Biomarkers for the diagnosis, prognosis, and evaluation of treatment efficacy for traumatic brain injury


Traumatic brain injury (TBI) remains a serious health concern, and TBI is one of the leading causes of death and disability, especially among young adults. Although preventive education, increased usage of safety devices, and TBI management have dramatically increased the potential for surviving a brain injury, there is still a need to develop reliable methods to diagnose TBI, the secondary pathologies associated with TBI, and predicting the outcomes of TBI. Biomarkers (changes of amount or activity in a biomolecule that reflect injury or disease) have shown promise in the diagnosis of several conditions, including cancer, heart failure, infection, and genetic disorders. A variety of proteins, small molecules, and lipid products have been proposed as potential biomarkers of brain damage from TBI. Although some of these changes have been reported to correlate with mortality and outcome, further research is required to identify prognostic biomarkers. This need is punctuated in mild injuries that cannot be readily detected using current techniques, as well as in defining patient risk for developing TBI-associated secondary injuries.


  1. 1.

    Hoge CW, Castro CA, Messer SC, McGurk D, Cotting DI, Koffman RL. Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. N Engl J Med 2004;351: 13–22.

  2. 2.

    Okie S. Traumatic brain injury in the war zone. N Engl J Med 2005;352: 2043–2047.

  3. 3.

    Holcomb JB, Stansbury LG, Champion HR, Wade C, Bellamy RF. Understanding combat casualty care statistics. J Trauma 2006;60: 397–401.

  4. 4.

    Kochanek PM, Clark RS, Ruppel RA, et al. Biochemical, cellular, and molecular mechanisms in the evolution of secondary damage after severe traumatic brain injury in infants and children: Lessons learned from the bedside. Pediatr Crit Care Med 2000;1: 4–19.

  5. 5.

    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.

  6. 6.

    Colicos MA, Dixon CE, Dash PK. Delayed, selective neuronal death following experimental cortical impact injury in rats: possible role in memory deficits. Brain Res 1996;739: 111–119.

  7. 7.

    Colicos MA, Dash PK. Apoptotic morphology of dentate gyrus granule cells following experimental cortical impact injury in rats: possible role in spatial memory deficits. Brain Res 1996;739: 120–131.

  8. 8.

    Hergenroeder G, Redell JB, Moore AN, et al. Identification of serum biomarkers in brain-injured adults: potential for predicting elevated intracranial pressure. J Neurotrauma 2008;25: 79–93.

  9. 9.

    States DJ, Omenn GS, Blackwell TW, et al. Challenges in deriving high-confidence protein identifications from data gathered by a HUPO plasma proteome collaborative study. Nat Biotechnol 2006;24: 333–338.

  10. 10.

    Gao J, Garulacan LA, Storm SM, et al. Biomarker discovery in biological fluids. Methods 2005;35: 291–302.

  11. 11.

    Petricoin EE, Paweletz CP, Liotta LA. Clinical applications of proteomics: proteomic pattern diagnostics. J Mammary Gland Biol Neoplasia 2002;7: 433–440.

  12. 12.

    Haskins WE, Kobeissy FH, Wolper RA, et al. Rapid discovery of putative protein biomarkers of traumatic brain injury by SDS-PAGE-capillary liquid chromatography-tandem mass spectrometry. J Neurotrauma 2005;22: 629–644.

  13. 13.

    Unden J, Astrand R, Waterloo K, et al. Clinical significance of serum S100B levels in neurointensive care. Neurocrit Care 2007;6: 94–99.

  14. 14.

    Savola O, Pyhtinen J, Leino TK, Siitonen S, Niemela O, Hillbom M. Effects of head and extracranial injuries on serum protein S100B levels in trauma patients. J Trauma 2004;56: 1229–1234.

  15. 15.

    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.

  16. 16.

    Pelinka LE, Harada N, Szalay L, Jafarmadar M, Redl H, Bahrami S. Release of S100B differs during ischemia and reperfusion of the liver, the gut, and the kidney in rats. Shock 2004;21: 72–76.

  17. 17.

    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.

  18. 18.

    Torabian S, Kashani-Sabet M. Biomarkers for melanoma. Curr Opin Oncol 2005;17: 167–171.

  19. 19.

    Piazza O, Storti MP, Cotena S, et al. S100B is not a reliable prognostic index in pediatric TBI. Pediatr Neurosurg 2007;43: 258–264.

  20. 20.

    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.

  21. 21.

    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.

  22. 22.

    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.

  23. 23.

    Nylen 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.

  24. 24.

    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.

  25. 25.

    Herrmann M, Jost S, Kutz S, et al. Temporal profile of release of neurobiochemical markers of brain damage after traumatic brain injury is associated with intracranial pathology as demonstrated in cranial computerized tomography. J Neurotrauma 2000;17: 113–122.

  26. 26.

    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.

  27. 27.

    Skogseid IM, Nordby HK, Urdal P, Paus E, Lilleaas F. Increased serum creatine kinase BB and neuron specific enolase following head injury indicates brain damage. Acta Neurochir (Wien) 1992; 115: 106–111.

  28. 28.

    Fridriksson T, KM 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.

  29. 29.

    Herrmann M, Curio N, Jost S, et al. Release of biochemical markers of damage to neuronal and glial brain tissue is associated with short and long term neuropsychological outcome after traumatic brain injury. J Neurol Neurosurg Psychiatry 2001;70: 95–100.

  30. 30.

    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.

  31. 31.

    Glatz JF, van der Vusse GJ. Cellular fatty acid-binding proteins: their function and physiological significance. Prog Lipid Res 1996;35: 243–282.

  32. 32.

    Pelsers MM, Hanhoff T, Van der Voort D, et al. Brain- and heart-type fatty acid-binding proteins in the brain: tissue distribution and clinical utility. Clin Chem 2004;50: 1568–1575.

  33. 33.

    Gabbita SP, Scheff SW, Menard RM, Roberts K, Fugaccia I, Zemlan FP. Cleaved-tau: a biomarker of neuronal damage after traumatic brain injury. J Neurotrauma 2005;22: 83–94.

  34. 34.

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

  35. 35.

    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.

  36. 36.

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

  37. 37.

    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.

  38. 38.

    Anderson KJ, Scheff SW, Miller KM, et al. The phosphorylated axonal form of the neurofilament subunit NF-H (pNF-H) as a blood biomarker of traumatic brain injury. J Neurotrauma 2008; 25: 1079–1085.

  39. 39.

    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 2009 Sep 1 [Epub ahead of print].

  40. 40.

    Morganti-Kossmann MC, Rancan M, Otto VI, Stahel PF, Kossmann T. Role of cerebral inflammation after traumatic brain injury: a revisited concept. Shock 2001;16: 165–177.

  41. 41.

    Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci 2001;2: 734–744.

  42. 42.

    Kadhim HJ, Duchateau J, Sebire G. Cytokines and brain injury: invited review. J Intensive Care Med 2008;23: 236–249.

  43. 43.

    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.

  44. 44.

    Buttram SD, Wisniewski SR, Jackson EK, et al. Multiplex assessment of cytokine and chemokine levels in cerebrospinal fluid following severe pediatric traumatic brain injury: effects of moderate hypothermia. J Neurotrauma 2007;24: 1707–1717.

  45. 45.

    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.

  46. 46.

    Giulian D, Lachman LB. Interleukin-1 stimulation of astroglial proliferation after brain injury. Science 1985;228: 497–499.

  47. 47.

    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.

  48. 48.

    Chiaretti A, Genovese O, Aloe L, et al. Interleukin 1beta and interleukin 6 relationship with paediatric head trauma severity and outcome. Childs Nerv Syst 2005;21: 185–193.

  49. 49.

    Brenner T, Yamin A, Abramsky O, Gallily R. Stimulation of tumor necrosis factor-alpha production by mycoplasmas and inhibition by dexamethasone in cultured astrocytes. Brain Res 1993;608: 273–279.

  50. 50.

    Sawada M, Kondo N, Suzumura A, Marunouchi T. Production of tumor necrosis factor-alpha by microglia and astrocytes in culture. Brain Res 1989;491: 394–397.

  51. 51.

    Mier JW, Vachino G, van der Meer JW, et al. Induction of circulating tumor necrosis factor (TNF alpha) as the mechanism for the febrile response to interieukin-2 (IL-2) in cancer patients. J Clin Immunol 1988;8: 426–436.

  52. 52.

    Shohami E, Gallily R, Mechoulam R, Bass R, Ben-Hur T. Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF-alpha inhibitor and an effective neuroprotectant. J Neuroimmunol 1997;72: 169–177.

  53. 53.

    Crespo AR, Da Rocha AB, Jotz GP, et al. Increased serum sFas and TNFalpha following isolated severe head injury in males. Brain Inj 2007;21: 441–447.

  54. 54.

    Goodman JC, Robertson CS, Grossman RG, Narayan RK. Elevation of tumor necrosis factor in head injury. J Neuroimmunol 1990;30: 213–217.

  55. 55.

    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.

  56. 56.

    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.

  57. 57.

    Minambres E, Cemborain A, Sanchez-Velasco P, et al. Correlation between transcranial interleukin-6 gradient and outcome in patients with acute brain injury. Crit Care Med 2003;31: 933–938.

  58. 58.

    Winter CD, Ringle AK, Clough GF, Church MK. Raised parenchymal interleukin-6 levels correlate with improved outcome after traumatic brain injury. Brain 2004;127: 315–320.

  59. 59.

    Chiaretti A, Antonelli A, Mastrangelo A, et al. Interleukin-6 and nerve growth factor upregulation correlates with improved outcome in children with severe traumatic brain injury. J Neurotrauma 2008;25: 225–234.

  60. 60.

    Aibiki M, Maekawa S, Nishiyama T, Seki K, Yokono S. Activated cytokine production in patients with accidental hypothermia. Resuscitation 1999;41: 263–268.

  61. 61.

    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.

  62. 62.

    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.

  63. 63.

    Bell MJ, Kochanek PM, Doughty LA, et al. Comparison of the interleukin-6 and interleukin-10 response in children after severe traumatic brain injury or septic shock. Acta Neurochir Suppl (Wien) 1997;70: 96–97.

  64. 64.

    Attisano L, Wrana JL, Lopez-Casillas F, Massague J. TGF-beta receptors and actions. Biochim Biophys Acta 1994; 1222: 71–80.

  65. 65.

    Morganti-Kossmann MC, Hans VH, Lenzlinger PM, et al. TGF-beta is elevated in the CSF of patients with severe traumatic brain injuries and parallels blood-brain barrier function. J Neurotrauma 1999;16: 617–628.

  66. 66.

    Pleines UE, Stover JF, Kossmann T, Trentz O, Morganti-Kossmann MC. Soluble ICAM-1 in CSF coincides with the extent of cerebral damage in patients with severe traumatic brain injury. J Neurotrauma 1998;15: 399–409.

  67. 67.

    Bye N, Habgood MD, Callaway JK, et al. Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration. Exp Neurol 2007;204: 220–233.

  68. 68.

    Palmer AM, Marion DW, Botscheller ML, Bowen DM, DeKosky ST. Increased transmitter amino acid concentration in human ventricular CSF after brain trauma. Neuroreport 1994;6: 153–156.

  69. 69.

    Reinert M, Khaldi A, Zauner A, Doppenberg E, Choi S, Bullock R. High level of extracellular potassium and its correlates after severe head injury: relationship to high intracranial pressure. J Neurosurg 2000;93: 800–807.

  70. 70.

    Kochanek PM, Berger RP, Bayir H, Wagner AK, Jenkins LW, Clark RS. Biomarkers of primary and evolving damage in traumatic and ischemic brain injury: diagnosis, prognosis, probing mechanisms, and therapeutic decision making. Curr Opin Crit Care 2008;14: 135–141.

  71. 71.

    Goodman JC, Robertson CS. Microdialysis: is it ready for prime time? Curr Opin Crit Care 2009;15: 110–117.

  72. 72.

    Rudman D, Fleischer A, Kutner MH. Concentration of 3′,5′ cyclic adenosine monophosphate in ventricular cerebrospinal fluid of patients with prolonged coma after head trauma or intracranial hemorrhage. N Engl J Med 1976;295: 635–638.

  73. 73.

    Fleischer AS, Rudman DR, Fresh CB, Tindall GT. Concentration of 3′,5′ cyclic adenosine monophosphate in ventricular CSF of patients following severe head trauma. J Neurosurg 1977;47: 517–524.

  74. 74.

    Clifton GL, Ziegler MG, Grossman RG. Circulating catecholamines and sympathetic activity after head injury. Neurosurgery 1981;8: 10–14.

  75. 75.

    Porta M, Bareggi SR, Collice M, et al. Homovanillic acid and 5-hydroxyindole-acetic acid in the csf of patients after a severe head injury. II. Ventricular csf concentrations in acute brain post-traumatic syndromes. Eur Neurol 1975;13: 545–554.

  76. 76.

    Inagawa T, Ishikawa S, Uozumi T. Homovanillic acid and 5-hydroxyindoleacetic acid in the ventricular CSF of comatose patients with obstructive hydrocephalus. J Neurosurg 1980;52: 635–641.

  77. 77.

    Czemicki Z, Grochowski W. [Cerebrospinal fluid lactates following craniocerebral injuries]. Neurol Neurochir Pol 1976;10: 651–653.

  78. 78.

    Soukup J, Zauner A, Doppenberg EM, et al. Relationship between brain temperature, brain chemistry and oxygen delivery after severe human head injury: the effect of mild hypothermia. Neurol Res 2002;24: 161–168.

  79. 79.

    Narayanan S, De SN, Francis GS, et al. Axonal metabolic recovery in multiple sclerosis patients treated with interferon beta-1b. J Neurol 2001;248: 979–986.

  80. 80.

    Yeo RA, Phillips JP, Jung RE, Brown AJ, Campbell RC, Brooks WM. Magnetic resonance spectroscopy detects brain injury and predicts cognitive functioning in children with brain injuries. J Neurotrauma 2006;23: 1427–1435.

  81. 81.

    Montuschi P, Barnes PJ, Roberts LJ. Isoprostanes: markers and mediators of oxidative stress. FASEB J 2004;18: 1791–1800.

  82. 82.

    Bayir H, Adelson PD, Wisniewski SR, et al. Therapeutic hypothermia preserves antioxidant defenses after severe traumatic brain injury in infants and children. Crit Care Med 2009;37: 689–695.

  83. 83.

    Seifman MA, Adamides AA, Nguyen PN, et al. Endogenous melatonin increases in cerebrospinal fluid of patients after severe traumatic brain injury and correlates with oxidative stress and metabolic disarray. J Cereb Blood Flow Metab 2008;28: 684–696.

  84. 84.

    Wagner AK, Bayir H, Ren D, Puccio A, Zafonte RD, Kochanek PM. Relationships between cerebrospinal fluid markers of excitotoxicity, ischemia, and oxidative damage after severe TBI: the impact of gender, age, and hypothermia. J Neurotrauma 2004;21: 125–136.

  85. 85.

    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.

  86. 86.

    Bayir H, Marion DW, Puccio AM, et al. Marked gender effect on lipid peroxidation after severe traumatic brain injury in adult patients. J Neurotrauma 2004;21: 1–8.

  87. 87.

    Poli G, Schaur RJ, Siems WG, Leonarduzzi G. 4-hydroxynonenal: a membrane lipid oxidation product of medicinal interest. Med Res Rev 2008;28: 569–631.

  88. 88.

    Hall ED, Detloff MR, Johnson K, Kupina NC. Peroxynitrite-mediated protein nitration and lipid peroxidation in a mouse model of traumatic brain injury. J Neurotrauma 2004;21: 9–20.

  89. 89.

    Singh IN, Sullivan PG, Deng Y, Mbye LH, Hall ED. Time course of post-traumatic mitochondrial oxidative damage and dysfunction in a mouse model of focal traumatic brain injury: implications for neuroprotective therapy. J Cereb Blood Flow Metab 2006;26: 1407–1418.

  90. 90.

    Singh IN, Sullivan PG, Hall ED. Peroxynitrite-mediated oxidative damage to brain mitochondria: Protective effects of peroxynitrite scavengers. J Neurosci Res 2007;85: 2216–2223.

  91. 91.

    Markesbery WR, Carney JM. Oxidative alterations in Alzheimer’s disease. Brain Pathol 1999;9: 133–146.

  92. 92.

    Smith RG, Henry YK, Mattson MP, Appel SH. Presence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis. Ann Neurol 1998;44: 696–699.

  93. 93.

    Agre P. Molecular physiology of water transport: aquaporin nomenclature workshop. Mammalian aquaporins. Biol Cell 1997; 89: 255–257.

  94. 94.

    Dikmen SS, Temkin NR, Machamer JE, Holubkov AL, Fraser RT, Winn HR. Employment following traumatic head injuries. Arch Neurol 1994;51: 177–186.

  95. 95.

    Muller K, Townend W, Biasca N, et al. S100B serum level predicts computed tomography findings after minor head injury. J Trauma 2007;62: 1452–1456.

  96. 96.

    Unden J, Romner B. A new objective method for CT triage after minor head injury—serum S100B. Scand J Clin Lab Invest 2009; 69: 13–17.

  97. 97.

    Bazarian JJ, Beck C, Blyth B, von AN, Hasselblatt M. Impact of creatine kinase correction on the predictive value of S-100B after mild traumatic brain injury. Restor Neurol Neurosci 2006;24: 163–172.

  98. 98.

    Ingebrigtsen T, Romner B, Marup-Jensen S, et al. The clinical value of serum S-100 protein measurements in minor head injury: a Scandinavian multicentre study. Brain Inj 2000;14: 1047–1055.

  99. 99.

    Nygren De BC, Fredman P, Lundin A, Andersson K, Edman G, Borg J. S100 in mild traumatic brain injury. Brain Inj 2004;18: 671–683.

  100. 100.

    Ingebrigtsen T, Romner B. Biochemical serum markers for brain damage: a short review with emphasis on clinical utility in mild head injury. Restor Neurol Neurosci 2003;21: 171–176.

  101. 101.

    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.

  102. 102.

    Kavalci C, Pekdemir M, Durukan P, et al. The value of serum tau protein for the diagnosis of intracranial injury in minor head trauma. Am J Emerg Med 2007;25: 391–395.

  103. 103.

    Bazarian JJ, Zemlan FP, Mookerjee S, Stigbrand T. Serum S-100B and cleaved-tau are poor predictors of long-term outcome after mild traumatic brain injury. Brain Inj 2006;20: 759–765.

  104. 104.

    Vasterling JJ, Duke LM, Brailey K, Constans JI, Allain AN Jr., Sutker PB. Attention, learning, and memory performances and intellectual resources in Vietnam veterans: PTSD and no disorder comparisons. Neuropsychology 2002; 16: 5–14.

  105. 105.

    Weiss SJ. Neurobiological alterations associated with traumatic stress. Perspect Psychiatr Care 2007;43: 114–122.

  106. 106.

    Kitayama N, Vaccarino V, Kutner M, Weiss P, Bremner JD. Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. J Affect Disord 2005;88: 79–86.

  107. 107.

    Smith ME. Bilateral hippocampal volume reduction in adults with post-traumatic stress disorder: a meta-analysis of structural MRI studies. Hippocampus 2005;15: 798–807.

  108. 108.

    Gilbertson MW, Shenton ME, Ciszewski A, et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat Neurosci 2002;5: 1242–1247.

  109. 109.

    Phillips RG, LeDoux JE. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 1992;106: 274–285.

  110. 110.

    Koren D, Hemel D, Klein E. Injury increases the risk for PTSD: an examination of potential neurobiological and psychological mediators. CNS Spectr 2006;11: 616–624.

  111. 111.

    Yehuda R, Flory JD, Southwick S, Charney DS. Developing an agenda for translational studies of resilience and vulnerability following trauma exposure. Ann N Y Acad Sci 2006; 1071: 379–396.

  112. 112.

    Buckley TC, Kaloupek DG. A meta-analytic examination of basal cardiovascular activity in posttraumatic stress disorder. Psychosom Med 2001;63: 585–594.

  113. 113.

    Shalev AY, Sahar T, Freedman S, et al. A prospective study of heart rate response following trauma and the subsequent development of posttraumatic stress disorder. Arch Gen Psychiatry 1998;55: 553–559.

  114. 114.

    Yehuda R, Brand SR, Golier JA, Yang RK. Clinical correlates of DHEA associated with post-traumatic stress disorder. Acta Psychiatr Scand 2006;114: 187–193.

  115. 115.

    Rasmusson AM, Vasek J, Lipschitz DS, et al. An increased capacity for adrenal DHEA release is associated with decreased avoidance and negative mood symptoms in women with PTSD. Neuropsychopharmacology 2004;29: 1546–1557.

  116. 116.

    Bell RS, Vo AH, Neal CJ, et al. Military traumatic brain and spinal column injury: a 5-year study of the impact blast and other military grade weaponry on the central nervous system. J Trauma 2009;66: S104-S111.

  117. 117.

    Yao C, Williams AJ, Ottens AK, et al. Detection of protein biomarkers using high-throughput immunoblotting following focal ischemic or penetrating ballistic-like brain injuries in rats. Brain Inj 2008;22: 723–732.

  118. 118.

    Treggiari MM, Schutz N, Yanez ND, Romand JA. Role of infracranial pressure values and patterns in predicting outcome in traumatic brain injury: a systematic review. Neurocrit Care 2007; 6: 104–112.

  119. 119.

    Hlatky R, Valadka AB, Robertson CS. Intracranial hypertension and cerebral ischemia after severe traumatic brain injury. Neurosurg Focus 2003;14: e2.

  120. 120.

    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.

  121. 121.

    Hellman NE, Gitlin JD. Ceruloplasmin metabolism and function. Annu Rev Nute 2002;22: 439–458.

  122. 122.

    Dash PK, Redell JB, Hergenroeder GW, Zhao J, Clifton GL, Moore AN. Serum ceruloplasmin and copper are early biomarkers of elevated intracranial pressure. J Neurosci Res 2009(in press).

  123. 123.

    Habgood MD, Bye N, Dziegielewska KM, et al. Changes in blood-brain barrier permeability to large and small molecules following traumatic brain injury in mice. Eur J Neurosci 2007; 25: 231–238.

  124. 124.

    Kirchhoff C, Buhmann S, Braunstein V, et al. Cerebrospinal s100-B: a potential marker for progressive intracranial hemorrhage in patients with severe traumatic brain injury. Eur J Med Res 2008;13: 511–516.

  125. 125.

    Signorini DF, Andrews PJ, Jones PA, Wardlaw JM, Miller JD. Adding insult to injury: the prognostic value of early secondary insults for survival after traumatic brain injury. J Neurol Neurosurg Psychiatry 1999;66: 26–31.

  126. 126.

    Orefice G, Ames PR, Coppola M, Campanella G. Antiphospholipid antibodies and cerebrovascular disease. Acta Neurol (Napoli) 1993;15: 303–310.

  127. 127.

    Brey RL. Antiphospholipid antibodies in young adults with stroke. J Thromb Thrombolysis 2005;20: 105–112.

  128. 128.

    Agrawal A, Timothy J, Pandit L, Manju M. Post-traumatic epilepsy: an overview. Clin Neurol Neurosurg 2006; 108: 433–439.

  129. 129.

    Lowenstein DH. Epilepsy after head injury: an overview. Epilepsia 2009;50(suppl 2): 4–9.

  130. 130.

    Temkin NR, Haglund MM, Winn HR. Causes, prevention, and treatment of post-traumatic epilepsy. New Horiz 1995;3: 518–522.

  131. 131.

    Lowenstein DH. Epilepsy after head injury: an overview. Epilepsia 2009;50(suppl 2): 4–9.

  132. 132.

    Annegers JF, Hauser WA, Coan SP, Rocca WA. A population-based study of seizures after traumatic brain injuries. N Engl J Med 1998;338: 20–24.

  133. 133.

    Bratton SL, Chestnut RM, Ghajar J, et al. Guidelines for the management of severe traumatic brain injury. XIII. Antiseizure prophylaxis. J Neurotrauma 2007;24(suppl 1): S83-S86.

  134. 134.

    Kumar R, Gupta RK, Husain M, et al. Magnetization transfer MR imaging in patients with posttraumatic epilepsy. AJNR Am J Neuroradiol 2003;24: 218–224.

  135. 135.

    Diaz-Arrastia R, Gong Y, Fair S, et al. Increased risk of late posttraumatic seizures associated with inheritance of APOE epsilon4 allele. Arch Neurol 2003;60: 818–822.

  136. 136.

    Schuff N, Meyerhoff DJ, Mueller S, et al. N-acetylaspartate as a marker of neuronal injury in neurodegenerative disease. Adv Exp Med Biol 2006;576: 241–262.

  137. 137.

    Czech T, Yang JW, Csaszar E, Kappler J, Baumgartner C, Lubec G. Reduction of hippocampal collapsin response mediated protein-2 in patients with mesial temporal lobe epilepsy. Neurochem Res 2004;29: 2189–2196.

  138. 138.

    Raabe A, Grolms C, Keller M, Dohnert J, Sorge O, Seifert V. Correlation of computed tomography findings and serum brain damage markers following severe head injury. Acta Neurochir (Wien) 1998;140: 787–791.

  139. 139.

    Liliang PC, Liang CL, Weng HC, et al. tau proteins in serum predict outcome after severe traumatic brain injury. J Surg Res 2009 Jan 10 [Epub ahead of print].

  140. 140.

    Bandyopadhyay S, Hennés 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. 141.

    Department of Veterans Affairs, Veterans Health Administration Directive, Polytrauma Rehabilitation Centers. Veterans Health Administration. Washington DC, 2005:2

  142. 142.

    Pape HC, Giannoudis P, Krettek C. The timing of fracture treatment in polytrauma patients: relevance of damage control orthopedic surgery. Am J Surg 2002;183: 622–629.

  143. 143.

    Rotstein OD. Modeling the two-hit hypothesis for evaluating strategies to prevent organ injury after shock/resuscitation. J Trauma 2003;54: S203-S206.

  144. 144.

    Keel M, Mica L, Stover J, Stocker R, Trentz O, Harter L. Thiopental-induced apoptosis in lymphocytes is independent of CD95 activation. Anesthesiology 2005;103: 576–584.

  145. 145.

    Bose D, Tejwani NC. Evolving trends in the care of polytrauma patients. Injury 2006;37: 20–28.

  146. 146.

    Maier B, Lefering R, Lehnert M, et al. Early versus late onset of multiple organ failure is associated with differing patterns of plasma cytokine biomarker expression and outcome after severe trauma. Shock 2007;28: 668–674.

  147. 147.

    da Rocha AB, Schneider RF, de Freitas GR, et al. Role of serum S100B as a predictive marker of fatal outcome following isolated severe head injury or multitrauma in males. Clin Chem Lab Med 2006;44: 1234–1242.

  148. 148.

    Zethelius B, Berglund L, Sundstrom J, et al. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. N Engl J Med 2008;358: 2107–2116.

  149. 149.

    Su JQ, Liu J. Linear combinations of multiple diagnostic markers. J Am Stat Assoc 1993;88: 1350–1355.

  150. 150.

    Liu A, Schisterman EF, Zhu Y. On linear combinations of biomarkers to improve diagnostic accuracy. Stat Med 2005;24: 37–47.

  151. 151.

    Qu Y, Adam BL, Yasui Y, et al. Boosted decision tree analysis of surface-enhanced laser desorption/ionization mass spectral serum profiles discriminates prostate cancer from noncancer patients. Clin Chem 2002;48: 1835–1843.

  152. 152.

    Kahraman S, Ozgurtas T, Kayali H, et al. Monitoring of serum ionized magnesium in neurosurgical intensive care unit: preliminary results. Clin Chim Acta 2003;334: 211–215.

  153. 153.

    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.

  154. 154.

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

  155. 155.

    Schwartz JG, Baxan III C, Gage CL, et al. Serum creatine kinase isoenzyme BB is a poor index to the size of various brain lesions. Clin Chem 1989;35: 651–654.

  156. 156.

    Smith DH, Uryu K, Saatman KE, et al. Protein accumulation in traumatic brain injury. Neuromolecular Med 2003;4: 59–72.

  157. 157.

    Newell KL, Boyer P, Gomez-Tortosa E, et al. Alpha-synuclein immunoreactivity is present in axonal swellings in neuroaxonal dystrophy and acute traumatic brain injury. J Neuropathol Exp Neurol 1999;12: 1263–1268.

Download references

Author information

Correspondence to Pramod K. Dash.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dash, P.K., Zhao, J., Hergenroeder, G. et al. Biomarkers for the diagnosis, prognosis, and evaluation of treatment efficacy for traumatic brain injury. Neurotherapeutics 7, 100–114 (2010).

Download citation

Key Words

  • Blast injury
  • diffused axonal injury
  • intracranial pressure
  • loss of consciousness
  • post-concussive symptoms
  • PTSD