The deposition of B-sheet fibrils in Alzheimer's disease (AD) brain is widely regarded as the primary cause of this devastating neurodegenerative disease. These deposits include the amyloid-beta (AB) protein in plaques and vascular amyloid and hyper-phosphorylated tau protein in neurofibrillary tangles, dystrophic neurites and neuropil threads. Despite the presence of this characteristic neuropathology and its critical importance in the pathophysiology of the disease, no non-invasive technique exists to assess the presence of these deposits in living patients. The absence of such a technique hinders early and presymptomatic diagnosis and will severely hinder the development of therapies aimed at prevention or reversal of B-sheet fibril deposition. The major theme of the candidate's funded research over the past decade has been the development of small- molecule probes to image B-sheet fibril deposits with non-invasive neuroimaging techniques. The overall goals of this Independent Scientist Award are to obtain training in PET radiochemistry, imaging technology and the neuropathology/neuroanatomy of AD in the context of the final pre-clinical stages of development of these B-sheet probes. The benefits of this training to the candidate's research are numerous. First, by gaining an understanding of radiotracer labeling techniques, the candidate will be better able direct the development of B-sheet fibril imaging probe precursors for radiolabeling. Second, by gaining an understanding of PET imaging technology, data analysis and pertinent neuroradiology, the candidate will be able to participate fully in the translation of the basic medicinal chemistry work already completed in the candidate's laboratory into human studies. Third, by gaining a more detailed understanding of the neuropathology of AD, the candidate will be better able to critically interpret the PET data. The research plan will occur in the setting of and extends currently funded studies aimed at improving the diagnosis and understanding of the pathophysiological progression of AD, including a funded study aimed at developing B-sheet probes for amyloid in AD. The long term goal of the candidate's research is in vivo quantitation of B- sheet fibril deposition in AD to aid in the diagnosis of early and pre- symptomatic AD, to improve the understanding of the pathophysiologic progression of AD and to allow efficacy monitoring of therapies aimed at slowing or halting B-sheet fibril deposition.
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