine, serotonin, glutamate, GABAss • Inflammatory responses

13. New Neuropath Mechanisms • Amyloid PreProtein (APP - ch21) (early changes) • metabolism occurs on cholesterol “rafts” • Cholesterol transport by APOE (ch 19), provides, removes • alpha-secretase vs beta/gamma secretase metabolism • influence toward alpha-secretase by Acetylcholine • gamma-secretase (PreSenilin genes, ch14,1) • break down - Insulin Degrading Enzyme (ch10), etc. • prevention of fibril formation by melatonin • Tau hyperphosphorylation (relation to dementia) • glycogen-synthase-kinase (GSK) 3-beta • inhibition by Ach, lithium, valproic acid

14. Early Recognition of AD: Consensus Statement(AAGP, AGS, Alzheimer’s Association) • AD continues to be missed as diagnosis • AD is unrecognized and under-reported • patients do not realize • families tend to compensate • Effective treatment and management techniques are available • (AChEIs, memantine FDA approved) • Several other approaches are beneficial Small et al., JAMA, 1997

15. UNDERLYING CONTINUUM OF ALZHEIMER SEVERITY(unidimensional) • CROSS-SECTIONAL MEASURES • DEMENTIA SEVERITY (cognitive, ADL) • COGNITIVE SCALE SCORE • Z-SCORE • PRINCIPAL COMPONENT ANALYSIS • BRAIN ATROPHY, DYSFUNCTION • AUTOPSY MEASURES: plaques, tangles • TIME TO DEATH • LONGITUDINAL MEASUREMENT • TIME INTO THE DISEASE PROCESS • CONSIDERABLE HETEROGENEITY IN DISEASE PRESENTATION AND BRAIN DISTRIBUTION

16. MILD COGNITIVE IMPAIRMENT CRITERIA (Amer. Acad. Neurology)(Petersen et al., 2001 – Neurology 56:1133) • Memory complaint, preferably corroborated by an informant • Objective memory impairment • Normal general cognitive function • Intact activities of daily living • Not demented - Earlier descriptions by: Jonker, Hooyer, 1990 Flicker, Ferris, Reisberg, 1991 Zaudig, 1992

17. MILD COGNITIVE IMPAIRMENT ISSUES IN DEFINITION(Petersen et al., 2001 – Neurology 56:1133)

18. Age-Associated Memory ImpairmentvsMild Cognitive Impairment • Memory declines with age – need to consider relative to APOE genotype! • Age - related memory decline corresponds with atrophy of the hippocampus • Older individuals remember more complex items and relationships • Older individuals are slower to respond • Memory problems predispose to development of Alzheimer’s disease • Thus --- screening for MCI / early AD must consider age! • And should consider APOE genotype!

19. ALZHEIMER’S DISEASE COURSE AAMI / MCI/ early AD -- DEMENTIA Ashford et al., 1995

20. Yesavavage et al., 2002 Markov Chain model

21. Dementia Assessment History Of The Development Of The Dementia • Ask the Patient What Problem Has Brought Him to See You • Ask the Family, Companion about the Problem • Specifically Ask about Memory Problems • Ask about the First Symptoms • Enquire about Time of Onset • Ask about Any Unusual Events Around the Time of Onset, e.g., stress, trauma, surgery • Ask about Nature and Rate of Progression • Physical Examination • Neurological Examination • Laboratory Tests • Neuropsychological / Cognitive Assessment • Brain Scan

22. LABORATORY TESTS (routine) • BLOOD TESTS • electrolytes, liver, kidney function tests, glucose • thyroid function tests (T3, T4, FTI, TSH) • vitamin B12, folate (consider homocysteine) • complete blood count, ESR • VDRL, HIV (if indicated) • EKG (if indicated) • CHEST X-RAY (if indicated) • URINALYSIS • ANATOMICAL BRAIN SCAN – CT (cheaper ?), MRI • Scripps = $880 (min); Modesto = $6,600 (max)

23. SPECIAL LABORATORY TESTS • FUNCTIONAL BRAIN IMAGING (SPECT, PET – Medicare will pay special cases) • EEG, Evoked Potentials (P300) • REACTION TIMES (slowed in the elderly, especially when complex response is required • CSF ANALYSIS - ROUTINE STUDIES • ELEVATED TAU (future possible) • DECREASED AMYLOID (future possible) • HEAVY METAL SCREEN (24 hr urine) • GENOTYPING • APO-LIPOPROTEIN-E (for supporting dx) • AUTOSOMAL DOMINANT (young onset)

24. 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 DISFUNCTIONS

25. Justification for Brain Scan in Dementia Diagnosis • Differential Diagnosis: Tumor, Stroke, Subdural Hematoma, Normal Pressure Hydrocephalus, Encephalomalacia • Confirmation of atrophy pattern • Estimation of severity of brain atrophy • MRI shows T2 white matter changes • Periventricular, basal ganglia, focal vs confluent • These may indicate vascular pathology • SPECT, PET - estimation of regions of physiologic dysfunction, areas of infarction • Helps family to visualize problem • ---(NOT A SCREENING TEST!!!)

26. Need to Develop Better Screening and Early Assessment Tools • Genetic vulnerability testing (trait risk) • Vulnerability factors (education, occupation, head injury) • Early recognition (10 warning signs), ADLs • Screening tools (6th vital sign in elderly) • Positive diagnostic tests • CSF – tau levels elevated, amyloid levels low • Brain scan – PET – • NFTs: DDNP • Amyloid: Thioflavin-S, Congo-red derivatives • Mild Dementia severity assessments • Detecting early change over time • predicting progression, measuring rate

27. Need for a Brief Screening Test for Alzheimer’s Disease • Recent evidence of benefits of anti-cholinesterase agents in the treatment of mild Alzheimer’s disease • Improvement of cognition • Slowing of progression

28. Alzheimer Warning SignsTop TenAlzheimer Association 1. Recent memory loss affecting job 2. Difficulty performing familiar tasks 3. Problems with language 4. Disorientation to time or place 5. Poor or decreased judgment 6. Problems with abstract thinking 7. Misplacing things 8. Changes in mood or behavior 9. Changes in personality 10. Loss of initiative

29. CLINICAL TOOLS FOR COGNITIVE ASSESSMENT • MINI-MENTAL STATE EXAM • CLOCK DRAWING • ANIMAL NAMING (1 minute) • MATTIS DEMENTIA RATING SCALE • ALZHEIMER’S DISEASE ASSESSEMENT SCALE (ADAS) • ACTIVITIES OF DAILY LIVING • GLOBAL CLINICAL SCALE • CLINICAL DEMENTIA RATING SCALE • GLOBAL DETERIORATION SCALE / FAST

30. Time to Administer Available Short Screening Tests • MMSE 10 -- 15 min • Too long • 7-Minute Screen 7 – 10 min • Too complex • Clock Drawing Test 2 – 4 min • Not sensitive • Mini-cog 3 – 5 min • Complex scoring, unclear adequacy • Memory Impairment Screen 4 min • Need for slightly shorter, easier test • (a suitably accurate test that takes less than 2 minutes is not available)

31. MMSE items Mini-Mental State Exam items

33. JW Ashford, MD PhD, 2001

35. 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

36. Mendiondo et al., 2004 JW Ashford, MD PhD, 2001

37. JW Ashford, MD PhD, 2003

38. CONCLUSIONS on the BAS • A single cut-off score provides reasonable sensitivity and specificity for the diagnosis of AD within 2 – 3 minutes • Two cut-off points divide the population into 3 tiers • the first cut-off indicates a low likelihood of dementia • the second indicates a high likelihood of dementia • the remaining group falls into a ‘gray area’ in need of closer scrutiny, follow-up, and more extensive testing • A suitably short screen can be administered yearly to individuals over 60 y/o as a 6th vital sign • Next direction – use of IRT to locate level of impairment

39. Dementia Screening Test Requirements • Need test to screen patients for Alzheimer’s disease • Test needs to be on multiple platforms: • Doctor’s offices • Best if computerized for rapid, objective assessment • World-Wide Web – based testing, • CD-distribution • KIOSK administration – drug stores, shopping malls • Test needs to be very brief (about 1-minute) • Multiple test forms needed so it can be repeated often(quarterly) • Screening should be done yearly after age 50, and repeated every 3 months for individuals over 65 years of age or with concerns • Any change over time needs to be detected • The test cost should be nominal

40. MEMTRAX - Memory Test(to detect AD onset) • New test to screen patients for AD: • World-Wide Web – based testing, • CD-distribution • KIOSK administration • Determine level of ability / impairment • Test takes about 1-minute • Test can be repeated often (e.g., quarterly) • Any change over time can be detected • Free test is at: www.medafile.com

41. Issues in Screening • ROC analysis provides independent values for how the screening test values affect the normal and patient populations, then plots their relationship with respect to each other (specificity vs sensitivity respectively) – data must be derived from the represented population!!! • The value of the test must be calculated with respect to the risk of the disease, in the specific population to which it is being applied • Risk is affected by age, genotype, many other factors • Accounting for a priori probability is Bayesian analysis • The cost of the applying the test and the costs of false positive and false negative results as well as the benefits of correct positive and negative results must be assessed • Alzheimer’s disease is not a dichotomous diagnosis in early stages, but a continuum, which would be better assessed with a probabilistic statement, that would be better calculated from Item Response Theory • Item Response Theory and Factor Analysis allow combination of many test component items Kraemer, 1992; Ashford & Schmitt, 2001

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

43. Testing: What happens with testing? Total Population P’ P AD No AD Se Se’ Sp’ Sp Unnecessary intervention OK No effective intervention Effective intervention $ Testing $Testing $ Testing $ Testing $ Intervention $ Intervention Iatragenic Damage? Clinical Wash Clinical Wash Clinical Gain Major(?) Loss Minor (?) Loss Minor(?) Loss Major(?) Gain Some gain Helena Kraemer, 2003

44. Cost – Benefit Calculation • I = incidence P = Total Population • X = cost of test, time to take (subject, ? Tester) • Se = sensitivity of test = 1- False negative (Fn) • Sp = specificity of test = 1- False positive (Fp) • Cost: • Total cost of test = P*X • Fp = $1000 * P * (1-I) * (1-Sp) (+false hope) • Tn = 0 (real peace of mind) • Fn = false peace of mind • Tp = (-$49,000 * P * I * Se) => $50,000 = NH cost/1year • Avg Person Benefit= 49000*I*Se -X -1000*(1-I)*(1-Sp)

45. JW Ashford, MD PhD, 2003

46. Cost-Benefit Analysis per IndividualCOST: brain scan - $1000, CSF - $100, Computer memory test - $10Benefit: $50,000 approximate savings by nursing home placement delay

47. APO-E genotype and AD risk46 Million in US > 60 y/o //// 4 Million have AD(data from Saunders et al., 1993; Farrer et al., 1997) JW Ashford, MD PhD, 2003

48. J. W. Ashford, 2004

49. J. W. Ashford, 2004

50. Raber, Huang, Ashford, 2004, Neurobiol Aging. 25:641-650