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While current clinically validated total tau assays target mid-domain epitopes, comparison of these assays with new biomarkers targeting N-terminal epitopes using the same analytical platform may be important to increase the understanding of tau pathophysiology.<\/jats:p>\n                  <jats:p>We developed three total tau immunoassays targeting specific N-terminal (NTA and NTB total tau) or mid-region (MR total tau) epitopes, using single molecule array technology. After analytical validation, the diagnostic performance of these biomarkers was evaluated in CSF and compared with the Innotest total tau (and as proof of concept, with N-p-tau181 and N-p-tau217) in three clinical cohorts (n\u2009=\u2009342 total). The cohorts included participants across the Alzheimer\u2019s disease continuum (n\u2009=\u2009276), other dementias (n\u2009=\u200922), Creutzfeldt\u2013Jakob disease (n\u2009=\u200924), acute neurological disorders (n\u2009=\u200918) and progressive supranuclear palsy (n\u2009=\u200922). Furthermore, we evaluated all three new total tau biomarkers in plasma (n\u2009=\u200944) and replicated promising findings with NTA total tau in another clinical cohort (n\u2009=\u200950).<\/jats:p>\n                  <jats:p>In CSF, all total tau biomarkers were increased in Alzheimer\u2019s disease compared with controls (P\u2009&amp;lt;\u20090.0001) and correlated with each other (rs\u2009=\u20090.53\u22120.95). NTA and NTB total tau, but not other total tau assays, distinguished amyloid-positive and amyloid-negative mild cognitive impairment with high accuracies (AUCs 84% and 82%, P &amp;lt; 0.001) matching N-p-tau217 (AUC 83%; DeLong test P\u2009=\u20090.93 and 0.88). All total tau assays were excellent in differentiating Alzheimer\u2019s disease from other dementias (P\u2009&amp;lt;\u20090.001, AUCs 89\u2013100%). In Creutzfeldt\u2013Jakob disease and acute neurological disorders, N-terminal total tau biomarkers had significantly higher fold changes versus controls in CSF (45\u2013133-fold increase) than Innotest or MR total tau (11\u201342-fold increase, P\u2009&amp;lt;\u20090.0001 for all). In progressive supranuclear palsy, CSF concentrations of all total tau biomarkers were similar to those in controls. Plasma NTA total tau concentrations were increased in Alzheimer\u2019s disease compared with controls in two independent cohorts (P\u2009=\u20090.0056 and 0.0033), while Quanterix total tau performed poorly (P\u2009=\u20090.55 and 0.44).<\/jats:p>\n                  <jats:p>Taken together, N-terminal-directed CSF total tau biomarkers increase ahead of standard total tau alternatives in the Alzheimer\u2019s disease continuum, increase to higher degrees in Creutzfeldt\u2013Jakob disease and acute neurological diseases and show better potential than Quanterix total tau as Alzheimer\u2019s disease blood biomarkers. For progressive supranuclear palsy, other tau biomarkers should continue to be investigated.<\/jats:p>","DOI":"10.1093\/brain\/awab481","type":"journal-article","created":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T07:35:24Z","timestamp":1640676924000},"page":"2834-2848","source":"Crossref","is-referenced-by-count":54,"title":["N-terminal and mid-region tau fragments as fluid biomarkers in neurological diseases"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6191-0954","authenticated-orcid":false,"given":"Anniina","family":"Snellman","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg , M\u00f6lndal , Sweden"},{"name":"Turku PET Centre, University of Turku , Turku , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Lantero-Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg , M\u00f6lndal , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreja","family":"Emer\u0161i\u010d","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Centre Ljubljana , Ljubljana , Slovenia"},{"name":"Faculty of Pharmacy, University of Ljubljana , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agathe","family":"Vrillon","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Cognitive Neurology Center, GHU Nord APHP Hospital Lariboisi\u00e8re Fernand Widal , Paris , France"},{"name":"Universit\u00e9 de Paris, Inserm UMR S11-44 Therapeutic Optimization in Neuropsychopharmacology , Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1422-4358","authenticated-orcid":false,"given":"Thomas K","family":"Karikari","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg , M\u00f6lndal , Sweden"},{"name":"Department of Psychiatry, University of Pittsburgh , Pittsburgh, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J","family":"Ashton","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg , M\u00f6lndal , Sweden"},{"name":"Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg , Gothenburg , Sweden"},{"name":"Department of Old Age Psychiatry, Maurice Wohl Clinical Neuroscience Institute, King\u2019s College London , London , UK"},{"name":"NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milica","family":"Gregori\u010d Kramberger","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Centre Ljubljana , Ljubljana , Slovenia"},{"name":"Faculty of Medicine, University of Ljubljana , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sa\u0161a","family":"\u010cu\u010dnik","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Centre Ljubljana , Ljubljana , Slovenia"},{"name":"Faculty of Pharmacy, University of Ljubljana , Ljubljana , Slovenia"},{"name":"Department of Rheumatology, University Medical Centre Ljubljana , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Paquet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Cognitive Neurology Center, GHU Nord APHP Hospital Lariboisi\u00e8re Fernand Widal , Paris , France"},{"name":"Universit\u00e9 de Paris, Inserm UMR S11-44 Therapeutic Optimization in Neuropsychopharmacology , Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uro\u0161","family":"Rot","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Centre Ljubljana , Ljubljana , Slovenia"},{"name":"Faculty of Medicine, University of Ljubljana , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3930-4354","authenticated-orcid":false,"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the 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 , Queen Square, London , UK"},{"name":"UK Dementia Research Institute at UCL , London , UK"},{"name":"Hong Kong Center for Neurodegenerative Diseases , Hong Kong , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg , M\u00f6lndal , Sweden"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , M\u00f6lndal , 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