The Quest for A Biological Marker for Alzheimer Disease

1
The Quest for A Biological Marker for Alzheimer
Disease

• Sami I. Harik, MD
• Professor Chairman of Neurology
• University of Arkansas College of Medicine

2
Is There A Need for AD Marker

• Good clinical judgment diagnoses de-mentia (loss
  of cognitive powers), but not its underlying
  pathology.
• Alzheimer disease (AD) diagnosis can only be made
  pathologically, although it may be clinically
  suspected. Even the pathologic diagnosis of AD is
  sometimes questionable.

3
Is There A Need for AD Marker (continued)

• For these reasons, every demented patient
  deserves a full dementia work-up to rule out a
  reversible cause of dementia.
• Whenever possible, particularly in a clinical
  research setting, every demented patient should
  have his/her diagnosis confirmed by post-mortem
  pathological examination.

4
Yes! We desperately need a good biological
marker for Alzheimer disease.
5
Importance of Disease Markers

• Confirm diagnosis.
• Predictive testing, including prenatal.
• Epidemiologic screening.
• Monitor progression, or response to Rx.
• To prevent the disease if preventive Rx is
  available.

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The Ideal Bio-Marker

• Should reflect on a major feature of disease.
• High sensitivity.
• High specificity.
• Reliable.
• As non-invasive as possible.
• Simple and easy to perform.
• Inexpensive.

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Bio-Marker Should Be Non-, or Minimally-Invasive

• Minimally-invasive tests include studies on
  blood, urine, saliva, buccal scrapings, etc..
• Moderately-invasive tests include studies on CSF,
  biopsies of skin, rectal mucosa, bone marrow,
  etc..
• Highly-invasive tests include those that require
  sampling of hard to obtain tissues. Brain biopsy
  is very high on this list.

8
Examples of Good Bio-Markers

• Serum VDRL for syphilis.
• Simplicity Sensitivity Specificity
• Serum acid phosphatase enzyme activity in
  metastatic cancer of prostate.
• High specificity.
• Serum Prostate Specific Antigen (PSA) in prostate
  cancer.
• Biologically relevant Sensitive but not
  specific.

9
Steps to Establish a Biomarker

• Two independent studies of biomarkers
  sensitivity specificity (gt 80 ).
• Studies must have adequate statistical power,
  good methodology peer reviewed.
• Good controls. Multiple control groups.
• Follow up data collection to monitor accuracy and
  diagnostic value.

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Brain Capillary GLUT in AD
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Brain Membranes GLUT in AD
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Our Interpretation of Our Data

• Although GLUT-1 was significantly decreased in
  brain capillaries and membranes of AD patients,
  it was not a useful marker because
• Major overlap between groups.
• Impracticality of obtaining tissue.
• Difficult and expensive assays.
• We believed that the data were the result, not
  the cause, of the low CMRgluc in AD.

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Erythrocyte GLUT in Aging
14
Erythrocyte GLUT as AD Marker
15
Molecular Genetic Markers of AD

• Amyloid precursor protein mutations on chromosome
  21. 25 families worldwide.
• Presenilin 1 mutations. Accounts for 30-50 of
  early onset autosomal dominant FAD.
• Presenilin 2 mutations. 2 families.
• Apolipoprotein allele types. Apo e 4 is a sig.
  risk factor for late onset sporadic AD, but the
  sensitivity specificity are low, conferring
  only 10-15 accuracy to diagnosis.

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Neuropathologic Markers of AD

• CSF content of amyloid ß (40 or 42 residue) is
  significantly decreased in AD, but there is
  overlap with controls.
• CSF content of tau protein is significantly
  increased in AD, but there also is overlap with
  controls.
• CSF amyloid ß tau are promising, but so far
  they lack the necessary S S.
• Blood urine amyloid ß tau are of no use

17
CSF Neurotransmitters in AD

• Numerous neurotransmitters that are deficient in
  the brains of AD subjects, and their metabolites,
  were assessed in CSF of AD patients. Overall,
  there are no promising markers among them because
  of poor sensitivity and specificity. The ranges
  of findings were simply too wide.

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Other Tissue Alterations in AD

• Olfactory epithelium. ?smell is known to occur in
  AD, but 15 of older adults are anosmic.
  Dystrophic neurites were described, in AD but
  biopsy of OE is risky.
• Skin amyloid fibroblasts ion channels
  abnormalities were described. These techniques
  have not gained followers.
• Platelets. ? cytochrome c oxidase other
  mitochondrial abnormalities were described but
  not accepted thus far.

19
Look at The Pupil, Stupid

• In 1994, Scinto et al reported in Science that
  the pupillary dilation in response to a dilute
  solution of tropicamide was ?, consistent with ?
  central cholinergic activity in AD.
• The authors claimed that the test diagnosed AD at
  a 95 sensitivity 94 specificity.
• That would have been the ideal marker, but alas,
  the findings could not be replicated.