Current Neurology and Neuroscience Reports

, Volume 12, Issue 5, pp 560–569

Biomarkers in Traumatic Brain Injury

Neurotrauma (J Levine, Section Editor)

Abstract

Traumatic brain injury (TBI) is a common cause of neurological morbidity globally, and neurologic sequelae may occur even in the setting of mild injury. At present, the tools that guide diagnostic and prognostic evaluation of patients who suffer from TBI remain limited, especially for prehospital evaluation. Biomarkers of brain injury hold promise in facilitating early management and triage decisions in the civilian and military settings. The identification of biomarkers of brain injury may also be helpful in guiding end-of-life decision making and may facilitate the design of neuroprotective trials.

Keywords

Traumatic brain injury Biomarkers Glasgow Coma Score S100B GFAP NSE Alpha II spectrin End-of-life decisions Clinical trials Diffuse axonal injury Hematoma Concussion Inflammation 

References

  1. 1.
    Faul M, Xu L., Wald MM, Coronado VG, Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths.In: Centers for Disease Control and Prevention, Editor. Atlanta(GA): Centers for Disease Control and Prevention; 2010.Google Scholar
  2. 2.
    Neurological disorders: public health challenges. In: W.H. Organization, Editor. Geneva, Switzerland: WHO Press; 2006.Google Scholar
  3. 3.
    Thornhill S, et al. Disability in young people and adults one year after head injury: prospective cohort study. BMJ. 2000;320(7250):1631–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Povlishock JT. The classification of traumatic brain injury (TBI) for targeted therapies. J Neurotrauma. 2008;25(7):717–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Maas AI, Stocchetti N, Bullock R. Moderate and severe traumatic brain injury in adults. Lancet Neurol. 2008;7(8):728–41.PubMedCrossRefGoogle Scholar
  6. 6.
    Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974;2(7872):81–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Bruns Jr JJ, Jagoda AS. Mild traumatic brain injury. Mt Sinai J Med. 2009;76(2):129–37.PubMedCrossRefGoogle Scholar
  8. 8.
    Affairs D.o.D.a.D.o.V. Traumatic brain Injury Task Force. 2008.Google Scholar
  9. 9.
    Saatman KE, Creed J, Raghupathi R. Calpain as a therapeutic target in traumatic brain injury. Neurotherapeutics. 2010;7(1):31–42.PubMedCrossRefGoogle Scholar
  10. 10.
    McCullagh S, et al. Prediction of neuropsychiatric outcome following mild trauma brain injury: an examination of the Glasgow Coma Scale. Brain Inj. 2001;15(6):489–97.PubMedCrossRefGoogle Scholar
  11. 11.
    Shenton ME, et al. A review of magnetic resonance imaging and diffusion tensor imaging findings in mild traumatic brain injury. Brain Imaging Behav. 2012.Google Scholar
  12. 12.
    Garnett MR, et al. Early proton magnetic resonance spectroscopy in normal-appearing brain correlates with outcome in patients following traumatic brain injury. Brain. 2000;123(Pt 10):2046–54.PubMedCrossRefGoogle Scholar
  13. 13.
    Al-Samsam RH, Alessandri B, Bullock R. Extracellular N-acetyl-aspartate as a biochemical marker of the severity of neuronal damage following experimental acute traumatic brain injury. J Neurotrauma. 2000;17(1):31–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Babikian T, et al. Metabolic levels in the corpus callosum and their structural and behavioral correlates after moderate to severe pediatric TBI. J Neurotrauma. 2010;27(3):473–81.PubMedCrossRefGoogle Scholar
  15. 15.
    Du Y, Li Y, Lan Q. 1 H-Magnetic resonance spectroscopy correlates with injury severity and can predict coma duration in patients following severe traumatic brain injury. Neurol India. 2011;59(5):679–84.PubMedCrossRefGoogle Scholar
  16. 16.
    Wendle J. Traumatic brain injury: Hidden Peril of U.S. Soldiers in Combat, in Time Magazine. March 19, 2012.Google Scholar
  17. 17.
    Healey C, et al. Improving the Glasgow Coma Scale score: motor score alone is a better predictor. J Trauma. 2003;54(4):671–8. discussion 678–80.PubMedCrossRefGoogle Scholar
  18. 18.
    Daubin C, et al. Serum neuron-specific enolase as predictor of outcome in comatose cardiac-arrest survivors: a prospective cohort study. BMC Cardiovasc Disord. 2011;11:48.PubMedCrossRefGoogle Scholar
  19. 19.
    Paraforou T, et al. Cerebral perfusion pressure, microdialysis biochemistry and clinical outcome in patients with traumatic brain injury. BMC Res Notes. 2011;4:540.PubMedCrossRefGoogle Scholar
  20. 20.
    Frugier T, et al. In situ detection of inflammatory mediators in post mortem human brain tissue after traumatic injury. J Neurotrauma. 2010;27(3):497–507.PubMedCrossRefGoogle Scholar
  21. 21.
    Eddleston M, Mucke L. Molecular profile of reactive astrocytes–implications for their role in neurologic disease. Neuroscience. 1993;54(1):15–36.PubMedCrossRefGoogle Scholar
  22. 22.
    Sawada M, et al. Production of tumor necrosis factor-alpha by microglia and astrocytes in culture. Brain Res. 1989;491(2):394–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Rosenberg GA, et al. Tumor necrosis factor-alpha-induced gelatinase B causes delayed opening of the blood–brain barrier: an expanded therapeutic window. Brain Res. 1995;703(1–2):151–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Ahn MJ, et al. The effects of traumatic brain injury on cerebral blood flow and brain tissue nitric oxide levels and cytokine expression. J Neurotrauma. 2004;21(10):1431–42.PubMedCrossRefGoogle Scholar
  25. 25.
    Chen J, et al. Increased expression of TNF receptor-associated factor 6 after rat traumatic brain injury. Cell Mol Neurobiol. 2011;31(2):269–75.PubMedCrossRefGoogle Scholar
  26. 26.
    Csuka E, et al. 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(2):211–21.PubMedCrossRefGoogle Scholar
  27. 27.
    Goodman JC, et al. Elevation of tumor necrosis factor in head injury. J Neuroimmunol. 1990;30(2–3):213–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Ross SA, et al. The presence of tumour necrosis factor in CSF and plasma after severe head injury. Br J Neurosurg. 1994;8(4):419–25.PubMedCrossRefGoogle Scholar
  29. 29.
    Gourin CG, Shackford SR. Production of tumor necrosis factor-alpha and interleukin-1beta by human cerebral microvascular endothelium after percussive trauma. J Trauma. 1997;42(6):1101–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Zhang X, et al. Caspase-8 expression and proteolysis in human brain after severe head injury. FASEB J. 2003;17(10):1367–9.PubMedGoogle Scholar
  31. 31.
    Helmy A, et al. The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production. J Cereb Blood Flow Metab. 2011;31(2):658–70.PubMedCrossRefGoogle Scholar
  32. 32.
    Giulian D, Lachman LB. Interleukin-1 stimulation of astroglial proliferation after brain injury. Science. 1985;228(4698):497–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Carlson NG, et al. Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways. J Immunol. 1999;163(7):3963–8.PubMedGoogle Scholar
  34. 34.
    Shiozaki T, et al. Cerebrospinal fluid concentrations of anti-inflammatory mediators in early-phase severe traumatic brain injury. Shock. 2005;23(5):406–10.PubMedCrossRefGoogle Scholar
  35. 35.
    Hutchinson PJ, et al. Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1beta, and their endogenous inhibitor IL-1ra. J Neurotrauma. 2007;24(10):1545–57.PubMedCrossRefGoogle Scholar
  36. 36.
    Hillman J, et al. A microdialysis technique for routine measurement of macromolecules in the injured human brain. Neurosurgery. 2005;56(6):1264–8. discussion 1268–70.PubMedCrossRefGoogle Scholar
  37. 37.
    Hillman J, et al. Variations in the response of interleukins in neurosurgical intensive care patients monitored using intracerebral microdialysis. J Neurosurg. 2007;106(5):820–5.PubMedCrossRefGoogle Scholar
  38. 38.
    Yoshioka N, et al. Small molecule inhibitor of type I transforming growth factor-beta receptor kinase ameliorates the inhibitory milieu in injured brain and promotes regeneration of nigrostriatal dopaminergic axons. J Neurosci Res. 2011;89(3):381–93.PubMedCrossRefGoogle Scholar
  39. 39.
    Huang RQ, et al. Preliminary study on the effect of trauma-induced secondary cellular hypoxia in brain injury. Neurosci Lett. 2010;473(1):22–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Morganti-Kossmann MC, 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(7):617–28.PubMedCrossRefGoogle Scholar
  41. 41.
    Polentarutti N, et al. Inducible expression of the long pentraxin PTX3 in the central nervous system. J Neuroimmunol. 2000;106(1–2):87–94.PubMedCrossRefGoogle Scholar
  42. 42.
    Ravizza T, et al. Dynamic induction of the long pentraxin PTX3 in the CNS after limbic seizures: evidence for a protective role in seizure-induced neurodegeneration. Neuroscience. 2001;105(1):43–53.PubMedCrossRefGoogle Scholar
  43. 43.
    Gullo Jda S, et al. Hospital mortality of patients with severe traumatic brain injury is associated with serum PTX3 levels. Neurocrit Care. 2011;14(2):194–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Ahima RS, et al. Regulation of neuronal and glial proteins by leptin: implications for brain development. Endocrinology. 1999;140(6):2755–62.PubMedCrossRefGoogle Scholar
  45. 45.
    Hayashi T, et al. Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab. 2003;23(2):166–80.PubMedCrossRefGoogle Scholar
  46. 46.
    Dong XQ, et al. Resistin is associated with mortality in patients with traumatic brain injury. Crit Care. 2010;14(5):R190.PubMedCrossRefGoogle Scholar
  47. 47.
    Kossmann T, 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(3):280–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Semple BD, et al. Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2−/− mice. J Cereb Blood Flow Metab. 2010;30(4):769–82.PubMedCrossRefGoogle Scholar
  49. 49.
    Lumpkins K, et al. Plasma levels of the beta chemokine regulated upon activation, normal T cell expressed, and secreted (RANTES) correlate with severe brain injury. J Trauma. 2008;64(2):358–61.PubMedCrossRefGoogle Scholar
  50. 50.
    Ghirnikar RS, et al. Chemokine expression in rat stab wound brain injury. J Neurosci Res. 1996;46(6):727–33.PubMedCrossRefGoogle Scholar
  51. 51.
    Hughes PM, et al. Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during acute and chronic inflammation in the rodent CNS. Glia. 2002;37(4):314–27.PubMedCrossRefGoogle Scholar
  52. 52.
    Rancan M, et al. The chemokine fractalkine in patients with severe traumatic brain injury and a mouse model of closed head injury. J Cereb Blood Flow Metab. 2004;24(10):1110–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Bellander BM, et al. Complement activation in the human brain after traumatic head injury. J Neurotrauma. 2001;18(12):1295–311.PubMedCrossRefGoogle Scholar
  54. 54.
    Griffiths MR, Gasque P, Neal JW. The multiple roles of the innate immune system in the regulation of apoptosis and inflammation in the brain. J Neuropathol Exp Neurol. 2009;68(3):217–26.PubMedCrossRefGoogle Scholar
  55. 55.
    Bellander BM, et al. Secondary insults following traumatic brain injury enhance complement activation in the human brain and release of the tissue damage marker S100B. Acta Neurochir (Wien). 2011;153(1):90–100.CrossRefGoogle Scholar
  56. 56.
    Heizmann CW, Fritz G, Schafer BW. S100 proteins: structure, functions and pathology. Front Biosci. 2002;7:d1356–68.PubMedCrossRefGoogle Scholar
  57. 57.
    Sorci G, et al. The many faces of S100B protein: when an extracellular factor inactivates its own receptor and activates another one. Ital J Anat Embryol. 2010;115(1–2):147–51.PubMedGoogle Scholar
  58. 58.
    Goncalves CA, Leite MC, Guerra MC. Adipocytes as an Important Source of Serum S100B and Possible Roles of This Protein in Adipose Tissue. Cardiovasc Psychiatry Neurol. 2010;2010:790431.PubMedGoogle Scholar
  59. 59.
    Pang X, et al. S100B protein as a possible participant in the brain metastasis of NSCLC. Med Oncol, 2012.Google Scholar
  60. 60.
    Egea-Guerrero JJ, et al. Accuracy of the S100beta protein as a marker of brain damage in traumatic brain injury. Brain Inj. 2012;26(1):76–82.PubMedCrossRefGoogle Scholar
  61. 61.
    Rainey T, et al. Predicting outcome after severe traumatic brain injury using the serum S100B biomarker: results using a single (24 h) time-point. Resuscitation. 2009;80(3):341–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Kleinert K, et al. Is there a correlation between S100 beta and post-concussion symptoms after mild traumatic brain injury? Zentralbl Chir. 2010;135(3):277–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Unden J, et al. Serum S100B levels in patients with cerebral and extracerebral infectious disease. Scand J Infect Dis. 2004;36(1):10–3.PubMedCrossRefGoogle Scholar
  64. 64.
    Savola O, et al. Effects of head and extracranial injuries on serum protein S100B levels in trauma patients. J Trauma. 2004;56(6):1229–34. discussion 1234.PubMedCrossRefGoogle Scholar
  65. 65.
    Torabian S, Kashani-Sabet M. Biomarkers for melanoma. Curr Opin Oncol. 2005;17(2):167–71.PubMedCrossRefGoogle Scholar
  66. 66.
    Buttner T, et al. S-100 protein: serum marker of focal brain damage after ischemic territorial MCA infarction. Stroke. 1997;28(10):1961–5.PubMedCrossRefGoogle Scholar
  67. 67.
    Missler U, et al. S-100 protein and neuron-specific enolase concentrations in blood as indicators of infarction volume and prognosis in acute ischemic stroke. Stroke. 1997;28(10):1956–60.PubMedCrossRefGoogle Scholar
  68. 68.
    Elting JW, et al. Comparison of serum S-100 protein levels following stroke and traumatic brain injury. J Neurol Sci. 2000;181(1–2):104–10.PubMedCrossRefGoogle Scholar
  69. 69.
    Herrmann M, et al. Release of glial tissue-specific proteins after acute stroke: A comparative analysis of serum concentrations of protein S-100B and glial fibrillary acidic protein. Stroke. 2000;31(11):2670–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Vos PE, et al. GFAP and S100B are biomarkers of traumatic brain injury: an observational cohort study. Neurology. 2010;75(20):1786–93.PubMedCrossRefGoogle Scholar
  71. 71.
    Metting Z, et al. GFAP and S100B in the acute phase of mild traumatic brain injury. Neurology. 2012;78(18):1428–33.PubMedCrossRefGoogle Scholar
  72. 72.
    Foerch C, et al. Diagnostic accuracy of plasma glial fibrillary acidic protein for differentiating intracerebral hemorrhage and cerebral ischemia in patients with symptoms of acute stroke. Clin Chem. 2012;58(1):237–45.PubMedCrossRefGoogle Scholar
  73. 73.
    Marangos PJ, Schmechel DE. Neuron specific enolase, a clinically useful marker for neurons and neuroendocrine cells. Annu Rev Neurosci. 1987;10:269–95.PubMedCrossRefGoogle Scholar
  74. 74.
    Ross SA, et al. Neuron-specific enolase as an aid to outcome prediction in head injury. Br J Neurosurg. 1996;10(5):471–6.PubMedCrossRefGoogle Scholar
  75. 75.
    Meric E, et al. The prognostic value of neuron-specific enolase in head trauma patients. J Emerg Med. 2010;38(3):297–301.PubMedCrossRefGoogle Scholar
  76. 76.
    Kies MW. Myelin basic protein. Scand J Immunol Suppl. 1982;9:125–46.PubMedCrossRefGoogle Scholar
  77. 77.
    Liu MC, et al. Extensive degradation of myelin basic protein isoforms by calpain following traumatic brain injury. J Neurochem. 2006;98(3):700–12.PubMedCrossRefGoogle Scholar
  78. 78.
    Ottens AK, et al. Proteolysis of multiple myelin basic protein isoforms after neurotrauma: characterization by mass spectrometry. J Neurochem. 2008;104(5):1404–14.PubMedCrossRefGoogle Scholar
  79. 79.
    Thomas DG, Palfreyman JW, Ratcliffe JG. Serum-myelin-basic-protein assay in diagnosis and prognosis of patients with head injury. Lancet. 1978;1(8056):113–5.PubMedCrossRefGoogle Scholar
  80. 80.
    Yamazaki Y, et al. Diagnostic significance of serum neuron-specific enolase and myelin basic protein assay in patients with acute head injury. Surg Neurol. 1995;43(3):267–70. discussion 270–1.PubMedCrossRefGoogle Scholar
  81. 81.
    Setsuie R, Wada K. The functions of UCH-L1 and its relation to neurodegenerative diseases. Neurochem Int. 2007;51(2–4):105–11.PubMedCrossRefGoogle Scholar
  82. 82.
    Papa L, et al. Ubiquitin C-terminal hydrolase is a novel biomarker in humans for severe traumatic brain injury. Crit Care Med. 2010;38(1):138–44.PubMedCrossRefGoogle Scholar
  83. 83.
    Brophy GM, et al. Biokinetic analysis of ubiquitin C-terminal hydrolase-L1 (UCH-L1) in severe traumatic brain injury patient biofluids. J Neurotrauma. 2011;28(6):861–70.PubMedCrossRefGoogle Scholar
  84. 84.
    Hulsmeier J, et al. Distinct functions of alpha-Spectrin and beta-Spectrin during axonal pathfinding. Development. 2007;134(4):713–22.PubMedCrossRefGoogle Scholar
  85. 85.
    Pineda JA, et al. Clinical significance of alphaII-spectrin breakdown products in cerebrospinal fluid after severe traumatic brain injury. J Neurotrauma. 2007;24(2):354–66.PubMedCrossRefGoogle Scholar
  86. 86.
    Cardali S, Maugeri R. Detection of alphaII-spectrin and breakdown products in humans after severe traumatic brain injury. J Neurosurg Sci. 2006;50(2):25–31.PubMedGoogle Scholar
  87. 87.
    Ikeda Y, Long DM. The molecular basis of brain injury and brain edema: the role of oxygen free radicals. Neurosurgery. 1990;27(1):1–11.PubMedCrossRefGoogle Scholar
  88. 88.
    Zhang QG, et al. Critical role of NADPH oxidase in neuronal oxidative damage and microglia activation following traumatic brain injury. PLoS One. 2012;7(4):e34504.PubMedCrossRefGoogle Scholar
  89. 89.
    Kochanek PM, 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(1):4–19.PubMedCrossRefGoogle Scholar
  90. 90.
    Wei EP, Kontos HA, Beckman JS. Mechanisms of cerebral vasodilation by superoxide, hydrogen peroxide, and peroxynitrite. Am J Physiol. 1996;271(3 Pt 2):H1262–6.PubMedGoogle Scholar
  91. 91.
    Varma S, et al. F2-isoprostane and neuron-specific enolase in cerebrospinal fluid after severe traumatic brain injury in infants and children. J Neurotrauma. 2003;20(8):781–6.PubMedCrossRefGoogle Scholar
  92. 92.
    Musiek ES, et al. Quantification of F-ring isoprostane-like compounds (F4-neuroprostanes) derived from docosahexaenoic acid in vivo in humans by a stable isotope dilution mass spectrometric assay. J Chromatogr B Analyt Technol Biomed Life Sci. 2004;799(1):95–102.PubMedCrossRefGoogle Scholar
  93. 93.
    Roof RL, Hall ED. Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma. 2000;17(5):367–88.PubMedCrossRefGoogle Scholar
  94. 94.
    Bayir H, et al. Marked gender effect on lipid peroxidation after severe traumatic brain injury in adult patients. J Neurotrauma. 2004;21(1):1–8.PubMedCrossRefGoogle Scholar
  95. 95.
    Bayir H, et al. Assessment of antioxidant reserves and oxidative stress in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatr Res. 2002;51(5):571–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.School of MedicineDuke University Medical CenterDurhamUSA
  2. 2.Department of Medicine (Neurology)Duke University Medical CenterDurhamUSA

Personalised recommendations