MCIdif ppt DIAGNOSIS OF AZLHEIMER S DISEASE amnesia by mikesanye

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									MILD COGNITIVE IMPAIRMENT
     DIFFERENTIAL DIAGNOSIS



  J. Wesson Ashford, M.D., Ph.D.
 Stanford / VA Alzheimer’s Center
    VAMC, Palo Alto, California

          May 14, 2004
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
          MILD COGNITIVE IMPAIRMENT
             ISSUES IN DEFINITION
            (Petersen et al., 2001 – Neurology 56:1133)

Study       Mean     Criteria                       Annual
            Age                                     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
             100%

             90%

             80%

             70%
Percentage




             60%
                                                                                    AD
             50%                                                                    MCI
             40%                                                                    Non-Affected
             30%

             20%

             10%

              0%
                60

                     62

                          64

                               66

                                    68

                                         70

                                              72

                                                   74

                                                        76

                                                             78

                                                                  80

                                                                       82

                                                                            84
Markov Chain model                             Age                      Yesavavage et al., 2002
                                ALZHEIMER’S DISEASE

                             Estimate MMSE as a function of time

             30
             25
MMSE score




             20
             15
             10
             5
             0
                  -10   -8      -6   -4    -2     0     2      4    6         8       10
                                     Estimated years into illness

                             AAMI / MCI               DEMENTIA
                                                                        Ashford et al., 1995
      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!
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
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
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
10.   Amnesia, Autoimmune, Apnea, AAMI
11.   VA – consider PTSD, Gulf War Syndrome
         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
 Alzheimer’s Disease versus
         Dementia

– 50 - 70% of dementias are AD
– Probable AD - 30% of cases, 90% correct
      – 20% have other contributing diagnoses
– Possible AD - 40% of cases, 70% correct
      – 40% have other contributing diagnoses
– Unlikely AD - 30% of cases, 30% are AD
      – 80% have other contributing diagnoses
         Vascular Dementia
                 (DSM-IV - APA, 1994)

A. Multiple Cogntive Impairments
  1. Memory Impairment
  2. Other Cognitive Disturbances
B. Deficits Impair Social/Occupational
C. Focal Neurological Signs and Symptoms or
   Laboratory Evidence Indicating
   Cerebrovascular Disease Etiologically Related
   to the Deficits
D. Not Due to Delirium
Factors Associated with Multi-infarct Dementia

 • History of stroke (especially in Nursing Home)
    – Followed by onset of dementia within 3 months
 • Abrupt onset, Step-wise deterioration
 • Cardiovascular disease - HTD, ASCVD, & Atrial Fib
 • Depression (left anterior strokes), personality change
 • More gait problems than in AD
 • MRI evidence of T2 changes (?? Binswanger’s disease)
    – Basal ganglia, putamen
    – Periventricular white matter
 • SPECT / PET show focal areas of dysfunction
 • Neuropsychological dysfunctions are patchy
        VASCULAR DEMENTIA CHANGE ON
         THE MINI-MENTAL STATE EXAM
                  OVERTIME

        30                   < event
SCORE




        20                         < event
        10                               < event
         0
             -5             0           5           10
                  AVERAGE TIME OF ILLNESS (years)
        Post-Cardiac Surgery
• 53% post-surgical confusion at discharge (delirium)
• 42% impaired 5 years later (dementia)
• May be related to anoxic brain injury, apnea
• May be related to narcotic/other medication
• May occur in those patients who would have
      developed dementia anyway (? genetic risk)
• Cardio-vascular disease and stress may start
      Alzheimer pathology
• Any surgery may have a similar effect related to
  peri-op or post-op anoxia or vascular stress

                                    Newman et al., 2001, NEJM
         Drug Interactions
• Anticholinergics: amitriptyline, atropine,
  benztropine, scopolamine, hyoscyamine,
  oxybutynin, diphenhydramine,
  chlorpheniramine, many anti-histaminics
  – May aggravate Alzheimer pathology
• GABA agonists: benzodiazepines,
  barbiturates, ethanol, anti-convulsants
• Beta-blockers: propranolol
• Dopaminergics: l-dopa, alpha-methyl-dopa
• Narcotics: may contribute to dementia
           Drug Toxicity
• Anti-cholinergic
  – Peripheral: blurred vision, dry mouth,
    constipation, urinary obstruction
  – Central: confusion, memory encoding
    block
• Gaba-agonist:
  – Muscle relaxant, anti-convulsant,
    sedative, anti-anxiety, amnesic, confusion
• Medication induced electrolyte
  imbalance
  – Confusion (watch for in nursing home)
              Depression
• Onset: rapid
• Precipitants: psycho-social (not organic)
• Duration: less than 3 months to presentation
• Mood: depressed, anxious
• Behavior: decreased activity or agitation
• Cognition: unimpaired or poor responses
• Somatic symptoms: fatigue, lethargy, sleep,
  appetite disruption
• Course: rapid resolution with treatment,
     but may precede Alzheimer’s disease
             Delirium Definition
        (more often a problem in medical in-patients)

   Disturbance of consciousness
       i.e., reduced clarity of awareness of the
        environment with reduced ability to focus,
        sustain, or shift attention
   Change in cognition (memory,
    orientation, language, perception)
   Development over a short period (hours
    to days), tends to fluctuate
   Evidence of medical etiology
                  Delirium
 Susceptibility may be symptom of early dementia,
  or delirium may predispose to later dementia
 Predisposing factors - Age, infections,
  dementia
 Medical conditions
    Infections:
        G.U. - urinary
        Respiratory (URI, pneumonia)
        G.I.
    Constipation
 Drug toxicity
 Fracture (especially related to hip fracture)
                 Ethanol
• Possibly Neuroprotective
  – May not kill neurons directly (?Dietary
    recommendation?)
• Accidents, Head Injury
• Dietary Deficiency
  – Thiamine – Wernicke-Korsakoff syndrome
• Hepatic Encephalopathy
• Withdrawal Damage (seizures) Delayed
  Alcohol Withdrawal
  – Watch for in hospitalized patients
• Chronic Neurodegeneration
  – Cerebellum, gray matter nuclei
            Medical / Endocrine
• Thyroid dysfunction
    – Hypothyoidism – elevated TSH
        • Compensated hypothyroidism may have normal T4, FTI
    – Hyperthyroidism
        • Apathetic, with anorexia, fatigue, weight loss, increased T4
•   Diabetes
•   Hypoglycemia (loss of recent memory since episode)
•   Hyperglycemia
•   Hypercalcemia
•   Nephropathy, Uremia
•   Hepatic dysfunction (Wilson’s disease)
•   Vitamin Deficiency (B12, thiamine, niacin)
    – Pernicious anemia – B12 deficiency, ?homocysteine
    Eyes, Ears, Environment

• Must consider sensory deficits might contribute
  to the appearance of the patient being
  demented
• Central Auditory Processing Deficits (CAPD)
• Hearing problems are socially isolating
• Visual problems are difficult to accommodate
  by a demented patient, ?To do cataract op?
• Environmental stress factors can predispose to
  a variety of conditions
• Nutritional deficiencies (tea & toast syndrome)
        Neurological Conditions
• Primary Neurodegenerative Disease
   – Diffuse Lewy Body Dementia (? 7 - 50%)
          – Note relation to Parkinson’s disease, symptoms
          – Hallucinations, fluctuating course, neuroleptic hypersensitivity)
   – Fronto-temporal dementia (tau gene)
          – Impaired attention, behavioral dyscontrol
          – Decrease blood flow, hypometaboism on SPECT / PET
          – (Pick’s disease, Argyrophylic grain disease)
• Focal cortical atrophy
   – Primary progressive aphasia (many causes)
   – Unilateral atrophy, hypofunction on EEG, SPECT, PET
• Normal pressure hydrocephalus
   – Dementia with gait impairment, incontinence
   – Suggested on CT, MRI; need tap, ventriculography
Other Neurologic Conditions
– Subdural hematoma
– Huntington’s disease
– Creutzfeldt-Jakob disease
     • Rapid progression
     • Characteristic EEG changes
–   Multiple sclerosis
–   Corticobasal degeneraton
–   Cerebellar degeneration
–   Progressive supranuclear palsey
• Tumor
 – Primary brain tumor
    • Meningioma (treatable)
    • Glioma (usually not responsive to therapy)


 – Metastatic brain tumor

 – Remote effects of carcinoma


• Toxins
 – Heavy metal screen if considered
                    Trauma

– Concussion, Contusion
   • Occult head trauma if recent fall
– Subdural hematoma
– Hydrocephalus:
   • Normal pressure (late effect of bleed)
– Dementia pugilistica
– Possible contributor to Alzheimer‟s disease
  initiation and progression (? 4% of cases)
– Concern re: physical abuse by caretakers
      Infectious Conditions
       Affecting the Brain

–   HIV
–   Neurosyphilis
–   Viral encephalitis (herpes)
–   Bacterial meningitis
–   Fungal (cryptococcus)
–   Prion (Creutzfeldt-Jakob disease); (mad
    cow disease)
         AMNESIC DISORDER
                           DSM-IV

A. Memory impairment
    - inability to learn new information, or
    - Inability to recall previously learned information
•   Memory disturbance significantly impairs social,
      occupational function, deterioration from past
•   Memory not due to delirium, dementia
•   Physiological basis or substance induced
    - Distinguish from dissociative disorders, dissociative
       amnesia, dissociative identity disorders
•   Specify
    - Transient – less than 1 month
    - Chronic - more than 1 month
Causes of Amnesic Disorders
  • Amnesia
    – Dissociative: localized, selective,
      generalized
    – Organic - damage to CA1 of hippocampus
       • thiamine deficiency (WKE), hypoglycemia,
         hypoxia
  • Epileptic events
    – Partial complex seizures
  • Specific brain diseases
    – Transient global amnesia
    – Multiple sclerosis
Etiology of Alzheimer’s Disease
• Age (initial genesis vs response to stress)
   – Bigger factor than for mortality
   – Design in a plastic (memory) system, energy demands
   – Stressor response (inadequate repair mechanisms)
       • Trauma (head injury), vascular (stroke), surgery, loss,
         grief, immunological response, etc.
• Genetics (amyloid related)
   – Familial, early onset: APP (21), PS (14, 1) (less than 5%)
   – Late onset: APOE e4 (ch19) (40% to 90% of AD)
       • relation to brain cholesterol metabolism?
       • APOE e2 may be most protective
   – many other candidate genes
• Relation to vascular factors, cholesterol, BP
• Education (? design vs protection)
• Environment - diet, exercise, toxin, smoking, infectious agent
           AD Is Often Misdiagnosed
       Patient initially diagnosed                             Patient‟s first diagnosis
       with AD                                                 other than AD
                                                                                              35%

                                                                              14%
                                                                              14%
                             No
                             72%                                         9%

                Yes                                                     7%
                28%                                                                 21%


                                                                 Dementia (not AD)        Stroke
                                                                 Depression               No diagnosis
                                                                 Normal aging             Other


Source: Consumer Health Sciences, LLC. Alzheimer’s Caregiver Project. 1999.
           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
 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
                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
 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
   FACTORS INFLUENCING
    ALZHEIMER‟S DISEASE
(age at onset, rate of progression)
• age
• sex
• genotype (presenilin, APO-E)
• education
• environment (head injury)
• surgery
• psychological problems: depression,
  agitation, anxiety, sleep disturbance
• medication
PHYSICAL/NEUROLOGICAL
     EXAMINATION
 • CHECK BLOOD PRESSURE
 • IDENTIFY SYSTEMIC DISORDERS
 • CRANIAL NERVES
    – Olfactory dysfunction, poor eye tracking
    – Check for hearing, vision deficits
 • SENSORY DEFICITS
    – Proprioception, vibration
 • DEEP TENDON REFLEXES
    – Brisk, check for focal reflexes
 • PATHOLOGIC REFLEXES
    – Hyperactive snout reflex, Gegenhalten
    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
CURRENT APPROACHES TO
 SEVERITY 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
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
SPECIAL LABORATORY TESTS
• FUNCTIONAL BRAIN IMAGING
     (SPECT, PET)
• 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 diagnosis)
  – AUTOSOMAL DOMINANT (young onset)
  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
UCLA compound   Shoghi-Jadid et al.,
     67-year-old control                   Alzheimer patient




                     PET brain images
2-(4’-methylamino-phenyl)-6-hydroxybenzothiazole (Pittsburgh Compound)
      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
          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)


       GenT %pop %AD                 #pop      #AD      risk If all US

       E2/2         1% 0.1%          0.5M .004M 0.8%               .4 M

       E2/3       12 %       4%      5.5M .18M 3.2%              1.5 M

       E3/3        60%      35% 27.6M 1.4M 5.1%                  2.3 M

       E3/4        21%      42%      9.6M 1.7M 18%               8.2 M

       E4/4         2%      16%        .9M      .6M 67%         30.7M

JW Ashford, MD PhD, 2003
      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
                               U.S. Census 2000 by age
                               www.census.gov
                                                                             Males,
                 2,500,000                                                   138,053,563
                 2,250,000                                                   Females,
                 2,000,000                                                   143,368,343
                 1,750,000
      # people




                 1,500,000
                 1,250,000
                 1,000,000         Total = 281,421,906
                  750,000          >60 = 45,809,291
                  500,000
                                   >65 = 35,003,844
                                   >85 = 4,251,678
                  250,000          >100=        62,545
                           0
                               0    10   20   30   40    50   60   70   80   90 100

                                                        Age
JW Ashford, MD PhD, 2003
                                     U.S. mortality by age - 1999
                                                                    www.cdc.gov

                                          Males, 1,175,460
                    45,000
                    40,000
      Number of people



                                          Females, 1,215,939
                    35,000
                    30,000
                    25,000
                    20,000
                    15,000
                    10,000
                         5,000
                            0
                                 0   10    20    30   40       50   60   70   80   90   100

                                                             Age
JW Ashford, MD PhD, 2003
                                          U.S. mortality rate by age
                                          1999 CDC / 2000 census

                                       Males, 2t = 8.2yrs
                     1.0000            Females, 2t = 7.5 yrs
                                       Alzheimer incidence

                     0.1000
     Yearly Hazard




                     0.0100


                     0.0010


                     0.0001
                              0   10     20     30      40 Age 50   60   70   80   90   100


JW Ashford, MD PhD, 2003
      Proportion of population          Probability Not Demented

                                   1
                                 0.9
                                 0.8
                                 0.7
                                 0.6
                                 0.5
                                 0.4
                                 0.3
                                 0.2
                                 0.1
                                   0
                                       50   60    70         80   90   100

                                                       Age


JW Ashford, MD PhD, 2003
                                        U.S.
                                Alzheimer Incidence
                                   (4 million / 8yr)
               16000                 male=170,603
               14000                 female=329,115
               12000
               10000
      # / yr




                8000
                6000
                4000
                2000
                   0
                           50       60     70         80   90   100
                                                Age
JW Ashford, MD PhD, 2003
JW Ashford, MD PhD, 2003
                           (Incidence for a to a + 1 year)
                                          Probability Not Demented
        Proportion of population

                                     1
                                   0.9
                                   0.8
                                   0.7
                                   0.6        mean rate
                                   0.5
                                   0.4        APOE 4/4
                                   0.3        APOE 3/4
                                   0.2
                                   0.1        APOE 3/3
                                     0
                                         50   60          70         80   90   100

                                                               Age

JW Ashford, MD PhD, 2003
                                      U.S. AD Incidence by APOE
                                         (proportion of cases)
                             1                4/4
       Proportion / Year



                           0.9                3/4
                           0.8                3/3
                           0.7
                           0.6
                           0.5
                           0.4
                           0.3
                           0.2
                           0.1
                             0
                                 50      60         70         80   90   100
                                                         Age

JW Ashford, MD PhD, 2000
                                       Probability of Dementia Onset
                                                   APOE 4/4-M
                                                   APOE 4/4-F
        prob/ yr * live population

                                     0.04          APOE 3/4-M
                                                   APOE 3/4-F
                                                   APOE 3/3-M
                                     0.03          APOE 3/3-F

                                     0.02

                                     0.01

                                       0
                                            50      60      70      80      90       100

                                                 Age (single mortality correction)

JW Ashford, MD PhD, 2003
        Cache County, probability
        of incident dementia
        Circles – females
        Squares - males
        Open – ApoE-e44
        Gray – ApoE-e4/x
        Black – ApoE-ex/x




Miech et al., 2002
      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
    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
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
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
    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)
                            Anim als nam ed in 1 m in (m m s>19) - CERAD data set


                   12

                   10
percent of total




                   8

                   6

                   4

                   2

                   0
                        0               10                20               30       40
                                             num ber of anim als nam ed

                                             Normal Controls, CS = 1, n = 386
                                             Alzheimer patients, CS = 0, n = 380
                              Animals name d in 30 se conds (mms>19)


                     16

                     14

                     12
  percent of total




                     10

                      8

                      6

                      4

                      2

                      0
                          0         5         10             15            20   25
                                        number of animals named

                                          Normal Controls, n=386
                                          Mild Alzheimer Patients, n=380
JW Ashford, MD PhD, 2001
                                                           Animal naming ROCs
                                                (AUC 15: 0.74; 30: 0.83; 45: 0.86; 60: 0.87)


                   100
                                                                       17                          .
                                                                16
                    90                                  15
                                               14                11              8
                    80                    13            10
                    70                                          7
                                  12           9
Sensitivity (% )




                    60                                                                      animals in 15 secs
                             11
                                           8        6                                       animals in 30 secs
                    50 10
                                                                                            animals in 45 secs
                    40            7                                                         animals in 60 secs

                    30                5

                    20

                    10

                     0
                         0            10       20       30     40       50      60     70              80        90   100

                                                             False Positive Rate (%)
    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
     Percent of Validation Sample
                                    90
                                    80
                                                     Mild AD
                                    70
                                                     Control
                                    60
                                    50
                                    40
                                    30
                                    20
                                    10
                                    0
                                         3-22   23   24        25   26      27-39

JW Ashford, MD PhD, 2001
                                                     BAS Score      Mendiondo et al., 2004
                                                              BRIEF ALZHEIMER SCREEN
                                                               (Normal vs Mild AD, MMS>19)


                                                                                               20
                                       100
                                                          27                              13
True Positive Rate (%) (Sensitivity)


                                        90                                      12
                                                  26           14
                                                 25                       11
                                        80
                                                                    10
                                        70
                                                               9
                                        60
                                        50                8              animals 1 m      AUC = 0.868

                                        40                               animals 30 s     AUC = 0.828
                                                 97
                                                                         MMSE             AUC = 0.965
                                        30
                                                 6
                                        20                               Date+3 Rec       AUC = 0.875

                                                                         BAS              AUC = 0.983
                                        10
                                         0
                                             0       10       20    30   40    50    60   70        80   90 100
                                                          False Positive Rate (%) (1-Specificity)
JW Ashford, MD PhD, 2003
       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
    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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