Part B – AD and brain systems (1.4 MB)

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Part B – AD and brain systems (1.4 MB)

  1. 1. 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)
  2. 2. 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
  3. 3. 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
  4. 4. 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) intracellularextra cellular NEXIN ? To establish new connections Amyloid –beta: ? Free-radical generator ? To remove old synapses Turn-over – 8 hours Clearance – IDE, APOEJW Ashford, MD PhD, APP – formed during learning - XS in Downs Residual (not processed by α-secretase)
  5. 5. Acetylcholine activity stimulates alpha-secretase and inhibits tau phosphorylation
  6. 6. Estimate MMSE as a function of time 0 5 10 15 20 25 30 -10 -8 -6 -4 -2 0 2 4 6 8 10 Estimated years into illness MMSEscore AAMI / MCI/ early AD -- DEMENTIA ALZHEIMER’S DISEASE COURSE Ashford et al., 1995
  7. 7. 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).
  8. 8. Ashford et al., 1998 J Neuropathol Exp Neurol.57:972
  9. 9. Progression of tau hyperphosphorylation to neuropil threads and neurofibrillary tangles Ashford et al., 1998, J Neuropathol Exp Neurol.57:972
  10. 10. 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
  11. 11. Dementia rate, for Td = 5 yrs 0.0001 0.001 0.01 0.1 1 10 100 1000 50 60 70 80 90 100 Age Numberofpeople/yr mean rate APOE 4/4 APOE 3/4 APOE 3/3 presenilin JW Ashford, MD PhD, 2003; See: Raber et al., 2004
  12. 12. Probability Not Demented 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 50 60 70 80 90 100 Age Proportionofpopulation mean rate APOE 4/4 APOE 3/4 APOE 3/3 JW Ashford, MD PhD, 2003
  13. 13. JW Ashford, MD PhD, 2000 U.S. AD Incidence by APOE (proportion of cases) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 50 60 70 80 90 100 Age Proportion/Year 4/4 3/4 3/3 e4/4 – 2% of pop, 20% of cases e3/4 - 20% of pop, 40% of cases e3/3 - 65% of pop, 35% of cases
  14. 14. APOE AND EVOLUTION (The original allele was APOE-ε4, the ε3 allele appeared about 300,000 years ago, and the ε2 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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