Neuropathologically, Alzheimer's disease (AD) is defined by the presence of plaques composed of the amyloid-beta (Abeta) protein. This alone makes identification of AD pathology in living subjects an important goal because it could allow refinement of early diagnosis and identification of pre-symptomatic pathology for use as a biomarker. In addition, the optimal development of new anti-amyloid therapies will require a means to monitor brain amyloid load. Our group has developed a novel amyloid-imaging positron emission tomography (PET) radiotracer termed """"""""Pittsburgh compound-B"""""""" (PIB) that, in proof-of-concept studies, performed well to distinguish AD from control subjects and localized in brain with a regional distribution consistent with that of the post-mortem distribution of plaques. While these results are exciting, certain basic and fundamental characteristics of this PIB PET technology must be further defined before this amyloid imaging technology can reach its potential as a diagnostic tool or a surrogate marker of efficacy. One of these fundamental characteristics is the variation of PIB retention (as a marker of amyloid load) across the full spectrum of disease severity in AD. This will be the focus of Project 1 of this Program Project (P01). To address this question, we will recruit 20 control subjects, 20 MCI patients, 20 mild and 20 moderate AD patients and 10 severe AD patients. All will be clinically evaluated and diagnosed by the University of Pittsburgh Alzheimer Disease Research Center and further evaluated with a neuropsychological battery through the P01 Clinical Core. All subjects will be studied cross-sectionally with a fully dynamic PIB PET scan. In addition, volumetric MRI and FDG PET will be performed so we can directly compare these current neuroimaging standards with the new PIB PET technology. Image analysis will be performed in the P01 Imaging, Methodology and Statistics Core. The control subjects, MCI and AD patients will be referred to Project 2 for the longitudinal studies and the control subjects also will serve as controls for Project 3. A simplified protocol will be used for the severe AD patients. The quantitative PIB PET data will be compared to neuropsychological measures to explore possible correlations between regional amyloid load and performance on function-specific cognitive testing (e.g. frontal or visuospatial tasks). The association of apolipoprotein-E genotype and education with PIB retention also will be explored. We hypothesize that PIB retention will be greater in subjects with more severe cognitive impairment through moderate AD and then plateau and that increased PIB retention will be of larger magnitude and will be detectable earlier than decreased hippocampal volume or decreased cerebral metabolic rate.
Showing the most recent 10 out of 106 publications
