1. Screening Elderly Clinic Patients for 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)www.medafile.com

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. 7.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 Disease versus Dementia –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!! Donepezil 1 38 weeks Rivastigmine 2 38–42 weeks Galantamine 3 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 AD NEUROPLASTIC 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) 1.Memory complaint, preferably corroborated by an informant 2.Objective memory impairment 3.Normal general cognitive function 4.Intact activities of daily living 5.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) StudyMean Age CriteriaAnnual conversion rate to AD % Mayo 81MCI 12 Toronto 74Memory Impairment 14 Columbia 66Questionable dementia 15 MGH 72CDR 0.5 6 Seattle 74Isolated memory loss 12 NYU 71GDS 3 25

18. Age-Associated Memory Impairment vs Mild 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. AAMI / MCI/ early AD -- DEMENTIA ALZHEIMER’S DISEASE COURSE 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 Signs Top Ten Alzheimer 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. Mini-Mental State Exam items MMSE 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. JW Ashford, MD PhD, 2001 Mendiondo et al., 2004

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 6 th 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.comwww.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 Have AD No effective intervention Do not have AD P’ Helena Kraemer, 2003

43. Testing: What happens with testing? Total Population No AD AD Unnecessary intervention OKNo effective interventionEffective intervention $ Testing$Testing$ Testing $ Testing $ Intervention Iatragenic Damage?Clinical WashClinical Wash Clinical Gain Major(?) LossMinor (?) LossMinor(?) Loss Major(?) Gain Some gain PP’ Se Se’ SpSp’ 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 Individual COST: brain scan - $1000, CSF - $100, Computer memory test - $10 Benefit: $50,000 approximate savings by nursing home placement delay Sp10.99 0.9 cost incidence (age) Se10.990.90.80.90.8 100.001623928.5224.119.2-65.8-70.7 100.00573235222.620117611186.5 100.0176480465.2421372332283 100.0589244024062186194121001855 1000.00162-51-61.5-65.9-71-156-161 1000.00573145132.611186.121-3.5 1000.0176390375.2331282242193 1000.0589235023162096185120101765 10000.00162-951-961-966-971-1056-1061 10000.00573-755-767-789-814-879-904 10000.0176-510-525-569-618-658-707 10000.05891450141611969511110865

47. APO-E genotype and AD risk 46 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

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

51. Genes and Alzheimer’s disease (60% - 80 % of causation) (all known familial genes relate to  amyloid) Familial AD (onset < 60 y/o) (<5%) –Presenilin I, II (ch 14, 1) –APP (ch 21) Non-familial (late onset) –APOE (apo-lipo-protein-E) Clinical studies suggest 40 – 50% due to  4 If  is considered, may be 95% of causation Population studies suggest > 10 – 20% cause Evolution over last 300,000 to 200,000 years –At least 20 other genes

52. Are we ready to do genetic testing to predict AD? The family members want it –They consider recommendations against genetic testing to be “paternalistic” Family members can make more powerful financial decisions based on this knowledge than the relevance of insurance companies implementing changes in actuarial calculations Those at risk can seek more frequent testing –This is the best opportunity for early recognition Those at risk will be better advocates for research Specific preventive treatments can be developed for each genetic factor

53. RELATIVE RISK FACTORS FOR ALZHEIMER’S DISEASE Family history of dementia3.5 (2.6 - 4.6) Family history – Downs2.7 (1.2 - 5.7) Family history - Parkinson’s2.4 (1.0 - 5.8) 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) NSAID use or statin use0.2 (0.05 – 0.83) Roca, 1994, t’Veldt, 2002

54. Summary Requirements for Screening Test Evaluation Sensitivity, specificity for the population to which test is to be applied – values change with level of disease being screened Portion of population at risk –Risks according to age, gender, genotype, family hx, education, etc. Cost of test -$1, $10, $100, $1000 –Need brief screen to replace MMSE (ASAP) - $10 Medicare allowance Costs of false positive, false negative tests Benefits of true positive, true negative –Longevity is increasing over time, needs to be factored in. Cascaded tests – preliminary screen, confirmatory exam Longitudinal tests may provide much more reliable information Different tests for clinic (cascaded), research (outcomes) –Clinic: brief screen, brain scan; Research: CSF - is disease stopped? Benefit to society relative to other societal needs.

55. Future Directions for Alzheimer’s Disease Need more precise assessment of cognition from normal to severe dementia Need to use Item Response Theory and Computerized Adaptive Testing Screening tests need to be widely used, that implement computer administration Test analyses need to be risk/benefit-related Better tests will lead to better treatments Better treatments will lead to prevention

56. THE TOP TEN TREATMENTS FOR PREVENTING ALZHEIMER’S DISEASE www.medafile.com 1. Take blood pressure regularly, assure systolic pressure is always < 130. 2. Watch your cholesterol; if cholesterol is above 200, talk to your clinician about treatment. Consider “statin” medications. Increase dietary intake of omega-3-fatty acids. 3. Exercise your body, mind, and spirit regularly. Physical exercise best 10-30 mins after each meal for 10-30 minutes, 3 times per day. Maximize your education. Do mental puzzles (like crossword puzzles). Stay active. 4. Physically protect your brain. Wear your car seat-belt. Wear a helmet when riding a bicycle or participating in activity where you might hit your head. 5. Decrease your risk of type II diabetes. Monitor your fasting blood sugar yearly. Keep your BMI (Basal Metabolic Index) in the optimal range (19-25) by controlling food intake and exercise. If you have diabetes, make sure that blood sugar is optimally controlled. 1. 6. Consult your clinician about pains (treat arthritis with ibuprofen, sulindac, or indocin). 7. Take your vitamins daily (folate - 400mcg, B12 - 25mcg, C - 250 mg, and E - 200iu's). Check yearly that your homocysteine levels are low and no signs of B12 deficiency. 8. Discuss sex-hormone replacement therapy with your clinician. 9. For sleep difficulty, try 3 - 6 milligrams of melatonin at bedtime. 1. 10. Monitor your memory regularly. If you have significant difficulty with your memory, talk to your clinician. Consider therapy with cholinesterase inhibitors and memantine.

57. Future Developments to Prevent AD Anti-cholinesterase treatments to prevent AD –May need to be started early at very low doses NMDA receptor modulators (memantine) –Early treatment may prevent neuroplastic neuron damage Immunologic therapy to eliminate beta-amyloid –Preliminary trials appear to remove deposits Prevention of beta-amyloid-42 –Certain NSAIDs may prevent formation Medication to prevent tau hyperphosphorylation –Lithium and valproic acid may be helpful Specific treatments for APOE modulation –This may be related to statin effects