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J. Wesson Ashford, M.D., Ph.D. UNIVERSITY OF KENTUCKY

Recent Advances in Alzheimer’s Disease - Understanding Neuropath - Evaluation - New Treatments - Early Detection. J. Wesson Ashford, M.D., Ph.D. UNIVERSITY OF KENTUCKY Depts. Of Psychiatry, Neurology, Sanders-Brown Center on Aging Veterans Affairs Medical Center September 24, 2002

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J. Wesson Ashford, M.D., Ph.D. UNIVERSITY OF KENTUCKY

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  1. Recent Advances inAlzheimer’s Disease- Understanding Neuropath- Evaluation- New Treatments- Early Detection J. Wesson Ashford, M.D., Ph.D. UNIVERSITY OF KENTUCKY Depts. Of Psychiatry, Neurology, Sanders-Brown Center on Aging Veterans Affairs Medical Center September 24, 2002 Slides at: www.medafile.com/ascr924.ppt (some slides removed for space reduction)

  2. General Support Bill Markesbery David Wekstein Mark Mattson Cathie Cool Alzheimer Neuropath Jim Geddes Natalie Sultanian Brief Screening Fred Schmitt Marta Mendiondo Dick Kryscio Brain Imaging Wei-Jen Shih Gary Small (UCLA) David Kuhl (U.Mich) Genetic Mark Kindy (MUSC) Wei-Jen Shih Bahar Aleem Doug Tsanatos Leah Cobb Jim Mortimar (USF) Cholinesterase Rx Lissy Jarvik (UCLA) Collaborations

  3. DEMENTIA DEFINITION • Multiple Cognitive Deficits that include: • Memory dysfunction (especially new learning) • a prominent early symptom • at least one additional cognitive deficit: • (aphasia, apraxia, agnosia, or executive dysfunction) • Cognitive disturbances must be 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 1. Alzheimer Disease (pure ~40%, + mixed~70%) 2. Vascular Disease, MID 5-20% 3. Drugs, Depression, Delirium 4. Ethanol 5-15% 5. Medical / Metabolic Systems 6. Endocrine (thyroid, diabetes), Ears, Eyes, Envir 7. Neurologic (other primary degenerations, etc.) 8. Tumor, Toxin, Trauma 9. Infection, Idiopathic, Immunologic 10. Amnesia, Autoimmune, Apnea, AAMI

  5. DIAGNOSTIC CRITERIA FOR DEMENTIA OF THE ALZHEIMER TYPE(DSM-IV, APA, 1994) A. DEVELOPMENT OF MULTIPLE COGNITIVE DEFICITS 1. MEMORY IMPAIRMENT 2, OTHER COGNITIVE IMPAIRMENT B. THESE IMPAIRMENTS CAUSE DYSFUNCTION IN IN SOCIAL OR OCCUPATIONAL ACTIVITIES C. COURSE SHOWS GRADUAL ONSET AND DECLINE D. DEFICITS ARE NOT DUE TO: 1. OTHER CNS CONDITIONS 2. SUBSTANCE INDUCED CONDITIONS F. DO NOT OCCUR EXCLUSIVELY DURING DELIRIUM G. 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. ECONOMIC IMPACT OF AD • 2 million AD patients in nursing homes • Projection to Kentucky – 22,000 current cases • Nursing homes cost - $120 to $160 per day • Annualized cost of nursing homes ranges from $40 to $70,000 per year • Care of AD patients costs $80 billion per year • 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 Kentucky – $1.5 billion annually!

  8. BIOPSYCHOSOCIAL SYSTEMS AFFECTED BY ADNEUROPLASTIC MECHANISMS AFFECTED AT ALL LEVELS (Ashford & Jarvik, 1985; Ashford, Mattson, Kumar, 1998) • 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

  9. Relative Risk Factors for Alzheimer’s Disease • Family history of dementia 3.5 (2.6 - 4.6) • Family history - Downs 2.7 (1.2 - 5.7) • Family history - Parkinson’s 2.4 (1.0 - 5.8) • Maternal age > 40 years 1.7 (1.0 - 2.9) • Head trauma (with LOC) 1.8 (1.3 - 2.7) • History of depression 1.8 (1.3 - 2.7) • History of hypothyroidism 2.3 (1.0 - 5.4) • History of severe headache 0.7 (0.5 - 1.0) • History of “statin” use 0.3 • NSAID use 0.2 (0.05 – 0.83) • Use of NSAIDs, ASA, H2-blcks 0.09 Roca, 1994; ‘t Veld et al., 2001, Breitner et al., 1998, Wolozin et al., 2000

  10. Genes and Alzheimer’s disease(60% - 80 % of causation)(all known genes relate to bamyloid) • Familial AD (onset < 60 y/o) (<5%) • Presenilin I, II (ch 14, 1) • APP (ch 21) • Non-familial (late onset) • APOE • Clinical studies suggest 40 – 50% due to e4 • Population studies suggest 10 – 20% cause • Evolution over last 300,000 to 200,000 years • At least 20 other genes

  11. 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)

  12. Age at Onsetage of onset for e3/3 vs e4/4, p<0.02; for e3/3 vs e3/4, p<0.05(in preparation, Ashford, Kindy, Shih, Aleem, Cobb, Tsanatos, Cool)

  13. ONLY SUCCESSFUL INTERVENTION • CHOLINESTERASE INHIBITION • (1st double blind study – Ashford, Soldinger, Schaefer, Cochran, Jarvik, 1981) • Presumably increases acetylcholine at functional synapses • Improvement in cognition (? 6 months better) • Improvement in function (ADLs, variable) • Improvement in behavior (? basal ganglia) • Slowing of disease course • Delays nursing home placement (by 2 years, maybe more if early rx) • Not yet adequately characterized prospectively • Proposed need for early intervention

  14. 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., AChEases may work very well in mild patients, but not in nursing home patients • 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? • do early, chronic benefits suggest prevention?

  15. 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 (necessary) • 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 • Ask about the current level of difficulites • Medical History • Family History (of dementia) • Physical Examination • Neurological Examination • Psychological Exam (MMSE-extended) • and animal naming in 1 min, clock-draw, cube

  16. 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

  17. SPECIAL LABORATORY TESTS • FUNCTIONAL BRAIN IMAGING(SPECT, PET) • EEG, Evoked Potentials (P300) • REACTION TIMES (slowed in the elderly, especially when complex response is required, e.g., driving) • 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)

  18. 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

  19. BEHAVIORAL PROBLEMS IN DEMENTIA PATIENTS • MOOD DISORDERS – depression – early in AD • PSYCHOTIC DISORDERS • Particularly paranoia, e.g, people stealing things • INAPPROPRIATE BEHAVIORS (sexual • AGGRESSION: verbal, physical • PURPOSELESS ACTIVITY: verbal, motor • MEAL TIME BEHAVIORS • SLEEP DISORDERS

  20. Age-Associated Memory Impairment(loss of memory without loss of social function)vsMild Cognitive Impairment • Memory declines with age • At what point is memory abnormal? • How does age affect consideration of abnormality? • 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

  21. 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 • Specific treatments now available, may delay nursing home placement longer if started earlier

  22. AD is Underdiagnosed • Early Alzheimer’s disease is subtle – it is easy for family members and physicians 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 • Undiagnosed AD patients often face avoidable social, financial, and medical problems • Early diagnosis and appropriate intervention may lessen disease burden • No definitive laboratory test for diagnosing AD exists Evans DA. Milbank Quarterly. 1990; 68:267-289

  23. 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 • Recent evidence of benefits of anti-cholinesterase agents in the treatment of mild Alzheimer’s disease • Improvement of cognition • Slowing of progression • Effective management techniques are available Small et al., JAMA, 1997

  24. Early Detection Approachespossible considerations • Genetic vulnerability testing • Early recognition (10 warning signs – Alz Assoc) • Screening tools (6th vital sign in elderly) • Regular memory check-ups • BLT/Ashford Memory Test – on the web • Early positive diagnostic tests • CSF – ?tau levels elevated, ?amyloid levels low • ?Brain scan – PET – DDNP, Congo-red derivatives

  25. 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

  26. 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

  27. CONCLUSIONS on the BAS • A single cut-off score provides reasonable sensitivity and specificity for the diagnosis of AD • 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

  28. A-Screen (see www.medafile.com) • Repeat these three words: “apple, table, penny”. • So you will remember these words, repeat them again, twice. • What is today’s date? • 1 point if within 2 days. • “Name as many animals as you can in 30 seconds, GO!” • 1 point for naming 10 animals • “What were the 3 words I asked you to repeat?” (no prompts) • 1 for each word, • TOTAL (max = 5) • A score of 4 or 5 indicate a very low likelihood of dementia. • A score of 2 or 3 suggests that more testing is needed. • A score of 0 or 1 indicate a very high likelihood of dementia. • (palm-pilot administration – www.medafile.com) • If score of 2 or 3: • Spell World Backwards • Draw a Clock (gives some impression of visuospatial problems) • If continued difficulties, ask questions about ADLs, depression

  29. BLT/Ashford Memory Test • New test to screen patients for Alzheimer’s disease using the World-Wide Web – based testing • Test only takes 1-minute • Test can be repeated often (quarterly) • Any change over time can be detected • Test is at: www.ibaglobal.com/BLT • For info, see: www.medafile.com

  30. THE TOP TEN TREATMENTSFOR PREVENTING ALZHEIMER’S DISEASEwww.medafile.com • Take your blood pressure regularly, keep systolic pressure always less than 130. • Watch your cholesterol; if your cholesterol is elevated, get treated with “statin” drugs and be sure your cholesterol is fully controlled. • Exercise your body and mind regularly. Physical exercise best 10-30 mins after each meal for 10-30 mins (3x/d). • Wear your seat-belt.  Wear a helmet when you are riding a bicycle or participating in any activity where you might hit your head (head injury is associated with Alzheimer’s disease). • If you have diabetes, make sure that your blood sugar is optimally controlled. • Consult your doctor about  arthritis pain (treat with ibuprofen, sulindac, or indomethacin). • Take your vitamins daily (folate - 400mcg, B12 - 25mcg, C - 250 mg, and E - 400iu's). • Discuss sex-hormone replacement therapy with your physician (only women for now). • If you have difficulty getting to sleep, consider trying 6 milligrams of melatonin at bedtime. • If you have significant memory difficulty, talk to your doctor about cholinesterase inhibitors. See - latest version in Long Island Alzheimer Foundtion Newsletter, 7/2002

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