Neuropathologically, Alzheimer's disease (AD) is defined by the presence of plaques composed of the amyloid-beta (Abeta) protein. This alone makes definition of the natural history of amyloid deposition in living subjects an important goal, but this longitudinal information is not obtainable through post-mortem studies. This information will be essential in the assessment of anti-amyloid drugs intended to alter the natural history of amyloid deposition. Our group has developed a novel amyloid-imaging positron emission tomography (PET) radiotracer termed """"""""Pittsburgh compound-B"""""""" (PIB) that, in initial 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 diagnostic tool or a surrogate marker of efficacy for anti-amyloid therapies. One of these characteristics is the variation of the quantity and regional distribution of PIB retention over time in individuals. This will be the focus of Project 2 of this Program Project (P01). To address this question, we will perform 12- and 24-month follow-up e studies on 15 control subjects, 15 MCI patients, 15 mild and 15 moderate AD patients who had identical bas line studies in Project 1 of this P01 (or in pilot studies during the year prior to initiation of this P01). All will have been clinically evaluated and diagnosed at the University of Pittsburgh Alzheimer Disease Research Center and further evaluated at each study point with a neuropsychological battery through the P01 Clinical Core. All subjects will be studied longitudinally with fully dynamic PIB PET scans at 12- and 24-months after their baseline evaluation in Project 1. In addition, volumetric MRI and FDG PET will be performed so we can directly compare changes in PIB retention to changes in hippocampal volume and cerebral metabolic rate. Image analysis will be performed in the P01 Imaging, Methodology and Statistics Core. The quantitative PIB PET data will be compared to neuropsychological measures to explore correlations between changes in regional amyloid load and changes in cognition. The association of apolipoprotein-E genotype and education with PIB retention also will be explored. We hypothesize that PIB retention in individual subjects will increase through moderate stages of AD and then plateau and that the rate of increase in PIB retention in individual subjects will be of larger magnitude and be detectable earlier than the rate of decrease in hippocampal volume or cerebral metabolic rate.
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