P.I.: Chester A Mathis, Ph.D.
The neuropathologic definition of Alzheimer's disease (AD) relies on the presence of two well-characterized protein aggregates in the brain, amyloid-beta (Aβ) plaques and hyperphosphorylated tau in the form of neurofibrillary tangles. The widespread use of Aβ positron emission tomography (PET) imaging technology has helped identify the prevalence of significant Aβ deposition in vivo in the elderly population, in which elevated levels of Aβ are found in about 30% of cognitively normal elderly (NC) subjects at a mean age of about 75 years old, 60% of mild cognitive impairment (MCI) subjects, and 90% of clinically diagnosed AD subjects. Efforts to develop tau-selective PET imaging agents have been successful with the application of several new tau PET radioligands, including the radioligand [18F]AV-1451. This project seeks to characterize the behavior of [18F]AV-1451, in concert with other biomarkers of neurodegeneration, in NC, MCI, and AD subjects. In cross-sectional studies, the project will investigate regional differences in brain tau load in the different subject groups and compare the in vivo topology of abnormal tau deposition with the pattern predicted by postmortem Braak staging. We will leverage existing data on [18F]2-fluoro-2-deoxy-D-glucose (FDG) hypometabolism, hippocampal volume (HV) loss, [11C]Pittsburgh Compound-B (PiB) measures of Aβ load, and cognitive performance measures in subjects recruited from NC, MCI and AD cohorts. Following cross-sectional evaluation of tau load in the different groups, we will rescan all subjects using [18F]AV-1451 at 30 months to evaluate longitudinal changes in T807 signal and compare tau changes with changes in the other biomarker measures in the same subjects. The combination of in vivo tau and Aβ imaging has the potential to provide a more complete view of the pathological progression of AD from prodromal to end-stage phases.
Sullivan KJ, Liu A, Chang CH, Cohen AD, Lopresti BJ, Minhas DS, Laymon CM, Klunk WE, Aizenstein H, Nadkarni NK, Loewenstein D, Kamboh MI, Ganguli M, Snitz BE. (2020) Alzheimer’s disease pathology in a community-based sample of older adults without dementia: The MYHAT neuroimaging study. Brain Imaging Behav. Aug 3. Epub ahead of print.
Snitz BE, Tudorascu DL, Yu Z, Campbell E, Lopresti BJ, Laymon CM, Minhas DS, Nadkarni NK, Aizenstein HJ, Klunk WE, Weintraub S, Gershon RC, Cohen AD (2020). Associations between NIH toolbox cognition battery and in vivo brain amyloid and tau pathology in non-demented older adults. Alzheimer’s & Dement. (Amst.)12(1):e12018.
Ikonomovic MD, Buckley CJ, Abrahamson EE, Kofler JK, Mathis CA, Klunk WE, Farrar G. (2020). Post-mortem analyses of PiB and Flutemetamol in diffuse and cored amyloid-β plaques in Alzheimer’s disease. Acta Neuropathol. 140:463-476.