HOW CAN NEUROIMAGING HELP UNDERSTAND, DIAGNOSE, AND DEVELOP TREATMENTS FOR ALZHEIMER'S DISEASE?
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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)


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


BIOPSYCHOSOCIAL SYSTEMS AFFECTED BY AD a high capacity and responsibility for memory storageNEUROPLASTIC 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


  • intracellular a high capacity and responsibility for memory storage

    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



    ALZHEIMER’S DISEASE COURSE inhibits tau phosphorylation

    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 inhibits tau phosphorylation 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).


    Ashford et al., 1998 inhibits tau phosphorylation

    J Neuropathol Exp Neurol.57:972


    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 and neurofibrillary tangles

    • 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



    JW Ashford, MD PhD, 2003 and neurofibrillary tangles


    e4/4 – 2% of pop, 20% of cases and neurofibrillary tangles

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

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

    JW Ashford, MD PhD, 2000


    APOE AND EVOLUTION and neurofibrillary tangles(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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