{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T04:18:28Z","timestamp":1789100308207,"version":"build-2803163510"},"reference-count":161,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T00:00:00Z","timestamp":1731024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Rodent models are important research tools for studying the pathophysiology of traumatic brain injury (TBI) and developing new therapeutic interventions for this devastating neurological disorder. However, the failure rate for the translation of drugs from animal testing to human treatments for TBI is 100%. While there are several potential explanations for this, previous clinical trials have relied on extrapolation from preclinical studies for critical design considerations, including drug dose optimization, post-injury drug treatment initiation and duration. Incorporating clinically relevant biomarkers in preclinical studies may provide an opportunity to calibrate preclinical models to identical (or similar) measurements in humans, link to human TBI biomechanics and pathophysiology, and guide therapeutic decisions. To support this translational goal, we conducted a systematic literature review of preclinical TBI studies in rodents measuring blood levels of clinically used GFAP, UCH-L1, NfL, total-Tau (t-Tau) or phosphorylated-Tau (p-Tau) published in PubMed\/EMBASE up to 10 April 2024. Although many factors influence clinical TBI outcomes, many of those cannot routinely be assessed in rodent studies (e.g. intracranial pressure monitoring). Thus we focused on blood biomarkers\u2019 temporal trajectories and discuss our findings in the context of the latest clinical TBI biomarker data.<\/jats:p>\n                  <jats:p>Of 805 original preclinical studies, 74 met the inclusion criteria, with a median quality score of 5 (25th\u201375th percentiles: 4\u20137) on the CAMARADES checklist. GFAP was measured in 43 studies, UCH-L1 in 21, NfL in 20, t-Tau in 19 and p-Tau in seven. Data from rodent models indicate that all biomarkers exhibited injury severity-dependent elevations with distinct temporal profiles. GFAP and UCH-L1 peaked within the first day after TBI (30- and 4-fold increases, respectively, in moderate-to-severe TBI versus sham), with the highest levels observed in the contusion TBI model. NfL peaked within days (18-fold increase) and remained elevated up to 6\u2005months post-injury. GFAP and NfL show a pharmacodynamic response in 64.7% and 60%, respectively, of studies evaluating neuroprotective therapies in preclinical models. However, GFAP's rapid decline post-injury may limit its utility for understanding the response to new therapeutics beyond the hyperacute phase after experimental TBI. Furthermore, as in humans, subacute NfL levels inform on chronic white matter loss after TBI. t-Tau and p-Tau levels increased over weeks after TBI (up to 6- and 16-fold, respectively); however, their relationship with underlying neurodegeneration has yet to be addressed. Further investigation into biomarker levels in the subacute and chronic phases after TBI will be needed to fully understand the pathomechanisms underpinning blood biomarkers\u2019 trajectories and select the most suitable experimental model to optimally relate preclinical mechanistic studies to clinical observations in humans. This new approach could accelerate the translation of neuroprotective treatments from laboratory experiments to real-world clinical practices.<\/jats:p>","DOI":"10.1093\/brain\/awae350","type":"journal-article","created":{"date-parts":[[2024,11,1]],"date-time":"2024-11-01T08:17:00Z","timestamp":1730449020000},"page":"1062-1080","source":"Crossref","is-referenced-by-count":34,"title":["Exploiting blood-based biomarkers to align preclinical models with human traumatic brain injury"],"prefix":"10.1093","volume":"148","author":[{"given":"Ilaria","family":"Lisi","sequence":"first","affiliation":[{"name":"Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS , Milan 20156 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2682-5583","authenticated-orcid":false,"given":"Federico","family":"Moro","sequence":"additional","affiliation":[{"name":"Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS , Milan 20156 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Mazzone","sequence":"additional","affiliation":[{"name":"Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS , Milan 20156 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Marklund","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Lund, Neurosurgery, Lund University and Sk\u00e5ne University Hospital , Lund 222 42 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7151-0812","authenticated-orcid":false,"given":"Francesca","family":"Pischiutta","sequence":"additional","affiliation":[{"name":"Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS , Milan 20156 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5008-6944","authenticated-orcid":false,"given":"Firas","family":"Kobeissy","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Center for Neurotrauma, Multiomics & Biomarkers, Morehouse School of Medicine , Atlanta, GA 30310 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1897-2751","authenticated-orcid":false,"given":"Xiang","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Affiliated Hospital of Anhui Medical University , Hefei, Anhui, 230022 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Corrigan","sequence":"additional","affiliation":[{"name":"School of Biomedicine, Faculty of Health and Medical Sciences, The University of Adelaide , Adelaide 5005 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adel","family":"Helmy","sequence":"additional","affiliation":[{"name":"Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7385-9559","authenticated-orcid":false,"given":"Fatima","family":"Nasrallah","sequence":"additional","affiliation":[{"name":"Queensland Brain Institute, The University of Queensland , St Lucia, QLD 4067 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina Di","family":"Pietro","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham , Birmingham B15 2TT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura B","family":"Ngwenya","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Cincinnati College of Medicine , Cincinnati, OH 670715 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis V","family":"Portela","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, ICBS, Federal University of Rio Grande do Sul\u2014UFRGS , Porto Alegre, RS 90040-060, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridgette D","family":"Semple","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, School of Translational Medicine, Monash University , Melbourne, VIC 3800 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea L C","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104-6021 ,","place":["USA"]},{"name":"Department of Neurology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon Diaz","family":"Arrastia","sequence":"additional","affiliation":[{"name":"Department of Neurology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3228-9692","authenticated-orcid":false,"given":"David K","family":"Menon","sequence":"additional","affiliation":[{"name":"Division of Anaesthesia, University of Cambridge , Cambridge CB2 2QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas H","family":"Smith","sequence":"additional","affiliation":[{"name":"Center for Brain Injury and Repair and the Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl","family":"Wellington","sequence":"additional","affiliation":[{"name":"Department of Pathology, Djavad Mowafaghain Centre for Brain Health, International Collaboration on Repair Discoveries, School of Biomedical Engineering, University of British Columbia , Vancouver, BC V6T 1Z3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0393-3503","authenticated-orcid":false,"given":"David J","family":"Loane","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology, Trinity College Dublin , Dublin 152-160 ,","place":["Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin K W","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Center for Neurotrauma, Multiomics & Biomarkers, Morehouse School of Medicine , 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