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Screening for Mild Cognitive Impairment and Alzheimer's Disease: Relevance of Age and APOE genotype

Screening for Mild Cognitive Impairment and Alzheimer's Disease: Relevance of Age and APOE genotype. Memory & Aging Center Team University of California, San Francisco May 21, 2004 J. Wesson Ashford, M.D., Ph.D. Stanford / VA Alzheimer’s Center VAMC, Palo Alto, California

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Screening for Mild Cognitive Impairment and Alzheimer's Disease: Relevance of Age and APOE genotype

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  1. Screening for Mild Cognitive Impairment and Alzheimer's Disease: Relevance of Age and APOE genotype Memory & Aging Center Team University of California, San Francisco May 21, 2004 J. Wesson Ashford, M.D., Ph.D. Stanford / VA Alzheimer’s Center VAMC, Palo Alto, California Slides at: www.medafile.com/MCIscra.ppt

  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. 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. ARE NOT DUE TO OTHER PSYCHIATRIC DISORDER

  4. 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

  5. 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

  6. 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

  7. Differential Diagnosis: Top Ten (commonly used mnemonic device: AVDEMENTIA) 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, Environ. 7. Neurologic (other primary degenerations, etc.) 8. Tumor, Toxin, Trauma 9. Infection, Idiopathic, Immunologic • Amnesia, Autoimmune, Apnea, AAMI • VA – consider PTSD, Gulf War Syndrome

  8. 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

  9. 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

  10. 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

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

  12. ALZHEIMER’S DISEASE AAMI / MCI DEMENTIA Ashford et al., 1995

  13. 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!

  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 realized • families tend to compensate • Effective treatment and management techniques are available • (AChEIs FDA approved) • Several other approaches are beneficial Small et al., JAMA, 1997

  15. 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

  16. AD Can Be Readily Diagnosed McKhann G et al. Neurology. 1984;34:939-944. Kazee AM et al. Alzheimer Dis Assoc Disord. 1993;7:152-164. • 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

  17. 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

  18. 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) • NSAID use or statin use 0.2 (0.05 – 0.83) Roca, 1994, t’Veldt, 2002

  19. 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

  20. BRIEF 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

  21. 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

  22. Etiology • Age (initial genesis vs response to stress) • Bigger factor than for mortality (a = 5 yrs vs 7.5 or 8.2 yrs) • Degree of natural vulnerability of neuroplastic (memory) systems • Stressor response (pathology - vulnerability during activity of repair mechanisms): trauma (head injury), vascular (stroke), surgery, loss, grief, etc. • Genetics (neuroplasticity related - amyloid and cell membrane) • Familial, early onset: APP (21), PS (14, 1) (less than 5%) • Late onset: APOE e4 (ch19) (?50% - 90% of AD) • relation to brain cholesterol metabolism? – cell membranes • APOE e2 may be most protective • many other candidate genes • Relation to vascular factors, cholesterol, BP • Education (more reserve) • (? design – larger brain vs better development vs protection – wiser choices) • Environment - diet, exercise, smoking

  23. 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 • 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

  24. 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

  25. 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

  26. 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

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

  28. JW Ashford, MD PhD, 2003

  29. JW Ashford, MD PhD, 2003

  30. JW Ashford, MD PhD, 2003

  31. (Incidence for a to a + 1 year) JW Ashford, MD PhD, 2003

  32. JW Ashford, MD PhD, 2003

  33. JW Ashford, MD PhD, 2000

  34. JW Ashford, MD PhD, 2003

  35. 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 slow underlying disease process • May delay nursing home placement longer if started earlier

  36. Need for 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

  37. 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

  38. 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

  39. Available 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)

  40. JW Ashford, MD PhD, 2001

  41. 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

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

  43. JW Ashford, MD PhD, 2003

  44. 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

  45. BLT/Ashford 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 • Test is at: www.ibaglobal.com/BLT • For info, new tests, see: www.medafile.com, www.brainlane.net

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