Research progress on biomarkers of traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a common disorder of the nervous system and has become a leading cause of death and disability worldwide, imposing a substantial burden on patients and their social circles. Its main symptoms include dyskinesia, language acquisition difficulties, and cognitive decline. Because of its complexity and diversity, the diagnosis and treatment of TBI have consistently been key areas of focus in medical research. Traditional imaging methods, including X-ray computed tomography (CT) scans and magnetic resonance imaging (MRI), are proficient at identifying overt structural abnormalities; however, their sensitivity in detecting subtle or hidden brain injuries is somewhat restricted. CT is insensitive to nonhemorrhagic lesions and cannot accurately evaluate the degree of injury. The detection rate of microhemorrhagic foci and specific types of TBI by MRI is low; other technologies have complicated operation and high equipment requirements. Therefore, the utilization of biological indicators, or biomarkers, in assessing and predicting the course and outcome of TBI holds immense importance in both diagnostic and prognostic evaluations. This overview reviews the research progress of biomarkers in TBI. Recognizing the significance of TBI-related biomarkers, understanding the pertinent key molecular pathways, and staying informed about the latest advancements in treatment methods are of utmost importance. However, research on TBI biomarkers continues to face challenges. To advance the field, future efforts should focus on delving deeper into the mechanisms, refining more sensitive and tailored detection methodologies, conducting extensive clinical validations, and exploring the potential of personalized treatment plans.

Keywords

biomarkers / diagnostics / head injury / serum biomarkers / traumatic brain injury (TBI)

References

[1] Young L, Rule GT, Bocchieri RT, Walilko TJ, Burns JM, Ling G. When physics meets biology: low and high-velocity penetration, blunt impact, and blast injuries to the brain. Front Neurol. 2015; 6:89.

[2] Hoffman SW, Harrison C. The interaction between psychological health and traumatic brain injury: a neuroscience perspective. Clin Neuropsychol. 2009; 23: 1400-1415.

[3] Maas AIR, Menon DK, Manley GT, et al. Traumatic brain injury: progress and challenges in prevention, clinical care, and research. Lancet Neurol. 2022; 21: 1004-1060.

[4] Faul M, Coronado V. Epidemiology of traumatic brain injury. Handb Clin Neurol. 2015; 127: 3-13.

[5] Alikunju S, Abdul Muneer PM, Zhang Y, Szlachetka AM, Haorah J. The inflammatory footprints of alcohol-induced oxidative damage in neurovascular components. Brain Behav Immun. 2011; 25(Suppl 1): S129-S136.

[6] Haorah J, Ramirez SH, Floreani N, Gorantla S, Morsey B, Persidsky Y. Mechanism of alcohol-induced oxidative stress and neuronal injury. Free Radic Biol Med. 2008; 45: 1542-1550.

[7] Vandevord PJ, Bolander R, Sajja VS, Hay K, Bir CA. Mild neurotrauma indicates a range-specific pressure response to low level shock wave exposure. Ann Biomed Eng. 2012; 40: 227-236.

[8] Haorah J, Floreani NA, Knipe B, Persidsky Y. Stabilization of superoxide dismutase by acetyl-l-carnitine in human brain endothelium during alcohol exposure: novel protective approach. Free Radic Biol Med. 2011; 51: 1601-1609.

[9] Trudeau DL, Anderson J, Hansen LM, et al. Findings of mild traumatic brain injury in combat veterans with PTSD and a history of blast concussion. J Neuropsychiatry Clin Neurosci. 1998; 10: 308-313.

[10] Santiago PN, Wilk JE, Milliken CS, Castro CA, Engel CC, Hoge CW. Screening for alcohol misuse and alcohol-related behaviors among combat veterans. Psychiatr Serv. 2010; 61: 575-581.

[11] Otis JD, McGlinchey R, Vasterling JJ, Kerns RD. Complicating factors associated with mild traumatic brain injury: impact on pain and posttraumatic stress disorder treatment. J Clin Psychol Med Settings. 2011; 18: 145-154.

[12] Muneer PMA, Alikunju S, Szlachetka AM, Haorah J. The mechanisms of cerebral vascular dysfunction and neuroinflammation by MMP-mediated degradation of VEGFR-2 in alcohol ingestion. Arterioscler Thromb Vasc Biol. 2012; 32: 1167-1177.

[13] Higashida T, Kreipke CW, Rafols JA, et al. The role of hypoxia-inducible factor-1α, aquaporin-4, and matrix metalloproteinase-9 in blood-brain barrier disruption and brain edema after traumatic brain injury. J Neurosurg. 2011; 114: 92-101.

[14] Vasterling JJ, Verfaellie M, Sullivan KD. Mild traumatic brain injury and posttraumatic stress disorder in returning veterans: perspectives from cognitive neuroscience. Clin Psychol Rev. 2009; 29: 674-684.

[15] Johnson WD, Griswold DP. Traumatic brain injury: a global challenge. Lancet Neurol. 2017; 16: 949-950.

[16] Chen W, Zheng P, Hong T, et al. Astrocytes-derived exosomes induce neuronal recovery after traumatic brain injury via delivering gap junction alpha 1-20 k. J Tissue Eng Regen Med. 2020; 14: 412-423.

[17] Kaur P, Sharma S. Recent advances in pathophysiology of traumatic brain injury. Curr Neuropharmacol. 2018; 16: 1224-1238.

[18] Martinez B, Peplow PV. MicroRNAs as diagnostic markers and therapeutic targets for traumatic brain injury. Neural Regen Res. 2017; 12: 1749-1761.

[19] Zhang W, Hong J, Zhang H, Zheng W, Yang Y. Astrocyte-derived exosomes protect hippocampal neurons after traumatic brain injury by suppressing mitochondrial oxidative stress and apoptosis. Aging (Albany NY). 2021; 13: 21642-21658.

[20] de Rivero Vaccari JP, Dietrich WD, Keane RW. Activation and regulation of cellular inflammasomes: gaps in our knowledge for central nervous system injury. J Cereb Blood Flow Metab. 2014; 34: 369-375.

[21] Gilkerson R. A disturbance in the force: cellular stress sensing by the mitochondrial network. Antioxidants (Basel). 2018; 7(10):126.

[22] Oswald MCW, Garnham N, Sweeney ST, Landgraf M. Regulation of neuronal development and function by ROS. FEBS Lett. 2018; 592: 679-691.

[23] Blennow K, Brody DL, Kochanek PM, et al. Traumatic brain injuries. Nat Rev Dis Primers. 2016; 2:16084.

[24] Guan B, Anderson DB, Chen L, Feng S, Zhou H. Global, regional and national burden of traumatic brain injury and spinal cord injury, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. BMJ Open. 2023; 13:e075049.

[25] Whiffin CJ, Gracey F, Ellis-Hill C. The experience of families following traumatic brain injury in adult populations: a meta-synthesis of narrative structures. Int J Nurs Stud. 2021; 123:104043.

[26] Dixon KJ. Pathophysiology of traumatic brain injury. Phys Med Rehabil Clin N Am. 2017; 28: 215-225.

[27] Williams AJ, Hartings JA, Lu XC, Rolli ML, Tortella FC. Penetrating ballistic-like brain injury in the rat: differential time courses of hemorrhage, cell death, inflammation, and remote degeneration. J Neurotrauma. 2006; 23: 1828-1846.

[28] Mondello S, Muller U, Jeromin A, Streeter J, Hayes RL, Wang KK. Blood-based diagnostics of traumatic brain injuries. Expert Rev Mol Diagn. 2011; 11: 65-78.

[29] Finnie JW. Neuroinflammation: beneficial and detrimental effects after traumatic brain injury. Inflammopharmacology. 2013; 21: 309-320.

[30] Johnson VE, Meaney DF, Cullen DK, Smith DH. Animal models of traumatic brain injury. Handb Clin Neurol. 2015; 127: 115-128.

[31] Davalos D, Grutzendler J, Yang G, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci. 2005; 8: 752-758.

[32] Haynes SE, Hollopeter G, Yang G, et al. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci. 2006; 9: 1512-1519.

[33] Mioni G, Grondin S, Stablum F. Temporal dysfunction in traumatic brain injury patients: primary or secondary impairment? Front Hum Neurosci. 2014; 8:269.

[34] McKee AC, Daneshvar DH. The neuropathology of traumatic brain injury. Handb Clin Neurol. 2015; 127: 45-66.

[35] Hanscom M, Loane DJ, Shea-Donohue T. Brain-gut axis dysfunction in the pathogenesis of traumatic brain injury. J Clin Invest. 2021; 131(12):e143777.

[36] Das M, Leonardo CC, Rangooni S, Pennypacker KR, Mohapatra S, Mohapatra SS. Lateral fluid percussion injury of the brain induces CCL20 inflammatory chemokine expression in rats. J Neuroinflammation. 2011; 8:148.

[37] Sofroniew MV. Astrocyte reactivity: subtypes, states, and functions in CNS innate immunity. Trends Immunol. 2020; 41: 758-770.

[38] Werner C, Engelhard K. Pathophysiology of traumatic brain injury. Br J Anaesth. 2007; 99: 4-9.

[39] Kabadi SV, Faden AI. Neuroprotective strategies for traumatic brain injury: improving clinical translation. Int J Mol Sci. 2014; 15: 1216-1236.

[40] Shetty AK, Mishra V, Kodali M, Hattiangady B. Blood brain barrier dysfunction and delayed neurological deficits in mild traumatic brain injury induced by blast shock waves. Front Cell Neurosci. 2014; 8:232.

[41] Mustafa AG, Alshboul OA. Pathophysiology of traumatic brain injury. Neurosciences (Riyadh). 2013; 18: 222-234.

[42] Seule M, Brunner T, Mack A, Hildebrandt G, Fournier JY. Neurosurgical and intensive care management of traumatic brain injury. Facial Plast Surg. 2015; 31: 325-331.

[43] Maas AI, Stocchetti N, Bullock R. Moderate and severe traumatic brain injury in adults. Lancet Neurol. 2008; 7: 728-741.

[44] Hall ED, Braughler JM. Free radicals in CNS injury. Res Publ Assoc Res Nerv Ment Dis. 1993; 71: 81-105.

[45] Hall ED, Vaishnav RA, Mustafa AG. Antioxidant therapies for traumatic brain injury. Neurotherapeutics. 2010; 7: 51-61.

[46] Floyd CL, Lyeth BG. Astroglia: important mediators of traumatic brain injury. Prog Brain Res. 2007; 161: 61-79.

[47] Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996; 19: 312-318.

[48] Block ML, Hong JS. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol. 2005; 76: 77-98.

[49] Loane DJ, Byrnes KR. Role of microglia in neurotrauma. Neurotherapeutics. 2010; 7: 366-377.

[50] Herrmann JE, Imura T, Song B, et al. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci. 2008; 28: 7231-7243.

[51] Povlishock JT, Katz DI. Update of neuropathology and neurological recovery after traumatic brain injury. J Head Trauma Rehabil. 2005; 20: 76-94.

[52] Marion CM, Radomski KL, Cramer NP, Galdzicki Z, Armstrong RC. Experimental traumatic brain injury identifies distinct early and late phase axonal conduction deficits of white matter pathophysiology, and reveals intervening recovery. J Neurosci. 2018; 38: 8723-8736.

[53] Johnson VE, Stewart W, Smith DH. Axonal pathology in traumatic brain injury. Exp Neurol. 2013; 246: 35-43.

[54] Pearn ML, Niesman IR, Egawa J, et al. Pathophysiology associated with traumatic brain injury: current treatments and potential novel therapeutics. Cell Mol Neurobiol. 2017; 37: 571-585.

[55] Davis AE. Mechanisms of traumatic brain injury: biomechanical, structural and cellular considerations. Crit Care Nurs Q. 2000; 23: 1-13.

[56] Giza CC, Hovda DA. The neurometabolic cascade of concussion. J Athl Train. 2001; 36: 228-235.

[57] McAllister TW. Neurobiological consequences of traumatic brain injury. Dialogues Clin Neurosci. 2011; 13: 287-300.

[58] McIntosh TK, Smith DH, Meaney DF, Kotapka MJ, Gennarelli TA, Graham DI. Neuropathological sequelae of traumatic brain injury: relationship to neurochemical and biomechanical mechanisms. Lab Investig. 1996; 74: 315-342.

[59] Prins M, Greco T, Alexander D, Giza CC. The pathophysiology of traumatic brain injury at a glance. Dis Model Mech. 2013; 6: 1307-1315.

[60] Tran LV. Understanding the pathophysiology of traumatic brain injury and the mechanisms of action of neuroprotective interventions. J Trauma Nurs. 2014; 21: 30-35.

[61] Ladak AA, Enam SA, Ibrahim MT. A review of the molecular mechanisms of traumatic brain injury. World Neurosurg. 2019; 131: 126-132.

[62] Maas AIR, Menon DK, Adelson PD, et al. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017; 16: 987-1048.

[63] Ciurli P, Formisano R, Bivona U, Cantagallo A, Angelelli P. Neuropsychiatric disorders in persons with severe traumatic brain injury: prevalence, phenomenology, and relationship with demographic, clinical, and functional features. J Head Trauma Rehabil. 2011; 26: 116-126.

[64] Dijkers MP. Quality of life after traumatic brain injury: a review of research approaches and findings. Arch Phys Med Rehabil. 2004; 85: S21-S35.

[65] Polinder S, Cnossen MC, Real RGL, et al. A multidimensional approach to post-concussion symptoms in mild traumatic brain injury. Front Neurol. 2018; 9:1113.

[66] Williams MW, Rapport LJ, Millis SR, Hanks RA. Psychosocial outcomes after traumatic brain injury: life satisfaction, community integration, and distress. Rehabil Psychol. 2014; 59: 298-305.

[67] Rauen K, Reichelt L, Probst P, et al. Quality of life up to 10 years after traumatic brain injury: a cross-sectional analysis. Health Qual Life Outcomes. 2020; 18:166.

[68] Harris JK, Godfrey HP, Partridge FM, Knight RG. Caregiver depression following traumatic brain injury (TBI): a consequence of adverse effects on family members? Brain Inj. 2001; 15: 223-238.

[69] Carlozzi NE, Lange RT, Boileau NR, et al. TBI-CareQOL family disruption: family disruption in caregivers of persons with TBI. Rehabil Psychol. 2020; 65: 390-400.

[70] Dijkland SA, Foks KA, Polinder S, et al. Prognosis in moderate and severe traumatic brain injury: a systematic review of contemporary models and validation studies. J Neurotrauma. 2020; 37: 1-13.

[71] Mondello S, Guedes VA, Lai C, et al. Circulating brain injury exosomal proteins following moderate-to-severe traumatic brain injury: temporal profile, outcome prediction and therapy implications. Cells. 2020; 9(4):977.

[72] Yue JK, Upadhyayula PS, Avalos LN, Deng H, Wang KKW. The role of blood biomarkers for magnetic resonance imaging diagnosis of traumatic brain injury. Medicina (Kaunas). 2020; 56(2):87.

[73] Mondello S, Hayes RL. Biomarkers. Handb Clin Neurol. 2015; 127: 245-265.

[74] Huie JR, Mondello S, Lindsell CJ, et al. Biomarkers for traumatic brain injury: data standards and statistical considerations. J Neurotrauma. 2021; 38: 2514-2529.

[75] Dadas A, Washington J, Diaz-Arrastia R, Janigro D. Biomarkers in traumatic brain injury (TBI): a review. Neuropsychiatr Dis Treat. 2018; 14: 2989-3000.

[76] Ghaith HS, Nawar AA, Gabra MD, et al. A literature review of traumatic brain injury biomarkers. Mol Neurobiol. 2022; 59: 4141-4158.

[77] Deshetty UM, Periyasamy P. Potential biomarkers in experimental animal models for traumatic brain injury. J Clin Med. 2023; 12(12):3923.

[78] Sandler SJ, Figaji AA, Adelson PD. Clinical applications of biomarkers in pediatric traumatic brain injury. Childs Nerv Syst. 2010; 26: 205-213.

[79] Daoud H, Alharfi I, Alhelali I, Charyk Stewart T, Qasem H, Fraser DD. Brain injury biomarkers as outcome predictors in pediatric severe traumatic brain injury. Neurocrit Care. 2014; 20: 427-435.

[80] Sugimoto M, Kuwata S, Kurishima C, Kim JH, Iwamoto Y, Senzaki H. Cardiac biomarkers in children with congenital heart disease. World J Pediatr. 2015; 11: 309-315.

[81] Lesko LJ, Atkinson AJ Jr. Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: criteria, validation, strategies. Annu Rev Pharmacol Toxicol. 2001; 41: 347-366.

[82] Robb MA, McInnes PM, Califf RM. Biomarkers and surrogate endpoints: developing common terminology and definitions. JAMA. 2016; 315: 1107-1108.

[83] Azar S, Hasan A, Younes R, et al. Biofluid proteomics and biomarkers in traumatic brain injury. Methods Mol Biol. 2017; 1598: 45-63.

[84] Kerr N, Lee SW, Perez-Barcena J, et al. Inflammasome proteins as biomarkers of traumatic brain injury. PLoS One. 2018; 13:e0210128.

[85] Yokobori S, Hosein K, Burks S, Sharma I, Gajavelli S, Bullock R. Biomarkers for the clinical differential diagnosis in traumatic brain injury—a systematic review. CNS Neurosci Ther. 2013; 19: 556-565.

[86] Swift A, Heale R, Twycross A. What are sensitivity and specificity? Evid Based Nurs. 2020; 23: 2-4.

[87] Gonçalves CA, Leite MC, Nardin P. Biological and methodological features of the measurement of S100B, a putative marker of brain injury. Clin Biochem. 2008; 41: 755-763.

[88] Papa L, Robinson G, Oli M, et al. Use of biomarkers for diagnosis and management of traumatic brain injury patients. Expert Opin Med Diagn. 2008; 2: 937-945.

[89] Zetterberg H, Blennow K. Fluid biomarkers for mild traumatic brain injury and related conditions. Nat Rev Neurol. 2016; 12: 563-574.

[90] Wang KK, Yang Z, Zhu T, et al. An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Rev Mol Diagn. 2018; 18: 165-180.

[91] Tolonen A, Turkka J, Salonen O, Ahoniemi E, Alaranta H. Traumatic brain injury is under-diagnosed in patients with spinal cord injury. J Rehabil Med. 2007; 39: 622-626.

[92] Marshall LF, Marshall SB, Klauber MR, et al. The diagnosis of head injury requires a classification based on computed axial tomography. J Neurotrauma. 1992; 9(Suppl 1): S287-S292.

[93] Cook GA, Hawley JS. A review of mild traumatic brain injury diagnostics: current perspectives, limitations, and emerging technology. Mil Med. 2014; 179: 1083-1089.

[94] Stein SC, Georgoff P, Meghan S, Mizra K, Sonnad SS. 150 years of treating severe traumatic brain injury: a systematic review of progress in mortality. J Neurotrauma. 2010; 27: 1343-1353.

[95] Mohamadpour M, Whitney K, Bergold PJ. The importance of therapeutic time window in the treatment of traumatic brain injury. Front Neurosci. 2019; 13: 7.

[96] Bruns J Jr, Hauser WA. The epidemiology of traumatic brain injury: a review. Epilepsia. 2003; 44: 2-10.

[97] Perel P, Arango M, Clayton T, et al. Predicting outcome after traumatic brain injury: practical prognostic models based on large cohort of international patients. BMJ. 2008; 336: 425-429.

[98] Silvestro S, Raffaele I, Quartarone A, Mazzon E. Innovative insights into traumatic brain injuries: biomarkers and new pharmacological targets. Int J Mol Sci. 2024; 25(4):2372.

[99] Mac Donald CL, Barber J, Jordan M, et al. Early clinical predictors of 5-year outcome after concussive blast traumatic brain injury. JAMA Neurol. 2017; 74: 821-829.

[100] Di Pietro V, Ragusa M, Davies D, et al. MicroRNAs as novel biomarkers for the diagnosis and prognosis of mild and severe traumatic brain injury. J Neurotrauma. 2017; 34: 1948-1956.

[101] Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974; 2: 81-84.

[102] Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet. 1975; 1: 480-484.

[103] Jennett B, Teasdale G, Braakman R, Minderhoud J, Knill-Jones R. Predicting outcome in individual patients after severe head injury. Lancet. 1976; 1: 1031-1034.

[104] Saatman KE, Duhaime AC, Bullock R, Maas AI, Valadka A, Manley GT. Classification of traumatic brain injury for targeted therapies. J Neurotrauma. 2008; 25: 719-738.

[105] Hawryluk GW, Manley GT. Classification of traumatic brain injury: past, present, and future. Handb Clin Neurol. 2015; 127: 15-21.

[106] Papa L, Edwards D, Ramia M. Frontiers in Neuroengineering exploring serum biomarkers for mild traumatic brain injury. In: FH Kobeissy, ed. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. CRC Press/Taylor & Francis; 2015.

[107] Menon DK, Silverberg ND, Ferguson AR, et al. Clinical assessment on days 1-14 for the characterization of traumatic brain injury: recommendations from the 2024 NINDS traumatic brain injury classification and nomenclature initiative clinical/symptoms working group. J Neurotrauma. 2025; 42: 1038-1055.

[108] De Guzman E, Ament A. Neurobehavioral management of traumatic brain injury in the critical care setting: an update. Crit Care Clin. 2017; 33: 423-440.

[109] Salmond CH, Menon DK, Chatfield DA, et al. Diffusion tensor imaging in chronic head injury survivors: correlations with learning and memory indices. NeuroImage. 2006; 29: 117-124.

[110] Steyerberg EW, Mushkudiani N, Perel P, et al. Predicting outcome after traumatic brain injury: development and international validation of prognostic scores based on admission characteristics. PLoS Med. 2008; 5:e165; discussion e165.

[111] Raj R, Siironen J, Kivisaari R, Hernesniemi J, Skrifvars MB. Predicting outcome after traumatic brain injury: development of prognostic scores based on the IMPACT and the APACHE II. J Neurotrauma. 2014; 31: 1721-1732.

[112] Borg J, Holm L, Cassidy JD, et al. Diagnostic procedures in mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med. 2004; 2004: 61-75.

[113] Belanger HG, Vanderploeg RD, Curtiss G, Warden DL. Recent neuroimaging techniques in mild traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2007; 19: 5-20.

[114] Hofman PA, Stapert SZ, van Kroonenburgh MJ, Jolles J, de Kruijk J, Wilmink JT. MR imaging, single-photon emission CT, and neurocognitive performance after mild traumatic brain injury. AJNR Am J Neuroradiol. 2001; 22: 441-449.

[115] Arfanakis K, Haughton VM, Carew JD, Rogers BP, Dempsey RJ, Meyerand ME. Diffusion tensor MR imaging in diffuse axonal injury. AJNR Am J Neuroradiol. 2002; 23: 794-802.

[116] Inglese M, Makani S, Johnson G, et al. Diffuse axonal injury in mild traumatic brain injury: a diffusion tensor imaging study. J Neurosurg. 2005; 103: 298-303.

[117] Silverberg ND, Iaccarino MA, Panenka WJ, et al. Management of concussion and mild traumatic brain injury: a synthesis of practice guidelines. Arch Phys Med Rehabil. 2020; 101: 382-393.

[118] Stocchetti N, Pagan F, Calappi E, et al. Inaccurate early assessment of neurological severity in head injury. J Neurotrauma. 2004; 21: 1131-1140.

[119] Rugg-Gunn FJ, Symms MR, Barker GJ, Greenwood R, Duncan JS. Diffusion imaging shows abnormalities after blunt head trauma when conventional magnetic resonance imaging is normal. J Neurol Neurosurg Psychiatry. 2001; 70: 530-533.

[120] Mettler FA Jr, Bhargavan M, Faulkner K, et al. Radiologic and nuclear medicine studies in the United States and worldwide: frequency, radiation dose, and comparison with other radiation sources—1950-2007. Radiology. 2009; 253: 520-531.

[121] Fazel R, Krumholz HM, Wang Y, et al. Exposure to low-dose ionizing radiation from medical imaging procedures. N Engl J Med. 2009; 361: 849-857.

[122] Servadei F, Murray GD, Penny K, et al. The value of the “worst” computed tomographic scan in clinical studies of moderate and severe head injury. European brain injury consortium. Neurosurgery. 2000; 46: 70-75; discussion 75–77.

[123] Smith-Bindman R, Miglioretti DL, Johnson E, et al. Use of diagnostic imaging studies and associated radiation exposure for patients enrolled in large integrated health care systems, 1996-2010. JAMA. 2012; 307: 2400-2409.

[124] Vos PE, Alekseenko Y, Battistin L, et al. Mild traumatic brain injury. Eur J Neurol. 2012; 19: 191-198.

[125] Zetterberg H, Blennow K. Fluid markers of traumatic brain injury. Mol Cell Neurosci. 2015; 66: 99-102.

[126] Liu MC, Akle V, Zheng W, et al. Comparing calpain- and caspase-3-mediated degradation patterns in traumatic brain injury by differential proteome analysis. Biochem J. 2006; 394: 715-725.

[127] Wang KK. Calpain and caspase: can you tell the difference? Trends Neurosci. 2000; 23: 20-26.

[128] Zhang Z, Mondello S, Kobeissy F, et al. Protein biomarkers for traumatic and ischemic brain injury: from bench to bedside. Transl Stroke Res. 2011; 2: 455-462.

[129] Strathmann FG, Schulte S, Goerl K, Petron DJ. Blood-based biomarkers for traumatic brain injury: evaluation of research approaches, available methods and potential utility from the clinician and clinical laboratory perspectives. Clin Biochem. 2014; 47: 876-888.

[130] Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol. 2010; 6: 131-144.

[131] Good DM, Thongboonkerd V, Novak J, et al. Body fluid proteomics for biomarker discovery: lessons from the past hold the key to success in the future. J Proteome Res. 2007; 6: 4549-4555.

[132] Ballabh P, Braun A, Nedergaard M. The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis. 2004; 16: 1-13.

[133] Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med. 2013; 19: 1584-1596.

[134] Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006; 7: 41-53.

[135] Tibbling G, Link H, Ohman S. Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values. Scand J Clin Lab Invest. 1977; 37: 385-390.

[136] Thelin E, Al Nimer F, Frostell A, et al. Serum protein biomarker panel improves outcome prediction in human traumatic brain injury. J Neurotrauma. 2019; 36: 2850-2862.

[137] Li XY, Feng DF. Diffuse axonal injury: novel insights into detection and treatment. J Clin Neurosci. 2009; 16: 614-619.

[138] de Kruijk JR, Leffers P, Menheere PP, Meerhoff S, Twijnstra A. S-100B and neuron-specific enolase in serum of mild traumatic brain injury patients. A comparison with health controls. Acta Neurol Scand. 2001; 103: 175-179.

[139] Wu HM, Huang SC, Hattori N, et al. Selective metabolic reduction in gray matter acutely following human traumatic brain injury. J Neurotrauma. 2004; 21: 149-161.

[140] Bandyopadhyay S, Hennes H, Gorelick MH, Wells RG, Walsh-Kelly CM. Serum neuron-specific enolase as a predictor of short-term outcome in children with closed traumatic brain injury. Acad Emerg Med. 2005; 12: 732-738.

[141] Moore BW, McGregor D. Chromatographic and electrophoretic fractionation of soluble proteins of brain and liver. J Biol Chem. 1965; 240: 1647-1653.

[142] Kövesdi E, Lückl J, Bukovics P, et al. Update on protein biomarkers in traumatic brain injury with emphasis on clinical use in adults and pediatrics. Acta Neurochir. 2010; 152: 1-17.

[143] Berger RP, Pierce MC, Wisniewski SR, et al. Neuron-specific enolase and S100B in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatrics. 2002; 109:E31.

[144] Žurek J, Fedora M. The usefulness of S100B, NSE, GFAP, NF-H, secretagogin and Hsp70 as a predictive biomarker of outcome in children with traumatic brain injury. Acta Neurochir. 2012; 154: 93-103; discussion 103.

[145] Park DW, Park SH, Hwang SK. Serial measurement of S100B and NSE in pediatric traumatic brain injury. Childs Nerv Syst. 2019; 35: 343-348.

[146] Beers SR, Berger RP, Adelson PD. Neurocognitive outcome and serum biomarkers in inflicted versus non-inflicted traumatic brain injury in young children. J Neurotrauma. 2007; 24: 97-105.

[147] Berger RP, Adelson PD, Pierce MC, Dulani T, Cassidy LD, Kochanek PM. Serum neuron-specific enolase, S100B, and myelin basic protein concentrations after inflicted and noninflicted traumatic brain injury in children. J Neurosurg. 2005; 103: 61-68.

[148] Berger RP, Beers SR, Richichi R, Wiesman D, Adelson PD. Serum biomarker concentrations and outcome after pediatric traumatic brain injury. J Neurotrauma. 2007; 24: 1793-1801.

[149] Berger RP, Hayes RL, Richichi R, Beers SR, Wang KK. Serum concentrations of ubiquitin C-terminal hydrolase-L1 and αII-spectrin breakdown product 145 kDa correlate with outcome after pediatric TBI. J Neurotrauma. 2012; 29: 162-167.

[150] Fridriksson T, Kini N, Walsh-Kelly C, Hennes H. Serum neuron-specific enolase as a predictor of intracranial lesions in children with head trauma: a pilot study. Acad Emerg Med. 2000; 7: 816-820.

[151] Park SH, Hwang SK. Prognostic value of serum levels of S100 calcium-binding protein B, neuron-specific enolase, and Interleukin-6 in Pediatric patients with traumatic brain injury. World Neurosurg. 2018; 118: e534-e542.

[152] Thelin EP, Zeiler FA, Ercole A, et al. Serial sampling of serum protein biomarkers for monitoring human traumatic brain injury dynamics: a systematic review. Front Neurol. 2017; 8:300.

[153] Gyorgy A, Ling G, Wingo D, et al. Time-dependent changes in serum biomarker levels after blast traumatic brain injury. J Neurotrauma. 2011; 28: 1121-1126.

[154] Lorente L. Biomarkers associated with the outcome of traumatic brain injury patients. Brain Sci. 2017; 7(11):142.

[155] Stammet P, Collignon O, Hassager C, et al. Neuron-specific enolase as a predictor of death or poor neurological outcome after out-of-hospital cardiac arrest and targeted temperature management at 33°C and 36°C. J Am Coll Cardiol. 2015; 65: 2104-2114.

[156] Hans VH, Kossmann T, Lenzlinger PM, et al. Experimental axonal injury triggers interleukin-6 mRNA, protein synthesis and release into cerebrospinal fluid. J Cereb Blood Flow Metab. 1999; 19: 184-194.

[157] Begaz T, Kyriacou DN, Segal J, Bazarian JJ. Serum biochemical markers for post-concussion syndrome in patients with mild traumatic brain injury. J Neurotrauma. 2006; 23: 1201-1210.

[158] Gradisek P, Osredkar J, Korsic M, Kremzar B. Multiple indicators model of long-term mortality in traumatic brain injury. Brain Inj. 2012; 26: 1472-1481.

[159] Stefanović B, Đurić O, Stanković S, et al. Elevated serum protein S100B and neuron specific enolase values as predictors of early neurological outcome after traumatic brain injury. J Med Biochem. 2017; 36: 314-321.

[160] Olsson B, Zetterberg H, Hampel H, Blennow K. Biomarker-based dissection of neurodegenerative diseases. Prog Neurobiol. 2011; 95: 520-534.

[161] Scarna H, Delafosse B, Steinberg R, et al. Neuron-specific enolase as a marker of neuronal lesions during various comas in man. Neurochem Int. 1982; 4: 405-411.

[162] Donato R. Functional roles of S100 proteins, calcium-binding proteins of the EF-hand type. Biochim Biophys Acta. 1999; 1450: 191-231.

[163] Böhmer AE, Oses JP, Schmidt AP, et al. Neuron-specific enolase, S100B, and glial fibrillary acidic protein levels as outcome predictors in patients with severe traumatic brain injury. Neurosurgery. 2011; 68: 1624-1630; discussion 1630–1621.

[164] Chiaretti A, Barone G, Riccardi R, et al. NGF, DCX, and NSE upregulation correlates with severity and outcome of head trauma in children. Neurology. 2009; 72: 609-616.

[165] Varma S, Janesko KL, Wisniewski SR, et al. F2-isoprostane and neuron-specific enolase in cerebrospinal fluid after severe traumatic brain injury in infants and children. J Neurotrauma. 2003; 20: 781-786.

[166] Ross SA, Cunningham RT, Johnston CF, Rowlands BJ. Neuron-specific enolase as an aid to outcome prediction in head injury. Br J Neurosurg. 1996; 10: 471-476.

[167] Chabok SY, Moghadam AD, Saneei Z, Amlashi FG, Leili EK, Amiri ZM. Neuron-specific enolase and S100BB as outcome predictors in severe diffuse axonal injury. J Trauma Acute Care Surg. 2012; 72: 1654-1657.

[168] Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011; 155: 529-536.

[169] Mochetti MM, Silva EGP, Correa AAF, et al. Neuron-specific enolase at admission as a predictor for stroke volume, severity and outcome in ischemic stroke patients: a prognostic biomarker review. Sci Rep. 2024; 14:2688.

[170] Hu J, Xie S, Xia W, et al. Meta-analysis of evaluating neuron specific enolase as a serum biomarker for sepsis-associated encephalopathy. Int Immunopharmacol. 2024; 131:111857.

[171] Ekmektzoglou KA, Xanthos T, Papadimitriou L. Biochemical markers (NSE, S-100, IL-8) as predictors of neurological outcome in patients after cardiac arrest and return of spontaneous circulation. Resuscitation. 2007; 75: 219-228.

[172] Mu RZ, Liu S, Liang KG, Jiang D, Huang YJ. A meta-analysis of neuron-specific enolase levels in cerebrospinal fluid and serum in children with epilepsy. Front Mol Neurosci. 2020; 13:24.

[173] Johnsson P, Blomquist S, Lührs C, et al. Neuron-specific enolase increases in plasma during and immediately after extracorporeal circulation. Ann Thorac Surg. 2000; 69: 750-754.

[174] Pelinka LE, Hertz H, Mauritz W, et al. Nonspecific increase of systemic neuron-specific enolase after trauma: clinical and experimental findings. Shock. 2005; 24: 119-123.

[175] Babkina AS, Lyubomudrov MA, Golubev MA, Pisarev MV, Golubev AM. Neuron-specific enolase-what are we measuring? Int J Mol Sci. 2024; 25(9):5040.

[176] Jackson P, Thompson RJ. The demonstration of new human brain-specific proteins by high-resolution two-dimensional polyacrylamide gel electrophoresis. J Neurol Sci. 1981; 49: 429-438.

[177] Vos PE, Jacobs B, Andriessen TM, et al. GFAP and S100B are biomarkers of traumatic brain injury: an observational cohort study. Neurology. 2010; 75: 1786-1793.

[178] Pike BR, Flint J, Dave JR, et al. Accumulation of calpain and caspase-3 proteolytic fragments of brain-derived alphaII-spectrin in cerebral spinal fluid after middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab. 2004; 24: 98-106.

[179] Pineda JA, Lewis SB, Valadka AB, et al. Clinical significance of alphaII-spectrin breakdown products in cerebrospinal fluid after severe traumatic brain injury. J Neurotrauma. 2007; 24: 354-366.

[180] Mondello S, Robicsek SA, Gabrielli A, et al. αII-spectrin breakdown products (SBDPs): diagnosis and outcome in severe traumatic brain injury patients. J Neurotrauma. 2010; 27: 1203-1213.

[181] Krabill AD, Chen H, Hussain S, et al. Ubiquitin C-terminal hydrolase L1: biochemical and cellular characterization of a covalent cyanopyrrolidine-based inhibitor. ChemBioChem. 2020; 21: 712-722.

[182] Luo L. Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity. Annu Rev Cell Dev Biol. 2002; 18: 601-635.

[183] Mondello S, Linnet A, Buki A, et al. Clinical utility of serum levels of ubiquitin C-terminal hydrolase as a biomarker for severe traumatic brain injury. Neurosurgery. 2012; 70: 666-675.

[184] Mondello S, Papa L, Buki A, et al. Neuronal and glial markers are differently associated with computed tomography findings and outcome in patients with severe traumatic brain injury: a case control study. Crit Care. 2011; 15:R156.

[185] Mondello S, Jeromin A, Buki A, et al. Glial neuronal ratio: a novel index for differentiating injury type in patients with severe traumatic brain injury. J Neurotrauma. 2012; 29: 1096-1104.

[186] Brophy GM, Mondello S, Papa L, et al. Biokinetic analysis of ubiquitin C-terminal hydrolase-L1 (UCH-L1) in severe traumatic brain injury patient biofluids. J Neurotrauma. 2011; 28: 861-870.

[187] Czeiter E, Mondello S, Kovacs N, et al. Brain injury biomarkers may improve the predictive power of the IMPACT outcome calculator. J Neurotrauma. 2012; 29: 1770-1778.

[188] Chmielewska N, Szyndler J, Makowska K, Wojtyna D, Maciejak P, Płaźnik A. Looking for novel, brain-derived, peripheral biomarkers of neurological disorders. Neurol Neurochir Pol. 2018; 52: 318-325.

[189] Gong B, Leznik E. The role of ubiquitin C-terminal hydrolase L1 in neurodegenerative disorders. Drug News Perspect. 2007; 20: 365-370.

[190] Kobeissy FH, Ottens AK, Zhang Z, et al. Novel differential neuroproteomics analysis of traumatic brain injury in rats. Mol Cell Proteomics. 2006; 5: 1887-1898.

[191] Liu MC, Akinyi L, Scharf D, et al. Ubiquitin C-terminal hydrolase-L1 as a biomarker for ischemic and traumatic brain injury in rats. Eur J Neurosci. 2010; 31: 722-732.

[192] Li J, Yu C, Sun Y, Li Y. Serum ubiquitin C-terminal hydrolase L1 as a biomarker for traumatic brain injury: a systematic review and meta-analysis. Am J Emerg Med. 2015; 33: 1191-1196.

[193] Mondello S, Thelin EP, Shaw G, et al. Extracellular vesicles: pathogenetic, diagnostic and therapeutic value in traumatic brain injury. Expert Rev Proteomics. 2018; 15: 451-461.

[194] Papa L, Akinyi L, Liu MC, et al. Ubiquitin C-terminal hydrolase is a novel biomarker in humans for severe traumatic brain injury. Crit Care Med. 2010; 38: 138-144.

[195] Papa L, Robertson CS, Wang KK, et al. Biomarkers improve clinical outcome predictors of mortality following non-penetrating severe traumatic brain injury. Neurocrit Care. 2015; 22: 52-64.

[196] Siman R, Roberts VL, McNeil E, et al. Biomarker evidence for mild central nervous system injury after surgically-induced circulation arrest. Brain Res. 2008; 1213: 1-11.

[197] Siman R, Toraskar N, Dang A, et al. A panel of neuron-enriched proteins as markers for traumatic brain injury in humans. J Neurotrauma. 2009; 26: 1867-1877.

[198] Lewis SB, Wolper R, Chi YY, et al. Identification and preliminary characterization of ubiquitin C terminal hydrolase 1 (UCHL1) as a biomarker of neuronal loss in aneurysmal subarachnoid hemorrhage. J Neurosci Res. 2010; 88: 1475-1484.

[199] Blyth BJ, Farahvar A, He H, et al. Elevated serum ubiquitin carboxy-terminal hydrolase L1 is associated with abnormal blood-brain barrier function after traumatic brain injury. J Neurotrauma. 2011; 28: 2453-2462.

[200] Douglas-Escobar M, Yang C, Bennett J, et al. A pilot study of novel biomarkers in neonates with hypoxic-ischemic encephalopathy. Pediatr Res. 2010; 68: 531-536.

[201] Mondello S, Kobeissy F, Vestri A, Hayes RL, Kochanek PM, Berger RP. Serum concentrations of ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein after Pediatric traumatic brain injury. Sci Rep. 2016; 6:28203.

[202] Helmrich I, Czeiter E, Amrein K, et al. Incremental prognostic value of acute serum biomarkers for functional outcome after traumatic brain injury (CENTER-TBI): an observational cohort study. Lancet Neurol. 2022; 21: 792-802.

[203] Vos PE, Lamers KJ, Hendriks JC, et al. Glial and neuronal proteins in serum predict outcome after severe traumatic brain injury. Neurology. 2004; 62: 1303-1310.

[204] Papa L, Lewis LM, Silvestri S, et al. Serum levels of ubiquitin C-terminal hydrolase distinguish mild traumatic brain injury from trauma controls and are elevated in mild and moderate traumatic brain injury patients with intracranial lesions and neurosurgical intervention. J Trauma Acute Care Surg. 2012; 72: 1335-1344.

[205] Missler U, Wiesmann M, Wittmann G, Magerkurth O, Hagenström H. Measurement of glial fibrillary acidic protein in human blood: analytical method and preliminary clinical results. Clin Chem. 1999; 45: 138-141.

[206] Okonkwo DO, Puffer RC, Puccio AM, et al. Point-of-care platform blood biomarker testing of glial fibrillary acidic protein versus S100 calcium-binding protein B for prediction of traumatic brain injuries: a transforming research and clinical knowledge in traumatic brain injury study. J Neurotrauma. 2020; 37: 2460-2467.

[207] Eng LF, Ghirnikar RS, Lee YL. Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000). Neurochem Res. 2000; 25: 1439-1451.

[208] Webster MJ, Knable MB, Johnston-Wilson N, Nagata K, Inagaki M, Yolken RH. Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depression. Brain Behav Immun. 2001; 15: 388-400.

[209] Diaz-Arrastia R, Wang KK, Papa L, et al. Acute biomarkers of traumatic brain injury: relationship between plasma levels of ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein. J Neurotrauma. 2014; 31: 19-25.

[210] Messing A, Brenner M. GFAP at 50. ASN Neuro. 2020; 12:1759091420949680.

[211] Mahan MY, Thorpe M, Ahmadi A, et al. Glial fibrillary acidic protein (GFAP) outperforms S100 calcium-binding protein B (S100B) and ubiquitin C-terminal hydrolase L1 (UCH-L1) as predictor for positive computed tomography of the head in trauma subjects. World Neurosurg. 2019; 128: e434-e444.

[212] Cho W, Brenner M, Peters N, Messing A. Drug screening to identify suppressors of GFAP expression. Hum Mol Genet. 2010; 19: 3169-3178.

[213] Martin EM, Lu WC, Helmick K, French L, Warden DL. Traumatic brain injuries sustained in the Afghanistan and Iraq wars. Am J Nurs. 2008; 108: 40-47; quiz 47-48.

[214] Jaffee MS, Meyer KS. A brief overview of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) within the department of Defense. Clin Neuropsychol. 2009; 23: 1291-1298.

[215] McMahon PJ, Panczykowski DM, Yue JK, et al. Measurement of the glial fibrillary acidic protein and its breakdown products GFAP-BDP biomarker for the detection of traumatic brain injury compared to computed tomography and magnetic resonance imaging. J Neurotrauma. 2015; 32: 527-533.

[216] Zoltewicz JS, Mondello S, Yang B, et al. Biomarkers track damage after graded injury severity in a rat model of penetrating brain injury. J Neurotrauma. 2013; 30: 1161-1169.

[217] Svetlov SI, Prima V, Glushakova O, et al. Neuro-glial and systemic mechanisms of pathological responses in rat models of primary blast overpressure compared to “composite” blast. Front Neurol. 2012; 3:15.

[218] Pelinka LE, Kroepfl A, Leixnering M, Buchinger W, Raabe A, Redl H. GFAP versus S100B in serum after traumatic brain injury: relationship to brain damage and outcome. J Neurotrauma. 2004; 21: 1553-1561.

[219] Pelinka LE, Kroepfl A, Schmidhammer R, et al. Glial fibrillary acidic protein in serum after traumatic brain injury and multiple trauma. J Trauma. 2004; 57: 1006-1012.

[220] van Geel WJ, de Reus HP, Nijzing H, Verbeek MM, Vos PE, Lamers KJ. Measurement of glial fibrillary acidic protein in blood: an analytical method. Clin Chim Acta. 2002; 326: 151-154.

[221] Lei J, Gao G, Feng J, et al. Glial fibrillary acidic protein as a biomarker in severe traumatic brain injury patients: a prospective cohort study. Crit Care. 2015; 19:362.

[222] Stein DM, Lindell AL, Murdock KR, et al. Use of serum biomarkers to predict cerebral hypoxia after severe traumatic brain injury. J Neurotrauma. 2012; 29: 1140-1149.

[223] Okonkwo DO, Yue JK, Puccio AM, et al. GFAP-BDP as an acute diagnostic marker in traumatic brain injury: results from the prospective transforming research and clinical knowledge in traumatic brain injury study. J Neurotrauma. 2013; 30: 1490-1497.

[224] Papa L, Lewis LM, Falk JL, et al. Elevated levels of serum glial fibrillary acidic protein breakdown products in mild and moderate traumatic brain injury are associated with intracranial lesions and neurosurgical intervention. Ann Emerg Med. 2012; 59: 471-483.

[225] Zhang Z, Zoltewicz JS, Mondello S, et al. Human traumatic brain injury induces autoantibody response against glial fibrillary acidic protein and its breakdown products. PLoS One. 2014; 9:e92698.

[226] Nylén K, Ost M, Csajbok LZ, et al. Increased serum-GFAP in patients with severe traumatic brain injury is related to outcome. J Neurol Sci. 2006; 240: 85-91.

[227] Honda M, Tsuruta R, Kaneko T, et al. Serum glial fibrillary acidic protein is a highly specific biomarker for traumatic brain injury in humans compared with S-100B and neuron-specific enolase. J Trauma. 2010; 69: 104-109.

[228] Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002; 347: 161-167.

[229] Reichlin T, Hochholzer W, Bassetti S, et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med. 2009; 361: 858-867.

[230] Metting Z, Wilczak N, Rodiger LA, Schaaf JM, van der Naalt J. GFAP and S100B in the acute phase of mild traumatic brain injury. Neurology. 2012; 78: 1428-1433.

[231] Papa L, Silvestri S, Brophy GM, et al. GFAP out-performs S100β in detecting traumatic intracranial lesions on computed tomography in trauma patients with mild traumatic brain injury and those with extracranial lesions. J Neurotrauma. 2014; 31: 1815-1822.

[232] Zhang ZY, Zhang LX, Dong XQ, et al. Comparison of the performances of copeptin and multiple biomarkers in long-term prognosis of severe traumatic brain injury. Peptides. 2014; 60: 13-17.

[233] Welch RD, Ayaz SI, Lewis LM, et al. Ability of serum glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, and S100B to differentiate normal and abnormal head computed tomography findings in patients with suspected mild or moderate traumatic brain injury. J Neurotrauma. 2016; 33: 203-214.

[234] Bazarian JJ, Biberthaler P, Welch RD, et al. Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study. Lancet Neurol. 2018; 17: 782-789.

[235] Papa L, Zonfrillo MR, Ramirez J, et al. Performance of glial fibrillary acidic protein in detecting traumatic intracranial lesions on computed tomography in children and youth with mild head trauma. Acad Emerg Med. 2015; 22: 1274-1282.

[236] Papa L, Mittal MK, Ramirez J, et al. In children and youth with mild and moderate traumatic brain injury, glial fibrillary acidic protein out-performs S100β in detecting traumatic intracranial lesions on computed tomography. J Neurotrauma. 2016; 33: 58-64.

[237] Papa L, Mittal MK, Ramirez J, et al. Neuronal biomarker ubiquitin C-terminal hydrolase detects traumatic intracranial lesions on computed tomography in children and youth with mild traumatic brain injury. J Neurotrauma. 2017; 34: 2132-2140.

[238] Korley FK, Datwyler SA, Jain S, et al. Comparison of GFAP and UCH-L1 measurements from two prototype assays: the Abbott i-STAT and ARCHITECT assays. Neurotrauma Rep. 2021; 2: 193-199.

[239] Kou Z, Gattu R, Kobeissy F, et al. Combining biochemical and imaging markers to improve diagnosis and characterization of mild traumatic brain injury in the acute setting: results from a pilot study. PLoS One. 2013; 8:e80296.

[240] Bazarian JJ, Welch RD, Caudle K, et al. Accuracy of a rapid glial fibrillary acidic protein/ubiquitin carboxyl-terminal hydrolase L1 test for the prediction of intracranial injuries on head computed tomography after mild traumatic brain injury. Acad Emerg Med. 2021; 28: 1308-1317.

[241] Posti JP, Takala RS, Runtti H, et al. The levels of glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 during the first week after a traumatic brain injury: correlations with clinical and imaging findings. Neurosurgery. 2016; 79: 456-464.

[242] Papa L, Brophy GM, Welch RD, et al. Time course and diagnostic accuracy of glial and neuronal blood biomarkers GFAP and UCH-L1 in a large cohort of trauma patients with and without mild traumatic brain injury. JAMA Neurol. 2016; 73: 551-560.

[243] Donato R, Sorci G, Riuzzi F, et al. S100B's double life: intracellular regulator and extracellular signal. Biochim Biophys Acta. 2009; 1793: 1008-1022.

[244] Herrmann M, Curio N, Jost S, Wunderlich MT, Synowitz H, Wallesch CW. Protein S-100B and neuron specific enolase as early neurobiochemical markers of the severity of traumatic brain injury. Restor Neurol Neurosci. 1999; 14: 109-114.

[245] Zetterberg H, Smith DH, Blennow K. Biomarkers of mild traumatic brain injury in cerebrospinal fluid and blood. Nat Rev Neurol. 2013; 9: 201-210.

[246] Katada R, Akdemir G, Asavapanumas N, Ratelade J, Zhang H, Verkman AS. Greatly improved survival and neuroprotection in aquaporin-4-knockout mice following global cerebral ischemia. FASEB J. 2014; 28: 705-714.

[247] Jeter CB, Hergenroeder GW, Hylin MJ, Redell JB, Moore AN, Dash PK. Biomarkers for the diagnosis and prognosis of mild traumatic brain injury/concussion. J Neurotrauma. 2013; 30: 657-670.

[248] Donato R, Cannon BR, Sorci G, et al. Functions of S100 proteins. Curr Mol Med. 2013; 13: 24-57.

[249] Ingebrigtsen T, Romner B, Kongstad P, Langbakk B. Increased serum concentrations of protein S-100 after minor head injury: a biochemical serum marker with prognostic value? J Neurol Neurosurg Psychiatry. 1995; 59: 103-104.

[250] Schulte S, Podlog LW, Hamson-Utley JJ, Strathmann FG, Strüder HK. A systematic review of the biomarker S100B: implications for sport-related concussion management. J Athl Train. 2014; 49: 830-850.

[251] Filippidis AS, Papadopoulos DC, Kapsalaki EZ, Fountas KN. Role of the S100B serum biomarker in the treatment of children suffering from mild traumatic brain injury. Neurosurg Focus. 2010; 29:E2.

[252] Thelin EP, Johannesson L, Nelson D, Bellander BM. S100B is an important outcome predictor in traumatic brain injury. J Neurotrauma. 2013; 30: 519-528.

[253] Raabe A, Grolms C, Keller M, Döhnert J, Sorge O, Seifert V. Correlation of computed tomography findings and serum brain damage markers following severe head injury. Acta Neurochir. 1998; 140: 787-791; discussion 791–782.

[254] Romner B, Ingebrigtsen T, Kongstad P, Børgesen SE. Traumatic brain damage: serum S-100 protein measurements related to neuroradiological findings. J Neurotrauma. 2000; 17: 641-647.

[255] Woertgen C, Rothoerl RD, Metz C, Brawanski A. Comparison of clinical, radiologic, and serum marker as prognostic factors after severe head injury. J Trauma. 1999; 47: 1126-1130.

[256] Raabe A, Grolms C, Sorge O, Zimmermann M, Seifert V. Serum S-100B protein in severe head injury. Neurosurgery. 1999; 45: 477-483.

[257] Rothoerl RD, Woertgen C, Holzschuh M, Metz C, Brawanski A. S-100 serum levels after minor and major head injury. J Trauma. 1998; 45: 765-767.

[258] McKeating EG, Andrews PJ, Mascia L. Relationship of neuron specific enolase and protein S-100 concentrations in systemic and jugular venous serum to injury severity and outcome after traumatic brain injury. Acta Neurochir Suppl. 1998; 71: 117-119.

[259] Woertgen C, Rothoerl RD, Holzschuh M, Metz C, Brawanski A. Comparison of serial S-100 and NSE serum measurements after severe head injury. Acta Neurochir. 1997; 139: 1161-1164; discussion 1165.

[260] Vajtr D, Benada O, Linzer P, et al. Immunohistochemistry and serum values of S-100B, glial fibrillary acidic protein, and hyperphosphorylated neurofilaments in brain injuries. Soud Lek. 2012; 57: 7-12.

[261] Hayakata T, Shiozaki T, Tasaki O, et al. Changes in CSF S100B and cytokine concentrations in early-phase severe traumatic brain injury. Shock. 2004; 22: 102-107.

[262] Le Sage N, Tardif PA, Frenette J, et al. Detection of S-100β protein in plasma and urine after a mild traumatic brain injury. Can J Neurol Sci. 2019; 46: 599-602.

[263] Anderson RE, Hansson LO, Nilsson O, Dijlai-Merzoug R, Settergren G. High serum S100B levels for trauma patients without head injuries. Neurosurgery. 2001; 48: 1255-1258; discussion 1258–1260.

[264] Bechtel K, Frasure S, Marshall C, Dziura J, Simpson C. Relationship of serum S100B levels and intracranial injury in children with closed head trauma. Pediatrics. 2009; 124: e697-e704.

[265] Berger RP, Pierce MC, Wisniewski SR, Adelson PD, Kochanek PM. Serum S100B concentrations are increased after closed head injury in children: a preliminary study. J Neurotrauma. 2002; 19: 1405-1409.

[266] Portela LV, Tort AB, Schaf DV, et al. The serum S100B concentration is age dependent. Clin Chem. 2002; 48: 950-952.

[267] Undén J, Bellner J, Eneroth M, Alling C, Ingebrigtsen T, Romner B. Raised serum S100B levels after acute bone fractures without cerebral injury. J Trauma. 2005; 58: 59-61.

[268] Stein DM, Kufera JA, Lindell A, et al. Association of CSF biomarkers and secondary insults following severe traumatic brain injury. Neurocrit Care. 2011; 14: 200-207.

[269] Undén J, Ingebrigtsen T, Romner B. Scandinavian guidelines for initial management of minimal, mild and moderate head injuries in adults: an evidence and consensus-based update. BMC Med. 2013; 11:50.

[270] Schmitt FO, Geren BB. The fibrous structure of the nerve axon in relation to the localization of “neurotubules”. J Exp Med. 1950; 91: 499-504.

[271] Hasselblatt M, Mooren FC, von Ahsen N, et al. Serum S100beta increases in marathon runners reflect extracranial release rather than glial damage. Neurology. 2004; 62: 1634-1636.

[272] Constantinescu R, Zetterberg H, Holmberg B, Rosengren L. Levels of brain related proteins in cerebrospinal fluid: an aid in the differential diagnosis of parkinsonian disorders. Parkinsonism Relat Disord. 2009; 15: 205-212.

[273] Khalil M, Teunissen CE, Otto M, et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018; 14: 577-589.

[274] Park E, Liu E, Shek M, Park A, Baker AJ. Heavy neurofilament accumulation and alpha-spectrin degradation accompany cerebellar white matter functional deficits following forebrain fluid percussion injury. Exp Neurol. 2007; 204: 49-57.

[275] Smith DH, Meaney DF, Shull WH. Diffuse axonal injury in head trauma. J Head Trauma Rehabil. 2003; 18: 307-316.

[276] Friede RL, Samorajski T. Axon caliber related to neurofilaments and microtubules in sciatic nerve fibers of rats and mice. Anat Rec. 1970; 167: 379-387.

[277] Kinnunen KM, Greenwood R, Powell JH, et al. White matter damage and cognitive impairment after traumatic brain injury. Brain. 2011; 134: 449-463.

[278] Zetterberg H, Hietala MA, Jonsson M, et al. Neurochemical aftermath of amateur boxing. Arch Neurol. 2006; 63: 1277-1280.

[279] Lépinoux-Chambaud C, Eyer J. Review on intermediate filaments of the nervous system and their pathological alterations. Histochem Cell Biol. 2013; 140: 13-22.

[280] Shahim P, Zetterberg H, Tegner Y, Blennow K. Serum neurofilament light as a biomarker for mild traumatic brain injury in contact sports. Neurology. 2017; 88: 1788-1794.

[281] Zurek J, Bartlová L, Fedora M. Hyperphosphorylated neurofilament NF-H as a predictor of mortality after brain injury in children. Brain Inj. 2011; 25: 221-226.

[282] Bacioglu M, Maia LF, Preische O, et al. Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases. Neuron. 2016; 91: 56-66.

[283] Neselius S, Brisby H, Theodorsson A, Blennow K, Zetterberg H, Marcusson J. CSF-biomarkers in olympic boxing: diagnosis and effects of repetitive head trauma. PLoS One. 2012; 7:e33606.

[284] Shahim P, Tegner Y, Gustafsson B, et al. Neurochemical aftermath of repetitive mild traumatic brain injury. JAMA Neurol. 2016; 73: 1308-1315.

[285] Yuan A, Rao MV, Veeranna , Nixon RA. Neurofilaments and neurofilament proteins in health and disease. Cold Spring Harb Perspect Biol. 2017; 9:a018309.

[286] Oliver JM, Jones MT, Kirk KM, et al. Serum neurofilament light in American football athletes over the course of a season. J Neurotrauma. 2016; 33: 1784-1789.

[287] Al Nimer F, Thelin E, Nyström H, et al. Comparative assessment of the prognostic value of biomarkers in traumatic brain injury reveals an independent role for serum levels of neurofilament light. PLoS One. 2015; 10:e0132177.

[288] Neselius S, Zetterberg H, Blennow K, Marcusson J, Brisby H. Increased CSF levels of phosphorylated neurofilament heavy protein following bout in amateur boxers. PLoS One. 2013; 8:e81249.

[289] Posti JP, Takala RSK, Lagerstedt L, et al. Correlation of blood biomarkers and biomarker panels with traumatic findings on computed tomography after traumatic brain injury. J Neurotrauma. 2019; 36: 2178-2189.

[290] Shahim P, Politis A, van der Merwe A, et al. Time course and diagnostic utility of NfL, tau, GFAP, and UCH-L1 in subacute and chronic TBI. Neurology. 2020; 95: e623-e636.

[291] Gaetani L, Blennow K, Calabresi P, Di Filippo M, Parnetti L, Zetterberg H. Neurofilament light chain as a biomarker in neurological disorders. J Neurol Neurosurg Psychiatry. 2019; 90: 870-881.

[292] Martínez-Morillo E, Childs C, García BP, et al. Neurofilament medium polypeptide (NFM) protein concentration is increased in CSF and serum samples from patients with brain injury. Clin Chem Lab Med. 2015; 53: 1575-1584.

[293] Gill J, Latour L, Diaz-Arrastia R, et al. Glial fibrillary acidic protein elevations relate to neuroimaging abnormalities after mild TBI. Neurology. 2018; 91: e1385-e1389.

[294] Iverson GL, Reddi PJ, Posti JP, et al. Serum neurofilament light is elevated differentially in older adults with uncomplicated mild traumatic brain injuries. J Neurotrauma. 2019; 36: 2400-2406.

[295] Hossain I, Mohammadian M, Takala RSK, et al. Early levels of glial fibrillary acidic protein and Neurofilament light protein in predicting the outcome of mild traumatic brain injury. J Neurotrauma. 2019; 36: 1551-1560.

[296] Shahim P, Politis A, van der Merwe A, et al. Neurofilament light as a biomarker in traumatic brain injury. Neurology. 2020; 95: e610-e622.

[297] Shahim P, Gren M, Liman V, et al. Serum neurofilament light protein predicts clinical outcome in traumatic brain injury. Sci Rep. 2016; 6:36791.

[298] Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA. 1975; 72: 1858-1862.

[299] Castellani RJ, Perry G. Tau biology, tauopathy, traumatic brain injury, and diagnostic challenges. J Alzheimer's Dis. 2019; 67: 447-467.

[300] Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA. 1986; 83: 4913-4917.

[301] Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem. 1986; 261: 6084-6089.

[302] Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991; 82: 239-259.

[303] Feinstein HE, Benbow SJ, LaPointe NE, et al. Oligomerization of the microtubule-associated protein tau is mediated by its N-terminal sequences: implications for normal and pathological tau action. J Neurochem. 2016; 137: 939-954.

[304] Sato C, Barthélemy NR, Mawuenyega KG, et al. Tau kinetics in neurons and the human central nervous system. Neuron. 2018; 97: 1284-1298.e1287.

[305] Pattinson CL, Shahim P, Taylor P, et al. Elevated tau in military personnel relates to chronic symptoms following traumatic brain injury. J Head Trauma Rehabil. 2020; 35: 66-73.

[306] Hanes J, Zilka N, Bartkova M, Caletkova M, Dobrota D, Novak M. Rat tau proteome consists of six tau isoforms: implication for animal models of human tauopathies. J Neurochem. 2009; 108: 1167-1176.

[307] Olivera A, Lejbman N, Jeromin A, et al. Peripheral Total tau in military personnel who sustain traumatic brain injuries during deployment. JAMA Neurol. 2015; 72: 1109-1116.

[308] Trojanowski JQ, Schuck T, Schmidt ML, Lee VM. Distribution of tau proteins in the normal human central and peripheral nervous system. J Histochem Cytochem. 1989; 37: 209-215.

[309] Sivanandam TM, Thakur MK. Traumatic brain injury: a risk factor for Alzheimer's disease. Neurosci Biobehav Rev. 2012; 36: 1376-1381.

[310] Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001; 24: 1121-1159.

[311] Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci. 2003; 4: 49-60.

[312] Hyman BT, Augustinack JC, Ingelsson M. Transcriptional and conformational changes of the tau molecule in Alzheimer's disease. Biochim Biophys Acta. 2005; 1739: 150-157.

[313] Edwards G 3rd, Moreno-Gonzalez I, Soto C. Amyloid-beta and tau pathology following repetitive mild traumatic brain injury. Biochem Biophys Res Commun. 2017; 483: 1137-1142.

[314] Mendez MF, Paholpak P, Lin A, Zhang JY, Teng E. Prevalence of traumatic brain injury in early versus late-onset Alzheimer's disease. J Alzheimer's Dis. 2015; 47: 985-993.

[315] Gilbert M, Snyder C, Corcoran C, Norton MC, Lyketsos CG, Tschanz JT. The association of traumatic brain injury with rate of progression of cognitive and functional impairment in a population-based cohort of Alzheimer's disease: the Cache County dementia progression study. Int Psychogeriatr. 2014; 26: 1593-1601.

[316] Smith DH, Uryu K, Saatman KE, Trojanowski JQ, McIntosh TK. Protein accumulation in traumatic brain injury. NeuroMolecular Med. 2003; 4: 59-72.

[317] Grady MS, McLaughlin MR, Christman CW, Valadka AB, Fligner CL, Povlishock JT. The use of antibodies targeted against the neurofilament subunits for the detection of diffuse axonal injury in humans. J Neuropathol Exp Neurol. 1993; 52: 143-152.

[318] Johnson VE, Stewart W, Smith DH. Widespread τ and amyloid-β pathology many years after a single traumatic brain injury in humans. Brain Pathol. 2012; 22: 142-149.

[319] Kawata K, Liu CY, Merkel SF, Ramirez SH, Tierney RT, Langford D. Blood biomarkers for brain injury: what are we measuring? Neurosci Biobehav Rev. 2016; 68: 460-473.

[320] Rubenstein R, Chang B, Yue JK, et al. Comparing plasma phospho tau, total tau, and phospho tau-total tau ratio as acute and chronic traumatic brain injury biomarkers. JAMA Neurol. 2017; 74: 1063-1072.

[321] Gonzalez-Ortiz F, Dulewicz M, Ashton NJ, et al. Association of serum brain-derived tau with clinical outcome and longitudinal change in patients with severe traumatic brain injury. JAMA Netw Open. 2023; 6:e2321554.

[322] Edwards G 3rd, Zhao J, Dash PK, Soto C, Moreno-Gonzalez I. Traumatic brain injury induces tau aggregation and spreading. J Neurotrauma. 2020; 37: 80-92.

[323] Dugger BN, Whiteside CM, Maarouf CL, et al. The presence of select tau species in human peripheral tissues and their relation to Alzheimer's disease. J Alzheimer's Dis. 2016; 51: 345-356.

[324] Fischer I, Baas PW. Resurrecting the mysteries of big tau. Trends Neurosci. 2020; 43: 493-504.

[325] Liliang PC, Liang CL, Weng HC, et al. Tau proteins in serum predict outcome after severe traumatic brain injury. J Surg Res. 2010; 160: 302-307.

[326] Ost M, Nylén K, Csajbok L, et al. Initial CSF total tau correlates with 1-year outcome in patients with traumatic brain injury. Neurology. 2006; 67: 1600-1604.

[327] Zemlan FP, Jauch EC, Mulchahey JJ, et al. C-tau biomarker of neuronal damage in severe brain injured patients: association with elevated intracranial pressure and clinical outcome. Brain Res. 2002; 947: 131-139.

[328] Franz G, Beer R, Kampfl A, et al. Amyloid beta 1-42 and tau in cerebrospinal fluid after severe traumatic brain injury. Neurology. 2003; 60: 1457-1461.

[329] Hirad AA, Bazarian JJ, Merchant-Borna K, et al. A common neural signature of brain injury in concussion and subconcussion. Sci Adv. 2019; 5:eaau3460.

[330] Rubenstein R, McQuillan L, Wang KKW, et al. Temporal profiles of P-tau, T-tau, and P-tau:tau ratios in cerebrospinal fluid and blood from moderate-severe traumatic brain injury patients and relationship to 6-12 month global outcomes. J Neurotrauma. 2024; 41: 369-392.

[331] Boggs JM. Myelin basic protein: a multifunctional protein. Cell Mol Life Sci. 2006; 63: 1945-1961.

[332] Deber CM, Reynolds SJ. Central nervous system myelin: structure, function, and pathology. Clin Biochem. 1991; 24: 113-134.

[333] Liu MC, Akle V, Zheng W, et al. Extensive degradation of myelin basic protein isoforms by calpain following traumatic brain injury. J Neurochem. 2006; 98: 700-712.

[334] Ottens AK, Golden EC, Bustamante L, Hayes RL, Denslow ND, Wang KK. Proteolysis of multiple myelin basic protein isoforms after neurotrauma: characterization by mass spectrometry. J Neurochem. 2008; 104: 1404-1414.

[335] Chiaretti A, Piastra M, Polidori G, et al. Correlation between neurotrophic factor expression and outcome of children with severe traumatic brain injury. Intensive Care Med. 2003; 29: 1329-1338.

[336] Chiaretti A, Antonelli A, Riccardi R, et al. Nerve growth factor expression correlates with severity and outcome of traumatic brain injury in children. Eur J Paediatr Neurol. 2008; 12: 195-204.

[337] Lamers KJ, Vos P, Verbeek MM, Rosmalen F, van Geel WJ, van Engelen BG. Protein S-100B, neuron-specific enolase (NSE), myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) and blood of neurological patients. Brain Res Bull. 2003; 61: 261-264.

[338] Sharp DJ, Ham TE. Investigating white matter injury after mild traumatic brain injury. Curr Opin Neurol. 2011; 24: 558-563.

[339] Shenton ME, Hamoda HM, Schneiderman JS, et al. A review of magnetic resonance imaging and diffusion tensor imaging findings in mild traumatic brain injury. Brain Imaging Behav. 2012; 6: 137-192.

[340] Ringger NC, O'Steen BE, Brabham JG, et al. A novel marker for traumatic brain injury: CSF alphaII-spectrin breakdown product levels. J Neurotrauma. 2004; 21: 1443-1456.

[341] Berger RP, Adelson PD, Richichi R, Kochanek PM. Serum biomarkers after traumatic and hypoxemic brain injuries: insight into the biochemical response of the pediatric brain to inflicted brain injury. Dev Neurosci. 2006; 28: 327-335.

[342] Berger RP, Dulani T, Adelson PD, Leventhal JM, Richichi R, Kochanek PM. Identification of inflicted traumatic brain injury in well-appearing infants using serum and cerebrospinal markers: a possible screening tool. Pediatrics. 2006; 117: 325-332.

[343] Su E, Bell MJ, Kochanek PM, et al. Increased CSF concentrations of myelin basic protein after TBI in infants and children: absence of significant effect of therapeutic hypothermia. Neurocrit Care. 2012; 17: 401-407.

[344] Thomas DG, Palfreyman JW, Ratcliffe JG. Serum-myelin-basic-protein assay in diagnosis and prognosis of patients with head injury. Lancet. 1978; 1: 113-115.

[345] Yamazaki Y, Yada K, Morii S, Kitahara T, Ohwada T. Diagnostic significance of serum neuron-specific enolase and myelin basic protein assay in patients with acute head injury. Surg Neurol. 1995; 43: 267-270; discussion 270-261.

[346] Kadhim HJ, Duchateau J, Sébire G. Cytokines and brain injury: invited review. J Intensive Care Med. 2008; 23: 236-249.

[347] Morganti-Kossmann MC, Rancan M, Stahel PF, Kossmann T. Inflammatory response in acute traumatic brain injury: a double-edged sword. Curr Opin Crit Care. 2002; 8: 101-105.

[348] Whitney NP, Eidem TM, Peng H, Huang Y, Zheng JC. Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders. J Neurochem. 2009; 108: 1343-1359.

[349] Woodcock T, Morganti-Kossmann MC. The role of markers of inflammation in traumatic brain injury. Front Neurol. 2013; 4: 18.

[350] Jassam YN, Izzy S, Whalen M, McGavern DB, El Khoury J. Neuroimmunology of traumatic brain injury: time for a paradigm shift. Neuron. 2017; 95: 1246-1265.

[351] Hickey WF. Basic principles of immunological surveillance of the normal central nervous system. Glia. 2001; 36: 118-124.

[352] Webster KM, Sun M, Crack P, O'Brien TJ, Shultz SR, Semple BD. Inflammation in epileptogenesis after traumatic brain injury. J Neuroinflammation. 2017; 14: 10.

[353] Hudome S, Palmer C, Roberts RL, Mauger D, Housman C, Towfighi J. The role of neutrophils in the production of hypoxic-ischemic brain injury in the neonatal rat. Pediatr Res. 1997; 41: 607-616.

[354] Owen CA, Campbell EJ. The cell biology of leukocyte-mediated proteolysis. J Leukoc Biol. 1999; 65: 137-150.

[355] Norden DM, Fenn AM, Dugan A, Godbout JP. TGFβ produced by IL-10 redirected astrocytes attenuates microglial activation. Glia. 2014; 62: 881-895.

[356] Dunn AJ, Swiergiel AH, Zhang H, Quan N. Reduced ingestion of sweetened milk induced by interleukin-1 and lipopolysaccharide is associated with induction of cyclooxygenase-2 in brain endothelia. Neuroimmunomodulation. 2006; 13: 96-104.

[357] Cekic M, Sayeed I, Stein DG. Combination treatment with progesterone and vitamin D hormone may be more effective than monotherapy for nervous system injury and disease. Front Neuroendocrinol. 2009; 30: 158-172.

[358] Thelin EP, Hall CE, Gupta K, et al. Elucidating pro-inflammatory cytokine responses after traumatic brain injury in a human stem cell model. J Neurotrauma. 2018; 35: 341-352.

[359] Stein DG, Cekic MM. Progesterone and vitamin d hormone as a biologic treatment of traumatic brain injury in the aged. PM R. 2011; 3: S100-S110.

[360] Kumar RG, Rubin JE, Berger RP, Kochanek PM, Wagner AK. Principal components derived from CSF inflammatory profiles predict outcome in survivors after severe traumatic brain injury. Brain Behav Immun. 2016; 53: 183-193.

[361] Kumar RG, Diamond ML, Boles JA, et al. Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome. Brain Behav Immun. 2015; 45: 253-262.

[362] Crichton A, Ignjatovic V, Babl FE, et al. Interleukin-8 predicts fatigue at 12 months post-injury in children with traumatic brain injury. J Neurotrauma. 2021; 38: 1151-1163.

[363] Csuka E, Morganti-Kossmann MC, Lenzlinger PM, Joller H, Trentz O, Kossmann T. IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-alpha, TGF-beta1 and blood-brain barrier function. J Neuroimmunol. 1999; 101: 211-221.

[364] Ross SA, Halliday MI, Campbell GC, Byrnes DP, Rowlands BJ. The presence of tumour necrosis factor in CSF and plasma after severe head injury. Br J Neurosurg. 1994; 8: 419-425.

[365] Tobinick E, Kim NM, Reyzin G, Rodriguez-Romanacce H, DePuy V. Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs. 2012; 26: 1051-1070.

[366] Aisiku IP, Yamal JM, Doshi P, et al. Plasma cytokines IL-6, IL-8, and IL-10 are associated with the development of acute respiratory distress syndrome in patients with severe traumatic brain injury. Crit Care. 2016; 20:288.

[367] Kossmann T, Stahel PF, Lenzlinger PM, et al. Interleukin-8 released into the cerebrospinal fluid after brain injury is associated with blood-brain barrier dysfunction and nerve growth factor production. J Cereb Blood Flow Metab. 1997; 17: 280-289.

[368] Rhodes J, Sharkey J, Andrews P. Serum IL-8 and MCP-1 concentration do not identify patients with enlarging contusions after traumatic brain injury. J Trauma. 2009; 66: 1591-1597; discussion 1598.

[369] Timmerman KL, Amonette WE, Markofski MM, et al. Blunted IL-6 and IL-10 response to maximal aerobic exercise in patients with traumatic brain injury. Eur J Appl Physiol. 2015; 115: 111-118.

[370] Dalla Libera AL, Regner A, de Paoli J, Centenaro L, Martins TT, Simon D. IL-6 polymorphism associated with fatal outcome in patients with severe traumatic brain injury. Brain Inj. 2011; 25: 365-369.

[371] Karpiak SE, Serokosz M, Rapport MM. Effects of antisera to S-100 protein and to synaptic membrane fraction on maze performance and EEG. Brain Res. 1976; 102: 313-321.

[372] Frugier T, Morganti-Kossmann MC, O'Reilly D, McLean CA. In situ detection of inflammatory mediators in post mortem human brain tissue after traumatic injury. J Neurotrauma. 2010; 27: 497-507.

[373] Hagberg H, Gilland E, Bona E, et al. Enhanced expression of interleukin (IL)-1 and IL-6 messenger RNA and bioactive protein after hypoxia-ischemia in neonatal rats. Pediatr Res. 1996; 40: 603-609.

[374] Williams AJ, Wei HH, Dave JR, Tortella FC. Acute and delayed neuroinflammatory response following experimental penetrating ballistic brain injury in the rat. J Neuroinflammation. 2007; 4:17.

[375] Shreeniwas R, Koga S, Karakurum M, et al. Hypoxia-mediated induction of endothelial cell interleukin-1 alpha. An autocrine mechanism promoting expression of leukocyte adhesion molecules on the vessel surface. J Clin Invest. 1992; 90: 2333-2339.

[376] Clark RS, Kochanek PM, Dixon CE, et al. Early neuropathologic effects of mild or moderate hypoxemia after controlled cortical impact injury in rats. J Neurotrauma. 1997; 14: 179-189.

[377] Matsushita Y, Bramlett HM, Alonso O, Dietrich WD. Posttraumatic hypothermia is neuroprotective in a model of traumatic brain injury complicated by a secondary hypoxic insult. Crit Care Med. 2001; 29: 2060-2066.

[378] Ishige N, Pitts LH, Hashimoto T, Nishimura MC, Bartkowski HM. Effect of hypoxia on traumatic brain injury in rats: part 1. Changes in neurological function, electroencephalograms, and histopathology. Neurosurgery. 1987; 20: 848-853.

[379] Van Putten HP, Bouwhuis MG, Muizelaar JP, Lyeth BG, Berman RF. Diffusion-weighted imaging of edema following traumatic brain injury in rats: effects of secondary hypoxia. J Neurotrauma. 2005; 22: 857-872.

[380] Bramlett HM, Dietrich WD, Green EJ. Secondary hypoxia following moderate fluid percussion brain injury in rats exacerbates sensorimotor and cognitive deficits. J Neurotrauma. 1999; 16: 1035-1047.

[381] Robertson CL, Clark RS, Dixon CE, et al. No long-term benefit from hypothermia after severe traumatic brain injury with secondary insult in rats. Crit Care Med. 2000; 28: 3218-3223.

[382] Beaumont A, Marmarou A, Czigner A, et al. The impact-acceleration model of head injury: injury severity predicts motor and cognitive performance after trauma. Neurol Res. 1999; 21: 742-754.

[383] Cai Z, Lin S, Pang Y, Rhodes PG. Brain injury induced by intracerebral injection of interleukin-1beta and tumor necrosis factor-alpha in the neonatal rat. Pediatr Res. 2004; 56: 377-384.

[384] Lu KT, Wang YW, Wo YY, Yang YL. Extracellular signal-regulated kinase-mediated IL-1-induced cortical neuron damage during traumatic brain injury. Neurosci Lett. 2005; 386: 40-45.

[385] Stahel PF, Kossmann T, Joller H, Trentz O, Morganti-Kossmann MC. Increased interleukin-12 levels in human cerebrospinal fluid following severe head trauma. Neurosci Lett. 1998; 249: 123-126.

[386] Singhal A, Baker AJ, Hare GM, Reinders FX, Schlichter LC, Moulton RJ. Association between cerebrospinal fluid interleukin-6 concentrations and outcome after severe human traumatic brain injury. J Neurotrauma. 2002; 19: 929-937.

[387] Whalen MJ, Carlos TM, Kochanek PM, et al. Interleukin-8 is increased in cerebrospinal fluid of children with severe head injury. Crit Care Med. 2000; 28: 929-934.

[388] Ikeda T, Xia XY, Xia YX, Ikenoue T, Han B, Choi BH. Glial cell line-derived neurotrophic factor protects against ischemia/hypoxia-induced brain injury in neonatal rat. Acta Neuropathol. 2000; 100: 161-167.

[389] Kossmann T, Hans V, Imhof HG, Trentz O, Morganti-Kossmann MC. Interleukin-6 released in human cerebrospinal fluid following traumatic brain injury may trigger nerve growth factor production in astrocytes. Brain Res. 1996; 713: 143-152.

[390] Shen LJ, Yang SB, Lv QW, et al. High plasma adiponectin levels in patients with severe traumatic brain injury. Clin Chim Acta. 2014; 427: 37-41.

[391] Wang KY, Yu GF, Zhang ZY, Huang Q, Dong XQ. Plasma high-mobility group box 1 levels and prediction of outcome in patients with traumatic brain injury. Clin Chim Acta. 2012; 413: 1737-1741.

[392] Gao TL, Yuan XT, Yang D, et al. Expression of HMGB1 and RAGE in rat and human brains after traumatic brain injury. J Trauma Acute Care Surg. 2012; 72: 643-649.

[393] Shen YF, Yu WH, Dong XQ, et al. The change of plasma galectin-3 concentrations after traumatic brain injury. Clin Chim Acta. 2016; 456: 75-80.

[394] Pan JW, Gao XW, Jiang H, Li YF, Xiao F, Zhan RY. Low serum ficolin-3 levels are associated with severity and poor outcome in traumatic brain injury. J Neuroinflammation. 2015; 12:226.

[395] Yu W, Le HW, Lu YG, et al. High levels of serum mannose-binding lectins are associated with the severity and clinical outcomes of severe traumatic brain injury. Clin Chim Acta. 2015; 451: 111-116.

[396] Dietrich WD, Chatzipanteli K, Vitarbo E, Wada K, Kinoshita K. The role of inflammatory processes in the pathophysiology and treatment of brain and spinal cord trauma. Acta Neurochir Suppl. 2004; 89: 69-74.

[397] Amick JE, Yandora KA, Bell MJ, et al. The Th1 versus Th2 cytokine profile in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatr Crit Care Med. 2001; 2: 260-264.

[398] Woiciechowsky C, Schöning B, Cobanov J, Lanksch WR, Volk HD, Döcke WD. Early IL-6 plasma concentrations correlate with severity of brain injury and pneumonia in brain-injured patients. J Trauma. 2002; 52: 339-345.

[399] Li HH, Lee SM, Cai Y, Sutton RL, Hovda DA. Differential gene expression in hippocampus following experimental brain trauma reveals distinct features of moderate and severe injuries. J Neurotrauma. 2004; 21: 1141-1153.

[400] Giza CC, Prins ML. Is being plastic fantastic? Mechanisms of altered plasticity after developmental traumatic brain injury. Dev Neurosci. 2006; 28: 364-379.

[401] Nonaka M, Chen XH, Pierce JE, et al. Prolonged activation of NF-kappaB following traumatic brain injury in rats. J Neurotrauma. 1999; 16: 1023-1034.

[402] Sherwood ER, Prough DS. Interleukin-8, neuroinflammation, and secondary brain injury. Crit Care Med. 2000; 28: 1221-1223.

[403] Lo TY, Jones PA, Minns RA. Pediatric brain trauma outcome prediction using paired serum levels of inflammatory mediators and brain-specific proteins. J Neurotrauma. 2009; 26: 1479-1487.

[404] Castellani C, Bimbashi P, Ruttenstock E, Sacherer P, Stojakovic T, Weinberg AM. Neuroprotein s-100B—a useful parameter in paediatric patients with mild traumatic brain injury? Acta Paediatr. 2009; 98: 1607-1612.

[405] Sordillo PP, Sordillo LA, Helson L. Bifunctional role of pro-inflammatory cytokines after traumatic brain injury. Brain Inj. 2016; 30: 1043-1053.

[406] Garcia JM, Stillings SA, Leclerc JL, et al. Role of Interleukin-10 in acute brain injuries. Front Neurol. 2017; 8:244.

[407] Zhu H, Hu S, Li Y, et al. Interleukins and ischemic stroke. Front Immunol. 2022; 13:828447.

[408] Tuttolomondo A, Pecoraro R, Pinto A. Studies of selective TNF inhibitors in the treatment of brain injury from stroke and trauma: a review of the evidence to date. Drug Des Devel Ther. 2014; 8: 2221-2238.

[409] Werhane ML, Evangelista ND, Clark AL, et al. Pathological vascular and inflammatory biomarkers of acute- and chronic-phase traumatic brain injury. Concussion. 2017; 2:Cnc30.

[410] North SH, Shriver-Lake LC, Taitt CR, Ligler FS. Rapid analytical methods for on-site triage for traumatic brain injury. Annu Rev Anal Chem (Palo Alto, Calif). 2012; 5: 35-56.

[411] Bogoslovsky T, Gill J, Jeromin A, Davis C, Diaz-Arrastia R. Fluid biomarkers of traumatic brain injury and intended context of use. Diagnostics (Basel). 2016; 6: 37.

[412] Goodman JC, Van M, Gopinath SP, Robertson CS. Pro-inflammatory and pro-apoptotic elements of the neuroinflammatory response are activated in traumatic brain injury. Acta Neurochir Suppl. 2008; 102: 437-439.

[413] Hergenroeder GW, Moore AN, McCoy JP Jr, et al. Serum IL-6: a candidate biomarker for intracranial pressure elevation following isolated traumatic brain injury. J Neuroinflammation. 2010; 7:19.

[414] Gentile NT, McIntosh TK. Antagonists of excitatory amino acids and endogenous opioid peptides in the treatment of experimental central nervous system injury. Ann Emerg Med. 1993; 22: 1028-1034.

[415] Faden AI, Demediuk P, Panter SS, Vink R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science. 1989; 244: 798-800.

[416] Xiong Y, Gu Q, Peterson PL, Muizelaar JP, Lee CP. Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. J Neurotrauma. 1997; 14: 23-34.

[417] Adamczak S, Dale G, de Rivero Vaccari JP, Bullock MR, Dietrich WD, Keane RW. Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomarkers of functional outcome: clinical article. J Neurosurg. 2012; 117: 1119-1125.

[418] Pérez-Bárcena J, Crespí C, Frontera G, et al. Levels of caspase-1 in cerebrospinal fluid of patients with traumatic brain injury: correlation with intracranial pressure and outcome. J Neurosurg. 2020; 134: 1644-1649.

[419] Berger RP, Ta'asan S, Rand A, Lokshin A, Kochanek P. Multiplex assessment of serum biomarker concentrations in well-appearing children with inflicted traumatic brain injury. Pediatr Res. 2009; 65: 97-102.

[420] Lagerstedt L, Egea-Guerrero JJ, Rodríguez-Rodríguez A, et al. Early measurement of interleukin-10 predicts the absence of CT scan lesions in mild traumatic brain injury. PLoS One. 2018; 13:e0193278.

[421] Hensler T, Sauerland S, Riess P, et al. The effect of additional brain injury on systemic interleukin (IL)-10 and IL-13 levels in trauma patients. Inflamm Res. 2000; 49: 524-528.

[422] Shiozaki T, Hayakata T, Tasaki O, et al. Cerebrospinal fluid concentrations of anti-inflammatory mediators in early-phase severe traumatic brain injury. Shock. 2005; 23: 406-410.

[423] Kumar A, Stoica BA, Loane DJ, et al. Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury. J Neuroinflammation. 2017; 14(1):47.

[424] Karttunen J, Heiskanen M, Lipponen A, Poulsen D, Pitkänen A. Extracellular vesicles as diagnostics and therapeutics for structural epilepsies. Int J Mol Sci. 2019; 20: 1259.

[425] Budnik V, Ruiz-Cañada C, Wendler F. Extracellular vesicles round off communication in the nervous system. Nat Rev Neurosci. 2016; 17: 160-172.

[426] Yáñez-Mó M, Siljander PR, Andreu Z, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015; 4:27066.

[427] Frühbeis C, Fröhlich D, Kuo WP, Krämer-Albers EM. Extracellular vesicles as mediators of neuron-glia communication. Front Cell Neurosci. 2013; 7:182.

[428] Yang Y, Boza-Serrano A, Dunning CJR, Clausen BH, Lambertsen KL, Deierborg T. Inflammation leads to distinct populations of extracellular vesicles from microglia. J Neuroinflammation. 2018; 15:168.

[429] Beard K, Meaney DF, Issadore D. Clinical applications of extracellular vesicles in the diagnosis and treatment of traumatic brain injury. J Neurotrauma. 2020; 37: 2045-2056.

[430] Guedes VA, Lai C, Devoto C, et al. Extracellular vesicle proteins and microRNAs are linked to chronic post-traumatic stress disorder symptoms in service members and veterans with mild traumatic brain injury. Front Pharmacol. 2021; 12:745348.

[431] Pascual M, Ibáñez F, Guerri C. Exosomes as mediators of neuron-glia communication in neuroinflammation. Neural Regen Res. 2020; 15: 796-801.

[432] Schnatz A, Müller C, Brahmer A, Krämer-Albers EM. Extracellular vesicles in neural cell interaction and CNS homeostasis. FASEB Bioadv. 2021; 3: 577-592.

[433] Wang S, Cesca F, Loers G, et al. Synapsin I is an oligomannose-carrying glycoprotein, acts as an oligomannose-binding lectin, and promotes neurite outgrowth and neuronal survival when released via glia-derived exosomes. J Neurosci. 2011; 31: 7275-7290.

[434] Li H, Luo Y, Zhu L, et al. Glia-derived exosomes: promising therapeutic targets. Life Sci. 2019; 239:116951.

[435] Sardar Sinha M, Ansell-Schultz A, Civitelli L, et al. Alzheimer's disease pathology propagation by exosomes containing toxic amyloid-beta oligomers. Acta Neuropathol. 2018; 136: 41-56.

[436] Delpech JC, Herron S, Botros MB, Ikezu T. Neuroimmune crosstalk through extracellular vesicles in health and disease. Trends Neurosci. 2019; 42: 361-372.

[437] Henson PM, Bratton DL, Fadok VA. Apoptotic cell removal. Curr Biol. 2001; 11: R795-R805.

[438] Bergsmedh A, Szeles A, Henriksson M, et al. Horizontal transfer of oncogenes by uptake of apoptotic bodies. Proc Natl Acad Sci USA. 2001; 98: 6407-6411.

[439] Zhao Z, Zhou Y, Tian Y, Li M, Dong JF, Zhang J. Cellular microparticles and pathophysiology of traumatic brain injury. Protein Cell. 2017; 8: 801-810.

[440] Nekludov M, Bellander BM, Gryth D, Wallen H, Mobarrez F. Brain-derived microparticles in patients with severe isolated TBI. Brain Inj. 2017; 31: 1856-1862.

[441] Harding CV, Heuser JE, Stahl PD. Exosomes: looking back three decades and into the future. J Cell Biol. 2013; 200: 367-371.

[442] Skotland T, Hessvik NP, Sandvig K, Llorente A. Exosomal lipid composition and the role of ether lipids and phosphoinositides in exosome biology. J Lipid Res. 2019; 60: 9-18.

[443] Li FX, Liu JJ, Xu F, et al. Role of tumor-derived exosomes in bone metastasis. Oncol Lett. 2019; 18: 3935-3945.

[444] Hu Y, Rao SS, Wang ZX, et al. Exosomes from human umbilical cord blood accelerate cutaneous wound healing through miR-21-3p-mediated promotion of angiogenesis and fibroblast function. Theranostics. 2018; 8: 169-184.

[445] Record M, Silvente-Poirot S, Poirot M, Wakelam MJO. Extracellular vesicles: lipids as key components of their biogenesis and functions. J Lipid Res. 2018; 59: 1316-1324.

[446] Chen CY, Rao SS, Ren L, et al. Exosomal DMBT1 from human urine-derived stem cells facilitates diabetic wound repair by promoting angiogenesis. Theranostics. 2018; 8: 1607-1623.

[447] Skog J, Würdinger T, van Rijn S, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008; 10: 1470-1476.

[448] Osier N, Motamedi V, Edwards K, et al. Exosomes in acquired neurological disorders: new insights into pathophysiology and treatment. Mol Neurobiol. 2018; 55: 9280-9293.

[449] Han Y, Chu X, Cui L, et al. Neuronal mitochondria-targeted therapy for Alzheimer's disease by systemic delivery of resveratrol using dual-modified novel biomimetic nanosystems. Drug Deliv. 2020; 27: 502-518.

[450] Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014; 30: 255-289.

[451] Ferreira JV, Rosa Soares A, Ramalho JS, et al. Exosomes and STUB1/CHIP cooperate to maintain intracellular proteostasis. PLoS One. 2019; 14:e0223790.

[452] Shi M, Sheng L, Stewart T, Zabetian CP, Zhang J. New windows into the brain: central nervous system-derived extracellular vesicles in blood. Prog Neurobiol. 2019; 175: 96-106.

[453] Lafourcade C, Ramírez JP, Luarte A, Fernández A, Wyneken U. MiRNAs in astrocyte-derived exosomes as possible mediators of neuronal plasticity. J Exp Neurosci. 2016; 10: 1-9.

[454] Chevillet JR, Kang Q, Ruf IK, et al. Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc Natl Acad Sci USA. 2014; 111: 14888-14893.

[455] Wan M, Ning B, Spiegel S, Lyon CJ, Hu TY. Tumor-derived exosomes (TDEs): how to avoid the sting in the tail. Med Res Rev. 2020; 40: 385-412.

[456] Duan P, Tan J, Miao Y, Zhang Q. Potential role of exosomes in the pathophysiology, diagnosis, and treatment of hypoxic diseases. Am J Transl Res. 2019; 11(3): 1184-1201.

[457] Nutma E, van Gent D, Amor S, Peferoen LAN. Astrocyte and oligodendrocyte cross-talk in the central nervous system. Cells. 2020; 9: 600.

[458] Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020; 367:eaau6977.

[459] Taylor DD, Gercel-Taylor C. The origin, function, and diagnostic potential of RNA within extracellular vesicles present in human biological fluids. Front Genet. 2013; 4:142.

[460] Snijders C, de Nijs L, Baker DG, et al. MicroRNAs in post-traumatic stress disorder. Curr Top Behav Neurosci. 2018; 38: 23-46.

[461] Ratajczak J, Miekus K, Kucia M, et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia. 2006; 20: 847-856.

[462] Peng P, Zhang B, Huang J, et al. Identification of a circRNA-miRNA-mRNA network to explore the effects of circRNAs on pathogenesis and treatment of spinal cord injury. Life Sci. 2020; 257:118039.

[463] Herrold AA, Kletzel SL, Foecking EM, et al. miRNAs as potential biomarkers for traumatic brain injury: pathway from diagnosis to neurorehabilitation. J Head Trauma Rehabil. 2021; 36: E155-e169.

[464] Liu Q, Zhu Y, Zhu W, Zhang G, Yang YP, Zhao C. The role of MicroRNAs in tendon injury, repair, and related tissue engineering. Biomaterials. 2021; 277:121083.

[465] Nam JW, Rissland OS, Koppstein D, et al. Global analyses of the effect of different cellular contexts on microRNA targeting. Mol Cell. 2014; 53: 1031-1043.

[466] Xiao X, Jiang Y, Liang W, et al. miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2. Mol Brain. 2019; 12: 78.

[467] Yin Z, Han Z, Hu T, et al. Neuron-derived exosomes with high miR-21-5p expression promoted polarization of M1 microglia in culture. Brain Behav Immun. 2020; 83: 270-282.

[468] Dash PK, Kobori N, Moore AN. A molecular description of brain trauma pathophysiology using microarray technology: an overview. Neurochem Res. 2004; 29: 1275-1286.

[469] Richardson RM, Sun D, Bullock MR. Neurogenesis after traumatic brain injury. Neurosurg Clin N Am. 2007; 18: 169-181, xi.

[470] Raghupathi R. Cell death mechanisms following traumatic brain injury. Brain Pathol. 2004; 14: 215-222.

[471] Bhomia M, Balakathiresan NS, Wang KK, Papa L, Maheshwari RK. A panel of serum MiRNA biomarkers for the diagnosis of severe to mild traumatic brain injury in humans. Sci Rep. 2016; 6:28148.

[472] Redell JB, Moore AN, Ward NH 3rd, Hergenroeder GW, Dash PK. Human traumatic brain injury alters plasma microRNA levels. J Neurotrauma. 2010; 27: 2147-2156.

[473] Yang T, Song J, Bu X, et al. Elevated serum miR-93, miR-191, and miR-499 are noninvasive biomarkers for the presence and progression of traumatic brain injury. J Neurochem. 2016; 137: 122-129.

[474] Lei P, Li Y, Chen X, Yang S, Zhang J. Microarray based analysis of microRNA expression in rat cerebral cortex after traumatic brain injury. Brain Res. 2009; 1284: 191-201.

[475] Redell JB, Liu Y, Dash PK. Traumatic brain injury alters expression of hippocampal microRNAs: potential regulators of multiple pathophysiological processes. J Neurosci Res. 2009; 87: 1435-1448.

[476] Nelson PT, Wang WX, Rajeev BW. MicroRNAs (miRNAs) in neurodegenerative diseases. Brain Pathol. 2008; 18: 130-138.

[477] Johnson JJ, Loeffert AC, Stokes J, Olympia RP, Bramley H, Hicks SD. Association of salivary MicroRNA changes with prolonged concussion symptoms. JAMA Pediatr. 2018; 172: 65-73.

[478] Taheri S, Tanriverdi F, Zararsiz G, et al. Circulating microRNAs as potential biomarkers for traumatic brain injury-induced hypopituitarism. J Neurotrauma. 2016; 33: 1818-1825.

[479] Bonauer A, Carmona G, Iwasaki M, et al. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science. 2009; 324: 1710-1713.

[480] Doebele C, Bonauer A, Fischer A, et al. Members of the microRNA-17-92 cluster exhibit a cell-intrinsic antiangiogenic function in endothelial cells. Blood. 2010; 115: 4944-4950.

[481] Brophy GM, Pineda JA, Papa L, et al. alphaII-Spectrin breakdown product cerebrospinal fluid exposure metrics suggest differences in cellular injury mechanisms after severe traumatic brain injury. J Neurotrauma. 2009; 26: 471-479.

[482] Hu Q, Wu X, Guo C, et al. Astrocyte-neuron crosstalk through extracellular vesicle-shuttled miRNA-382-5p promotes traumatic brain injury. Exp Mol Med. 2024; 56: 2642-2658.

[483] Ji W, Jiao J, Cheng C, Shao J. MicroRNA-21 in the pathogenesis of traumatic brain injury. Neurochem Res. 2018; 43: 1863-1868.

[484] Wu P, He B, Li X, Zhang H. Roles of microRNA-124 in traumatic brain injury: a comprehensive review. Front Cell Neurosci. 2023; 17:1298508.

[485] Büki A, Siman R, Trojanowski JQ, Povlishock JT. The role of calpain-mediated spectrin proteolysis in traumatically induced axonal injury. J Neuropathol Exp Neurol. 1999; 58: 365-375.

[486] Reeves TM, Greer JE, Vanderveer AS, Phillips LL. Proteolysis of submembrane cytoskeletal proteins ankyrin-G and αII-spectrin following diffuse brain injury: a role in white matter vulnerability at nodes of Ranvier. Brain Pathol. 2010; 20: 1055-1068.

[487] Riederer BM, Zagon IS, Goodman SR. Brain spectrin(240/235) and brain spectrin(240/235E): two distinct spectrin subtypes with different locations within mammalian neural cells. J Cell Biol. 1986; 102: 2088-2097.

[488] Wang KK, Posmantur R, Nath R, et al. Simultaneous degradation of alphaII- and betaII-spectrin by caspase 3 (CPP32) in apoptotic cells. J Biol Chem. 1998; 273: 22490-22497.

[489] Cardali S, Maugeri R. Detection of alphaII-spectrin and breakdown products in humans after severe traumatic brain injury. J Neurosurg Sci. 2006; 50: 25-31.

[490] Pike BR, Flint J, Dutta S, Johnson E, Wang KK, Hayes RL. Accumulation of non-erythroid alpha II-spectrin and calpain-cleaved alpha II-spectrin breakdown products in cerebrospinal fluid after traumatic brain injury in rats. J Neurochem. 2001; 78: 1297-1306.

[491] Wang KK, Ottens AK, Liu MC, et al. Proteomic identification of biomarkers of traumatic brain injury. Expert Rev Proteomics. 2005; 2: 603-614.

[492] Vartanian MG, Cordon JJ, Kupina NC, et al. Phenytoin pretreatment prevents hypoxic-ischemic brain damage in neonatal rats. Brain Res Dev Brain Res. 1996; 95: 169-175.

[493] Berger RP, Houle JF, Hayes RL, Wang KK, Mondello S, Bell MJ. Translating biomarkers research to clinical care: applications and issues for rehabilomics. PM R. 2011; 3: S31-S38.

[494] Yokobori S, Zhang Z, Moghieb A, et al. Acute diagnostic biomarkers for spinal cord injury: review of the literature and preliminary research report. World Neurosurg. 2015; 83: 867-878.

[495] Beer R, Franz G, Srinivasan A, et al. Temporal profile and cell subtype distribution of activated caspase-3 following experimental traumatic brain injury. J Neurochem. 2000; 75: 1264-1273.

[496] Hall ED, Sullivan PG, Gibson TR, Pavel KM, Thompson BM, Scheff SW. Spatial and temporal characteristics of neurodegeneration after controlled cortical impact in mice: more than a focal brain injury. J Neurotrauma. 2005; 22: 252-265.

[497] Lewis SB, Velat GJ, Miralia L, et al. Alpha-II spectrin breakdown products in aneurysmal subarachnoid hemorrhage: a novel biomarker of proteolytic injury. J Neurosurg. 2007; 107: 792-796.

[498] Farkas O, Polgár B, Szekeres-Barthó J, Dóczi T, Povlishock JT, Büki A. Spectrin breakdown products in the cerebrospinal fluid in severe head injury--preliminary observations. Acta Neurochir. 2005; 147: 855-861.

[499] Nicholson JK, Lindon JC, Holmes E. 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica. 1999; 29: 1181-1189.

[500] Dunn WB, Broadhurst DI, Atherton HJ, Goodacre R, Griffin JL. Systems level studies of mammalian metabolomes: the roles of mass spectrometry and nuclear magnetic resonance spectroscopy. Chem Soc Rev. 2011; 40: 387-426.

[501] Ma H, Sorokin A, Mazein A, et al. The Edinburgh human metabolic network reconstruction and its functional analysis. Mol Syst Biol. 2007; 3: 135.

[502] Giza CC, Hovda DA. The new neurometabolic cascade of concussion. Neurosurgery. 2014; 75(Suppl 4): S24-S33.

[503] Holmes E, Wilson ID, Nicholson JK. Metabolic phenotyping in health and disease. Cell. 2008; 134: 714-717.

[504] Nicholson JK, Holmes E, Kinross JM, Darzi AW, Takats Z, Lindon JC. Metabolic phenotyping in clinical and surgical environments. Nature. 2012; 491: 384-392.

[505] Orešič M, Posti JP, Kamstrup-Nielsen MH, et al. Human serum metabolites associate with severity and patient outcomes in traumatic brain injury. EBioMedicine. 2016; 12: 118-126.

[506] Jeter CB, Hergenroeder GW, Ward NH 3rd, Moore AN, Dash PK. Human mild traumatic brain injury decreases circulating branched-chain amino acids and their metabolite levels. J Neurotrauma. 2013; 30: 671-679.

[507] Posti JP, Dickens AM, Orešič M, Hyötyläinen T, Tenovuo O. Metabolomics profiling as a diagnostic tool in severe traumatic brain injury. Front Neurol. 2017; 8:398.

[508] Dickens AM, Posti JP, Takala RSK, et al. Serum metabolites associated with computed tomography findings after traumatic brain injury. J Neurotrauma. 2018; 35(22): 2673-2683.

[509] Thomas I, Dickens AM, Posti JP, et al. Integrative analysis of circulating metabolite profiles and magnetic resonance imaging metrics in patients with traumatic brain injury. Int J Mol Sci. 2020; 21: 1395.

[510] Huibregtse ME, Bazarian JJ, Shultz SR, Kawata K. The biological significance and clinical utility of emerging blood biomarkers for traumatic brain injury. Neurosci Biobehav Rev. 2021; 130: 433-447.

[511] Baslow MH. N-acetylaspartate in the vertebrate brain: metabolism and function. Neurochem Res. 2003; 28: 941-953.

[512] Gardner A, Iverson GL, Stanwell P. A systematic review of proton magnetic resonance spectroscopy findings in sport-related concussion. J Neurotrauma. 2014; 31: 1-18.

[513] Thomas I, Dickens AM, Posti JP, et al. Serum metabolome associated with severity of acute traumatic brain injury. Nat Commun. 2022; 13:2545.

[514] Steyerberg EW, Wiegers E, Sewalt C, et al. Case-mix, care pathways, and outcomes in patients with traumatic brain injury in CENTER-TBI: a European prospective, multicentre, longitudinal, cohort study. Lancet Neurol. 2019; 18: 923-934.

[515] Bittšanský M, Výbohová D, Dobrota D. Proton magnetic resonance spectroscopy and its diagnostically important metabolites in the brain. Gen Physiol Biophys. 2012; 31: 101-112.

[516] Kierans AS, Kirov II, Gonen O, et al. Myoinositol and glutamate complex neurometabolite abnormality after mild traumatic brain injury. Neurology. 2014; 82: 521-528.

[517] Ashwal S, Holshouser B, Tong K, et al. Proton spectroscopy detected myoinositol in children with traumatic brain injury. Pediatr Res. 2004; 56: 630-638.

[518] Bragge P, McNett M, Bayley M, et al. Starting with the end in mind: recommendations to optimize implementation of a novel TBI classification from the 2024 NINDS TBI classification and nomenclature Workshop's Knowledge to Practice Working Group. J Neurotrauma. 2025; 42: 1096-1108.

[519] Mac Donald CL, Yuh EL, Vande Vyvere T, et al. Neuroimaging characterization of acute traumatic brain injury with focus on frontline clinicians: recommendations from the 2024 National Institute of Neurological Disorders and Stroke Traumatic Brain Injury Classification and Nomenclature Initiative Imaging Working Group. J Neurotrauma. 2025; 42: 1056-1064.

[520] Corrigan JD, Alosco ML, van der Naalt J, et al. Retrospective identification and characterization of traumatic brain injury-recommendations from the 2024 National Institute of Neurological Disorders and Stroke Traumatic Brain Injury Classification and Nomenclature Initiative Retrospective Classification Working Group. J Neurotrauma. 2025; 42: 1086-1095.

[521] Banks WA, Kastin AJ. Differential permeability of the blood-brain barrier to two pancreatic peptides: insulin and amylin. Peptides. 1998; 19: 883-889.

[522] Wolahan SM, Hirt D, Glenn TC. Frontiers in neuroengineering translational metabolomics of head injury: exploring dysfunctional cerebral metabolism with ex vivo NMR spectroscopy-based metabolite quantification. In: FH Kobeissy, ed. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. CRC Press/Taylor & Francis; 2015.

[523] Vassy JL, Lautenbach DM, McLaughlin HM, et al. The MedSeq project: a randomized trial of integrating whole genome sequencing into clinical medicine. Trials. 2014; 15:85.

[524] Åkerlund CAI, Holst A, Bhattacharyay S, et al. Clinical descriptors of disease trajectories in patients with traumatic brain injury in the intensive care unit (CENTER-TBI): a multicentre observational cohort study. Lancet Neurol. 2024; 23: 71-80.

[525] Abboud T, Rohde V, Mielke D. Mini review: current status and perspective of S100B protein as a biomarker in daily clinical practice for diagnosis and prognosticating of clinical outcome in patients with neurological diseases with focus on acute brain injury. BMC Neurosci. 2023; 24:38.

[526] Tenenbaum JD. Translational bioinformatics: past, present, and future. Genomics Proteomics Bioinformatics. 2016; 14: 31-41.

[527] Hajiaghamemar M, Seidi M, Oeur RA, Margulies SS. Toward development of clinically translatable diagnostic and prognostic metrics of traumatic brain injury using animal models: a review and a look forward. Exp Neurol. 2019; 318: 101-123.

[528] Manley GT, Dams-O'Connor K, Alosco ML, et al. A new characterisation of acute traumatic brain injury: the NIH-NINDS TBI classification and nomenclature initiative. Lancet Neurol. 2025; 24: 512-523.

[529] Agoston DV, Shutes-David A, Peskind ER. Biofluid biomarkers of traumatic brain injury. Brain Inj. 2017; 31: 1195-1203.

[530] Geyer C, Ulrich A, Gräfe G, Stach B, Till H. Diagnostic value of S100B and neuron-specific enolase in mild pediatric traumatic brain injury. J Neurosurg Pediatr. 2009; 4: 339-344.

[531] Lugones M, Parkin G, Bjelosevic S, et al. Blood biomarkers in paediatric mild traumatic brain injury: a systematic review. Neurosci Biobehav Rev. 2018; 87: 206-217.

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