{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T20:24:18Z","timestamp":1790108658818,"version":"4.0.1"},"posted":{"date-parts":[[2025,2,21]]},"group-title":"Neurology","reference-count":188,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T00:00:00Z","timestamp":1740096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Blood-based protein biomarkers may provide important insights into the long-term neuropathology of traumatic brain injury (TBI). This is urgently required to identify mechanistic processes underlying post-traumatic neurodegeneration (PTND); a progressive post-recovery clinical decline experienced by a portion of TBI survivors. The aim of this study was to examine change over time in protein levels in a chronic TBI cohort. We selected six markers (A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  \/A\u03b2\n                  <jats:sub>40<\/jats:sub>\n                  , GFAP, NfL, BD-tau, p-tau231, and p-tau181) with known importance in acute TBI and\/or other neurodegenerative conditions.\n                <\/jats:p>\n                <jats:p>\n                  We used a longitudinal design with two time points approximately 3.5 years apart on average (SD 1.34). Proteins were measured in plasma using the ultrasensitive Single molecule array technology for 63 participants with mild to severe chronic TBI (sustained \u2265 1 year ago; M 28 years; SD 16.3 since their first blow to the head) from the Late Effects of TBI study (48% female; current age M 52 years; SD 13.4). Multivariate linear mixed effect models with adjustments for multiple comparisons were performed to examine trajectories in proteins over time with age and age squared as covariates. A series of sensitivity analyses were conducted to account for outliers and to explore effects of key covariates: sex,\n                  <jats:italic>APOE<\/jats:italic>\n                  \u03b54 carrier status, medical comorbidities, age at first blow to the head, time since first blow to the head, and injury severity.\n                <\/jats:p>\n                <jats:p>\n                  Over an average of 3.5 years, there were significant reductions in plasma A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  \/A\u03b2\n                  <jats:sub>40<\/jats:sub>\n                  (\u03b2 = \u22120.004, SE = 0.001, t = \u22123.75, q = .001) and significant increases in plasma GFAP (\u03b2 = 12.96, SE = 4.41, t = 2.94, q = .01). There were no significant changes in NFL, BD-tau, p-tau231, or p-tau181.\n                <\/jats:p>\n                <jats:p>\n                  Both plasma A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  \/A\u03b2\n                  <jats:sub>40<\/jats:sub>\n                  and GFAP have been associated with brain amyloidosis, suggesting a role for A\u03b2 mis-metabolism and aggregation in the long-term neuropathological consequences of TBI. These findings are hypothesis generating for future studies exploring the diverse biological mechanisms of PTND.\n                <\/jats:p>","DOI":"10.1101\/2025.02.16.25322303","type":"posted-content","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T16:20:15Z","timestamp":1740154815000},"source":"Crossref","is-referenced-by-count":4,"title":["Trajectories of blood-based protein biomarkers in chronic traumatic brain injury"],"prefix":"10.64898","author":[{"given":"Amelia J.","family":"Hicks","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Plourde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enna","family":"Selmanovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola L.","family":"de Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Dams-O\u2019Connor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025022403550538000_2025.02.16.25322303v1.1","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2024.0356"},{"key":"2025022403550538000_2025.02.16.25322303v1.2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2010.1358"},{"key":"2025022403550538000_2025.02.16.25322303v1.3","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2013.2997"},{"issue":"7","key":"2025022403550538000_2025.02.16.25322303v1.4","doi-asserted-by":"crossref","first-page":"e01018","DOI":"10.1002\/brb3.1018","article-title":"Disability and quality of life 20 years after traumatic brain injury","volume":"8","year":"2018","journal-title":"Brain Behav"},{"issue":"1","key":"2025022403550538000_2025.02.16.25322303v1.5","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.injury.2014.07.012","article-title":"Comparison of long-term outcomes following traumatic injury: what is the unique experience for those with brain injury compared with orthopaedic injury?","volume":"46","year":"2015","journal-title":"Injury"},{"key":"2025022403550538000_2025.02.16.25322303v1.6","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2012-302746"},{"key":"2025022403550538000_2025.02.16.25322303v1.7","doi-asserted-by":"crossref","first-page":"120","DOI":"10.3389\/fneur.2019.00120","article-title":"A Detailed Overview of Long-Term Outcomes in Severe Traumatic Brain Injury Eight Years Post-injury","volume":"10","year":"2019","journal-title":"Front Neurol"},{"key":"2025022403550538000_2025.02.16.25322303v1.8","unstructured":"Cummins T , Elias A , Lamb F , et al. 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