Pathology-guided 7T neuroimaging biomarker in FTLD-TDP

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TDP-43 proteinopathy is a common form of neurodegenerative dementia (i.e. frontotemporal dementia, FTD) in patients younger than 65 (i.e. frontotemporal lobar degeneration with TDP-43 proteinopathy, FTLD-TDP) and is a common co-pathology in Alzheimer’s disease and aging. There are currently no biomarker modalities that can accurately identify and track TDP-43 mediated neurodegeneration in living patients, which poses a major obstacle for clinical trials targeting TDP-43 associated mechanisms of disease. Indeed, FTLD-TDP is an incurable condition and cannot be reliably diagnosed and differentiated from clinically similar patients with tauopathy (FTLD-Tau) during life, making autopsy the gold-standard for diagnosis. The overarching goal of this project is to integrate digital histology of human brain tissue with high-resolution ex vivo 7 Tesla (7T) magnetic resonance imaging (MRI) to model TDP-43 disease in the human brain connectome. We aim to first use ex vivo 7T MRI guided sampling of grey matter (GM) regions important for neurocognitive networks that underly FTD clinical symptoms and contrast the distribution of TDP-43 and clinically indistinguishable FTLD-Tau to determine microscopic GM cellular patterns of TDP-43 protienopathy. Next, we will examine TDP-43 pathology in uniquely sampled deep white matter (WM) tracts and contrast the distribution of TDP-43 and tau pathology in WM pathways of neurocognitive networks using graph theoretic analysis. Finally, we will examine GM laminar features of TDP-43 pathology in 7T MRI ex vivo imaging. Successful completion of these aims will provide critically needed autopsy-data to guide development of histopathology-validated markers of progressive microscopic TDP-43 disease in macroscale neurocognitive networks implicated in FTD.