Disparate and shared transcriptomic signatures associated with cortical atrophy in genetic bvFTD

Abstract

AbstractCortical atrophy in behavioral variant frontotemporal degeneration (bvFTD) exhibits spatial heterogeneity across genetic subgroups, potentially driven by distinct biological mechanisms. Using an integrative imaging-transcriptomics approach, we identified disparate and shared transcriptomic signatures associated with cortical thickness inC9orf72,GRNorMAPT-related bvFTD. Genes associated with cortical thinning inGRN-bvFTD were implicated in neurotransmission, further supported by mapping synaptic density maps to cortical thickness maps. Previously identified genes linked to TDP-43 positive neurons were significantly overlapped with genes associated withC9orf72-bvFTD andGRN-bvFTD, but notMAPT-bvFTD providing specificity for our associations.C9orf72-bvFTD andGRN-bvFTD shared genes displaying consistent directionality of correlations with cortical thickness, whileMAPT-bvFTD displayed more pronounced differences in transcriptomic signatures with opposing directionality. Overall, we identified disparate and shared genes tied to regional vulnerability with increased biological interpretation including overlap with synaptic density maps and pathologically-specific gene expression, illuminating intricate molecular underpinnings contributing to heterogeneities in bvFTD.