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.
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.
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.
The concentration of truncated TDP-43 proteoforms—in particular, in vivo generated C-terminal fragments—have high diagnostic accuracy for FTLD-TDP.

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.

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This post is Copyright: Lauren M. Forgrave,
Kyung‐Mee Moon,
Jordan E. Hamden,
Yun Li,
Phoebe Lu,
Leonard J. Foster,
Ian R. A. Mackenzie,
Mari L. DeMarco | July 18, 2023

Wiley: Alzheimer’s & Dementia: Table of Contents