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Cited by 110Traumatic Brain Injury and Neurovascular DisturbancesTraumatic Brain Injury ResearchAutomotive and Human Injury Biomechanics

Serum Concentrations of Ubiquitin C-Terminal Hydrolase-L1 and Glial Fibrillary Acidic Protein after Pediatric Traumatic Brain Injury

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Mondello, Stefania, Kobeissy, Firas, Vestri, Annarita, Hayes, Ronald L., Kochanek, Patrick M., Berger, Rachel P.·2016·Scientific Reports
DOI 10.1038/srep28203PMC PMC4913316
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Abstract

Objective reliable markers to assess traumatic brain injury (TBI) and predict outcome soon after injury are a highly needed tool for optimizing management of pediatric TBI. We assessed serum concentrations of Glial Fibrillary Acidic Protein (GFAP) and Ubiquitin C-Terminal Hydrolase-L1 (UCH-L1) in a cohort of 45 children with clinical diagnosis of TBI (Glasgow Coma Scale [GCS] 3–15) and 40 healthy subjects, evaluated their associations with clinical characteristics and outcomes, and compared their performance to previously published data on two well-studied blood biomarkers, S100B and MBP. We observed higher serum levels of GFAP and UCH-L1 in brain-injured children compared with controls and also demonstrated a step-wise increase of biomarker concentrations over the continuum of severity from mild to severe TBI. Furthermore, while we found that only the neuronal biomarker UCH-L1 holds potential to detect acute intracranial lesions as assessed by computed tomography (CT), both markers were substantially increased in TBI patients even with a normal CT suggesting the presence of undetected microstructural injuries. Serum UCH-L1 and GFAP concentrations also strongly predicted poor outcome and performed better than S100B and MBP. Our results point to a role of GFAP and UCH-L1 as candidate biomarkers for pediatric TBI. Further studies are warranted.

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  • Studies evaluating reference ranges of biomarkers and neuroimaging in pediatric TBI are ongoing.

    “While these recommendations were predominantly geared towards adults, studies evaluating reference ranges of biomarkers and neuroimaging in pediatric TBI are ongoing (Marzano et al., 2022; Mondello et al., 2016; Munoz Pareja et al., 2022; Reisner et al., 2024).”

    From Evaluating cognitive performance using the National Institutes of Health Toolbox Cognitive Battery in children with traumatic brain injury (2025) · cites this paper as Mondello et al., 2016

    The Results (no page provided) report biomarker concentrations in children with TBI and controls, including age-related differences among controls; the Methods describe using head CT to assess intracranial injury. This supports ongoing work on pediatric biomarker levels and their relationship to imaging, but the paper does not evaluate neuroimaging reference ranges. (LLM, conf=0.86)

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References 48 · Cited by 110

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  1. Geneva, World Health Organization. World report on child injury prevention. http://whqlibdoc.who.int/publications/2008/9789241563574_eng.pdf, (2008) (Date of access: 21/01/2015). 26269872
  2. Field M., Collins M. W., Lovell M. R. & Maroon J. Does age play a role in recovery from sports-related concussion? A comparison of high school and collegiate athletes. J Pediatr 142, 546– 553 (2003). 12756388
  3. 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 32, 282– 290 (2000). 10971189
  4. Laribi S.. S100B blood level measurement to exclude cerebral lesions after minor head injury: the multicenter STIC-S100 French study. Clin Chem Lab Med: CCLM/FESCC 52, 527– 536 (2014). 24225131
  5. Berger R. P., Pierce M. C., Wisniewski S. R., Adelson P. D. & Kochanek P. M. Serum S100B concentrations are increased after closed head injury in children: A preliminary study. J Neurotrauma 19, 1405– 1409 (2002). 12490005
  6. Brouns R.. The role of tryptophan catabolism along the kynurenine pathway in acute ischemic stroke. Neurochem Res 35, 1315– 1322 (2010). 20490917
  7. Brouns R.. Belgian Fabry study: prevalence of Fabry disease in a cohort of 1000 young patients with cerebrovascular disease. Stroke 41, 863– 868 (2010). 20360539
  8. Portela L. V.. The serum S100B concentration is age dependent. Clin Chem 48, 950– 952 (2002). 12029017
  9. 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 124, e697– 704 (2009). 19786430
  10. Berger R. P., Adelson P. D., Richichi R. & Kochanek P. M. Serum biomarkers after traumatic and hypoxemic brain injuries: insight into the biochemical response of the pediatric brain to inflicted brain injury. Dev Neurosci 28, 327– 335 (2006). 16943655
  11. Brophy G. M.. Biokinetic analysis of ubiquitin C-terminal hydrolase-L1 (UCH-L1) in severe traumatic brain injury patient biofluids. J Neurotrauma 28, 861– 870 (2011). 21309726 PMC3113451
  12. Mondello S.. 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 15, R156 (2011). 21702960 PMC3219030
  13. Mondello S.. Clinical Utility of Serum Levels of Ubiquitin C-Terminal Hydrolase as a Biomarker for Severe Traumatic Brain Injury. Neurosurgery 70, 666– 675 (2012). 21937927 PMC3288385
  14. Berger R. P., Hayes R. L., Richichi R., Beers S. R. & Wang K. K. W. Serum Concentrations of Ubiquitin C-Terminal Hydrolase-L1 and alpha II-Spectrin Breakdown Product 145 kDa Correlate with Outcome after Pediatric TBI. J Neurotrauma 29 (2012). PMC3253308 22022780
  15. Mondello S.. Blood-based diagnostics of traumatic brain injuries. Expert Rev Mol Diagn 11, 65– 78 (2011). 21171922 PMC3063529
  16. Papa L.. 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 59, 471– 483 (2012). 22071014 PMC3830977
  17. Vos P. E.. GFAP and S100B are biomarkers of traumatic brain injury: an observational cohort study. Neurology 75, 1786– 1793 (2010). 21079180
  18. Mannix R., Eisenberg M., Berry M., Meehan W. P. 3rd & Hayes R. L. Serum biomarkers predict acute symptom burden in children after concussion: a preliminary study. J Neurotrauma 31, 1072– 1075 (2014). 24494742
  19. Fraser D. D.. Severe traumatic brain injury in children elevates glial fibrillary acidic protein in cerebrospinal fluid and serum. Pediatr Crit Care Med 12, 319– 324 (2011). 20625342
  20. Berger R. P.. Serum neuron-specific enolase, S100B, and myelin basic protein concentrations after inflicted and noninflicted traumatic brain injury in children. J Neurosurg 103, 61– 68 (2005). 16122007
  21. Berger R. P.. Identification of inflicted traumatic brain injury in well-appearing infants using serum and cerebrospinal markers: A possible screening tool. Pediatrics 117, 325– 332 (2006). 16452350
  22. Yuh E. L.. Magnetic resonance imaging improves 3-month outcome prediction in mild traumatic brain injury. Ann Neurol 73, 224– 235 (2013). 23224915 PMC4060890
  23. Yuh E. L.. Diffusion tensor imaging for outcome prediction in mild traumatic brain injury: a TRACK-TBI study. J Neurotrauma 31, 1457– 1477 (2014). 24742275 PMC4144386
  24. Huang Y. L.. Susceptibility-weighted MRI in mild traumatic brain injury. Neurology 84, 580– 585 (2015). 25576634
  25. Ryan J. B.. Familial dysalbuminaemic hyperthyroxinaemia: a rapid and novel mass spectrometry approach to diagnosis. Ann Clin Biochem (2015). 26169058
  26. Roozenbeek B., Maas A. I. & Menon D. K. Changing patterns in the epidemiology of traumatic brain injury. Nat Rev Neurol 9, 231– 236 (2013). 23443846
  27. Metting Z., Wilczak N., Rodiger L. A., Schaaf J. M. & van der Naalt J. GFAP and S100B in the acute phase of mild traumatic brain injury. Neurology 78, 1428– 1433 (2012). 22517109
  28. Kou Z.. 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 8, e80296 (2013). 24260364 PMC3833898
  29. Mondello S.. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is increased in cerebrospinal fluid and plasma of patients after epileptic seizure. BMC Neurol 12, 85 (2012). 22931063 PMC3500207
  30. Merlo Pich E.. Imaging as a biomarker in drug discovery for Alzheimer’s disease: is MRI a suitable technology? Alzheimers Res Ther 6, 51 (2014). 25484927 PMC4255417
  31. Mac Donald C. L.. Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury. Exp Neurol 205, 116– 131 (2007). 17368446 PMC1995439
  32. Raimondi A. J. & Hirschauer J. Head injury in the infant and toddler. Coma scoring and outcome scale. Childs brain 11, 12– 35 (1984). 6705608
  33. Godoy D. A., Rubiano A., Rabinstein A. A., Bullock R. & Sahuquillo J. Moderate Traumatic Brain Injury: The Grey Zone of Neurotrauma. Neurocrit Care (2016). 26927279
  34. Calcagnile O., Unden L. & Unden J. Clinical validation of S100B use in management of mild head injury. BMC Emerg Med 12, 13 (2012). 23102492 PMC3527238
  35. Diaz-Arrastia R.. Pharmacotherapy of traumatic brain injury: state of the science and the road forward: report of the Department of Defense Neurotrauma Pharmacology Workgroup. J Neurotrauma 31, 135– 158 (2014). 23968241 PMC3900003
  36. Mondello S.. CSF and plasma amyloid-beta temporal profiles and relationships with neurological status and mortality after severe traumatic brain injury. Sci Rep 4, 6446 (2014). 25300247 PMC4192636
  37. Zetterberg H.. Hypoxia due to cardiac arrest induces a time-dependent increase in serum amyloid beta levels in humans. PLoS One 6, e28263 (2011). 22194817 PMC3237426
  38. Saunders N. R., Liddelow S. A. & Dziegielewska K. M. Barrier mechanisms in the developing brain. Front Pharmacol 3, 46 (2012). 22479246 PMC3314990
  39. Sakurai M.. Ubiquitin C-terminal hydrolase L1 regulates the morphology of neural progenitor cells and modulates their differentiation. J Cell Sci 119, 162– 171 (2006). 16371654
  40. Lankes U., Brennan S. O., Walmsley T. A. & George P. M. 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 988, 121– 126 (2015). 25770789
  41. Gazzolo D.. Pediatric concentrations of S100B protein in blood: Age- and sex-related changes. Clin Chem 49, 967– 970 (2003). 12765999
  42. Savola O.. Effects of head and extracranial injuries on serum protein S100B levels in trauma patients. J Trauma 56, 1229– 1234 (2004). 15211130
  43. Pelinka L. E.. Release of S100B differs during ischemia and reperfusion of the liver, the gut, and the kidney in rats. Shock 21, 72– 76 (2004). 14676687
  44. De Witte L.. Cognitive, affective and behavioural disturbances following vascular thalamic lesions: a review. Cortex 47, 273– 319 (2011). 21111408
  45. Ren C.. Assessment of Serum UCH-L1 and GFAP in Acute Stroke Patients. Sci Rep 6, 24588 (2016). 27074724 PMC4830936
  46. Thaler H. W.. Evaluation of S100B in the diagnosis of suspected intracranial hemorrhage after minor head injury in patients who are receiving platelet aggregation inhibitors and in patients 65 years of age and older. J Neurosurg 123, 1202– 8 (2015). 26148794

Authors
Mondello, S., Kobeissy, F., Vestri, A., Hayes, R. L., Kochanek, P. M., & Berger, R. P.
Affiliations
  • University of Messina (IT)
  • University of Florida (US)
  • Sapienza University of Rome (IT)
  • Banyan Biomarkers (United States) (US)
  • University of Pittsburgh (US)
  • Children's Hospital of Pittsburgh (US)
Corresponding author
Mondello, Stefania
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2016-06-20
Volume
6
Issue
1
Pages
28203-28203
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep28203
PMC
PMC4913316
OpenAlex
W2461067695
Cited by
110
References
48
Citations by year
2026: 12 · 2025: 8 · 2024: 6 · 2023: 7 · 2022: 13 · 2021: 18 · 2020: 7 · 2019: 12 · 2018: 10 · 2017: 12 · 2016: 5
FWCI
9.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Defense (W81XWH0610517, W81XWH)
  • University of Pittsburgh
  • National Institutes of Health (W81XWH)
  • National Institute of Neurological Disorders and Stroke (R01NS052831)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (K23HD043843)
Topics
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Automotive and Human Injury Biomechanics
Keywords
pediatric traumatic brain injury, UCHL1, glial fibrillary acidic protein, serum biomarkers, S100B, myelin basic protein, prognostic factors, injury severity, outcome prediction
MeSH terms
Brain Injuries, Traumatic, Child, Child, Preschool, Myelin Basic Protein, Female, Glial Fibrillary Acidic Protein, Humans, Male, Prospective Studies, Tomography, X-Ray Computed, Biomarkers, Case-Control Studies, Treatment Outcome, Ubiquitin Thiolesterase, S100 Calcium Binding Protein beta Subunit

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