{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:11:32Z","timestamp":1792131092148,"version":"4.4.0"},"reference-count":37,"publisher":"American Medical Association (AMA)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n With blood-based phosphorylated tau biomarkers soon to be used for diagnosis of Alzheimer disease, analyzing tau levels in other conditions could enhance biomarker interpretability. Moreover, mechanisms of tau release into circulation remain unclear.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To evaluate concentrations of phosphorylated and nonphosphorylated tau variants in the blood of patients with multiple traumatic injuries on days 0, 1, 5, and 10 and investigate biological processes driving tau release.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This multiple-trauma cohort (injury severity score, \u226518) included 45 severely injured patients with (n\u2009=\u200927) and without (n\u2009=\u200918) moderate-to-severe traumatic brain injury on emergency computed tomographic imaging. Controls consisted of 24 healthy volunteers. Participants were recruited from December 1, 2013, to October 31, 2022. Blood samples were analyzed for brain-derived tau (BD-tau), total tau (t-tau), and phosphorylated tau 217 (p-tau217) and 231 (p-tau231) levels. Associations among tau concentrations, clinical data, and outcome (eg, Glasgow Coma Scale [GCS] score) were assessed. Data were analyzed from March 1, 2023, to September 30, 2024.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n Serum BD-tau, t-tau, p-tau217, and p-tau231 levels.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 214 serum samples were analyzed. Median age of the 45 patients was 48 (IQR, 33-60) years (35 [77.8%] male); median age of the 24 controls, 43 (IQR, 28-50) years (16 [66.7%] male). Median serum levels of tau variants were increased in patients with multiple traumatic injuries at day 0 compared with controls (t-tau: 43 [IQR, 21-95] vs 3 [IQR, 3-5] pg\/mL; BD-tau: 78 [IQR, 30-343] vs 2 [IQR, 2-3] pg\/mL; p-tau231: 61 [IQR, 21-79] vs 2 [IQR, 1-3] pg\/mL; all,\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001). Only median BD-tau levels remained elevated until day 10 (day 1, 25 [IQR, 14-69] pg\/mL; day 5, 9 [IQR, 4-15] pg\/mL; day 10, 8 [IQR, 4-18] pg\/mL). Median tau levels at admission were higher in patients with lower GCS scores (BD-tau: 107 [ IQR, 59-838] vs 33 [IQR, 24-78] pg\/mL [\n P<\/jats:italic>\n \u2009=\u2009.01]; p-tau231: 76 [IQR, 36-114] vs 28 [IQR, 9\u201363] pg\/mL [\n P<\/jats:italic>\n \u2009=\u2009.02]). Elevated median tau levels were also observed in patients with hemorrhagic shock vs those without shock (eg, BD-tau on day 0: 113 [IQR, 78-378] vs 31 [IQR, 24-61] pg\/mL;\n P<\/jats:italic>\n \u2009=\u2009.002) and in nonsurvivors vs survivors with uncomplicated courses (eg, BD-tau on day 1: 92 [IQR, 22-527] vs 16 [IQR, 7-23] pg\/mL;\n P<\/jats:italic>\n \u2009=\u2009.009).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this exploratory study among a cohort of patients with multiple traumatic injuries, levels of tau variants reflected both direct and indirect neurological injury, with BD-tau showing the most persistent elevation in the acute phase.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.58573","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T16:00:19Z","timestamp":1770739219000},"page":"e2558573","source":"Crossref","is-referenced-by-count":4,"title":["Blood-Based Analysis of Different Tau Variants in Patients With Multiple Traumatic Injuries"],"prefix":"10.1001","volume":"9","author":[{"given":"Rebecca","family":"Halbgebauer","sequence":"first","affiliation":[{"name":"Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Gonzalez-Ortiz","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, University of Gothenburg, M\u00f6lndal, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Mayer","sequence":"additional","affiliation":[{"name":"Institute for Epidemiology and Medical Biometry, Ulm University, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudius","family":"Berger","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Bergmann","sequence":"additional","affiliation":[{"name":"Translational and Experimental Trauma Research, Department of Trauma, Hand, and Reconstructive Surgery, Ulm University Medical Center, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Rinderknecht","sequence":"additional","affiliation":[{"name":"Translational and Experimental Trauma Research, Department of Trauma, Hand, and Reconstructive Surgery, Ulm University Medical Center, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eberhard","family":"Barth","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Ulm University Medical Center, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Wohlgemuth","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Mannes","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Otto","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Halle, Halle (Saale), Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayrettin","family":"Tumani","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ulm University Hospital, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borna","family":"Relja","sequence":"additional","affiliation":[{"name":"Translational and Experimental Trauma Research, Department of Trauma, Hand, and Reconstructive Surgery, Ulm University Medical Center, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Gebhard","sequence":"additional","affiliation":[{"name":"Translational and Experimental Trauma Research, Department of Trauma, Hand, and Reconstructive Surgery, Ulm University Medical Center, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Huber-Lang","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, University of Gothenburg, M\u00f6lndal, Sweden"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, M\u00f6lndal, Sweden"},{"name":"Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, United Kingdom"},{"name":"UK Dementia Research Institute at University College London, London, United Kingdom"},{"name":"Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Halbgebauer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ulm University Hospital, Ulm, Germany"},{"name":"German Center for Neurodegenerative Diseases, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, University of Gothenburg, M\u00f6lndal, Sweden"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, M\u00f6lndal, Sweden"},{"name":"Paris Brain Institute, Institut du Cerveau et de la Moelle Epini\u00e8re, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Sorbonne University, Paris, France"},{"name":"Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of University of Science and Technology of China, Hefei, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2026,2,10]]},"reference":[{"issue":"1","key":"zoi251559r1","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s13024-023-00605-8","article-title":"Plasma phospho-tau in Alzheimer\u2019s disease: towards diagnostic and therapeutic trial applications.","volume":"18","author":"Gonzalez-Ortiz","year":"2023","journal-title":"Mol Neurodegener"},{"issue":"1","key":"zoi251559r2","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/S1474-4422(21)00361-6","article-title":"Blood-based biomarkers for Alzheimer\u2019s disease: towards clinical implementation.","volume":"21","author":"Teunissen","year":"2022","journal-title":"Lancet Neurol"},{"issue":"1","key":"zoi251559r3","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/s42003-024-05920-4","article-title":"Phosphorylation regulates tau\u2019s phase separation behavior and interactions with chromatin.","volume":"7","author":"Abasi","year":"2024","journal-title":"Commun Biol"},{"issue":"11","key":"zoi251559r4","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1038\/s41580-024-00753-9","article-title":"Cellular and pathological functions of tau.","volume":"25","author":"Parra Bravo","year":"2024","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"7","key":"zoi251559r5","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/j.tins.2020.04.007","article-title":"Resurrecting the mysteries of big tau.","volume":"43","author":"Fischer","year":"2020","journal-title":"Trends Neurosci"},{"issue":"3","key":"zoi251559r6","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1002\/jcb.22287","article-title":"Microtubule-associated protein tau in human prostate cancer cells: isoforms, phosphorylation, and interactions.","volume":"108","author":"Souter","year":"2009","journal-title":"J Cell Biochem"},{"issue":"7","key":"zoi251559r7","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202300620RR","article-title":"Infection promotes Ser-214 phosphorylation important for generation of cytotoxic tau variants.","volume":"37","author":"Balczon","year":"2023","journal-title":"FASEB J"},{"issue":"17","key":"zoi251559r8","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1093\/eurheartj\/ehad205","article-title":"Big tau aggregation disrupts microtubule tyrosination and causes myocardial diastolic dysfunction: from discovery to therapy.","volume":"44","author":"Luciani","year":"2023","journal-title":"Eur Heart J"},{"issue":"1","key":"zoi251559r9","doi-asserted-by":"publisher","first-page":"2019","DOI":"10.1038\/s41467-025-57144-7","article-title":"Phosphorylated tau 181 and 217 are elevated in serum and muscle of patients with amyotrophic lateral sclerosis.","volume":"16","author":"Abu-Rumeileh","year":"2025","journal-title":"Nat Commun"},{"issue":"11","key":"zoi251559r10","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20200861","article-title":"Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer\u2019s disease.","volume":"217","author":"Barth\u00e9lemy","year":"2020","journal-title":"J Exp Med"},{"key":"zoi251559r11","doi-asserted-by":"publisher","first-page":"33","DOI":"10.3389\/fnins.2015.00033","article-title":"The relationship between truncation and phosphorylation at the C-terminus of tau protein in the paired helical filaments of Alzheimer\u2019s disease.","volume":"9","author":"Flores-Rodr\u00edguez","year":"2015","journal-title":"Front Neurosci"},{"issue":"6","key":"zoi251559r12","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcae375","article-title":"Plasma phosphorylated-tau217 is increased in Niemann-Pick disease type C.","volume":"6","author":"Gonzalez-Ortiz","year":"2024","journal-title":"Brain Commun"},{"issue":"4","key":"zoi251559r13","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000209129","article-title":"Association of plasma brain-derived tau with functional outcome after ischemic stroke.","volume":"102","author":"Stanne","year":"2024","journal-title":"Neurology"},{"key":"zoi251559r14","doi-asserted-by":"publisher","author":"Gonzalez-Ortiz","journal-title":"J Intern Med","DOI":"10.1111\/joim.20041"},{"issue":"7","key":"zoi251559r15","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.21554","article-title":"Association of serum brain-derived tau with clinical outcome and longitudinal change in patients with severe traumatic brain injury.","volume":"6","author":"Gonzalez-Ortiz","year":"2023","journal-title":"JAMA Netw Open"},{"key":"zoi251559r16","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.123.046117","article-title":"Plasma brain-derived tau in prognosis of large vessel occlusion ischemic stroke.","author":"Varela","journal-title":"Stroke"},{"issue":"2","key":"zoi251559r17","doi-asserted-by":"publisher","first-page":"447","DOI":"10.3233\/JAD-180721","article-title":"Tau biology, tauopathy, traumatic brain injury, and diagnostic challenges.","volume":"67","author":"Castellani","year":"2019","journal-title":"J Alzheimers Dis"},{"key":"zoi251559r18","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.619721","article-title":"Acute stroke biomarkers: are we there yet?","volume":"12","author":"Dagonnier","year":"2021","journal-title":"Front Neurol"},{"key":"zoi251559r19","doi-asserted-by":"publisher","first-page":"2989","DOI":"10.2147\/NDT.S125620","article-title":"Biomarkers in traumatic brain injury (TBI): a review.","volume":"14","author":"Dadas","year":"2018","journal-title":"Neuropsychiatr Dis Treat"},{"issue":"9952","key":"zoi251559r20","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1016\/S0140-6736(14)60687-5","article-title":"The systemic immune response to trauma: an overview of pathophysiology and treatment.","volume":"384","author":"Lord","year":"2014","journal-title":"Lancet"},{"issue":"4","key":"zoi251559r21","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/s41590-018-0064-8","article-title":"Innate immune responses to trauma.","volume":"19","author":"Huber-Lang","year":"2018","journal-title":"Nat Immunol"},{"issue":"11","key":"zoi251559r22","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1016\/S1474-4422(22)00309-X","article-title":"Traumatic brain injury: progress and challenges in prevention, clinical care, and research.","volume":"21","author":"Maas","year":"2022","journal-title":"Lancet Neurol"},{"issue":"20","key":"zoi251559r23","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1001\/jama.2013.281053","article-title":"World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.","volume":"310","author":"World Medical Association","year":"2013","journal-title":"JAMA"},{"issue":"3","key":"zoi251559r24","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1093\/brain\/awac407","article-title":"Brain-derived tau: a novel blood-based biomarker for Alzheimer\u2019s disease-type neurodegeneration.","volume":"146","author":"Gonzalez-Ortiz","year":"2023","journal-title":"Brain"},{"issue":"5","key":"zoi251559r25","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1007\/s00401-021-02275-6","article-title":"Plasma p-tau231: a new biomarker for incipient Alzheimer\u2019s disease pathology.","volume":"141","author":"Ashton","year":"2021","journal-title":"Acta Neuropathol"},{"issue":"1","key":"zoi251559r26","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1186\/s13054-024-04889-0","article-title":"Plasma glial fibrillary acidic protein and tau: predictors of neurological outcome after cardiac arrest.","volume":"28","author":"Arctaedius","year":"2024","journal-title":"Crit Care"},{"issue":"5","key":"zoi251559r27","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1002\/ana.25067","article-title":"Serum tau and neurological outcome in cardiac arrest.","volume":"82","author":"Mattsson","year":"2017","journal-title":"Ann Neurol"},{"issue":"17","key":"zoi251559r28","doi-asserted-by":"publisher","first-page":"9639","DOI":"10.3390\/ijms23179639","article-title":"Neurochemical monitoring of traumatic brain injury by the combined analysis of plasma beta-synuclein, NfL, and GFAP in polytraumatized patients.","volume":"23","author":"Halbgebauer","year":"2022","journal-title":"Int J Mol Sci"},{"key":"zoi251559r29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.918380","article-title":"Innate immunity and immunotherapy for hemorrhagic shock.","volume":"13","author":"Huang","year":"2022","journal-title":"Front Immunol"},{"key":"zoi251559r30","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.jcrc.2017.11.025","article-title":"Hemorrhagic shock drives glycocalyx, barrier and organ dysfunction early after polytrauma.","volume":"44","author":"Halbgebauer","year":"2018","journal-title":"J Crit Care"},{"issue":"2","key":"zoi251559r32","doi-asserted-by":"publisher","first-page":"345","DOI":"10.3233\/JAD-150859","article-title":"The presence of select tau species in human peripheral tissues and their relation to Alzheimer\u2019s disease.","volume":"51","author":"Dugger","year":"2016","journal-title":"J Alzheimers Dis"},{"issue":"2","key":"zoi251559r33","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14422","article-title":"Clinical value of novel blood-based tau biomarkers in Creutzfeldt-Jakob disease.","volume":"21","author":"Bentivenga","year":"2025","journal-title":"Alzheimers Dement"},{"key":"zoi251559r34","doi-asserted-by":"publisher","first-page":"36791","DOI":"10.1038\/srep36791","article-title":"Serum neurofilament light protein predicts clinical outcome in traumatic brain injury.","volume":"6","author":"Shahim","year":"2016","journal-title":"Sci Rep"},{"key":"zoi251559r35","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2023.1150510","article-title":"Effect of renal function on the diagnostic performance of plasma biomarkers for Alzheimer\u2019s disease.","volume":"15","author":"Zhang","year":"2023","journal-title":"Front Aging Neurosci"},{"issue":"1","key":"zoi251559r36","doi-asserted-by":"publisher","first-page":"9","DOI":"10.3233\/ADR-230163","article-title":"The association of body mass index with cognition and Alzheimer\u2019s disease biomarkers in the elderly with different cognitive status: a study from the Alzheimer\u2019s Disease Neuroimaging Initiative Database.","volume":"8","author":"Li","year":"2024","journal-title":"J Alzheimers Dis Rep"},{"issue":"11","key":"zoi251559r37","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1001\/jamaneurol.2021.2823","article-title":"Plasma biomarkers of tau and neurodegeneration during major cardiac and noncardiac surgery.","volume":"78","author":"Feinstein","year":"2021","journal-title":"JAMA Neurol"},{"key":"zoi251559r31","unstructured":"MAPT protein expression summary. The Human Protein Atlas. Accessed January 15, 2025. https:\/\/www.proteinatlas.org\/ENSG00000186868-MAPT"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2844876\/halbgebauer_2026_oi_251559_1770144436.03013.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T16:00:21Z","timestamp":1770739221000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2844876"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,10]]},"references-count":37,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2,2]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2025.58573","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,10]]}}}