Positron emission tomography (PET) imaging using Pittsburgh Compound-B (PiB) provides a regional map of amyloid pathology in living subjects and can assist clinical diagnosis of Alzheimer's disease (AD). Understanding the relationship between PiB PET retention patterns in vivo and the underlying pathological burden responsible for PiB retention is necessary to validate PiB as a biomarker in AD. Previous in vitro studies of PiB binding to synthetic p-amyloid (AP) peptide and autopsy brain tissues from AD subjects indicated that PiB PET retention likely reflects PiB binding to AB aggregates in plaques and cerebral vasculature. This idea is supported by our recent clinical-pathological study of AD. However the degree to which PiB PET signal is reflective of neuropathological changes in cognitively normal, MCI, and AD subjects, as well as the AB burden required for positive PiB PET signal in vivo remains to be determined. Furthermore, the degree to which regional synapse loss (the best structural correlate of AD dementia) is reflected by PiB PET retention patterns, and how this is influenced by cerebral vascular pathology (a significant contributor to the development of AD) is currently unknown. With increasing numbers of PiB PET imaged subjects coming to autopsy, we can now address these important issues. We propose to gain insight into these questions in three ways. First, we will characterize PiB's binding substrates in postmortem brain tissues from PiB PET scanned subjects, to determine the type and threshold level of AD pathology which is necessary to produce a positive PiB PET signal in vivo. We will do this in autopsy brain tissues from subjects with different clinical diagnoses, imaged in the previous and current PPG (Projects 4 and 5) at the University of Pittsburgh as well as in other collaborating PiB-PET imaging centers. In the second part of this proposal, we will perform postmortem assessment of synaptic markers and correlate them with region-matched PiB PET and FDG PET levels recorded antemortem (Projects 4 and 5). The third part of this proposal will investigate the extent to which vascular lesions, determined both postmortem and in vivo (Projects 4 and 5), influence the patterns of regional synapse changes and AB plaque load in the same subjects. These autopsy studies will complement clinical imaging and neuropsychological analyses in Projects 4 and 5;while providing greater insight into the AB and vascular pathology burden that influences PiB PET signal, they will secure a unique source of tissues to be utilized in this and future studies of neuropathological correlates of PiB PET imaging.

Public Health Relevance

The proposed autopsy study will provide postmortem validation of PiB PET diagnostic imaging in AD. We will determine how in vivo PiB retention signal correlates with postmortem measures of AB plaque load and synapse loss, and how these associations are modulated by the presence of vascular disease. The results of this study will assist the interpretation of PiB imaging in diagnosing AD and monitoring the effect of therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG025204-09
Application #
8572490
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2013
Total Cost
$274,558
Indirect Cost
$89,269
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Mizukami, Katsuyoshi; Akatsu, Hiroyasu; Abrahamson, Eric E et al. (2016) Immunohistochemical analysis of hippocampal butyrylcholinesterase: Implications for regional vulnerability in Alzheimer's disease. Neuropathology 36:135-45
Ikonomovic, Milos D; Abrahamson, Eric E; Price, Julie C et al. (2016) [F-18]AV-1451 positron emission tomography retention in choroid plexus: More than "off-target" binding. Ann Neurol 80:307-8
Perez, Sylvia E; He, Bin; Nadeem, Muhammad et al. (2015) Resilience of precuneus neurotrophic signaling pathways despite amyloid pathology in prodromal Alzheimer's disease. Biol Psychiatry 77:693-703
Klunk, William E; Koeppe, Robert A; Price, Julie C et al. (2015) The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alzheimers Dement 11:1-15.e1-4
Marquié, Marta; Normandin, Marc D; Vanderburg, Charles R et al. (2015) Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol 78:787-800
Nichols, Noah; Bras, Jose M; Hernandez, Dena G et al. (2015) EIF4G1 mutations do not cause Parkinson's disease. Neurobiol Aging 36:2444.e1-4
Goodheart, A E; Tamburo, E; Minhas, D et al. (2015) Reduced binding of Pittsburgh Compound-B in areas of white matter hyperintensities. Neuroimage Clin 9:479-83
Yau, Wai-Ying Wendy; Tudorascu, Dana L; McDade, Eric M et al. (2015) Longitudinal assessment of neuroimaging and clinical markers in autosomal dominant Alzheimer's disease: a prospective cohort study. Lancet Neurol 14:804-13
Chen, Yin J; Rosario, Bedda L; Mowrey, Wenzhu et al. (2015) Relative 11C-PiB Delivery as a Proxy of Relative CBF: Quantitative Evaluation Using Single-Session 15O-Water and 11C-PiB PET. J Nucl Med 56:1199-205
Mountz, James M; Laymon, Charles M; Cohen, Ann D et al. (2015) Comparison of qualitative and quantitative imaging characteristics of [11C]PiB and [18F]flutemetamol in normal control and Alzheimer's subjects. Neuroimage Clin 9:592-8

Showing the most recent 10 out of 88 publications