Serum biomarkers in traumatic brain injury: current clinical utility
DOI:
https://doi.org/10.70577/hcx64d58Keywords:
traumatic brain injury; serum biomarkers; GFAP; UCH-L1; S100B; computed tomography; prognosis.Abstract
Introduction: Traumatic brain injury is a heterogeneous clinical condition whose assessment, particularly in mild cases, may be limited when based solely on neurological examination, the Glasgow Coma Scale, and clinical decision rules. In this context, serum biomarkers have emerged as complementary tools for detecting intracranial injury, guiding computed tomography use, and estimating prognosis. Objective: To analyze the current clinical utility of the main serum biomarkers in traumatic brain injury, with emphasis on their diagnostic, prognostic, and follow-up value.
Methodology: A structured narrative review with a systematized literature search was conducted using PubMed, Scopus, and ScienceDirect. A total of 654 records were identified, 19 duplicates were removed, and 90 full-text articles were assessed. Finally, 25 studies were included based on their relevance to the objectives of the review and their contribution to the analysis of the current clinical utility of serum biomarkers in traumatic brain injury.
Results: GFAP and UCH-L1 showed the greatest utility for ruling out intracranial injuries because of their high sensitivity and negative predictive value, although their specificity was limited. S100B showed favorable results as a rule-out test, particularly in pediatric populations, but its performance depends on the sampling time window and the presence of extracranial injuries. NfL and tau showed greater potential for assessing axonal injury, neurological evolution, and functional outcomes. Conclusion: Serum biomarkers do not replace clinical assessment or computed tomography. Their greatest utility is achieved when they are integrated with clinical decision rules, neuroimaging, and temporal follow-up.
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References
Bazarian, J. J., Zetterberg, H., Buki, A., Dengler, B. A., Diaz-Arrastia, R., Korley, F. K., Lazarus, R., Meier, T. B., Mondello, S., Moritz, K., Okonkwo, D. O., Papa, L., Phillips, J. B., Posti, J. P., Puccio, A. M., Sloley, S., Steyerberg, E., Wang, K. K., Awwad, H. O., … Manley, G. T. (2025). Blood-Based Biomarkers for Improved Characterization of Traumatic Brain Injury: Recommendations from the 2024 National Institute for Neurological Disorders and Stroke Traumatic Brain Injury Classification and Nomenclature Initiative Blood-Based Biomarkers Working Group. Journal of Neurotrauma, 42(13–14), 1065–1085. https://doi.org/10.1089/neu.2024.0581 DOI: https://doi.org/10.1089/neu.2024.0581
Bouvier, D., Cantais, A., Laspougeas, A., Lorton, F., Plenier, Y., Cottier, M., Fournier, P., Tran, A., Moreau, E., Durif, J., Sarret, C., Mourgues, C., Sturtz, F., Oudart, J.-B., Raffort, J., Gonzalo, P., Cristol, J.-P., Masson, D., Pereira, B., & Sapin, V. (2024). Serum S100B Level in the Management of Pediatric Minor Head Trauma. JAMA Network Open, 7(3), e242366. https://doi.org/10.1001/jamanetworkopen.2024.2366 DOI: https://doi.org/10.1001/jamanetworkopen.2024.2366
Do, T. S., Carnes, C., Yang, Z., Kobeissy, F., Yadikar, H., Olbricht, G., Tenovuo, O., Posti, J. P., Steyerberg, E. W., Wilson, L., von Steinbüchel, N., Czeiter, E., Buki, A., Menon, D. K., Maas, A. I. R., Wang, K. K., & Obafemi-Ajayi, T. (2026). Serum biomarker trajectory clusters predict functional outcome and quality of life for traumatic brain injury. Brain Communications, 8(2). https://doi.org/10.1093/braincomms/fcag055 DOI: https://doi.org/10.1093/braincomms/fcag055
Faisal, M., Vedin, T., Edelhamre, M., & Forberg, J. L. (2023). Diagnostic performance of biomarker S100B and guideline adherence in routine care of mild head trauma. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, 31(1), 3. https://doi.org/10.1186/s13049-022-01062-w DOI: https://doi.org/10.1186/s13049-022-01062-w
Gardner, R. C., Puccio, A. M., Korley, F. K., Wang, K. K. W., Diaz-Arrastia, R., Okonkwo, D. O., Puffer, R. C., Yuh, E. L., Yue, J. K., Sun, X., Taylor, S. R., Mukherjee, P., Jain, S., Manley, G. T., Feeser, V. R., Ferguson, A. R., Gaudette, E., Gopinath, S., Keene, C. D., … Zafonte, R. (2022). Effects of age and time since injury on traumatic brain injury blood biomarkers: a TRACK-TBI study. Brain Communications, 5(1). https://doi.org/10.1093/braincomms/fcac316 DOI: https://doi.org/10.1093/braincomms/fcac316
Graham, N. S., Blissitt, G., Zimmerman, K., Orton, L., Friedland, D., Coady, E., Laban, R., Veleva, E., Heslegrave, A. J., Zetterberg, H., Schofield, S., Fear, N. T., Boos, C. J., Bull, A. M. J., Bennett, A., & Sharp, D. J. (2025). Poor long-term outcomes and abnormal neurodegeneration biomarkers after military traumatic brain injury: the ADVANCE study. Journal of Neurology, Neurosurgery & Psychiatry, 96(2), 105–113. https://doi.org/10.1136/jnnp-2024-333777 DOI: https://doi.org/10.1136/jnnp-2024-333777
Graham, N. S. N., Zimmerman, K. A., Moro, F., Heslegrave, A., Maillard, S. A., Bernini, A., Miroz, J.-P., Donat, C. K., Lopez, M. Y., Bourke, N., Jolly, A. E., Mallas, E.-J., Soreq, E., Wilson, M. H., Fatania, G., Roi, D., Patel, M. C., Garbero, E., Nattino, G., … Sharp, D. J. (2021). Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury. Science Translational Medicine, 13(613). https://doi.org/10.1126/scitranslmed.abg9922 DOI: https://doi.org/10.1126/scitranslmed.abg9922
Korley, F. K., Jain, S., Sun, X., Puccio, A. M., Yue, J. K., Gardner, R. C., Wang, K. K. W., Okonkwo, D. O., Yuh, E. L., Mukherjee, P., Nelson, L. D., Taylor, S. R., Markowitz, A. J., Diaz-Arrastia, R., Manley, G. T., Adeoye, O., Badatjia, N., Duhaime, A.-C., Ferguson, A., … Zafonte, R. (2022). Prognostic value of day-of-injury plasma GFAP and UCH-L1 concentrations for predicting functional recovery after traumatic brain injury in patients from the US TRACK-TBI cohort: an observational cohort study. The Lancet Neurology, 21(9), 803–813. https://doi.org/10.1016/S1474-4422(22)00256-3 DOI: https://doi.org/10.1016/S1474-4422(22)00256-3
Lagares, A., de la Cruz, J., Terrisse, H., Mejan, O., Pavlov, V., Vermorel, C., Payen, J.-F., Maignan, M., Viglino, D., Jacquin, L., Douplat, M., Laribi, S., Pes, P., Ray, P., Guenezan, J., Sebbane, M., Belen, F., Durand, G., Abric, C., … Alen, J. F. (2024). An automated blood test for glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) to predict the absence of intracranial lesions on head CT in adult patients with mild traumatic brain injury: BRAINI, a multicentre observational study in Europe. EBioMedicine, 110, 105477. https://doi.org/10.1016/j.ebiom.2024.105477 DOI: https://doi.org/10.1016/j.ebiom.2024.105477
Menditto, V. G., Moretti, M., Babini, L., Mattioli, A., Giuliani, A. R., Fratini, M., Pallua, F. Y., Andreoli, E., Nitti, C., Contucci, S., Gabrielli, A., Rocchi, M. B. L., & Pomponio, G. (2024). Minor head injury in anticoagulated patients: performance of biomarkers S100B, NSE, GFAP, UCH-L1 and Alinity TBI in the detection of intracranial injury. A prospective observational study. Clinical Chemistry and Laboratory Medicine (CCLM), 62(7), 1376–1382. https://doi.org/10.1515/cclm-2023-1169 DOI: https://doi.org/10.1515/cclm-2023-1169
Mondello, S., Amrein, K., Czeiter, E., Citerio, G., Diaz-Arrastia, R., Gao, G., Lagares, A., Manley, G. T., Menon, D. K., Newcombe, V., Posti, J. P., Wilson, L., Zetterberg, H., Steyerberg, E. W., Buki, A., & Maas, A. I. R. (2025). Prognostic Value of Blood-Based Protein Biomarkers in Traumatic Brain Injury: A Living Systematic Review and Meta-Analysis. Journal of Neurotrauma, 42(15–16), 1256–1286. https://doi.org/10.1089/neu.2024.0620 DOI: https://doi.org/10.1089/neu.2024.0620
Mondello, S., Sorinola, A., Czeiter, E., Vámos, Z., Amrein, K., Synnot, A., Donoghue, E., Sándor, J., Wang, K. K. W., Diaz-Arrastia, R., Steyerberg, E. W., Menon, D. K., Maas, A. I. R., & Buki, A. (2021). Blood-Based Protein Biomarkers for the Management of Traumatic Brain Injuries in Adults Presenting to Emergency Departments with Mild Brain Injury: A Living Systematic Review and Meta-Analysis. Journal of Neurotrauma, 38(8), 1086–1106. https://doi.org/10.1089/neu.2017.5182 DOI: https://doi.org/10.1089/neu.2017.5182
Morello, A., Schiavetti, I., Lo Bue, E., Portonero, I., Colonna, S., Gatto, A., Pavanello, M., Lanotte, M. M., Garbossa, D., & Cofano, F. (2024a). Update on the role of S100B in traumatic brain injury in pediatric population: a meta-analysis. Child’s Nervous System, 40(11), 3745–3756. https://doi.org/10.1007/s00381-024-06565-8
Morello, A., Schiavetti, I., Lo Bue, E., Portonero, I., Colonna, S., Gatto, A., Pavanello, M., Lanotte, M. M., Garbossa, D., & Cofano, F. (2024b). Update on the role of S100B in traumatic brain injury in pediatric population: a meta-analysis. Child’s Nervous System, 40(11), 3745–3756. https://doi.org/10.1007/s00381-024-06565-8 DOI: https://doi.org/10.1007/s00381-024-06565-8
Munoz Pareja, J. C., de Rivero Vaccari, J. P., Chavez, M. M., Kerrigan, M., Pringle, C., Guthrie, K., Swaby, K., Coto, J., Kobeissy, F., Avery, K. L., Ghosh, S., Dhanashree, R., Shanmugham, P., Lautenslager, L. A., Faulkenberry, S., Pareja Zabala, M. C., Al Fakhri, N., Loor-Torres, R., Governale, L. S., … Wang, K. K. (2024). Prognostic and Diagnostic Utility of Serum Biomarkers in Pediatric Traumatic Brain Injury. Journal of Neurotrauma, 41(1–2), 106–122. https://doi.org/10.1089/neu.2023.0039 DOI: https://doi.org/10.1089/neu.2023.0039
Newcombe, V. F. J., Ashton, N. J., Posti, J. P., Glocker, B., Manktelow, A., Chatfield, D. A., Winzeck, S., Needham, E., Correia, M. M., Williams, G. B., Simrén, J., Takala, R. S. K., Katila, A. J., Maanpää, H. R., Tallus, J., Frantzén, J., Blennow, K., Tenovuo, O., Zetterberg, H., & Menon, D. K. (2022). Post-acute blood biomarkers and disease progression in traumatic brain injury. Brain, 145(6), 2064–2076. https://doi.org/10.1093/brain/awac126 DOI: https://doi.org/10.1093/brain/awac126
Papa, L., Ladde, J. G., O’Brien, J. F., Thundiyil, J. G., Tesar, J., Leech, S., Cassidy, D. D., Roa, J., Hunter, C., Miller, S., Baker, S., Parrish, G. A., Davison, J., Van Dillen, C., Ralls, G. A., Briscoe, J., Falk, J. L., Weber, K., & Giordano, P. A. (2022). Evaluation of Glial and Neuronal Blood Biomarkers Compared With Clinical Decision Rules in Assessing the Need for Computed Tomography in Patients With Mild Traumatic Brain Injury. JAMA Network Open, 5(3), e221302. https://doi.org/10.1001/jamanetworkopen.2022.1302 DOI: https://doi.org/10.1001/jamanetworkopen.2022.1302
Papa, L., McKinley, W. I., Valadka, A. B., Newman, Z. C., Nordgren, R. K., Pramuka, P. E., Barbosa, C. E., Brito, A. M. P., Loss, L. J., Tinoco-Garcia, L., Hinson, H. E., Schreiber, M. A., & Rowell, S. E. (2024). Diagnostic Performance of GFAP, UCH-L1, and MAP-2 Within 30 and 60 Minutes of Traumatic Brain Injury. JAMA Network Open, 7(9), e2431115. https://doi.org/10.1001/jamanetworkopen.2024.31115 DOI: https://doi.org/10.1001/jamanetworkopen.2024.31115
Reyes, J., Spitz, G., Major, B. P., O’Brien, W. T., Giesler, L. P., Bain, J. W. P., Xie, B., Rosenfeld, J. V., Law, M., Ponsford, J. L., O’Brien, T. J., Shultz, S. R., Willmott, C., Mitra, B., & McDonald, S. J. (2023). Utility of Acute and Subacute Blood Biomarkers to Assist Diagnosis in CT-Negative Isolated Mild Traumatic Brain Injury. Neurology, 101(20). https://doi.org/10.1212/WNL.0000000000207881 DOI: https://doi.org/10.1212/WNL.0000000000207881
Richter, S., Czeiter, E., Amrein, K., Mikolic, A., Verheyden, J., Wang, K., Maas, A. I. R., Steyerberg, E., Büki, A., Menon, D. K., & Newcombe, V. F. J. (2023). Prognostic Value of Serum Biomarkers in Patients With Moderate-Severe Traumatic Brain Injury, Differentiated by Marshall Computer Tomography Classification. Journal of Neurotrauma, 40(21–22), 2297–2310. https://doi.org/10.1089/neu.2023.0029 DOI: https://doi.org/10.1089/neu.2023.0029
Rogan, A., Sik, A., Dickinson, E., Patel, V., Peckler, B., McQuade, D., & Larsen, P. D. (2023). Diagnostic performance of S100B as a rule-out test for intracranial pathology in head-injured patients presenting to the emergency department who meet NICE Head Injury Guideline criteria for CT-head scan. Emergency Medicine Journal, 40(3), 159–166. https://doi.org/10.1136/emermed-2022-212549 DOI: https://doi.org/10.1136/emermed-2022-212549
Spitz, G., Mitchell, J., Martins, B. D., Astridge, A., Copas, C., O’Brien, W. T., Symons, G. F., Law, M., O’Brien, T. J., Pase, M. P., Ponsford, J. L., Mitra, B., McDonald, S. J., & Shultz, S. R. (2026). Diagnostic Accuracy of Plasma Biomarkers for Mild Traumatic Brain Injury in Older Adults. JAMA Network Open, 9(5), e2615678. https://doi.org/10.1001/jamanetworkopen.2026.15678 DOI: https://doi.org/10.1001/jamanetworkopen.2026.15678
Whitehouse, D., Mikolić, A., Czeiter, E., Richter, S., Buki, A., Wang, K. K., Steyerberg, E., Maas, A., Menon, D., Lecky, F., & Newcombe, V. (2025). Serum Biomarkers as Adjuncts to the National Institute for Health and Care Excellence Head Injury Guidelines (NG232, 2023) When Selecting Patients with Traumatic Brain Injury for Computed Tomography: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Study. Journal of Neurotrauma, 42(17–18), 1509–1523. https://doi.org/10.1089/neu.2024.0276 DOI: https://doi.org/10.1089/neu.2024.0276
Whitehouse, D. P., Monteiro, M., Czeiter, E., Vyvere, T. Vande, Valerio, F., Ye, Z., Amrein, K., Kamnitsas, K., Xu, H., Yang, Z., Verheyden, J., Das, T., Kornaropoulos, E. N., Steyerberg, E., Maas, A. I. R., Wang, K. K. W., Büki, A., Glocker, B., Menon, D. K., & Newcombe, V. F. J. (2022). Relationship of admission blood proteomic biomarkers levels to lesion type and lesion burden in traumatic brain injury: A CENTER-TBI study. EBioMedicine, 75, 103777. https://doi.org/10.1016/j.ebiom.2021.103777 DOI: https://doi.org/10.1016/j.ebiom.2021.103777
Zimmer, L., McDade, C., Beyhaghi, H., Purser, M., Textoris, J., Krause, A., Blanc, E., Pavlov, V., & Earnshaw, S. (2023). Cost-Effectiveness of Blood-Based Brain Biomarkers for Screening Adults with Mild Traumatic Brain Injury in the French Health Care Setting. Journal of Neurotrauma, 40(7–8), 706–719. https://doi.org/10.1089/neu.2022.0270 DOI: https://doi.org/10.1089/neu.2022.0270
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Copyright (c) 2026 Jimmy Fernando Yaguana Torres, Wendy Scarlett Medina Yaguana, Irene Diana León Valdiviezo, Fernanda Nicole Iñiguez Navarrete, Yiliam Ahylie Rojas Hidalgo (Autor/a)
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