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 SciencesSenior 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 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

Alpha-secretase is stimulated by acetylcholinethrough muscarinic receptor

Favored when lipid raft too thick

Lipid raftFormed by cholesterolTransported by ApoE (from macroglia)

intracellularextra cellular

NEXIN? To establishnew connections Amyloid –beta:

? Free-radical generator? To remove old synapsesTurn-over – 8 hoursClearance – IDE, APOEJW Ashford, MD PhD, 2007

APP – formedduring learning- XS in Downs

Residual (not processed by -secretase)

Acetylcholine activity stimulates alpha-secretase and inhibits tau phosphorylation

Estimate MMSE as a function of time

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5

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-10 -8 -6 -4 -2 0 2 4 6 8 10

Estimated years into illness

MM

SE

scor

e

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., 1998J 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

Dementia rate, for Td = 5 yrs

0.0001

0.001

0.01

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50 60 70 80 90 100

Age

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mean rateAPOE 4/4APOE 3/4APOE 3/3presenilin

JW Ashford, MD PhD, 2003; See: Raber et al., 2004

Probability Not Demented

00.10.20.30.40.50.60.70.80.9

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50 60 70 80 90 100

Age

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mean rate

APOE 4/4

APOE 3/4

APOE 3/3

JW Ashford, MD PhD, 2003

JW Ashford, MD PhD, 2000

U.S. AD Incidence by APOE(proportion of cases)

00.10.20.30.40.50.60.70.80.9

1

50 60 70 80 90 100Age

Pro

po

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Yea

r 4/4

3/43/3

e4/4 – 2% of pop, 20% of casese3/4 - 20% of pop, 40% of casese3/3 - 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)