Review Article
Serum Biomarkers for Traumatic Brain Injury Miriam D. Neher, MD, Chesleigh N. Keene, and Philip F. Stahel, MD
MA,
Abstract: There is a lack of reliable serum biomarkers for routine use in the diagnostic workup of people with traumatic brain injury. Multiple biomediators and biomarkers have been described in the pertinent literature in recent years; however, only a few candidate molecules have been associated with high sensitivity and high specificity for risk stratification and outcome prediction after traumatic brain injury. This review was designed to provide an overview of the state of the art regarding established serum biomarkers in the field and to outline future directions of investigation. Key Words: astroglial injury, axonal injury, biomarkers, neuronal injury, outcome prediction, risk stratification, traumatic brain injury
T
raumatic brain injury (TBI) is the leading cause of death and disability in the young civilian population in the United States, with an annual incidence of 1.7 million and 950,000 deaths.1Y3 In addition, TBI represents one of the major root causes of long-term neuropathologic sequelae in deployed military personnel and veterans of armed conflicts.4Y6 Significant research efforts have been devoted to establishing sensitive biomarkers for TBI that reflect the severity of injury and risk of delayed deterioration and provide guidance for treatment and prediction of outcomes.7Y9 Technological innovation in recent years, with the introduction of neuroproteomics and new-generation laboratory testing modalities, has had a dramatic impact on the available options for the diagnostic workup of individuals with TBI.10Y13 Despite extensive clinical research in the field during the past 3 decades,14 no suitable biomarker has been identified that is easily detectable in peripheral blood samples and fulfills all required criteria with high sensitivity and specificity.15Y18 From Denver Health Medical Center, and the Departments of Orthopaedic Surgery, Trauma Surgery, and Neurosurgery, University of Colorado School of Medicine, Denver. Reprint requests to Dr Philip F. Stahel, Denver Health Medical Center, University of Colorado School of Medicine, 777 Bannock St, Denver, CO 80204. E-mail: [email protected] This work was partially supported by a grant from the Colorado TBI Trust Fund to P.F.S. P.F.S. has received grant funding from Stryker Medical and royalties for a US patent. The other authors have no financial relationships to disclose and no conflicts of interest to report. Accepted September 24, 2013. Copyright * 2014 by The Southern Medical Association 0038-4348/0Y2000/107-248 DOI: 10.1097/SMJ.0000000000000086
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Megan C. Rich,
BA,
Hunter B. Moore,
MD,
Quest for the ‘‘Ideal’’ Biomarker Research in the field dating back to the 1980s defined the properties of an ideal biomarker for TBI as the following: it must be highly specific for brain tissue, it must be released from the brain only after relevant tissue damage has occurred, it must appear in cerebrospinal fluid (CSF) and serum rapidly after trauma and mirror the time course of injury, it must reflect the extent of neurological injury, and it must be of clinical relevance.14,19 The terminology applied to individual biomarkers related to their sensitivity, specificity, and positive and negative predictive value is explained in the Table. Candidate biomarkers for TBI originate from injured neurons, axons, or glial cells (Fig.). Debate on the potential advantages of CSF versus peripheral blood samples is ongoing.20 Some authors argue that biomarkers in CSF are preferred over serum because of the close proximity of the intrathecal fluid to the injured brain, independent of the integrity of the bloodYbrain barrier (BBB).20 Highly sensitive bioassays are needed to allow the quantification of brain-derived proteins in blood samples because serum concentrations may lie below the lower detection limit of most available immunoassays.21 Furthermore, confounding factors may alter the serum levels of candidate biomarkers, for example, by the presence of
Key Points & Glial fibrillary acidic protein represents one of the most promising serum biomarkers for traumatic brain injury (TBI) because of its restricted expression in the central nervous system. In contrast, data have revealed that other promising molecules have multiple extracranial cellular sources and thus not specific to TBI. & There are several clinical applications of candidate biomarkers for TBI, including prediction of secondary cerebral insults and adverse outcome in patients with severe TBI, monitoring of neurocritical care modalities or pharmaceutical strategies in patients with severe TBI, and differentiation of focal intracerebral lesions from diffuse injury patterns. & A multibiomarker panel, in conjunction with clinical scoring, may increase the diagnostic accuracy of individual biomarkers. & Any novel biomarker used as a diagnostic risk stratification tool will not eliminate the crucial role of the subjectivity and individual judgment by experienced physicians, in conjunction with the selective indication for adjunctive radiographic studies.
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Review Article
Table. Definitions of the terminology applied to serum biomarkers for injury severity, outcome prediction, and risk stratification Definition
Calculation
Sensitivity
Proportion of people with the disease who will have a positive result
true positives truepositives þ falsenegatives
Specificity
Proportion of people without the disease who will have a negative result
truenegatives truenegatives þ falsepositives
Positive predictive value
Proportion of people with a positive test result who actually have the disease
true positives truepositives þ false positives
Negative predictive value
Proportion of people with a negative test result who do not have the disease
truenegatives true negatives þ false negatives
Clinical relevance for TBI A biomarker with high sensitivity will correctly identify a high number of patients with severe TBI and/or the increased risk of delayed deterioration A biomarker with high specificity will correctly identify a high number of patients without TBI and/or the absence of risk of delayed deterioration A biomarker with a high positive predictive value will reliably identify the presence of severe TBI and/or increased risk of delayed deterioration, when biomarker levels are elevated A biomarker with a high negative predictive value will reliably identify the absence of TBI and/or absence of risk for delayed deterioration, when marker levels are low or normal
TBI, traumatic brain injury.
extracranial injuries and/or hemorrhagic shock.22,23 Serum biomarkers, however, appear more appealing for routine sampling because of the ease of access to peripheral blood samples, either for prehospital field triage in armed conflicts or in clinical practice.24 This aspect is of particular importance, considering that most patients with head injury do not undergo
routine CSF sampling and only selected patients with severe TBI are candidates for CSF drainage through indwelling intraventricular catheters.25,26 The scope of the present review focuses on serum biomarkers in the adult population of patients with TBI, with a discussion of the strengths and limitations of established individual markers and future candidate molecules.
Fig. Cellular source of selected biomarkers for traumatic brain injury. GFAP, glial fibrillary acidic protein; MBP, myelin basic protein; NFL, neurofilament; NSE, neuron-specific enolase; SBDPs, spectrin breakdown products; UCH-L1, ubiquitin carboxyl-terminal hydrolase-L1. Southern Medical Journal
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Neuron-Specific Enolase Neuron-specific enolase (NSE) is a glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenol pyruvate during glucose metabolism.27 NSE is present in high concentrations in neurons and neuroendocrine cells, and its release into serum has been considered a surrogate marker that reflects the extent of brain damage.28,29 A serum NSE level G10 ng/mL is considered to be within the normal range.30 The rapid appearance of NSE in serum after TBI favors its potential for early stratification of at-risk patients for delayed deterioration.31Y33 NSE serum levels were found to correlate significantly with injury severity in experimental animal studies34 and in patients with head injury, as determined by an inverse correlation with Glasgow Coma Scale (GCS) scores.35 Furthermore, elevated serum NSE levels correlated with the presence of intracerebral pathology on initial computed tomography (CT) scans35Y37 and were strongly predictive of adverse outcomes and death after severe TBI.35,38Y41 A study of patients with severe diffuse axonal injury revealed 100% sensitivity and 100% specificity for predicting postinjury death by NSE levels 950 ng/mL.31 Despite its established value in predicting poor outcome after severe TBI, NSE has the shortcoming of a long half-life beyond 20 hours, which limits its value as a monitoring tool for injury progression and response to therapeutic interventions.42 Furthermore, NSE appears to have a low sensitivity for discriminating patients with mild TBI from healthy controls.43 Finally, the longstanding notion that NSE is exclusively produced by cells of neuronal origin was rebutted by a demonstrated release from hemolysed erythrocytes during cardiac bypass surgery.44 Other studies established additional extracranial sources of NSE, including hemorrhagic shock, long-bone fractures, ischemia/reperfusion injuries to the liver and kidney, and malignant tumors of the lung.45Y47 The finding of multiple extracerebral sources of NSE clearly limits its value as an isolated serum biomarker for CNS trauma.
S100 Calcium-Binding Protein B The astroglia-derived S100 calcium-binding protein B (S100B) represents the most widely investigated serum marker for TBI.48Y53 S100B is expressed by a subtype of mature astrocytes in the CNS and by Schwann cells in the peripheral nerve system.48 The physiologic functions of S100B have been extensively investigated but are not fully understood. Some of these functions include the induction of neurite extension, astrocytosis, and axonal proliferation.54 Although S100B is mainly expressed by astroglial cells, its source is not restricted to the CNS, and the protein also has been detected in adipocytes, chondrocytes, melanoma cells, and hematopoietic cells.55Y58 Significantly elevated S100B levels have been described in the serum of patients with head injury.59 S100B is released rapidly after trauma, and its short half-life of G60 minutes makes it an appealing marker during the early posttraumatic phase after head injury.49,60Y62 Elevated S100B serum levels were shown to
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be associated with but not predictive of secondary neurological complications during neurointensive care for head injury or cerebrovascular insults.63 Increased S100B serum levels have been shown to correlate with the clinical and radiographic severity of TBI and to predict adverse outcomes.38,51,64Y66 A prospective observational cohort study on 85 patients with severe TBI (GCS e8) revealed a sensitivity of 100% for elevated serum S100B levels 91.13 ng/mL as a predictor of death, with an adjusted odds ratio 95 for predicting poor outcomes.38 This notion was confirmed in other clinical studies, which demonstrated a high sensitivity (90%) for early prediction of mortality after severe TBI, even at lower thresholds of 90.461 ng/mL in serum or 90.025 ng/mL in urine samples.67 In a different study, 84 patients with moderate to severe TBI (GCS e12) were characterized with serum S100B temporal profiles as more powerful independent predictors of posttraumatic death than clinical and radiologic indicators.40 A proposed predictive model for S100B serum levels 90.90 ng/mL at 24 hours after TBI was associated with predictive values for the evolution of secondary brain injury and posttraumatic mortality.68 A different prospective observational study of 102 patients with severe TBI revealed that initial S100B serum levels 91.0 ng/mL were associated with a nearly threefold increased risk of death at 1 month postinjury.65 The authors also described a reduction of serum S100B levels after neurosurgical interventions, implying that this biomarker may represent a monitoring tool for guiding therapeutic efficacy in patients with severe TBI.65 In addition to the positive predictive value for adverse outcomes after severe TBI, S100B also represents a sensitive diagnostic tool for discriminating patients with mild head injury who are at risk for delayed neurologic deterioration.48,51,66,69Y71 From this perspective, risk stratification by S100B serum testing may reduce excessive CT scanning in patients with mild head injury (GCS 14 or 15) in the presence of minor neurologic symptoms, such as brief loss of consciousness, amnesia, headaches, nausea, or vomiting.50,52,72 Clinical studies revealed a high negative predictive value of serum S100B levels G0.13 ng/mL in discriminating patients with mild TBI at low risk of neuroradiologic pathology or clinical deterioration and a high sensitivity for detecting patients at risk for relevant intracranial injuries, with a cutoff at 90.21 ng/mL.51,73 Other studies confirmed this observation by revealing that low initial S100B serum levels G0.10 ng/mL had 100% sensitivity for predicting the absence of relevant intracranial pathology on CT.70,71 The dogma that S100B testing may be a panacea for the evaluation of mild TBI has undergone justified scrutiny.59,72,74 Despite the high sensitivity and high negative predictive value of serum S100B to rule out significant head injury in patients with mild TBI, the lack of specificity is one of the limitations of the diagnostic value of this biomarker.20,74 The finding of extracerebral sources of S100B in peripheral blood (eg, by hematopoietic cells)58 limits the diagnostic value of S100B, particularly in the presence of associated injuries and traumatic hemorrhagic shock.22,75 This notion is confirmed by the * 2014 Southern Medical Association
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observation that elevated serum S100B levels were detected under various clinical conditions with extracranial pathology, including peripheral trauma and burns, and even in healthy individuals after extensive physical exercise.76Y79 Multiple authors have challenged the role of S100B in predicting outcomes and correlations with neuroimaging findings in patients with mild TBI.80 Some authors provocatively suggest that elevated S100B levels are reflective of BBB damage, resulting in protein leakage from the periphery into the intrathecal compartment, rather than reflecting the extent of neuronal injury.81,82
Glial Fibrillary Acidic Protein Glial fibrillary acidic protein (GFAP) is an established astrocyte-specific cell marker.83 The exclusively CNS-restricted source renders GFAP a highly appealing candidate as a specific and sensitive biomarker after cerebral insults, including stroke and TBI.60,84 Clinical studies confirmed this notion by demonstrating up to 100-fold elevated GFAP levels in the sera of patients with severe head injuries, compared with controls, and a correlation with adverse outcomes.38,85 A clinical study revealed a drastically elevated mean GFAP serum level of 6.77 pg/mL in patients with TBI on the day of admission, compared with barely detectable levels (mean 0.7 pg/mL) in control subjects without head injuries.86 Serum GFAP levels in patients with TBI were found to peak in the first days postinjury, followed by a gradual decrease during the first week.86 A prospective multicenter study analyzed serum levels of GFAP breakdown products in 108 patients with mild or moderate TBI (GCS 9Y15), compared with 199 controls consisting of uninjured patients or trauma patients with orthopedic injuries in the absence of TBI.87 The authors found that GFAP breakdown products in the sera of patients with TBI were predictive of injury severity, presence of intracranial lesions on CT scan, and requirement for a neurosurgical intervention.87 Similar findings were described by other research groups in different clinical studies.13,38,85,86,88,89 In addition, median GFAP levels were found to be up to 20-fold elevated in patients with TBI with long-term unfavorable outcomes, as determined by the extended Glasgow Outcome Scale score, and 933-fold in patients who died of their head injuries.90 The unequivocal benefit of GFAP as a biomarker for head injury, above other candidate molecules (eg, S100B, NSE), lies in its brain-specific expression and release.83 This important benefit is further corroborated by studies that show that extracranial injuries do not contribute to the high GFAP serum levels seen in patients with TBI, and patients with multiple injuries in the absence of TBI were shown to have normal GFAP serum levels.85,89 Based on the available literature, there are no known shortcomings of and limitations to using serum levels of GFAP or its breakdown products, alone or in combination with other biomarkers,91 for assessing severity of injury, monitoring the efficiency of treatment modalities, and predicting outcomes in patients with TBI. Future validation studies in large-scale Southern Medical Journal
longitudinal multicenter studies must confirm the notion of GFAP being a panacea among the available serum biomarkers for head injury.
Novel and Experimental Biomarkers Ubiquitin Carboxyl Terminal Hydrolase-L1 Ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) represents a protein of neuronal origin92 that has been identified as an appealing candidate biomarker for TBI.93 Several clinical trials showed promising results regarding the diagnostic value of UCH-L1 in distinguishing focal from diffuse brain injury patterns and in predicting outcomes.94Y97 Preliminary case-control studies revealed significantly elevated mean levels of UCH-L1 in CSF and sera of patients with severe head injuries (GCS G9), compared with controls without TBI.94,97 The cumulative UCH-L1 serum levels above a cutoff at 5.22 ng/mL were predictive of posttraumatic mortality, with a nearly fivefold increased odds ratio for dying.97 Another prospective cohort study in patients with mild and moderate TBI (GCS 9Y15) was designed to determine the diagnostic value of UCH-L1 serum levels in predicting the presence of intracranial lesions on CT scans and the requirement for neurosurgical interventions.95 A total of 96 patients with TBI were compared with 199 controls, consisting of uninjured patients and trauma patients in the absence of TBI.95 The mean UCH-L1 serum levels in patients with TBI with normal CT findings were 0.62 ng/mL, compared with 1.62 ng/mL in patients with radiographic evidence of intracranial lesions.95 Patients requiring neurosurgical intervention had even higher mean UCH-L1 serum levels of 2.57 ng/mL.95 The authors concluded that UCH-L1 is readily detectable in the sera of patients with head injury within 1 hour after trauma, and increased levels are predictive of injury severity, based on decreased GCS, the increased likelihood of intracranial lesions on CT, and the requirement for neurosurgical intervention.95 In light of the novel findings that have been established almost exclusively by a single research team,94Y97 the clinical utility of UCH-L1 as a serum biomarker in TBI requires validation in prospective longitudinal studies by other groups.
Tau Protein and c-Tau Tau represents a cytoskeletal protein in neurons that contributes to the stabilization of axonal microtubules.98 Neuronal damage after TBI is associated with the proteolytic cleavage of tau protein by cysteine proteases, resulting in the release of cleaved tau (c-tau) into CSF and serum.98,99 One pilot study described an increase in plasma tau levels of 9300% above controls after a concussion in boxers.100 After severe TBI, total tau protein levels are significantly elevated in CSF, compared with control levels, and predictive of mortality and outcome at 1 year postinjury.101 c-Tau levels in CSF were found to be elevated up to 40,000-fold after head injury, compared with neurologic patients without TBI or to control patients without neurologic disorders.102 Another study showed tau protein levels
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to be significantly elevated in serum after severe TBI and predictive of adverse outcome, as determined by Glasgow Outcome Scale score at 6 months.103 Specifically, mean tau protein levels in the sera of patients with TBI with poor outcomes were elevated to 436.2 pg/mL, compared with 51.6 pg/mL in patients who had improved long-term recovery after trauma.103 The role of tau protein and c-tau is not as clearly defined with regard to the diagnostic potential for stratifying patients with mild head injury at risk for secondary deterioration, and further prospective studies are needed to validate the role of tau and c-tau as valid serum biomarkers in TBI.104Y106
Myelin Basic Protein Myelin basic protein (MBP) is a major component of the myelin sheath around neuronal axons, and increased MBP levels in CSF and serum have been described as a surrogate marker to reflect injury to myelinated axons.107,108 Multiple studies have proposed the use of serum MBP levels as a biomarker in TBI, in both the adult and pediatric patient populations.108Y110 Despite the high specificity of MBP serum levels for outcome prediction after severe TBI, the low sensitivity appears to limit the value of MBP as a reliable biomarker for risk stratification after mild head injury.15,20,29
Innate Immune Molecules Closed head injury is considered an inflammatory disease that is characterized by the activation of innate immunity and release of immune mediators from the intracranial compartment into peripheral blood.111 Innate immune molecules, such as proinflammatory cytokines, acute-phase proteins, complement components, and complement activation fragments have been shown to correlate with the extent of posttraumatic BBB damage and neuronal injury.112Y117 Although selected cytokines of interest, including tumor necrosis factor, interleukin-6, and interleukin-8, have been investigated as potential biomarkers of head injury for 92 decades, there is still a lack of proven evidence for the clinical and diagnostic utility of these inflammatory mediators for outcome prediction in TBI.118Y123
Conclusions We have outlined a restricted selection of candidate molecules (NSE, S100B, GFAP) that reflect the most extensively investigated biomarkers in the field. Numerous additional mediators have been investigated with regard to their potential value for risk stratification and outcome prediction after TBI. In general, any biomarker of interest is characterized as a CNSrestricted protein that leaks across the damaged BBB into the peripheral bloodstream.7,20 Alternatively, elevated serum mediators may be reflective of peripheral production after TBI, for example, through induction of the hepatic acute-phase response after CNS trauma.112,123 Representative molecules are derived from either direct traumatic impact to the brain, through acute neuronal injury, axonal injury, and astroglial injury or secondary host-derived inflammatory and reparative processes such as
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neuroinflammation, oxidative stress, and excitotoxicity, and other host-derived pathophysiological mechanisms. In spite of the multiple trials and available data, the ideal diagnostic biomarker in TBI with high sensitivity, specificity, and predictive value for adverse outcome remains to be determined. Some of the promising molecules, such as NSE or S100B, do not appear to be specific to CNS injuries, as was assumed. Other purely CNS-restricted proteins such as GFAP require further investigation in future well-designed, longitudinal, and controlled trials for validation in routine clinical use. It is likely that a multibiomarker panel, in conjunction with clinical scoring, may increase the diagnostic accuracy of individual biomarkers. Trajectory analysis represents a new approach to capturing the temporal variance in individual biomarker levels.124 This method was applied in the combined use of NSE, S100B, and MBP to predict adverse outcomes in children with TBI.125 Most important, the design of any future trial must take into consideration the specific question raised by the underlying a priori hypothesis, stratified by the following main clinical applications of candidate biomarkers: 1. Predicting secondary cerebral insults and adverse outcomes in patients with severe TBI 2. Monitoring the therapeutic efficacy of neurocritical care modalities or pharmaceutical strategies in patients with severe TBI 3. Differentiating focal intracerebral lesions from diffuse injury patterns and discriminating the subcohort of patients with mild or moderate TBI who are at risk for delayed deterioration.
It is hoped that the ‘‘ideal’’ biomarker, or panel of multiple biomarkers, in conjunction with clinical and radiological tests, will provide a clinically valid tool for establishing diagnosis and prognosis of patients with head injury admitted to the emergency department. No novel diagnostic risk stratification tool will eliminate the crucial role of subjective and individual judgment by experienced physicians.
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54. Kleindienst A, Ross Bullock M. A critical analysis of the role of the neurotrophic protein S100B in acute brain injury. J Neurotrauma 2006; 23:1185Y1200. 55. 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. 56. Gelse K, Ekici AB, Cipa F, et al. Molecular differentiation between osteophytic and articular cartilageVclues for a transient and permanent chondrocyte phenotype. Osteoarthritis Cartilage 2012;20:162Y171. 57. Torabian S, Kashani-Sabet M. Biomarkers for melanoma. Curr Opin Oncol 2005;17:167Y171. 58. Chan RW, Graham CA, Rainer TH, et al. Use of bone marrow transplantation model system to demonstrate the hematopoietic origin of plasma S100B mRNA. Clin Chem 2007;53:1874Y1876. 59. Graham CA, Rainer TH. Utility of S100B in head injury care. Ann Emerg Med 2013;61:120Y121. 60. Dash PK, Zhao J, Hergenroeder G, et al. Biomarkers for the diagnosis, prognosis, and evaluation of treatment efficacy for traumatic brain injury. Neurotherapeutics 2010;7:100Y114. 61. Jonsson H, Johnsson P, Hoglund P, et al. Elimination of S100B and renal function after cardiac surgery. J Cardiothorac Vasc Anesth 2000; 14:698Y701. 62. Thelin EP, Johannesson LK, Nelson DW, et al. S100B is an important outcome predictor in traumatic brain injury. J Neurotrauma 2013; 30:519Y528. 63. Unden J, Astrand R, Waterloo K, et al. Clinical significance of serum S100B levels in neurointensive care. Neurocrit Care 2007;6:94Y99. 64. Yates D. Traumatic brain injury: serum levels of GFAP and S100B predict outcomes in TBI. Nat Rev Neurol 2011;7:63. 65. Korfias S, Stranjalis G, Boviatsis E, et al. Serum S-100B protein monitoring in patients with severe traumatic brain injury. Intensive Care Med 2007;33:255Y260. 66. Cervellin G, Benatti M, Carbucicchio A, et al. Serum levels of protein S100B predict intracranial lesions in mild head injury. Clin Biochem 2012;45:408Y411. 67. Rodriguez-Rodriguez A, Egea-Guerrero JJ, Leon-Justel A, et al. Role of S100B protein in urine and serum as an early predictor of mortality after severe traumatic brain injury in adults. Clin Chim Acta 2012; 414:228Y233. 68. Gonzalez-Mao MC, Reparaz-Andrade A, Del Campo-Perez V, et al. Model predicting survival/exitus after traumatic brain injury: biomarker S100B 24h. Clin Lab 2011;57:587Y597. 69. Savola O, Hillbom M. Early predictors of post-concussion symptoms in patients with mild head injury. Eur J Neurol 2003;10:175Y181. 70. Calcagnile O, Unden L, Unden J. Clinical validation of S100B use in management of mild head injury. BMC Emerg Med 2012;12:13. 71. Unden J, Romner B. Can low serum levels of S100B predict normal CT findings after minor head injury in adults? An evidence-based review and meta-analysis. J Head Trauma Rehabil 2010;25:228Y240. 72. Breena RT. Biomarkers revisited: study design, validity and STARD. Will S100-B impact computed tomography use in head injury patients? Ann Emerg Med 2012;59:221Y222. 73. Muller K, Townend W, Biasca N, et al. S100B serum level predicts computed tomography findings after minor head injury. J Trauma 2007;62:1452Y1456. 74. Schriger DL, Newman DH. Medical decisionmaking: let’s not forget the physician. Ann Emerg Med 2012;59:219Y220. 75. Michetti F, Corvino V, Geloso MC, et al. The S100B protein in biological fluids: more than a lifelong biomarker of brain distress. J Neurochem 2012;120:644Y659. 76. Anderson RE, Hansson LO, Nilsson O, et al. High serum S100B levels for trauma patients without head injuries. Neurosurgery 2001;48:1255Y1258. 77. Dietrich MO, Tort AB, Schaf DV, et al. Increase in serum S100B protein level after a swimming race. Can J Appl Physiol 2003;28:710Y716.
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78. Stalnacke BM, Ohlsson A, Tegner Y, et al. Serum concentrations of two biochemical markers of brain tissue damage S-100B and neurone specific enolase are increased in elite female soccer players after a competitive game. Br J Sports Med 2006;40:313Y316. 79. Otto M, Holthusen S, Bahn E, et al. Boxing and running lead to a rise in serum levels of S-100B protein. Int J Sports Med 2000;21:551Y555. 80. Metting Z, Wilczak N, Rodiger LA, et al. GFAP and S100B in the acute phase of mild traumatic brain injury. Neurology 2012;78:1428Y1433. 81. Kapural M, Krizanac-Bengez L, Barnett G, et al. Serum S-100beta as a possible marker of blood-brain barrier disruption. Brain Res 2002; 940:102Y104. 82. Piazza O, Storti MP, Cotena S, et al. S100B is not a reliable prognostic index in paediatric TBI. Pediatr Neurosurg 2007;43:258Y264. 83. Eng LF, Ghirnikar RS, Lee YL. Glial fibrillary acidic protein: GFAPthirty-one years (1969Y2000). Neurochem Res 2000;25:1439Y1451. 84. Schiff L, Hadker N, Weiser S, et al. A literature review of the feasibility of glial fibrillary acidic protein as a biomarker for stroke and traumatic brain injury. Mol Diagn Ther 2012;16:79Y92. 85. 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;240:85Y91. 86. Lumpkins KM, Bochicchio GV, Keledjian K, et al. Glial fibrillary acidic protein is highly correlated with brain injury. J Trauma 2008;65:778Y782. 87. 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;59:471Y483. 88. 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; 69:104Y109. 89. Pelinka LE, Kroepfl A, Schmidhammer R, et al. Glial fibrillary acidic protein in serum after traumatic brain injury and multiple trauma. J Trauma 2004;57:1006Y1012. 90. Vos PE, Jacobs B, Andriessen TM, et al. GFAP and S100B are biomarkers of traumatic brain injury: an observational cohort study. Neurology 2010;75:1786Y1793. 91. 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 (UCH-L1) and glial fibrillary acidic protein (GFAP). J Neurotrauma 2014;31:19Y25. 92. Day IN, Thompson RJ. UCHL1 (PGP 9.5): neuronal biomarker and ubiquitin system protein. Prog Neurobiol 2010;90:327Y362. 93. Yokobori S, Hosein K, Burks S, et al. Biomarkers for the clinical differential diagnosis in traumatic brain injuryVa systematic review. CNS Neurosci Ther 2013;19:556Y565. 94. 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;38:138Y144. 95. 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;72:1335Y1344. 96. 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;28:861Y870. 97. 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;70:666Y675. 98. Tsitsopoulos PP, Marklund N. Amyloid-A peptides and tau protein as biomarkers in cerebrospinal and interstitial fluid following traumatic brain injury: a review of experimental and clinical studies. Front Neurol 2013;4:79.
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99. Park SY, Tournell C, Sinjoanu RC, et al. Caspase-3- and calpain-mediated tau cleavage are differentially prevented by estrogen and testosterone in betaamyloid-treated hippocampal neurons. Neuroscience 2007;144:119Y127. 100. Neselius S, Zetterberg H, Blennow K, et al. Olympic boxing is associated with elevated levels of the neuronal protein tau in plasma. Brain Inj 2013;27:425Y433. 101. Ost M, Nylen K, Csajbok L, et al. Initial CSF total tau correlates with 1-year outcome in patients with traumatic brain injury. Neurology 2006;67: 1600Y1604. 102. 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;947:131Y139. 103. Liliang PC, Liang CL, Weng HC, et al. Tau proteins in serum predict outcome after severe traumatic brain injury. J Surg Res 2010;160: 302Y307. 104. Bazarian JJ, Zemlan FP, Mookerjee S, et al. Serum S-100B and cleavedtau are poor predictors of long-term outcome after mild traumatic brain injury. Brain Inj 2006;20:759Y765. 105. Bulut M, Koksal O, Dogan S, et al. Tau protein as a serum marker of brain damage in mild traumatic brain injury: preliminary results. Adv Ther 2006;23:12Y22. 106. 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;25:391Y395. 107. Gyorgy A, Ling G, Wingo D, et al. Time-dependent changes in serum biomarker levels after blast traumatic brain injury. J Neurotrauma 2011;28:1121Y1126. 108. 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: 401Y407. 109. Berger RP, Adelson PD, Pierce MC, et al. Serum neuron-specific enolase, S100B, and myelin basic protein concentrations after inflicted and noninflicted traumatic brain injury in children. J Neurosurg 2005; 103:61Y68. 110. Korfias S, Papadimitriou A, Stranjalis G, et al. Serum biochemical markers of brain injury. Mini Rev Med Chem 2009;9:227Y234. 111. Schmidt OI, Heyde CE, Ertel W, Stahel PF. Closed head injuryVan inflammatory disease? Brain Res Rev 2005;48:388Y399. 112. Woodcock T, Morganti-Kossmann MC. The role of markers of inflammation in traumatic brain injury. Front Neurol 2013;4:18. 113. Helmy A, Carpenter KL, Menon DK, et al. The cytokine response to human traumatic brain injury: temporal profiles and evidence for
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cerebral parenchymal production. J Cereb Blood Flow Metab 2011; 31:658Y670. Is M, Coskun A, Sanus GZ, et al. High-sensitivity C-reactive protein levels in cerebrospinal fluid and serum in severe head injury: relationship to tumor necrosis factor-alpha and interleukin-6. J Clin Neurosci 2007; 14:1163Y1171. Stahel PF, Morganti-Kossmann MC, Perez D, et al. Intrathecal levels of complement-derived soluble membrane attack complex (sC5b-9) correlate with blood- brain barrier dysfunction in patients with traumatic brain injury. J Neurotrauma 2001;18:773Y781. Kossmann T, Stahel PF, Morganti-Kossmann MC, et al. Elevated levels of the complement components C3 and factor B in ventricular cerebrospinal fluid of patients with traumatic brain injury. J Neuroimmunol 1997; 73:63Y69. Bellander BM, Olafsson IH, Ghatan PH, 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;153:90Y100. Stein DM, Lindel AL, Murdock KR, et al. Use of serum biomarkers to predict secondary insults following severe traumatic brain injury. Shock 2012;37:563Y568. 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. Sogut O, Guloglu C, Orak M, et al. Trauma scores and neuron-specific enolase, cytokine and C-reactive protein levels as predictors of mortality in patients with blunt head trauma. J Int Med Res 2010; 38:1708Y1720. Kalabalikis P, Papazoglou K, Gouriotis D, et al. Correlation between serum IL-6 and CRP levels and severity of head injury in children. Intensive Care Med 1999;25:288Y292. 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;17:280Y289. Kossmann T, Hans VH, Imhof HG, et al. Intrathecal and serum interleukin-6 and the acute-phase response in patients with severe traumatic brain injuries. Shock 1995;4:311Y317. Niyonkuru C, Wagner AK, Ozawa H, et al. Group-based trajectory analysis applications for prognostic biomarker model development in severe TBI: a practical example. J Neurotrauma 2013;30:938Y945. Berger RP, Bazaco MC, Wagner AK, et al. Trajectory analysis of serum biomarker concentrations facilitates outcome prediction after pediatric traumatic and hypoxemic brain injury. Dev Neurosci 2010;32:396Y405.
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Serum Biomarkers for Traumatic Brain Injury Miriam D. Neher, MD, Chesleigh N. Keene, and Philip F. Stahel, MD
MA,
Abstract: There is a lack of reliable serum biomarkers for routine use in the diagnostic workup of people with traumatic brain injury. Multiple biomediators and biomarkers have been described in the pertinent literature in recent years; however, only a few candidate molecules have been associated with high sensitivity and high specificity for risk stratification and outcome prediction after traumatic brain injury. This review was designed to provide an overview of the state of the art regarding established serum biomarkers in the field and to outline future directions of investigation. Key Words: astroglial injury, axonal injury, biomarkers, neuronal injury, outcome prediction, risk stratification, traumatic brain injury
T
raumatic brain injury (TBI) is the leading cause of death and disability in the young civilian population in the United States, with an annual incidence of 1.7 million and 950,000 deaths.1Y3 In addition, TBI represents one of the major root causes of long-term neuropathologic sequelae in deployed military personnel and veterans of armed conflicts.4Y6 Significant research efforts have been devoted to establishing sensitive biomarkers for TBI that reflect the severity of injury and risk of delayed deterioration and provide guidance for treatment and prediction of outcomes.7Y9 Technological innovation in recent years, with the introduction of neuroproteomics and new-generation laboratory testing modalities, has had a dramatic impact on the available options for the diagnostic workup of individuals with TBI.10Y13 Despite extensive clinical research in the field during the past 3 decades,14 no suitable biomarker has been identified that is easily detectable in peripheral blood samples and fulfills all required criteria with high sensitivity and specificity.15Y18 From Denver Health Medical Center, and the Departments of Orthopaedic Surgery, Trauma Surgery, and Neurosurgery, University of Colorado School of Medicine, Denver. Reprint requests to Dr Philip F. Stahel, Denver Health Medical Center, University of Colorado School of Medicine, 777 Bannock St, Denver, CO 80204. E-mail: [email protected] This work was partially supported by a grant from the Colorado TBI Trust Fund to P.F.S. P.F.S. has received grant funding from Stryker Medical and royalties for a US patent. The other authors have no financial relationships to disclose and no conflicts of interest to report. Accepted September 24, 2013. Copyright * 2014 by The Southern Medical Association 0038-4348/0Y2000/107-248 DOI: 10.1097/SMJ.0000000000000086
248
Megan C. Rich,
BA,
Hunter B. Moore,
MD,
Quest for the ‘‘Ideal’’ Biomarker Research in the field dating back to the 1980s defined the properties of an ideal biomarker for TBI as the following: it must be highly specific for brain tissue, it must be released from the brain only after relevant tissue damage has occurred, it must appear in cerebrospinal fluid (CSF) and serum rapidly after trauma and mirror the time course of injury, it must reflect the extent of neurological injury, and it must be of clinical relevance.14,19 The terminology applied to individual biomarkers related to their sensitivity, specificity, and positive and negative predictive value is explained in the Table. Candidate biomarkers for TBI originate from injured neurons, axons, or glial cells (Fig.). Debate on the potential advantages of CSF versus peripheral blood samples is ongoing.20 Some authors argue that biomarkers in CSF are preferred over serum because of the close proximity of the intrathecal fluid to the injured brain, independent of the integrity of the bloodYbrain barrier (BBB).20 Highly sensitive bioassays are needed to allow the quantification of brain-derived proteins in blood samples because serum concentrations may lie below the lower detection limit of most available immunoassays.21 Furthermore, confounding factors may alter the serum levels of candidate biomarkers, for example, by the presence of
Key Points & Glial fibrillary acidic protein represents one of the most promising serum biomarkers for traumatic brain injury (TBI) because of its restricted expression in the central nervous system. In contrast, data have revealed that other promising molecules have multiple extracranial cellular sources and thus not specific to TBI. & There are several clinical applications of candidate biomarkers for TBI, including prediction of secondary cerebral insults and adverse outcome in patients with severe TBI, monitoring of neurocritical care modalities or pharmaceutical strategies in patients with severe TBI, and differentiation of focal intracerebral lesions from diffuse injury patterns. & A multibiomarker panel, in conjunction with clinical scoring, may increase the diagnostic accuracy of individual biomarkers. & Any novel biomarker used as a diagnostic risk stratification tool will not eliminate the crucial role of the subjectivity and individual judgment by experienced physicians, in conjunction with the selective indication for adjunctive radiographic studies.
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Table. Definitions of the terminology applied to serum biomarkers for injury severity, outcome prediction, and risk stratification Definition
Calculation
Sensitivity
Proportion of people with the disease who will have a positive result
true positives truepositives þ falsenegatives
Specificity
Proportion of people without the disease who will have a negative result
truenegatives truenegatives þ falsepositives
Positive predictive value
Proportion of people with a positive test result who actually have the disease
true positives truepositives þ false positives
Negative predictive value
Proportion of people with a negative test result who do not have the disease
truenegatives true negatives þ false negatives
Clinical relevance for TBI A biomarker with high sensitivity will correctly identify a high number of patients with severe TBI and/or the increased risk of delayed deterioration A biomarker with high specificity will correctly identify a high number of patients without TBI and/or the absence of risk of delayed deterioration A biomarker with a high positive predictive value will reliably identify the presence of severe TBI and/or increased risk of delayed deterioration, when biomarker levels are elevated A biomarker with a high negative predictive value will reliably identify the absence of TBI and/or absence of risk for delayed deterioration, when marker levels are low or normal
TBI, traumatic brain injury.
extracranial injuries and/or hemorrhagic shock.22,23 Serum biomarkers, however, appear more appealing for routine sampling because of the ease of access to peripheral blood samples, either for prehospital field triage in armed conflicts or in clinical practice.24 This aspect is of particular importance, considering that most patients with head injury do not undergo
routine CSF sampling and only selected patients with severe TBI are candidates for CSF drainage through indwelling intraventricular catheters.25,26 The scope of the present review focuses on serum biomarkers in the adult population of patients with TBI, with a discussion of the strengths and limitations of established individual markers and future candidate molecules.
Fig. Cellular source of selected biomarkers for traumatic brain injury. GFAP, glial fibrillary acidic protein; MBP, myelin basic protein; NFL, neurofilament; NSE, neuron-specific enolase; SBDPs, spectrin breakdown products; UCH-L1, ubiquitin carboxyl-terminal hydrolase-L1. Southern Medical Journal
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Neuron-Specific Enolase Neuron-specific enolase (NSE) is a glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenol pyruvate during glucose metabolism.27 NSE is present in high concentrations in neurons and neuroendocrine cells, and its release into serum has been considered a surrogate marker that reflects the extent of brain damage.28,29 A serum NSE level G10 ng/mL is considered to be within the normal range.30 The rapid appearance of NSE in serum after TBI favors its potential for early stratification of at-risk patients for delayed deterioration.31Y33 NSE serum levels were found to correlate significantly with injury severity in experimental animal studies34 and in patients with head injury, as determined by an inverse correlation with Glasgow Coma Scale (GCS) scores.35 Furthermore, elevated serum NSE levels correlated with the presence of intracerebral pathology on initial computed tomography (CT) scans35Y37 and were strongly predictive of adverse outcomes and death after severe TBI.35,38Y41 A study of patients with severe diffuse axonal injury revealed 100% sensitivity and 100% specificity for predicting postinjury death by NSE levels 950 ng/mL.31 Despite its established value in predicting poor outcome after severe TBI, NSE has the shortcoming of a long half-life beyond 20 hours, which limits its value as a monitoring tool for injury progression and response to therapeutic interventions.42 Furthermore, NSE appears to have a low sensitivity for discriminating patients with mild TBI from healthy controls.43 Finally, the longstanding notion that NSE is exclusively produced by cells of neuronal origin was rebutted by a demonstrated release from hemolysed erythrocytes during cardiac bypass surgery.44 Other studies established additional extracranial sources of NSE, including hemorrhagic shock, long-bone fractures, ischemia/reperfusion injuries to the liver and kidney, and malignant tumors of the lung.45Y47 The finding of multiple extracerebral sources of NSE clearly limits its value as an isolated serum biomarker for CNS trauma.
S100 Calcium-Binding Protein B The astroglia-derived S100 calcium-binding protein B (S100B) represents the most widely investigated serum marker for TBI.48Y53 S100B is expressed by a subtype of mature astrocytes in the CNS and by Schwann cells in the peripheral nerve system.48 The physiologic functions of S100B have been extensively investigated but are not fully understood. Some of these functions include the induction of neurite extension, astrocytosis, and axonal proliferation.54 Although S100B is mainly expressed by astroglial cells, its source is not restricted to the CNS, and the protein also has been detected in adipocytes, chondrocytes, melanoma cells, and hematopoietic cells.55Y58 Significantly elevated S100B levels have been described in the serum of patients with head injury.59 S100B is released rapidly after trauma, and its short half-life of G60 minutes makes it an appealing marker during the early posttraumatic phase after head injury.49,60Y62 Elevated S100B serum levels were shown to
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be associated with but not predictive of secondary neurological complications during neurointensive care for head injury or cerebrovascular insults.63 Increased S100B serum levels have been shown to correlate with the clinical and radiographic severity of TBI and to predict adverse outcomes.38,51,64Y66 A prospective observational cohort study on 85 patients with severe TBI (GCS e8) revealed a sensitivity of 100% for elevated serum S100B levels 91.13 ng/mL as a predictor of death, with an adjusted odds ratio 95 for predicting poor outcomes.38 This notion was confirmed in other clinical studies, which demonstrated a high sensitivity (90%) for early prediction of mortality after severe TBI, even at lower thresholds of 90.461 ng/mL in serum or 90.025 ng/mL in urine samples.67 In a different study, 84 patients with moderate to severe TBI (GCS e12) were characterized with serum S100B temporal profiles as more powerful independent predictors of posttraumatic death than clinical and radiologic indicators.40 A proposed predictive model for S100B serum levels 90.90 ng/mL at 24 hours after TBI was associated with predictive values for the evolution of secondary brain injury and posttraumatic mortality.68 A different prospective observational study of 102 patients with severe TBI revealed that initial S100B serum levels 91.0 ng/mL were associated with a nearly threefold increased risk of death at 1 month postinjury.65 The authors also described a reduction of serum S100B levels after neurosurgical interventions, implying that this biomarker may represent a monitoring tool for guiding therapeutic efficacy in patients with severe TBI.65 In addition to the positive predictive value for adverse outcomes after severe TBI, S100B also represents a sensitive diagnostic tool for discriminating patients with mild head injury who are at risk for delayed neurologic deterioration.48,51,66,69Y71 From this perspective, risk stratification by S100B serum testing may reduce excessive CT scanning in patients with mild head injury (GCS 14 or 15) in the presence of minor neurologic symptoms, such as brief loss of consciousness, amnesia, headaches, nausea, or vomiting.50,52,72 Clinical studies revealed a high negative predictive value of serum S100B levels G0.13 ng/mL in discriminating patients with mild TBI at low risk of neuroradiologic pathology or clinical deterioration and a high sensitivity for detecting patients at risk for relevant intracranial injuries, with a cutoff at 90.21 ng/mL.51,73 Other studies confirmed this observation by revealing that low initial S100B serum levels G0.10 ng/mL had 100% sensitivity for predicting the absence of relevant intracranial pathology on CT.70,71 The dogma that S100B testing may be a panacea for the evaluation of mild TBI has undergone justified scrutiny.59,72,74 Despite the high sensitivity and high negative predictive value of serum S100B to rule out significant head injury in patients with mild TBI, the lack of specificity is one of the limitations of the diagnostic value of this biomarker.20,74 The finding of extracerebral sources of S100B in peripheral blood (eg, by hematopoietic cells)58 limits the diagnostic value of S100B, particularly in the presence of associated injuries and traumatic hemorrhagic shock.22,75 This notion is confirmed by the * 2014 Southern Medical Association
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observation that elevated serum S100B levels were detected under various clinical conditions with extracranial pathology, including peripheral trauma and burns, and even in healthy individuals after extensive physical exercise.76Y79 Multiple authors have challenged the role of S100B in predicting outcomes and correlations with neuroimaging findings in patients with mild TBI.80 Some authors provocatively suggest that elevated S100B levels are reflective of BBB damage, resulting in protein leakage from the periphery into the intrathecal compartment, rather than reflecting the extent of neuronal injury.81,82
Glial Fibrillary Acidic Protein Glial fibrillary acidic protein (GFAP) is an established astrocyte-specific cell marker.83 The exclusively CNS-restricted source renders GFAP a highly appealing candidate as a specific and sensitive biomarker after cerebral insults, including stroke and TBI.60,84 Clinical studies confirmed this notion by demonstrating up to 100-fold elevated GFAP levels in the sera of patients with severe head injuries, compared with controls, and a correlation with adverse outcomes.38,85 A clinical study revealed a drastically elevated mean GFAP serum level of 6.77 pg/mL in patients with TBI on the day of admission, compared with barely detectable levels (mean 0.7 pg/mL) in control subjects without head injuries.86 Serum GFAP levels in patients with TBI were found to peak in the first days postinjury, followed by a gradual decrease during the first week.86 A prospective multicenter study analyzed serum levels of GFAP breakdown products in 108 patients with mild or moderate TBI (GCS 9Y15), compared with 199 controls consisting of uninjured patients or trauma patients with orthopedic injuries in the absence of TBI.87 The authors found that GFAP breakdown products in the sera of patients with TBI were predictive of injury severity, presence of intracranial lesions on CT scan, and requirement for a neurosurgical intervention.87 Similar findings were described by other research groups in different clinical studies.13,38,85,86,88,89 In addition, median GFAP levels were found to be up to 20-fold elevated in patients with TBI with long-term unfavorable outcomes, as determined by the extended Glasgow Outcome Scale score, and 933-fold in patients who died of their head injuries.90 The unequivocal benefit of GFAP as a biomarker for head injury, above other candidate molecules (eg, S100B, NSE), lies in its brain-specific expression and release.83 This important benefit is further corroborated by studies that show that extracranial injuries do not contribute to the high GFAP serum levels seen in patients with TBI, and patients with multiple injuries in the absence of TBI were shown to have normal GFAP serum levels.85,89 Based on the available literature, there are no known shortcomings of and limitations to using serum levels of GFAP or its breakdown products, alone or in combination with other biomarkers,91 for assessing severity of injury, monitoring the efficiency of treatment modalities, and predicting outcomes in patients with TBI. Future validation studies in large-scale Southern Medical Journal
longitudinal multicenter studies must confirm the notion of GFAP being a panacea among the available serum biomarkers for head injury.
Novel and Experimental Biomarkers Ubiquitin Carboxyl Terminal Hydrolase-L1 Ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) represents a protein of neuronal origin92 that has been identified as an appealing candidate biomarker for TBI.93 Several clinical trials showed promising results regarding the diagnostic value of UCH-L1 in distinguishing focal from diffuse brain injury patterns and in predicting outcomes.94Y97 Preliminary case-control studies revealed significantly elevated mean levels of UCH-L1 in CSF and sera of patients with severe head injuries (GCS G9), compared with controls without TBI.94,97 The cumulative UCH-L1 serum levels above a cutoff at 5.22 ng/mL were predictive of posttraumatic mortality, with a nearly fivefold increased odds ratio for dying.97 Another prospective cohort study in patients with mild and moderate TBI (GCS 9Y15) was designed to determine the diagnostic value of UCH-L1 serum levels in predicting the presence of intracranial lesions on CT scans and the requirement for neurosurgical interventions.95 A total of 96 patients with TBI were compared with 199 controls, consisting of uninjured patients and trauma patients in the absence of TBI.95 The mean UCH-L1 serum levels in patients with TBI with normal CT findings were 0.62 ng/mL, compared with 1.62 ng/mL in patients with radiographic evidence of intracranial lesions.95 Patients requiring neurosurgical intervention had even higher mean UCH-L1 serum levels of 2.57 ng/mL.95 The authors concluded that UCH-L1 is readily detectable in the sera of patients with head injury within 1 hour after trauma, and increased levels are predictive of injury severity, based on decreased GCS, the increased likelihood of intracranial lesions on CT, and the requirement for neurosurgical intervention.95 In light of the novel findings that have been established almost exclusively by a single research team,94Y97 the clinical utility of UCH-L1 as a serum biomarker in TBI requires validation in prospective longitudinal studies by other groups.
Tau Protein and c-Tau Tau represents a cytoskeletal protein in neurons that contributes to the stabilization of axonal microtubules.98 Neuronal damage after TBI is associated with the proteolytic cleavage of tau protein by cysteine proteases, resulting in the release of cleaved tau (c-tau) into CSF and serum.98,99 One pilot study described an increase in plasma tau levels of 9300% above controls after a concussion in boxers.100 After severe TBI, total tau protein levels are significantly elevated in CSF, compared with control levels, and predictive of mortality and outcome at 1 year postinjury.101 c-Tau levels in CSF were found to be elevated up to 40,000-fold after head injury, compared with neurologic patients without TBI or to control patients without neurologic disorders.102 Another study showed tau protein levels
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to be significantly elevated in serum after severe TBI and predictive of adverse outcome, as determined by Glasgow Outcome Scale score at 6 months.103 Specifically, mean tau protein levels in the sera of patients with TBI with poor outcomes were elevated to 436.2 pg/mL, compared with 51.6 pg/mL in patients who had improved long-term recovery after trauma.103 The role of tau protein and c-tau is not as clearly defined with regard to the diagnostic potential for stratifying patients with mild head injury at risk for secondary deterioration, and further prospective studies are needed to validate the role of tau and c-tau as valid serum biomarkers in TBI.104Y106
Myelin Basic Protein Myelin basic protein (MBP) is a major component of the myelin sheath around neuronal axons, and increased MBP levels in CSF and serum have been described as a surrogate marker to reflect injury to myelinated axons.107,108 Multiple studies have proposed the use of serum MBP levels as a biomarker in TBI, in both the adult and pediatric patient populations.108Y110 Despite the high specificity of MBP serum levels for outcome prediction after severe TBI, the low sensitivity appears to limit the value of MBP as a reliable biomarker for risk stratification after mild head injury.15,20,29
Innate Immune Molecules Closed head injury is considered an inflammatory disease that is characterized by the activation of innate immunity and release of immune mediators from the intracranial compartment into peripheral blood.111 Innate immune molecules, such as proinflammatory cytokines, acute-phase proteins, complement components, and complement activation fragments have been shown to correlate with the extent of posttraumatic BBB damage and neuronal injury.112Y117 Although selected cytokines of interest, including tumor necrosis factor, interleukin-6, and interleukin-8, have been investigated as potential biomarkers of head injury for 92 decades, there is still a lack of proven evidence for the clinical and diagnostic utility of these inflammatory mediators for outcome prediction in TBI.118Y123
Conclusions We have outlined a restricted selection of candidate molecules (NSE, S100B, GFAP) that reflect the most extensively investigated biomarkers in the field. Numerous additional mediators have been investigated with regard to their potential value for risk stratification and outcome prediction after TBI. In general, any biomarker of interest is characterized as a CNSrestricted protein that leaks across the damaged BBB into the peripheral bloodstream.7,20 Alternatively, elevated serum mediators may be reflective of peripheral production after TBI, for example, through induction of the hepatic acute-phase response after CNS trauma.112,123 Representative molecules are derived from either direct traumatic impact to the brain, through acute neuronal injury, axonal injury, and astroglial injury or secondary host-derived inflammatory and reparative processes such as
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neuroinflammation, oxidative stress, and excitotoxicity, and other host-derived pathophysiological mechanisms. In spite of the multiple trials and available data, the ideal diagnostic biomarker in TBI with high sensitivity, specificity, and predictive value for adverse outcome remains to be determined. Some of the promising molecules, such as NSE or S100B, do not appear to be specific to CNS injuries, as was assumed. Other purely CNS-restricted proteins such as GFAP require further investigation in future well-designed, longitudinal, and controlled trials for validation in routine clinical use. It is likely that a multibiomarker panel, in conjunction with clinical scoring, may increase the diagnostic accuracy of individual biomarkers. Trajectory analysis represents a new approach to capturing the temporal variance in individual biomarker levels.124 This method was applied in the combined use of NSE, S100B, and MBP to predict adverse outcomes in children with TBI.125 Most important, the design of any future trial must take into consideration the specific question raised by the underlying a priori hypothesis, stratified by the following main clinical applications of candidate biomarkers: 1. Predicting secondary cerebral insults and adverse outcomes in patients with severe TBI 2. Monitoring the therapeutic efficacy of neurocritical care modalities or pharmaceutical strategies in patients with severe TBI 3. Differentiating focal intracerebral lesions from diffuse injury patterns and discriminating the subcohort of patients with mild or moderate TBI who are at risk for delayed deterioration.
It is hoped that the ‘‘ideal’’ biomarker, or panel of multiple biomarkers, in conjunction with clinical and radiological tests, will provide a clinically valid tool for establishing diagnosis and prognosis of patients with head injury admitted to the emergency department. No novel diagnostic risk stratification tool will eliminate the crucial role of subjective and individual judgment by experienced physicians.
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