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Here, we tested the hypothesis that highly sensitive mass spectrometry with parallel reaction monitoring (MS\u2010PRM) can generate a high\u2010resolution map of pathological TDP\u201043 peptide ratios to form the basis for quantitation of abnormal C\u2010terminal TDP\u201043 fragment enrichment. Human cortex and spinal cord, microscopically staged for the presence of p\u2010TDP\u201043, p\u2010tau, alpha\u2010synuclein, and beta\u2010amyloid pathology, were biochemically fractionated and analyzed by immunoblot and MS for the detection of full\u2010length and truncated (disease\u2010specific) TDP\u201043 peptides. This informed the synthesis of heavy isotope\u2010labeled peptides for absolute quantification of TDP\u201043 by MS\u2010PRM across 16 ALS, 8 Parkinson\u2019s, 8 Alzheimer\u2019s disease, and 8 aged control cases. We confirmed by immunoblot the previously described enrichment of pathological C\u2010terminal fragments in ALS\u2010TDP urea fractions. Subsequent MS analysis resolved specific TDP\u201043\u00a0N\u2010 and C\u2010terminal peptides, including a novel N\u2010terminal truncation site\u2010specific peptide. Absolute quantification of peptides by MS\u2010PRM showed an increased C:N\u2010terminal TDP\u201043 peptide ratio in ALS\u2010TDP brain compared to normal and disease controls. A C:N\u2010terminal ratio &gt;1.5 discriminated ALS from controls with a sensitivity of 100% (CI 79.6\u2013100) and specificity of 100% (CI 68\u2013100), and from Parkinson\u2019s and Alzheimer\u2019s disease with a sensitivity of 93% (CI 70\u2013100) and specificity of 100% (CI 68\u2013100). N\u2010terminal truncation site\u2010specific peptides were increased in ALS in line with C\u2010terminal fragment enrichment, but were also found in a proportion of Alzheimer cases with normal C:N\u2010terminal ratio but coexistent limbic TDP\u201043 neuropathological changes. In conclusion this is a novel, sensitive, and specific method to quantify the enrichment of pathological TDP\u201043 fragments in human brain, which could form the basis for an antibody\u2010free assay. Our methodology has the potential to help clarify if specific pathological TDP\u201043 peptide signatures are associated with primary or secondary TDP\u201043 proteinopathies.<\/jats:p>","DOI":"10.1111\/bpa.12923","type":"journal-article","created":{"date-parts":[[2020,12,10]],"date-time":"2020-12-10T22:40:00Z","timestamp":1607640000000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Detection and quantification of novel C\u2010terminal TDP\u201043 fragments in ALS\u2010TDP"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5905-3826","authenticated-orcid":false,"given":"Emily","family":"Feneberg","sequence":"first","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences John Radcliffe Hospital University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip 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