Advisory Council July 2017 Meeting Presentation: Implications of a Biologically Based Definition

07/28/2017

ADVISORY COUNCIL ON ALZHEIMER'S RESEARCH, CARE, AND SERVICES

Friday, July 28, 2017

Printer Friendly Version in PDF Format (8 PDF pages)

 

Implications of a Biologically Based Definition of Alzheimer's Disease

Clifford R Jack Jr MD
Prof. of Radiology and Alexander Family Professor of Alzheimer's Disease Research
Dept. Radiology, Mayo Clinic, Rochester, MN

What is Alzheimers disease (AD)?

  • Symptoms (syndrome) vs disease
    • Shortness of breath vs heart, lung disease
    • Effect vs cause
  • Dementia vs Alzheimer's disease
  • Dementia -- progressive loss of cognitive ability leading to significant functional impairment (loss of independence)
  • Alzheimers disease
    • Plaques
    • Tangles
    • Inflammation
    • Loss of neurons

Diagnosis of Alzheimer's disease

  • Historic diagnosis (McKhann et al 1984): clinico-pathologic
    • Definite at autopsy
    • Probable or possible in life -- syndromal definition
    • Definition "creep"
  • Problems
    • Not all "AD" syndrome is AD (20%)
    • Some non AD syndromes are AD
    • Many AD are asymptomatic (up to 40%, depends on age)
  • Solution - biomarkers

What is a biomarker?

  • A measure of pathologic change that can be obtained in the living subject -- biomarkers are proxies for specific pathologic changes in the brain
  • Accepted Alzheimer's biomarkers are imaging or biofliud (CSF)*

Biomarkers are proxies for AD pathologic changes

  • Measures of brain A? deposition -- amyloid plaques
    • Amyloid PET
    • CSF AB 42
  • Measures of neuofibrially tangles - pathologic tau
    • CSF phospho tau
    • Tau PET
  • Measures of neurodegeneration
    • FDG PET
    • CSF total tau
    • Structural MRI

Amyloid PET - plaques

Screen Shots of Brain PET scans--Cognitively unimpaired versus demented.

Tau PET - tangles

Screen Shots of Brain PET scans--Cognitively unimpaired versus demented.

MRI -- neurodegenerative brain atrophy

Screen Shots of Brain MRI scans--Cognitively unimpaired versus demented.

75 yo F, amnestic multi domain dementia: A+T+N+ profile

Screen Shots of Brain Tau, Amyloid and MR scans.

Diagnosis of Alzheimer's disease

  • Historic diagnosis (1984)
    • Definite at autopsy
    • Probable or possible in life -- syndromal definition
  • Problems -- treatment discovery and application
    • Not all "AD" syndrome is AD (20%)
    • Some non AD syndromes are AD
    • Many AD are clinically asymptomatic (up to 40%, depends on age)

85 yo F, progressive memory problem, demented, clinical diagnosis "Alzheimer's disease"

Screen Shots of Brain Tau, Amyloid and MR scans.

Cognitively unimpaired, 67 yo, M

Screen Shots of Brain Tau, Amyloid and MR scans.

Hypothetical Model of Dynamic Biomarkers of the Alzheimer's Pathological Cascade

Biomarker chart.
Clifford R. Jack Jr, David S Knopman, William J Jagust, Leslie M Shaw, Paul S Aisen, Michael W Wiener, Ronald C Petersen, John Q. Trojanowski
Lancet Neurol 2010

Prevention - biomarkers

Biomarker chart.

Implications of biologically based (biomarker based) definition of Alzheimer's disease

  • Specificity of biomarkers -- AD treatment for those with AD
    • Clinical trials
    • Clinical practice
  • Sensitivity of biomarkers -- Prevention -- can not "treat" something that does "not exist"
    • Clinical trials
    • Clinical practice
  • Prevalence - higher

NIA-AA Research Framework: Towards a Biological Definition of Alzheimer's Disease

Clifford R. Jack, Jr. M.D., David A. Bennett, M.D., Kaj Blennow, M.D., Ph.D., Maria C. Carrillo, Ph.D., Billy Dunn, M.D., Cerise Elliott, Ph.D., Samantha Budd Haeberlein, Ph.D., David Holtzman, M.D., Ph.D., William Jagust, M.D., Frank Jessen, M.D., Jason Karlawish, M.D., Enchi Liu, Ph.D., Eliezer Masliah M.D., Jose Luis Molinuevo, M.D., Thomas Montine, M.D., Creighton Phelps, Ph.D., Katherine P. Rankin, Ph.D., Christopher Rowe, M.D., Laurie Ryan, Ph.D., Philip Scheltens, M.D., Eric Siemers, M.D., Nina Silverberg, Ph.D., Heather M. Snyder, Ph.D., Reisa Sperling, M.D.


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