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Using immunoprecipitation and mass spectrometry, we show that 4 repeat (4R) isoform-specific tau species from microtubule-binding region (MTBR-tau<jats:sub>275<\/jats:sub>and MTBR-tau<jats:sub>282<\/jats:sub>) increase in the brains of corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD)-<jats:italic>MAPT<\/jats:italic>and AD but decrease inversely in the cerebrospinal fluid (CSF) of CBD, FTLD-<jats:italic>MAPT<\/jats:italic>and AD compared to control and other FTLD-tau (for example, Pick\u2019s disease). CSF MTBR-tau measures are reproducible in repeated lumbar punctures and can be used to distinguish CBD from control (receiver operating characteristic area under the curve (AUC)\u2009=\u20090.889) and other FTLD-tau, such as PSP (AUC\u2009=\u20090.886). CSF MTBR-tau<jats:sub>275<\/jats:sub>and MTBR-tau<jats:sub>282<\/jats:sub>may represent the first affirmative biomarkers to aid in the diagnosis of primary tauopathies and facilitate clinical trial designs.<\/jats:p>","DOI":"10.1038\/s41591-022-02075-9","type":"journal-article","created":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T06:43:33Z","timestamp":1669358613000},"page":"2547-2554","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":96,"title":["CSF tau microtubule-binding region identifies pathological changes in primary tauopathies"],"prefix":"10.1038","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-2614","authenticated-orcid":false,"given":"Kanta","family":"Horie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas R.","family":"Barth\u00e9lemy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3570-9143","authenticated-orcid":false,"given":"Salvatore","family":"Spina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8304-6711","authenticated-orcid":false,"given":"Lawren","family":"VandeVrede","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2543-4553","authenticated-orcid":false,"given":"Yingxin","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9372-3635","authenticated-orcid":false,"given":"Ross W.","family":"Paterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenton A.","family":"Wright","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5133-5538","authenticated-orcid":false,"given":"Gregory S.","family":"Day","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2042-8445","authenticated-orcid":false,"given":"Albert A.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6854-5547","authenticated-orcid":false,"given":"Celeste M.","family":"Karch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William W.","family":"Seeley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3443-7716","authenticated-orcid":false,"given":"Richard J.","family":"Perrin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rama K.","family":"Koppisetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faris","family":"Shaikh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Argentina Lario","family":"Lago","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary W.","family":"Heuer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6680-6731","authenticated-orcid":false,"given":"Nupur","family":"Ghoshal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Gabelle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce L.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1215-5064","authenticated-orcid":false,"given":"Adam L.","family":"Boxer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7729-1702","authenticated-orcid":false,"given":"Randall J.","family":"Bateman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7639-8727","authenticated-orcid":false,"given":"Chihiro","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,24]]},"reference":[{"key":"2075_CR1","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1016\/j.jalz.2017.06.2266","volume":"13","author":"V Ovod","year":"2017","unstructured":"Ovod, V. et al. 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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., N.R.B., K.H. and C.S. may receive income based on technology (Methods to detect 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. RJB serves on the Roche Gantenerumab Steering Committee as an unpaid member. S.S. has received consultation fees from Techspert.io, Acsel Health and PRECISIONxtract. L.V. has served as a consultant for Retrotope. R.W.P. has received honoraria as an educational speaker for GE Healthcare. B.A.W. has participated or is currently participating in clinical research sponsored by Acadia, Biogen, Global Kinetics, Neurocrine, Prilenia, PTC, Roche, Sage, Vaccinex, Transposon and Triplet Therapeutics. G.S.D.\u2019s research is supported by the NIH (K23AG064029, U01AG057195, U19AG032438), the Alzheimer\u2019s Association and Chan Zuckerberg Initiative. He serves as a consultant for Parabon NanoLabs, as a topic editor (dementia) for DynaMed (EBSCO) and as the Clinical Director of the Anti-NMDA Receptor Encephalitis Foundation (Canada; uncompensated). He is the co-project principal investigator for a clinical trial in anti-<i>N<\/i>-methyl-D-aspartate receptor encephalitis, which receives support from Horizon Pharmaceuticals. He has developed educational materials for PeerView Media and Continuing Education. His institution has received support from Eli Lilly for the development and presentation of educational content at an academic conference. He owns stock in ANI Pharmaceuticals. A.A.D. received compensation for performing procedures related to a clinical trial sponsored by Roche and received honoraria as a speaker from the Glaucoma Research and BrightFocus Foundations. W.W.S. received consulting fees from Guidepoint Global, GLG Council and BridgeBio. N.G. has participated or is currently participating in clinical trials of anti-dementia drugs sponsored by the following companies: Bristol Myers Squibb, Eli Lilly\/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth and Roche. B.L.M. receives royalties from Cambridge University Press, Johns Hopkins University Press, Taylor & Francis Group, Guilford Publications, Oxford University Press and Elsevier, and honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, such as UCLA Grand Rounds, UCI MIND seminar series, Taipei Medical University, Dementia Center and Korean Dementia Society talks. A.L.B. has served as a consultant for Alector Therapeutics, Arkuda, Arvinas, AZTherapeutics, Boehringer Ingelheim, Denali, GSK, Humana, Oligomerix, Oscotec, Roche, Third Rock, Transposon Therapeutics, TrueBinding and Wave. Y.H., C.M.K., R.J.P., R.K.K., F.S., A.L.L., H.W.H. and A.G. declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}