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Part B – AD and brain systems (1.4 MB)

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Part B – AD and brain systems (1.4 MB) Part B – AD and brain systems (1.4 MB) Presentation Transcript

  • 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)
  • Sensory, Perception, Memory systems of cortex – Ashford, Coburn, Fuster, 1998 Alzheimer pathology affects regions of the cortex that have a high capacity and responsibility for memory storage
  • BIOPSYCHOSOCIAL SYSTEMS AFFECTED BY AD NEUROPLASTIC 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
  • Alpha-secretase is stimulated by acetylcholine through muscarinic receptor Favored when lipid raft too thick Lipid raft Formed by cholesterol Transported by ApoE (from macroglia) intracellular extra cellular NEXIN ? To establish new connections Amyloid –beta: ? Free-radical generator ? To remove old synapses Turn-over – 8 hours Clearance – IDE, APOE JW Ashford, MD PhD, 2007 APP – formed during learning - XS in Downs Residual (not processed by  -secretase)
  • Acetylcholine activity stimulates alpha-secretase and inhibits tau phosphorylation
  •  
  • AAMI / MCI/ early AD -- DEMENTIA ALZHEIMER’S DISEASE COURSE Ashford et al., 1995
  • 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).
  • Ashford et al., 1998 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 (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; See: Raber et al., 2004
  • JW Ashford, MD PhD, 2003
  • JW Ashford, MD PhD, 2000 e4/4 – 2% of pop, 20% of cases e3/4 - 20% of pop, 40% of cases e3/3 - 65% of pop, 35% of cases
  • APOE AND EVOLUTION (The original allele was APOE-  4, the  3 allele appeared about 300,000 years ago, and the  2 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)