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HOW CAN NEUROIMAGING HELP UNDERSTAND, DIAGNOSE, AND DEVELOP TREATMENTS FOR ALZHEIMER\'S DISEASE? Part B – AD and brain systems. NUCLEAR MEDICINE GRAND ROUNDS Stanford University J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated), Department of Psychiatry and Behavioral Sciences

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HOW CAN NEUROIMAGING HELP UNDERSTAND, DIAGNOSE, AND DEVELOP TREATMENTS FOR ALZHEIMER\'S DISEASE?Part B – AD and brain systems

NUCLEAR MEDICINE GRAND ROUNDS

Stanford University

J. Wesson Ashford, M.D., Ph.D.

Clinical Professor (affiliated), Department of Psychiatry and Behavioral Sciences

Senior Research Scientist, Stanford / VA Aging Clinical Research

Stanford University and VA Palo Alto Health Care System

January 5, 2010

Slides at: www.medafile.com(Dr. Ashford’s lectures)

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Alzheimer pathology affects regions of the cortex that have a high capacity and responsibility for memory storage

Sensory, Perception, Memory systems of cortex – Ashford, Coburn, Fuster, 1998

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BIOPSYCHOSOCIAL SYSTEMS AFFECTED BY ADNEUROPLASTIC MECHANISMS AFFECTED AT ALL LEVELS (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
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intracellular

extra cellular

APP – formed

during learning

- XS in Downs

Lipid raft

Formed by cholesterol

Transported by ApoE

(from macroglia)

Alpha-secretase is stimulated by acetylcholine

through muscarinic receptor

Residual

(not processed by a-secretase)

NEXIN

? To establish

new connections

Amyloid –beta:

? Free-radical generator

? To remove old synapses

Turn-over – 8 hours

Clearance – IDE, APOE

Favored when

lipid raft too thick

JW Ashford, MD PhD, 2007

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ALZHEIMER’S DISEASE COURSE

AAMI / MCI/ early AD -- DEMENTIA

Ashford et al., 1995

pathology in dendrites relates to high volumes of transport to support synaptic plasticity

PATHOLOGY IN DENDRITES RELATES TO HIGH VOLUMES OF TRANSPORT TO SUPPORT SYNAPTIC PLASTICITY

Shown on the next slides is a view which reflects observations from a double labeling (with PHF-1 and MAP-2) analysis of neurons in the cortex affected by Alzheimer’s disease (Ashford et al., 1998).

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Ashford et al., 1998

J Neuropathol Exp Neurol.57:972

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Progression of tau hyperphosphorylation to neuropil threads and neurofibrillary tangles

Ashford et al., 1998, J Neuropathol Exp Neurol.57:972

apoe alzheimer hypothesis
APOE, Alzheimer Hypothesis
  • APOE (apo-lipo-protein E) is a cholesterol chaperone
  • Cholesterol metabolsim is a central part of synaptic plasticity (Koudinov & Koudinov, 2001)
  • APOE genotype has a strongly established relationship with AD risk
  • CAVEAT – the APOE protein variations (e2, e3, e4) do not have a clear role in the causation of Alzheimer pathology
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e4/4 – 2% of pop, 20% of cases

e3/4 - 20% of pop, 40% of cases

e3/3 - 65% of pop, 35% of cases

JW Ashford, MD PhD, 2000

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APOE AND EVOLUTION(The original allele was APOE-e4, the e3 allele appeared about 300,000 years ago, and the e2 allele appeared about 200,000 years ago)

  • Does APOE-e2 or e3 do a safer job of supporting the remodelling of dendrites, to minimize the stress on a neuron over time?
  • Demented elderly cannot foster their young or compete
    • APOE AS AN AGENT TO SUPPORT SUCCESSFUL AGING IN GRANDMOTHERS
    • APOE AS AN AGENT TO SUPPORT THE DOMINANCE OF ELDERLY MALES OVER YOUNGER MALES
  • APOE genotype may be in close linkage-dysequilibrium with a neighboring gene that is specifically responsible for the vulnerability to Alzheimer’s disease (possibly TOMM-40)
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