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 A – AD definition, neuropath?. 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 A – AD definition, neuropath?

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)


Dementia definition
Dementia Definition TREATMENTS FOR ALZHEIMER'S DISEASE?

  • Multiple Cognitive Deficits:

    • Memory dysfunction

      • especially new learning, a prominent early symptom

    • At least one additional cognitive deficit

      • aphasia, apraxia, agnosia, or executive dysfunction

  • Cognitive Disturbances:

    • Sufficiently severe to cause impairment of occupational or social functioning and

    • Must represent a decline from a previous level of functioning


Alzheimer s disease
Alzheimer’s Disease TREATMENTS FOR ALZHEIMER'S DISEASE?

  • First described by Alois Alzheimer, a German neuropathologist, in 1906/7

  • Observed in a 51-year-old female patient with paranoia, memory loss, disorientation, and hallucinations

  • Postmortem studies characterized senile plaques and neurofibrillary tangles (NFTs) in the cerebral cortex

    • Senile plaques: Extracellularaccumulation of insoluble fragments of beta-amyloid (A1-42)

    • NFTs: Intracellular accumulation of hyperphosphorylated tau strands


Diagnostic criteria for dementia of the alzheimer type dsm iv apa 1994
Diagnostic Criteria For Dementia Of TREATMENTS FOR ALZHEIMER'S DISEASE? The Alzheimer Type(DSM-IV, APA, 1994)

  • Memory Impairment

    1. Multiple Cognitive Deficits

    2. Other Cognitive Impairment

  • Deficits Impair Social/Occupational Function

  • Course Shows Gradual Onset and Decline

  • Deficits Are Not Due to:

    1. Other CNS Conditions

    2. Substance Induced Conditions

  • Do Not Occur Exclusively during Delirium

  • Not Due to Another Psychiatric Disorder


Reprinted with permission from Brumback, RA, Leech RW, J. Ohio State Med Assoc. 1994: 87, 103-111


Yesavavage et al., 2002 Ohio State Med Assoc. 1994: 87, 103-111


Normal Brain Ohio State Med Assoc. 1994: 87, 103-111

Alzheimer Brain


Cholinergic changes in ad 1976
Cholinergic Changes in AD - 1976 Ohio State Med Assoc. 1994: 87, 103-111

  • The most prominent neurotransmitter abnormalities are cholinergic

    • Reduced activity of choline acetyltransferase (synthesis of acetylcholine)1

  • Reduced number of cholinergic neurons in late AD (particularly in basal forebrain)2

  • Selective loss of nicotinic receptor subtypes in hippocampus and cortex1,3

1. Bartus RT et al. Science. 1982;217:408-414.

2. Whitehouse PJ et al. Science. 1982;215:1237-1239.

3. Guan ZZ et al. J Neurochem. 2000;74:237-243.


Specific groups of cholinergic, serotonergic, and noradrenergic that project to the cortex, and glutamatergic neurons of discrete cortical regions are selectively affected in Alzheimer’s disease

Cortex

(glutamate neurons)


Discrete regions of the cerebral cortex are selectively affected by Alzheimer pathology

Brun & Englund, 1986


Braak & Braak, 1991; Braak et al., 2006 affected by Alzheimer pathology


(Braak & Braak, 1991) affected by Alzheimer pathology


Braak & Braak, 1991 affected by Alzheimer pathology


Tangle nft plaque np distribution in ad at autopsy
Tangle (NFT) & Plaque (NP) affected by Alzheimer pathologyDistribution In AD at Autopsy

NFT

NP

S. Arnold, Cortex, 1991


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