Truncated TDP-43 proteoforms diagnostic of frontotemporal dementia with TDP-43 pathology
Lauren M Forgrave1, Kyung-Mee Moon2, Jordan E Hamden1
1Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
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 <28 kDa have highest discriminatory power for TDP-43 pathology.
