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 #
5P01AG025204-08
Application #
8572482
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (J5))
Project Start
2005-05-15
Project End
2015-04-30
Budget Start
2012-05-15
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$287,620
Indirect Cost
$92,724
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Marquié, Marta; Normandin, Marc D; Meltzer, Avery C et al. (2017) Pathological correlations of [F-18]-AV-1451 imaging in non-alzheimer tauopathies. Ann Neurol 81:117-128
Edelman, Kathryn; Tudorascu, Dana; Agudelo, Christian et al. (2017) Amyloid-Beta Deposition is Associated with Increased Medial Temporal Lobe Activation during Memory Encoding in the Cognitively Normal Elderly. Am J Geriatr Psychiatry 25:551-560
Nadkarni, Neelesh K; Perera, Subashan; Snitz, Beth E et al. (2017) Association of Brain Amyloid-? With Slow Gait in Elderly Individuals Without Dementia: Influence of Cognition and Apolipoprotein E ?4 Genotype. JAMA Neurol 74:82-90
Mathis, Chester A; Lopresti, Brian J; Ikonomovic, Milos D et al. (2017) Small-molecule PET Tracers for Imaging Proteinopathies. Semin Nucl Med 47:553-575
Nadkarni, Neelesh K; Lopez, Oscar L; Perera, Subashan et al. (2017) Cerebral Amyloid Deposition and Dual-Tasking in Cognitively Normal, Mobility Unimpaired Older Adults. J Gerontol A Biol Sci Med Sci 72:431-437
Counts, Scott E; Ikonomovic, Milos D; Mercado, Natosha et al. (2017) Biomarkers for the Early Detection and Progression of Alzheimer's Disease. Neurotherapeutics 14:35-53
Mi, Zhiping; Abrahamson, Eric E; Ryu, Angela Y et al. (2017) Loss of precuneus dendritic spines immunopositive for spinophilin is related to cognitive impairment in early Alzheimer's disease. Neurobiol Aging 55:159-166
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
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

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