ALZHEIMER’S DISEASE DIAGNOSIS and TREATMENT

1. ALZHEIMER’S DISEASEDIAGNOSIS and TREATMENT J. Wesson Ashford, M.D., Ph.D. Stanford / VA Alzheimer’s Center VAMC, Palo Alto, California San Francisco, California October 5, 2004 Slides at: www.medafile.com (Dr. Ashford’s lectures)

2. Alzheimer Issues • Definition of dementia, differential diagnosis • Epidemiology (why diagnosis is important) • Diagnosis of Alzheimer’s disease (how to) • Treatment options • The need to treat • The benefits of cholinesterase inhibitors • The advantage of galantamine (Reminyl)

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. Differential Diagnosis: Top Ten (commonly used 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

5. Diagnostic Criteria For Dementia Of The Alzheimer Type(DSM-IV, APA, 1994) • Multiple Cognitive Deficits 1. Memory Impairment 2. Other Cognitive Impairment B. Deficits Impair Social/Occupational • Course Shows Gradual Onset And Decline • Deficits Are Not Due to: 1. Other CNS Conditions 2. Substance Induced Conditions E. Do Not Occur Exclusively during Delirium F. Not Due to Another Psychiatric Disorder

6. PREVALENCE of AD • Estimated 4 million cases in US (2000) • (2000 - 46 million individuals over 60 y/o) • Estimated 500,000 new cases per year • Increase with age (prevalence) • 1% of 60 - 65 (10.7m) = 107,000 • 2% of 65 - 70 ( 9.4m) = 188,000 • 4% of 70 - 75 ( 8.7m) = 350,000 • 8% of 75 - 80 ( 7.4m) = 595,000 • 16% of 80 - 85 ( 5.0m) = 800,000

7. www.census.gov Total = 281,421,906 >60 = 45,809,291 >65 = 35,003,844 >85 = 4,251,678 >100= 62,545 JW Ashford, MD PhD, 2003

8. www.cdc.gov JW Ashford, MD PhD, 2003

9. JW Ashford, MD PhD, 2003

10. Mortality Equationst = age in yearsTd = time for mortality rate to doubleRo = mortality rate at time zeroalpha = ln(2) / Td • Mortality rate u(t) R = Ro x exp (alpha x t) • Survival curve s(t) S = exp ( - Ro/alpha x (exp (alpha x t) –1 )) • Number of deaths per year d(t) D = -ds/dt = ( Ro + alpha x ln (1/s(t) )) x s(t) = u(t) x s(t)

11. JW Ashford, MD PhD, 2003

12. JW Ashford, MD PhD, 2003

13. Genes and Alzheimer’s disease(60% - 80 % of causation) • Familial AD (onset < 60 y/o) (<5%) • all known autosomal dominant genes relate to b-amyloid • Presenilin I, II (ch 14, 1) • APP (ch 21) • Non-familial (late onset) • APOE • Clinical studies suggest 40 – 50% due to e4 • If e2 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 suspected of relating to AD Ashford & Mortimer, 2002, J. Alz. Dis. 4:1-9.

14. 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

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20. Reprinted with permission from Brumback, RA, Leech RW, J. Ohio State Med Assoc. 1994: 87, 103-111

21. ECONOMIC IMPACT OF AD • 2 million AD patients in nursing homes • Projection to California – 240,000 • Nursing homes cost - $120 to $160 per day • Annualized cost of nursing homes ranges • from $40,000 to $70,000 per year • Nursing Home Care of AD patients costs $80 billion per year • for life-time cost – about $175,000 per patient • The majority of patients live at home and are cared for by family and friends • With lost wages of patients and families plus costs for non-nursing home patients: • Total costs: $120 billion annually (Am J Publ Hlth) • Projection to California – $14.5 billion annually!

22. 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 • 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.

23. Patient initially diagnosed with AD AD Is Often Misdiagnosed Patient’s first diagnosis other than AD 35% 14% 14% No 72% 9% 7% 21% Yes 28% Dementia (not AD) Stroke No diagnosis Depression Normal aging Other Source: Consumer Health Sciences, LLC. Alzheimer’s Caregiver Project. 1999.

24. 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 • Undiagnosed AD patients often face avoidable social, financial, and medical problems • Early diagnosis and appropriate intervention may lessen disease burden • Early treatment may improve overall course substantially • 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

25. 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, Activities of Daily Living • Physical Examination • Neurological Examination • Neuropsychological Assessment • Routine Laboratory Tests • Brain Scan

26. LABORATORY TESTS (routine) • BLOOD TESTS • electrolytes, liver, kidney function tests, glucose • thyroid function tests (T3, T4, FTI, TSH) • vitamin B12, folate • complete blood count, ESR • VDRL, HIV (if indicated) • EKG (if indicated) • CHEST X-RAY (if indicated) • URINALYSIS • ANATOMICAL BRAIN SCAN – CT (cheapest), MRI

27. 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)

28. Why Diagnose AD Early? • Safety (driving, compliance, cooking, etc.) • Family stress and misunderstanding (blame, denial) • 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) • Patient’s and Family’s right to know • Promotes advocacy for research and treatment development • Specific treatments now available • May slow underlying disease process, the sooner the better • May delay nursing home placement longer if started earlier • May prevent conversion from Mild Cognitive Impairment to AD

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

30. 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) • Screening tools (6th vital sign in elderly) • Positive diagnostic tests • CSF – tau levels elevated, amyloid levels low • Brain scan – PET – DDNP, Congo-red derivatives • Mild Dementia severity assessments • Detecting early change over time • predicting progression, measuring rate

31. 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

32. Need for a Brief Screening Test for Dementia, 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 • Delay of conversion to diagnosis • How to get elderly, clinicians interested in screening for dementia • How to handle positive screens sensitively and efficiently • Doctors have been reluctant to diagnose Alzheimer’s disease because of the time required to explain the problem to the family and to coordinate treatment.

33. 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 et al., 2003)

34. Dementia Screening Test • 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 should be free

35. 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

36. FIRST SUCCESSFUL TREATMENT: • CHOLINESTERASE INHIBITION • (1st double blind study - Ashford et al., 1981) • Presumably increases acetylcholine at synapses • Improvement in cognition (? 6-12 months better) • Improvement in function (ADLs, variable) • Improvement in behavior (? basal ganglia) • Slowing of disease course • Treatment delays nursing home placement • There is loss of benefit with delay of treatment • Need to consider early intervention

37. 904,600 Treated* Treatment of Alzheimer’s Disease 5 4,523,100 4 3 Patients (millions) 2,261,600 2 1 543,800 0 Prevalence Diagnosed Treated with AChEIs * Any drug treatment, not limited to acetylcholinesterase inhibitors. Source: Decision Resources, March 2000.

39. Cholinergic Changes in AD • The most prominent neurotransmitter abnormalities are cholinergic • Reduced activity of choline acetyltransferase (synthesis of acetylcholine)1 • Reduced number of cholinergic neurons in late AD (particularly in basal forebrain)2 • Selective loss of nicotinic receptor subtypes in hippocampus and cortex1,3 1. Bartus RT et al. Science. 1982;217:408-414. 2. Whitehouse PJ et al. Science. 1982;215:1237-1239. 3. Guan ZZ et al. J Neurochem. 2000;74:237-243.

41. intracellular extra cellular Lipid raft Formed by cholesterol Transported by ApoE From macroglia Stimulated by acetylcholine through muscarinic receptor Favored when lipid raft too large NEXIN ? To establish new connections ? Free-radical generator ? To remove old synapses JW Ashford, MD PhD, 2003

42. Need to divide effects of drug treatment into 2 groups • Acute effects of treatment • e.g., 3 months • are the acute effects related to severity? • e.g., do AChEases may work very well in mild patients, and in nursing home patients? • do these medications work in very early phases of the disease? • Chronic effects of treatment • rate of change, after acute effects • are the effects on rate of change related to severity • are very mild patients improved over time by AChEases? • are new AChEase molecules created which require dose increases? • does sudden discontinuation lead to catastrophic decline? • do early, chronic benefits suggest prevention?

44. ExelonImproves Cognitive Function: ADAS-Cog mean change from baseline† Placebo 1–4 mg/day Exelon® 6–12 mg/day Exelon® Improvement 2 1 0 –1 –2 –3 –4 –5 * * * 12 18 26 Weeks 4.94 Mean change inADAS-Cog score * * †B352 OC study analysis; *p<0.05 vs placebo Worsening Corey-Bloom J et al, for the ENA 713 B352 Study Group. Int J Geriatr Psychopharmacol. 1998;1:55-65.

45. Exelon Longterm Effects on Cognition:Mean Change in ADAS-Cog from Baseline at Week 52 * * * * * * * * * All Patients Taking Exelon B352 Patients in B353 (OC) at Week 52 * p< 0.05 vs projected placebo Sohn et al. In: Proceedings of the CPNP. April 2000.

48. REMINYL® (galantamine HBr) Pooled Analysis: Change in ADAS-cog Scores at 6 and 12 Months Advanced Moderate AD Patients With Baseline ADAS-cog Scores >30 –8 –6 –4 –2 0 2 4 6 8 10 12 * * * † † ‡ Mean (SE) Change in ADAS-cog From Baseline Improvement REMINYL 24 mg/d Placebo from RCTs Historical placebo Baseline 1 3 6 9 12 Time (mo) *p<0.001 vs placebo. †p<0.001 vs historical placebo. ‡Not significant vs baseline. Baseline ADAS-cog score: 37.3 (REMINYL 24 mg/d) vs 37.4 (placebo). Adapted from Blesa R et al. Dement Geriatr Cogn Discord. 2003;15:79-87.