PET Imaging of Macrophages and Amyloid in AD

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DESCRIPTION (provided by applicant): Neuropathologically, Alzheimer's disease (AD) is defined by the presence of tangles and plaques composed of the amyloid-beta (Abeta) protein and activated microglia. Identification of AD pathology in living subjects is an important goal because it could allow refinement of early diagnosis and identification of pre-symptomatic pathology. In addition, the optimal development of new anti-amyloid therapies will require a means to monitor brain amyloid load and its active removal. Our group has developed a novel amyloid-imaging positron emission tomography (PET) radiotracer termed "Pittsburgh compound-B" (PIB) that distinguish AD from control subjects and had a regional distribution consistent with that of the post-mortem distribution of plaques. Additionally we have used radiolabeled PK11195 a peripheral benzodiazepine receptor ligand that permits PET assessment of microglial activation. This R21 will examine the relationship between amyloid deposition and microglial activation in different stages of Alzheimer's Disease. We will recruit 5 control subjects, 5 minor cognitively impaired, 5 mild, and 5 moderate AD patients. All subjects will have been clinically evaluated and diagnosed by the University of Pittsburgh Alzheimer Disease Research Center (ADRC) and further evaluated with a neuropsychological battery through the ADRC. All subjects will be studied cross-sectionally with PIB and PK11195 PET scans. In addition, volumetric MRI will be performed so we can directly compare these current neuroimaging standards. The quantitative PIB and PK11195 PET data will be compared to neuropsychological measures to explore possible correlations between regional amyloid load, activated microglia and performance on function-specific cognitive testing (e.g. frontal or visuospatial tasks). We hypothesize that subjects with more severe cognitive impairment will show greater PIB retention consistent and greater amyloid burden and will show greater PK11195 retention consistent with increased microglial activation. Delineation of the relationship between amyloid deposition and microglial activation will help define the role of microglial activation in the pathogenesis of amyloid deposition and with development of immunotherapies, help discern the role of activated microglia in eliminating amyloid.