Molecular Network Degeneration in FTLD-Related Pathology

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Dementia is associated with selective degeneration of microscopic and macroscale neuronal networks resulting in heterogeneous clinical features. Data from human neuropathology and experimental models support the hypothesis that neurodegenerative disease pathologies spread through selectively vulnerable neuronal networks. Frontotemporal dementia can manifest clinically as behavioral variant of FTD (bvFTD) or primary progressive aphasia (PPA). Both clinical phenotypes can be associated with the accumulation of protein aggregates in affected brain regions composed of either TDP-43 or tau protein. Understanding how networks degenerate in fronototemporal dementia is important in terms of understanding the progression of disease as it relates to variable clinical and pathologic subtypes. The goal of this project is to perform single cell RNA sequencing (scRNAseq) of key regions that degenerate in frontotemporal lobar degeneration to identify cellular-level molecular networks that are specifically altered due to TDP-43 versus tau pathology in behavioral variant frontotemporal dementia and primary progressive aphasia. Novel bioinformatics approaches will be applied to scRNAseq datasets to identify neuronal cell types and molecular networks which are selectively vulnerable in frontotemporal dementia clinicopathologic subtypes.