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Accelerating rates of cognitive decline and imaging markers associated with β-amyloid pathology

Philip S Insel1, Niklas Mattsson2, R Scott Mackin2

  • 1From the Center for Imaging of Neurodegenerative Diseases (P.S.I., R.S.M., R.L.N., D.T., M.W.W.), Department of Veterans Affairs Medical Center, San Francisco; Departments of Radiology and Biomedical Imaging (P.S.I., D.T., M.W.W.) and Psychiatry (R.S.M.), University of California, San Francisco; Clinical Memory Research Unit, Faculty of Medicine (P.S.I., N.M.), Lund University; Memory Clinic (N.M.) and Department of Neurology (N.M.), Skåne University Hospital, Lund University; MedTech West and the Department of Clinical Neuroscience and Rehabilitation (M.S.), University of Gothenburg, Sweden; Department of Neurology (M.C.D., P.S.A.), Keck School of Medicine, University of Southern California, Los Angeles; Helen Wills Neuroscience Institute (W.J.J.), University of California, Berkeley; and Life Sciences Division (M.S., W.J.J.), Lawrence Berkeley National Laboratory, Berkeley CA. philipinsel@gmail.com.

Neurology
|May 11, 2016
PubMed
Abstract

Insights

Cognitive and functional decline accelerate early in Alzheimer's disease, even before amyloid positivity thresholds are met. This suggests revising trial criteria to capture earlier disease stages for better therapeutic targeting.

Area of Science:

  • Neuroscience
  • Biomarkers
  • Neurodegenerative Diseases

Background:

  • Alzheimer's disease (AD) is characterized by β-amyloid (Aβ) pathology.
  • Current diagnostic and trial criteria often rely on a threshold for amyloid positivity.

Purpose of the Study:

  • To identify the specific points in the spectrum of Aβ pathology where neuronal injury and cognitive decline accelerate.
  • To inform future clinical trial designs for early-stage AD.

Main Methods:

  • Analysis of 460 patients with mild cognitive impairment (MCI).
  • Estimation of acceleration points using mixed-effects regression based on florbetapir PET, FDG PET, MRI, and cognitive/functional decline measures relative to baseline CSF Aβ42.
  • Assessment of temporal lobe atrophy rates.

Main Results:

  • Rates of neuronal injury, cognitive, and functional decline accelerate significantly before the conventional amyloid positivity threshold.
  • Florbetapir PET and FDG PET measures show early acceleration.
  • Temporal lobe atrophy accelerates prior to the amyloid threshold but after cognitive/functional decline acceleration.

Conclusions:

  • Many MCI patients experiencing decline associated with pre-threshold Aβ levels would not qualify for current trials.
  • Revising β-amyloid positivity criteria in early AD trials may be beneficial to include individuals with early signs of accelerating decline.
  • This could improve the inclusion of relevant patient populations in therapeutic studies.

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