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Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R\/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values &gt;0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R\/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.<\/jats:p>","DOI":"10.1038\/s41591-024-02937-4","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T06:02:32Z","timestamp":1718690552000},"page":"1771-1783","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":216,"title":["Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and 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A. Schneider serves in a scientific advisory board for and receives honoraria from Biogen. She additionally received funding for a scientific collaboration from Eisai and honoraria for presentations from Eisai. M.C. is currently an employee of uniQure Biopharma B.V. and recipient of employee stock options. F.H. receives author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers. P.H. is an employee and owns stock in Alector LLC. K. Brockmann is a consultant for F. Hoffmann-La Roche Ltd, Vanqua Bio and the Michael J. Fox Foundation for Parkinson\u2019s Research and has received speaker honoraria from AbbVie, Lundbeck, UCB (Union Chimique Belge) and Zambon. N.H. has received travel support from Eli Lilly. A. Hermann has received honoraria for presentations and participation in advisory boards from Amylyx and IFT Pharma. He has received royalities from Elsevier Press and Kohlhammer. Washington University and R.J.B. have equity ownership interest in C2N Diagnostics and R.J.B. receives income from C2N Diagnostics for serving on the scientific advisory board. R.J.B. and N.R.B. may receive income based on technology (methods to detect microtubule binding region (MTBR) tau isoforms and use thereof) licensed by Washington University to C2N Diagnostics. R.J.B. has received research funding from Avid Radiopharmaceuticals, Janssen, Roche\/Genentech, Eli Lilly, Eisai, Biogen, AbbVie, Bristol Myers Squibb and Novartis. R.J.B. serves on the Roche Gantenerumab Steering Committee as an unpaid member. R.G. received speaker fees and nonfinancial support from Biogen, Roche, Zambon and research support from Biogen, ITF Pharma and Zambon outside this work. D.A. participated in advisory boards from Fujirebio-Europe, Roche Diagnostics, Grifols S.A. and Lilly, and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmac\u00e9utica S.L., Zambon S.A.U. and Esteve Pharmaceuticals S.A. D.A. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). J.W. received lecture honoraria from Beeijing Yibai Science and Technology Ltd, Gloryren, Janssen Cilag, Pfizer, Med Update GmbH, Roche Pharma, Lilly and serves on advisory boards for Biogen, Abbott, Boehringer Ingelheim, Lilly, MSD Sharp & Dohme and Roche. M. Brandt received speaker honoraria from Idorsia, Eisai and Bristol Myers Squibb. All other authors state no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}