Truncated TDP‐43 proteoforms diagnostic of frontotemporal dementia with TDP‐43 pathology

INTRODUCTION Biomarkers of TDP‐43 pathology are needed to distinguish frontotemporal lobar degeneration with TDP‐43 pathology (FTLD‐TDP) from phenotypically related disorders. While normal physiological TDP‐43 is not a promising biomarker, low‐resolution techniques have suggested truncated forms of TDP‐43 may be specific to TDP‐43 pathology. To advance biomarker efforts for FTLD‐TDP, we employed a high‐resolution structural technique to characterize TDP‐43 post‐translational modifications in FTLD‐TDP. METHODS High‐resolution mass spectrometry was used to characterize TDP‐43 proteoforms in brain tissue from FTLD‐TDP, non‐TDP‐43 dementias and neuropathologically unaffected cases. Findings were then verified in a larger cohort of FTLD‐TDP and non‐TDP‐43 dementias via targeted quantitative mass spectrometry. RESULTS In the discovery phase, truncated TDP‐43 identified FTLD‐TDP with 85% sensitivity and 100% specificity. The verification phase revealed similar findings, with 83% sensitivity and 89% specificity. DISCUSSION The concentration of truncated TDP‐43 proteoforms—in particular, in vivo generated C‐terminal fragments—have high diagnostic accuracy for FTLD‐TDP. Highlights Discovery: Truncated TDP‐43 differentiates FTLD‐TDP from related dementias. Verification: Truncated TDP‐43 concentration has high accuracy for FTLD‐TDP. TDP‐43 proteoforms