PROJECT SUMMARY Molecular tau PET imaging has been available for the past four years and is able to detect paired helical filament (PHF) tau in Alzheimer?s disease. The most extensively utilized tau PET ligand is flortaucipir ([18F]AV- 1451). Over the past four years, however, since the development of flortaucipir, the field has been stumped by the observation of flortaucipir uptake occurring in patients with a frontotemporal lobar degeneration (FTLD) syndrome who would be expected to have underlying TDP-43 or 4R tau pathology, but not PHF tau. This observation has not been addressed, mainly due to the lack of autopsy cohorts, which is necessary to address this issue. We have been accumulating autopsied cases over the past four years and were able to assess the relationship between flortaucipir PET uptake and histopathology in an autopsy cohort of 26 patients (25 with Alzheimer?s disease and 1 with FTLD). Using a validated meta-ROI (region of interest) cut-point that we developed to determine whether PHF tau is present or absent in Alzheimer?s disease, we found flortaucipir PET to have great sensitivity and specificity to PHF tau, and to the Braak neurofibrillary tangle staging scheme. Interestingly, however, the single FTLD patient in that autopsy cohort with 4R tau deposition was classified as positive, suggesting that flortaucipir PET may indeed be detecting 4R tau. To date, there are no other autopsy studies, and no FTLD autopsy cohort has been described. Hence, there remain important knowledge gaps in the field. We still do not know whether flortaucipir uptake is indeed reflecting underlying 4R tau, what flortaucipir uptake is reflecting in FTLD TDP-43 where there is no tau, and how our meta-ROI cut-point would perform in an FTLD cohort. We have now amassed a large autopsy cohort of 80 cases with antemortem flortaucipir PET (FTLD with TDP-43 or 4R tau, n = 42 and Alzheimer?s disease, n=38). In this R01, we will study the relationship between antemortem flortaucipir uptake and pathological protein immunohistochemistry. Specifically, we will evaluate the association of flortaucipir PET with pathological diagnoses, association between flortaucipir PET uptake and the Braak neurofibrillary tangle stage in an FTLD cohort, and assess for associations between regional quantitative flortaucipir uptake and quantitative protein immunohistochemistry, across all 80 cases, to determine whether flortaucipir uptake is influenced by non-PHF tau targets, such as ?- amyloid, 4R tau, TDP-43, microglia and astroglia, and whether uptake is influenced by the presence of multiple non-PHF tau protein deposition. This multi-PI proposal is led by two expert PIs with almost 40 years of combined research experience in FTLD neuroimaging, including with flortaucipir PET (Professor Whitwell), and in degenerative neuropathology (Professor Josephs). If the aims of the grant were achieved the field would not only have a better understanding of flortaucipir PET behavior, but better understanding of tau ligand behavior in general, which would aid with second and third generation tau ligand development. Development of sensitive and specific future tau PET ligands is important for biomarker utility in clinical trials.
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