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

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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 Alzheimers Center
• VAMC, Palo Alto, California
• Slides at www.medafile.com/MCIscra.ppt

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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

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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

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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

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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

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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

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Differential Diagnosis Top Ten (commonly used
mnemonic device AVDEMENTIA)

• 1. Alzheimer Disease (pure 40,
  mixed70)
• 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

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Alzheimers 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
• Alzheimers disease is a pathological condition
• Dementia is a clinical condition frequently
  caused by AD
• The AD dementia has some characteristics and some
  heterogeneity

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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

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MILD COGNITIVE IMPAIRMENT CRITERIA (Amer.
Acad. Neurology)(Petersen et al., 2001
Neurology 561133)

• 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

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MILD COGNITIVE IMPAIRMENT ISSUES IN
DEFINITION(Petersen et al., 2001 Neurology
561133)
Study Mean Age Criteria Annual conversion rate to AD
Mayo 81 MCI 12
Toronto 74 Memory Impairment 14
Columbia 66 Questionable dementia 15
MGH 72 CDR 0.5 6
Seattle 74 Isolated memory loss 12
NYU 71 GDS 3 25
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ALZHEIMERS DISEASE
AAMI / MCI DEMENTIA
Ashford et al., 1995
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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
  Alzheimers disease
• Thus --- screening for MCI / early AD must
  consider age!
• And should consider APOE genotype!

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Early Recognition of AD Consensus
Statement(AAGP, AGS, Alzheimers 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
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AD is Underdiagnosed

• Early Alzheimers 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 68267-289
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AD Can Be Readily Diagnosed
McKhann G et al. Neurology. 198434939-944.
Kazee AM et al. Alzheimer Dis Assoc Disord.
19937152-164.

• A diagnosis of Alzheimers 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

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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

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RELATIVE RISK FACTORS FOR ALZHEIMERS DISEASE

• Family history of dementia 3.5 (2.6 - 4.6)
• Family history Downs 2.7 (1.2 - 5.7)
• Family history - Parkinsons 2.4 (1.0 - 5.8)
• Maternal age gt 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, tVeldt, 2002
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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

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BRIEF CLINICAL TOOLS FOR COGNITIVE ASSESSMENT

• MINI-MENTAL STATE EXAM
• CLOCK DRAWING
• ANIMAL NAMING (1 minute)
• MATTIS DEMENTIA RATING SCALE
• ALZHEIMERS DISEASE ASSESSEMENT
  SCALE (ADAS)
• ACTIVITIES OF DAILY LIVING
• GLOBAL CLINICAL SCALE
• CLINICAL DEMENTIA RATING SCALE
• GLOBAL DETERIORATION SCALE / FAST

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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

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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

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Genes and Alzheimers disease(60 - 80 of
causation)(all known genes relate to bamyloid)

• Familial AD (onset lt 60 y/o) (lt5)
• 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

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APO-E genotype and AD risk46 Million in US gt 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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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

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www.census.gov
Total 281,421,906 gt60 45,809,291 gt65
35,003,844 gt85 4,251,678 gt100
62,545
JW Ashford, MD PhD, 2003
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www.cdc.gov
JW Ashford, MD PhD, 2003
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JW Ashford, MD PhD, 2003
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JW Ashford, MD PhD, 2003
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JW Ashford, MD PhD, 2003
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(Incidence for a to a 1 year)
JW Ashford, MD PhD, 2003
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JW Ashford, MD PhD, 2003
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JW Ashford, MD PhD, 2000
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JW Ashford, MD PhD, 2003
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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)
• Patients and Familys right to know
• Specific treatments now available
• May slow underlying disease process
• May delay nursing home placement longer if
  started earlier

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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

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Need for a Brief Screening Test for Alzheimers
Disease

• Recent evidence of benefits of anti-cholinesterase
  agents in the treatment of mild Alzheimers
  disease
• Improvement of cognition
• Slowing of progression

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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

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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)

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JW Ashford, MD PhD, 2001
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Brief Alzheimer Screen (BAS)

• Repeat these three words apple, table, penny.
• So you will remember these words, repeat them
  again.
• What is todays 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

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Mendiondo et al., 2004
JW Ashford, MD PhD, 2001
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JW Ashford, MD PhD, 2003
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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

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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