{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:16:59Z","timestamp":1790813819825,"version":"4.1.0"},"reference-count":178,"publisher":"SAGE Publications","issue":"19","license":[{"start":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T00:00:00Z","timestamp":1631577600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurotrauma"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:p>\n                    Blood-based protein biomarkers have revolutionized several fields of medicine by enabling molecular level diagnosis, as well as monitoring disease progression and treatment efficacy. Traumatic brain injury (TBI) so far has benefitted only moderately from using protein biomarkers to improve injury outcome. Because of its complexity and dynamic nature, TBI, especially its most prevalent mild form (mild TBI; mTBI), presents unique challenges toward protein biomarker discovery and validation given that blood is frequently obtained and processed outside of the clinical laboratory (e.g., athletic fields, battlefield) under variable conditions. As it stands, the field of mTBI blood biomarkers faces a number of outstanding questions. Do elevated blood levels of currently used biomarkers\u2014ubiquitin carboxy-terminal hydrolase L1, glial fibrillary acidic protein, neurofilament light chain, and tau\/p-tau\u2014truly mirror the extent of parenchymal damage? Do these different proteins represent distinct injury mechanisms? Is the blood\u2013brain barrier a \u201cbrick wall\u201d? What is the relationship between intra- versus extracranial values? Does prolonged elevation of blood levels reflect\n                    <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                    release or extended protein half-lives? Does biological sex affect the pathobiological responses after mTBI and thus blood levels of protein biomarkers? At the practical level, it is unknown how pre-analytical variables\u2014sample collection, preparation, handling, and stability\u2014affect the quality and reliability of biomarker data. The ever-increasing sensitivity of assay systems and lack of quality control of samples, combined with the almost complete reliance on antibody-based assay platforms, represent important unsolved issues given that false-negative results can lead to false clinical decision making and adverse outcomes. This article serves as a commentary on the state of mTBI biomarkers and the landscape of significant challenges. We highlight and discusses several biological and methodological \u201cknown unknowns\u201d and close with some practical recommendations.\n                  <\/jats:p>","DOI":"10.1089\/neu.2021.0011","type":"journal-article","created":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T04:41:27Z","timestamp":1619584887000},"page":"2652-2666","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":66,"title":["The Known Unknowns: An Overview of the State of Blood-Based Protein Biomarkers of Mild Traumatic Brain Injury"],"prefix":"10.1177","volume":"38","author":[{"given":"Stuart J.","family":"McDonald","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia."},{"name":"Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandy R.","family":"Shultz","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia."},{"name":"Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denes V.","family":"Agoston","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2021,9,14]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2008.0586"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2012.00107"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13049-018-0495-0"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2017.17020235"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2013.2984"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2015.03.001"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjsports-2017-097791"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws307"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjsports-2017-097699"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjsports-2016-097464"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1355617700655066"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjsports-2017-097729"},{"issue":"379","key":"e_1_3_4_14_2","first-page":"388","article-title":"Temporal window of metabolic brain vulnerability to concussions: mitochondrial-related impairment\u2014part I","volume":"61","author":"Vagnozzi R.","year":"2007","unstructured":"Vagnozzi R., , Tavazzi B., , Signoretti S., , Amorini A.M., , Belli A., , Cimatti M., , Delfini R., , Di Pietro V., , Finocchiaro A., , and Lazzarino G. 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