PET imaging of activated microglia in Alzheimer's Disease

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DESCRIPTION (provided by applicant): There is increasing preclinical evidence for a central the role of neuroinflammation in the progression of Alzheimer disease (AD). In pathologic studies, the transition of microglia from a quiescent to activated state is critical to neuroinflammation in AD. Despite strong preclinical evidence there have been no clinical studies of the role of microglial activation in the prognosis of AD. The hypothesis of this study is that greater numbers of activated microglia in selected brain regions will be associated with a more rapid rate of cognitive and functional decline over time. The candidate proposes to image microglial activation in in vivo patients with early AD using the PET ligand 11G-PK11195 which binds to peripheral benzodiazepine receptors which are associated with the number of activated microglia in the brain. METHOD: Forty well- characterized patients with early AD will be imaged with 11C-PK11195 at baseline and followed annually for two years using standard clinical cognitive, functional, and neuropsychiatric measures of progression. It is predicted that the degree of baseline retention of PK11195 in brain PET scans in key brain areas (indicative of more intense microglial activation and hence greater neuroinflammation) will be predictive of more rapid progression in the clinical measures. If 11C-PK11195 binding is associated with disease progression this would suggest the importance of neuroinflammation in AD disease course, and if not the role of neuroinflammation in AD disease course will be called into question. TRAINING GOALS: The overall goal is to acquire new methodological skills sufficient to allow the candidate to pursue a career as an independent investigator of biomarkers of AD. To accomplish these goals the candidate seeks training in: 1) Clinical study design in aging and AD (Drs. Lyketsos and Albert); 2) PET imaging and analysis (Drs. Pomper and Wong); 3) longitudinal data analysis (Dr. Frangakis); and 4) neuroinflammation (Dr. Nath). The training program integrates coursework, tutorials with mentors, and research experience in these four areas. RELEVANCE: This proposal could lead to the development of a biomarker reflecting neuroinflammation that for predicting prognosis of AD. The deep and broad training experience proposed will utilize the rich intellectual resources of Johns Hopkins to allow the candidate to become an independent investigator of biomarkers of AD.