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Biomarker discovery for frontotemporal dementia with TDP-43 pathology Forgrave, Lauren

Abstract

Background: Frontotemporal dementia (FTD) is the second most common form of early-onset dementia, presenting with behavior and language problems. FTD is the syndrome which is pathologically associated with frontotemporal lobar degeneration (FTLD) with pathological aggregates of transactive-response DNA binding protein (TDP-43; termed FTLD-TDP). Clinically, it can be difficult to distinguish dementia with underlying FTLD-TDP from other dementias; thus, biofluid diagnostics and imaging tracers for FTLD-TDP are desired. To address this, we investigated the wide-spread impact of TDP-43 pathology and current biomarker studies. Then we performed biomarker discovery and verification studies. Methods: To begin, we reviewed the literature on the aggregation of TDP-43 in neurodegenerative diseases. We then performed a systematic review and meta-analysis of the most studied biofluid biomarker in FTD–neurofilament light chain (NfL)–to assess its diagnostic performance for FTD. In experimental studies, we characterized human brain tissues from FTLD-TDP cases and assessed for disease-specific TDP-43 proteoforms and explored for proteins that co-segregate in the TDP-43-pathological tissue fraction. Results: Via a systemic review of 116 autopsy studies of TDP-43, we found that TDP-43 pathology is common, and its morphology and cellular localization are inadequately described by the current classification scheme developed for FTLD-TDP and amyotrophic lateral sclerosis. Through the synthesis of 65 studies on NfL, we found that NfL was likely not a disease-specific biomarker for FTD. Through our proteomic analysis of brain tissue, we identified disease-specific TDP-43 proteoforms and confirmed these findings in a verification study. Additionally, characterization of proteins that co-segregate with TDP-43 identified eight proteins that were enriched in FTLD-TDP cases compared to controls and verified these findings for four candidates. Conclusions: We show that TDP-43 pathology requires further classification to enable better comparison between studies. We show that NfL in CSF and blood has high diagnostic accuracy between FTD and healthy individuals, but it is likely unable to distinguish FTD from other dementias with high accuracy. Next, we identified TDP-43 proteoforms in brain tissue diagnostic of FTLD-TDP pathology and proteins that co-segregate with TDP-43 that warrant further assessment for their involvement in FTLD-TDP pathogenesis and as potential biofluid biomarkers and/or imaging tracer targets.

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Attribution-NonCommercial-NoDerivatives 4.0 International