Identification TDP‐43 fragments specific for frontotemporal lobar degeneration with TDP‐43 inclusions

Background Ante‐mortem biomarkers specific for TDP‐43 pathology are highly desired given the challenge in distinguishing frontotemporal lobar degeneration with TDP‐43 pathology (FTLD‐TDP) from phenotypically related disorders. TDP‐43 post‐translational modifications, like C‐terminal fragments, are regarded as disease‐specific TDP‐43 proteoforms; however, the exact structure of these proteoforms remains unclear. This lack of clarity is due in part to the use of instrumentation and techniques with low structural resolution and the study of small sample sizes. With this in mind, we performed high resolution mass spectrometry (HRMS) analysis of brain tissue from cases with and without TDP‐43 proteinopathy to identify TDP‐43 proteoforms unique to FTLD‐TDP. Method HRMS was used to determine TDP‐43 proteoform composition in insoluble frontal lobe brain tissue from immunohistochemically‐confirmed FTLD‐TDP (n=13), related dementias (i.e., Alzheimer’s disease and FTLD‐tau without TDP‐43 deposits; n=10) and neuropathologically‐unaffected controls (n=3). Brain tissue was fractioned by gel electrophoresis, with HRMS analysis performed on molecular weight regions corresponding to