|Year : 2016 | Volume
| Issue : 3 | Page : 129-132
Finding effective biomarkers for pediatric traumatic brain injury
Olena Y Glushakova1, Alexander V Glushakov2, Ronald L Hayes3
1 Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA
2 Single Breath, Inc., Gainesville, FL, USA
3 Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA; Banyan Biomarkers, Inc., Alachua, FL, USA
|Date of Submission||29-Aug-2016|
|Date of Decision||31-Aug-2016|
|Date of Acceptance||01-Sep-2016|
|Date of Web Publication||18-Oct-2016|
Ronald L Hayes
Banyan Biomarkers, Inc. 13400 Progress Blvd. Alachua, FL 32615
Source of Support: None, Conflict of Interest: None
As traumatic brain injury (TBI) continues to affect children and young adults worldwide, research on reliable biomarkers grows as a possible aid in determining the severity of injury. However, many studies have revealed that diverse biomarkers such as S100B and myelin basic protein (MBP) have many limitations, such as their elevated normative concentrations in young children. Therefore, the results of these studies have yet to be translated to clinical applications. However, despite the setbacks of research into S100B and MBP, investigators continue to research viable biomarkers, notably glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1), as possible aids in medical decision making. Studies have revealed that GFAP and UCH-L1 actually are better predictors of injury progression than the before-mentioned biomarkers S100B and MBP. In addition, UCH-L1 has demonstrated an ability to detect injury while CT is negative, suggesting an ability to detect acute intracranial lesions. Here, we evaluate research testing levels of GFAP and UCH-L1 on children diagnosed with TBI and compare our results to those of other tested biomarkers. In a recent study done by Hayes et al., GFAP and UCH-L1 demonstrated the potential to recognize children with the possibility of poor outcome, allowing for more specialized treatments with clinical and laboratory applications. Although studies on GFAP and UCH-L1 have for the most part warranted positive results, further studies will be needed to confirm their role as reliable markers for pediatric TBI.
Keywords: Biomarkers, brain injury, serum, traumatic brain injury
|How to cite this article:|
Glushakova OY, Glushakov AV, Hayes RL. Finding effective biomarkers for pediatric traumatic brain injury. Brain Circ 2016;2:129-32
| Ubiquitin C-Terminal Hydrolase-L1 and Glial Fibrillary Acidic Protein as Potential Biomarkers for Pediatric Traumatic Brain Injury|| |
Traumatic brain injury (TBI), a prominent cause of acquired disability and mortality, affects many children and young adults across the globe. Following TBI, a child can experience two outcomes: on the one hand, the child can display superior recovery rates to adults, on the other hand, they can demonstrate extended and exacerbated symptoms than those experienced by older patients., While knowledge of potential mortality following TBI and improved awareness of the biological mechanisms that contribute to the heightened vulnerability of the pediatric brain have increased in the past decade,, pediatric TBI continues to test clinicians. Therefore, reliable biomarkers indicative of damage to the central nervous system (CNS) in combination with other currently available clinical data would greatly aid medical decision-making.
Recently, a great number of investigations have attempted to find viable biomarkers, focusing on blood-based structurally and pathobiologically diverse biomarkers like S100B and myelin basic protein (MBP). Many of these studies revealed noticeable differences in biomarker concentration between affected and healthy children, the affected displaying significantly elevated concentrations. However, these results have yet to be translated to clinical applications,,, possibly due to the many limitations of biomarkers, such as elevated normative concentrations in young children and a belated presence in serum following the injury.,, Therefore, many investigators are attempting to discover novel blood-based biomarkers that overcome the previously discussed limitations.
Ubiquitin C-terminal hydrolase (UCH-L1), a proteolytically stable and plentiful protein present almost solely in neuronal cytoplasm, has been found to increase in concentration in serum after TBI.,, UCH-L1 demonstrates increased serum concentration in correlation with outcome, as demonstrated by a previous exploratory study. Another more well-known protein, glial fibrillary acidic protein (GFAP), is a long-standing marker of glial impairment in multiple neurologic diseases. Several studies on adults ,, and children , have demonstrated increased serum GFAP in the blood after TBI. These discoveries suggest the potential of UCH-L1 and GFAP to identify cerebral injury and aid in clinical decisions using the biomarkers as indications of TBI severity.
| Ubiquitin C-Terminal Hydrolase-L1 and Glial Fibrillary Acidic Protein Capable of Detecting Acute Intracranial Lesions|| |
A recent study conducted by Mondello et al. compared serum concentrations of UCH-L1 and GFAP between children who suffered mild to severe TBI and unharmed controls to determine if the levels of the two markers were significantly elevated in injured children. In addition, this study compared their performance to two extensively investigated biomarkers, S100B and MBP, using previously published data.,,
To properly assess and treat pediatric TBI, objective biomarkers are needed to predict and track the progression of TBI. With this in mind, serum concentrations of UCH-L1 and GFAP were evaluated to determine if they could be possible candidates. Testing involved 45 children clinically diagnosed with TBI (Glasgow Coma Scale 3–15) along with 40 healthy children. Levels of GFAP and UCH-L1 in comparison with S100B and MBP, two additional blood biomarkers, were examined. First noting the difference in concentration of GFAP and UCH-L1 between the controls and the children diagnosed with TBI, the researchers also showed a direct relationship between biomarker levels and the severity of the brain injury. In addition, they found that although UCH-L1 is the only neuronal biomarker with the ability to identify acute intracranial damage, elevated levels of both markers in TBI patients with normal computed tomography (CT) scans revealed their ability to demonstrate the presence of microstructural injuries not detected on a CT scan. Furthermore, in comparison to the levels of S100B and MBP, concentrations of GFAP and UCH-L1 acted as more accurate indicators of poor outcomes for patients. Although further studies are needed, these results suggest GFAP and UCH-L1 should be used as biomarkers for pediatric TBI.
| Validation of Biomarker-Based Therapy|| |
Interestingly, Hayes et al. discovered not only that TBI subjects with intracranial injury had the highest concentrations of GFAP and UCH-L1, but also that patient with a skull fracture or negative CT displayed increasing concentrations as well. This intriguing observation in the study proposes the possibility of undetected brain damage. Moreover, an increasing number of studies have revealed that, compared to magnetic resonance imaging (MRI), CT is a poor method to identify, quantify, and distinguish acute lesions and pathophysiological alterations that occur as a result of TBI.,, In addition, Hayes along with other investigators have provided evidence of increased serum biomarker concentrations in CT-negative TBI patients, further putting into question the viability of CT for patients with persisting symptoms or subtle abnormalities.,,, Therefore, the detected biomarker release in the cases involving skull fracture or a negative CT may have risen from molecular perturbation, limited structural damage, or specific pathoanatomic types of TBI, such as diffuse axonal injury or microbleeds, that CT did not previously detect.,, Due to GFAP and UCH-L1's capabilities to detect microbleeds and acute lesions, they may prove effective in diagnostic imagining in pediatric TBI. In addition, these findings put into question the reliability of CT as a dependable method to detect the incidence of brain injury and judge the success of biomarkers. However, these observations by no means provide sufficient conclusions as more studies are required to validate these markers in combination with MRI and other innovative imaging.
These observations suggest that these biomarkers may prove effective in risk determination, supporting their use to classify injury severity perhaps in combination with clinical and imaging data. These findings propose a classification system that may prove to be highly beneficial for pediatric use in TBI using acute serum markers. This may not only be valuable in diagnosis and prognosis but also could reveal information on the injury-specific and patient-specific vulnerability as it relates to translation to clinical trials.
The development of new and available technologies with the necessary precision and sensitivity will have the capabilities to fully demonstrate the dispersal of biomarkers in the bodies of healthy people, as well as the capability to identify minute changes in biomarker concentrations in individuals suffering from TBI., Specifically in Mondello et al.' study, they were able to identify low biomarker levels utilizing GFAP and UCH-L1 assays. In these patients, a strong and direct relationship was detected between age and serum UCH-L1. While it has been observed that UCH-L1 levels increase with age in healthy adults, it remains to be determined if the same relationship exists in children and young adults. The observation in Mondello et al.' investigation  that the serum UCH-L1 changed with age in children can be best explained by the fact that infant brains are underdeveloped and the blood–brain barrier has a higher permeability. It can also be explained by noting the distinctive age-related changes in cerebral biology and continuing CNS advancement associated with early stages of life. While it has been demonstrated that UCH-L1 plays a role in neuron survival and function, other recent investigations have shown that it plays a role in guiding neural progenitor cells through neurogenesis and differentiation.
It is worth noting that while GFAP and S100B can serve as glial markers, the results of Mondello et al.' demonstrate that GFAP is a more effective biomarker for TBI. The best explanation for S100B's limitations are its dependence on age, especially in young children, and its lack of particularity with extracranial damage.,,, Further investigations on children with acute orthopedic damage separate from the CNS would be essential in helping determine the specificity of UCH-L1 and GFAP in diagnosing pediatric TBI.
In summary, GFAP and UCH-L1 present as viable candidates for biomarkers for pediatric TBI. Considering the traumatic effects of TBI on the developing brain, such as incomplete neural connectivity, brain maturation, and impaired functional capabilities, serum biomarkers' capabilities to improve diagnostic precision and serve as evidence of TBI in the case of a normal CT scan make them important candidates for further research. In addition, serum biomarkers could also serve as potential guides for selecting patients for advanced neuroimaging. While both are indicators of TBI, only UCH-L1 can function as a biomarker for acute intracranial lesions. Moreover, UCH-L1 and GFAP have the potential to recognize children with the possibility of poor outcome, thereby granting further opportunities for more specialized treatments with clinical and laboratory applications. Further studies will need to be conducted to confirm the role of GFAP and UCH-L1 and their utility as markers of pediatric TBI.
Financial support and sponsorship
Conflicts of interest
Ronald L Hayes owns stock, receives compensation from, and is an executive officer of Banyan Biomarkers, Inc., and as such, may benefit financially as a result of the outcomes of this research or work reported in this publication.
| References|| |
Peden M, Oyegbite K, Ozanne-Smith J, Hyder AA, Branche C, Rahman AF, et al
. World Report on Child Injury Prevention. Geneva, Switzerland, New York: World Health Organization; 2008.
Field M, Collins MW, Lovell MR, Maroon J. Does age play a role in recovery from sports-related concussion? A comparison of high school and collegiate athletes. J Pediatr 2003;142:546-53.
Giza CC, Griesbach GS, Hovda DA. Experience-dependent behavioral plasticity is disturbed following traumatic injury to the immature brain. Behav Brain Res 2005;157:11-22.
Anderson V, Catroppa C, Morse S, Haritou F, Rosenfeld J. Recovery of intellectual ability following traumatic brain injury in childhood: Impact of injury severity and age at injury. Pediatr Neurosurg 2000;32:282-90.
Laribi S, Kansao J, Borderie D, Collet C, Deschamps P, Ababsa R, et al
. S100B blood level measurement to exclude cerebral lesions after minor head injury: The multicenter STIC-S100 French study. Clin Chem Lab Med 2014;52:527-36.
Berger RP, Pierce MC, Wisniewski SR, Adelson PD, Kochanek PM. Serum S100B concentrations are increased after closed head injury in children: A preliminary study. J Neurotrauma 2002;19:1405-9.
Brouns R, Thijs V, Eyskens F, Van den Broeck M, Belachew S, Van Broeckhoven C, et al
. Belgian Fabry study: Prevalence of Fabry disease in a cohort of 1000 young patients with cerebrovascular disease. Stroke 2010;41:863-8.
Brouns R, Verkerk R, Aerts T, De Surgeloose D, Wauters A, Scharpé S, et al
. The role of tryptophan catabolism along the kynurenine pathway in acute ischemic stroke. Neurochem Res 2010;35:1315-22.
Bechtel K, Frasure S, Marshall C, Dziura J, Simpson C. Relationship of serum S100B levels and intracranial injury in children with closed head trauma. Pediatrics 2009;124:e697-704.
Berger RP, Adelson PD, Richichi R, Kochanek PM. Serum biomarkers after traumatic and hypoxemic brain injuries: Insight into the biochemical response of the pediatric brain to inflicted brain injury. Dev Neurosci 2006;28:327-35.
Portela LV, Tort AB, Schaf DV, Ribeiro L, Nora DB, Walz R, et al
. The serum S100B concentration is age dependent. Clin Chem 2002;48(6 Pt 1):950-2.
Brophy GM, Mondello S, Papa L, Robicsek SA, Gabrielli A, Tepas J 3rd
, et al
. Biokinetic analysis of ubiquitin C-terminal hydrolase-L1 (UCH-L1) in severe traumatic brain injury patient biofluids. J Neurotrauma 2011;28:861-70.
Mondello S, Linnet A, Buki A, Robicsek S, Gabrielli A, Tepas J, et al
. Clinical utility of serum levels of ubiquitin C-terminal hydrolase as a biomarker for severe traumatic brain injury. Neurosurgery 2012;70:666-75.
Mondello S, Papa L, Buki A, Bullock MR, Czeiter E, Tortella FC, et al
. Neuronal and glial markers are differently associated with computed tomography findings and outcome in patients with severe traumatic brain injury: A case control study. Crit Care 2011;15:R156.
Berger RP, Hayes RL, Richichi R, Beers SR, Wang KK. Serum concentrations of ubiquitin C-terminal hydrolase-L1 and alphaII-spectrin breakdown product 145 kDa correlate with outcome after pediatric TBI. J Neurotrauma 2012;29:162-7.
Mondello S, Muller U, Jeromin A, Streeter J, Hayes RL, Wang KK. Blood-based diagnostics of traumatic brain injuries. Expert Rev Mol Diagn 2011;11:65-78.
Papa L, Lewis LM, Falk JL, Zhang Z, Silvestri S, Giordano P, et al
. Elevated levels of serum glial fibrillary acidic protein breakdown products in mild and moderate traumatic brain injury are associated with intracranial lesions and neurosurgical intervention. Ann Emerg Med 2012;59:471-83.
Vos PE, Jacobs B, Andriessen TM, Lamers KJ, Borm GF, Beems T, et al
. GFAP and S100B are biomarkers of traumatic brain injury: An observational cohort study. Neurology 2010;75:1786-93.
Fraser DD, Close TE, Rose KL, Ward R, Mehl M, Farrell C, et al
. Severe traumatic brain injury in children elevates glial fibrillary acidic protein in cerebrospinal fluid and serum. Pediatr Crit Care Med 2011;12:319-24.
Mannix R, Eisenberg M, Berry M, Meehan WP 3rd
, Hayes RL. Serum biomarkers predict acute symptom burden in children after concussion: A preliminary study. J Neurotrauma 2014;31:1072-5.
Mondello S, Kobeissy F, Vestri A, Hayes RL, Kochanek PM, Berger RP. Serum concentrations of ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein after pediatric traumatic brain injury. Sci Rep 2016;6:28203.
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;117:325-32.
Yuh EL, Mukherjee P, Lingsma HF, Yue JK, Ferguson AR, Gordon WA, et al
. Magnetic resonance imaging improves 3-month outcome prediction in mild traumatic brain injury. Ann Neurol 2013;73:224-35.
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 1 Suppl: 61-8.
Huang YL, Kuo YS, Tseng YC, Chen DY, Chiu WT, Chen CJ. Susceptibility-weighted MRI in mild traumatic brain injury. Neurology 2015;84:580-5.
Yuh EL, Cooper SR, Mukherjee P, Yue JK, Lingsma HF, Gordon WA, et al
. Diffusion tensor imaging for outcome prediction in mild traumatic brain injury: A TRACK-TBI study. J Neurotrauma 2014;31:1457-77.
Kou Z, Gattu R, Kobeissy F, Welch RD, O'Neil BJ, Woodard JL, et al
. Combining biochemical and imaging markers to improve diagnosis and characterization of mild traumatic brain injury in the acute setting: Results from a pilot study. PLoS One 2013;8:e80296.
Metting Z, Wilczak N, Rodiger LA, Schaaf JM, van der Naalt J. GFAP and S100B in the acute phase of mild traumatic brain injury. Neurology 2012;78:1428-33.
Roozenbeek B, Maas AI, Menon DK. Changing patterns in the epidemiology of traumatic brain injury. Nat Rev Neurol 2013;9:231-6.
Ryan JB, Brennan SO, Potter H, Wolmarans L, Florkowski CM, George PM. Familial dysalbuminaemic hyperthyroxinaemia: A rapid and novel mass spectrometry approach to diagnosis. Ann Clin Biochem 2016;53(Pt 4):504-7.
Calcagnile O, Undén L, Undén J. Clinical validation of S100B use in management of mild head injury. BMC Emerg Med 2012;12:13.
Merlo Pich E, Jeromin A, Frisoni GB, Hill D, Lockhart A, Schmidt ME, et al
. Imaging as a biomarker in drug discovery for Alzheimer's disease: Is MRI a suitable technology? Alzheimers Res Ther 2014;6:51.
Mondello S, Palmio J, Streeter J, Hayes RL, Peltola J, Jeromin A. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is increased in cerebrospinal fluid and plasma of patients after epileptic seizure. BMC Neurol 2012;12:85.
Diaz-Arrastia R, Kochanek PM, Bergold P, Kenney K, Marx CE, Grimes CJ, et al
. Pharmacotherapy of traumatic brain injury: State of the science and the road forward: Report of the department of defense neurotrauma pharmacology workgroup. J Neurotrauma 2014;31:135-58.
Mondello S, Buki A, Barzo P, Randall J, Provuncher G, Hanlon D, et al
. CSF and plasma amyloid-ß temporal profiles and relationships with neurological status and mortality after severe traumatic brain injury. Sci Rep 2014;4:6446.
Zetterberg H, Mörtberg E, Song L, Chang L, Provuncher GK, Patel PP, et al
. Hypoxia due to cardiac arrest induces a time-dependent increase in serum amyloid ß levels in humans. PLoS One 2011;6:e28263.
Ferguson I, Lewis L, Papa L, Wang K, Mondello S, Hayes R. Neuronal biomarkers may require age-adjusted norms. Ann Emerg Med 2011;58:S213.
Saunders NR, Liddelow SA, Dziegielewska KM. Barrier mechanisms in the developing brain. Front Pharmacol 2012;3:46.
Sakurai M, Ayukawa K, Setsuie R, Nishikawa K, Hara Y, Ohashi H, et al
. Ubiquitin C-terminal hydrolase L1 regulates the morphology of neural progenitor cells and modulates their differentiation. J Cell Sci 2006;119(Pt 1):162-71.
Gazzolo D, Michetti F, Bruschettini M, Marchese N, Lituania M, Mangraviti S, et al
. Pediatric concentrations of S100B protein in blood: Age- and sex-related changes. Clin Chem 2003;49(6 Pt 1):967-70.
Lankes U, Brennan SO, Walmsley TA, George PM. Relative quantification of albumin and fibrinogen modifications by liquid chromatography tandem mass spectrometry in the diagnosis and monitoring of acute pancreatitis. J Chromatogr B Analyt Technol Biomed Life Sci 2015;988:121-6.
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;21:72-6.
Savola O, Pyhtinen J, Leino TK, Siitonen S, Niemelä O, Hillbom M. Effects of head and extracranial injuries on serum protein S100B levels in trauma patients. J Trauma 2004;56:1229-34.
De Witte L, Brouns R, Kavadias D, Engelborghs S, De Deyn PP, Mariën P. Cognitive, affective and behavioural disturbances following vascular thalamic lesions: A review. Cortex 2011;47:273-319.