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Evaluating glial and neuronal blood biomarkers GFAP and UCH-L1 as gradients of brain injury in concussive, subconcussive and non-concussive trauma: a prospective cohort study
  1. Linda Papa1,
  2. Mark R Zonfrillo2,
  3. Robert D Welch3,
  4. Lawrence M Lewis4,
  5. Carolina F Braga5,
  6. Ciara N Tan6,
  7. Neema J Ameli1,
  8. Marco A Lopez1,
  9. Crystal A Haeussler1,
  10. Diego Mendez Giordano1,
  11. Philip A Giordano1,
  12. Jose Ramirez7,
  13. Manoj K Mittal8
  1. 1Department of Emergency Medicine, Orlando Regional Medical Center, Orlando, Florida, USA
  2. 2Hasbro Children's Hospital, Providence, Rhode Island, USA
  3. 3Wayne State University School of Medicine, Detroit, Michigan, USA
  4. 4Division of Emergency Medicine, Washington University in St. Louis, Saint Louis, Missouri, USA
  5. 5Department of Family Medicine and Community Health, Robert Wood Johnson University Hospital, New Brunswick, New Jersey, USA
  6. 6Department of Emergency Medicine, Orlando Regional Medical Center, Orlando, Florida, USA
  7. 7Department of Pediatric Emergency Medicine, Arnold Palmer Hospital for Children, Orlando, Florida, USA
  8. 8Division of Emergency Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  1. Correspondence to Dr Linda Papa; lpstat{at}


Objectives To evaluate the ability of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1) to detect concussion in children and adult trauma patients with a normal mental status and assess biomarker concentrations over time as gradients of injury in concussive and non-concussive head and body trauma.

Design Large prospective cohort study.

Setting Three level I trauma centres in the USA.

Participants Paediatric and adult trauma patients of all ages, with and without head trauma, presenting with a normal mental status (Glasgow Coma Scale score of 15) within 4 hours of injury. Rigorous screening for concussive symptoms was conducted. Of 3462 trauma patients screened, 751 were enrolled and 712 had biomarker data. Repeated blood sampling was conducted at 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180 hours postinjury in adults.

Main outcomes Detection of concussion and gradients of injury in children versus adults by comparing three groups of patients: (1) those with concussion; (2) those with head trauma without overt signs of concussion (non-concussive head trauma controls) and (3) those with peripheral (body) trauma without head trauma or concussion (non-concussive body trauma controls).

Results A total of 1904 samples from 712 trauma patients were analysed. Within 4 hours of injury, there were incremental increases in levels of both GFAP and UCH-L1 from non-concussive body trauma (lowest), to mild elevations in non-concussive head trauma, to highest levels in patients with concussion. In concussion patients, GFAP concentrations were significantly higher compared with body trauma controls (p<0.001) and with head trauma controls (p<0.001) in both children and adults, after controlling for multiple comparisons. However, for UCH-L1, there were no significant differences between concussion patients and head trauma controls (p=0.894) and between body trauma and head trauma controls in children. The AUC for initial GFAP levels to detect concussion was 0.80 (0.73–0.87) in children and 0.76 (0.71–0.80) in adults. This differed significantly from UCH-L1 with AUCs of 0.62 (0.53–0.72) in children and 0.69 (0.64–0.74) in adults.

Conclusions In a cohort of trauma patients with normal mental status, GFAP outperformed UCH-L1 in detecting concussion in both children and adults. Blood levels of GFAP and UCH-L1 showed incremental elevations across three injury groups: from non-concussive body trauma, to non-concussive head trauma, to concussion. However, UCH-L1 was expressed at much higher levels than GFAP in those with non-concussive trauma, particularly in children. Elevations in both biomarkers in patients with non-concussive head trauma may be reflective of a subconcussive brain injury. This will require further study.

  • biomarkers
  • concussion
  • mild traumatic brain injury
  • subconcussive, head trauma, trauma, children
  • paediatric
  • glial fibrillary acidic protein (GFAP)
  • Ubiquitin C-terminal hydrolase (UCH-L1)
  • blood test

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  • Contributors LP had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. LP conceived and designed the study. Data were acquired by LP, JR, PAG, CFB, CNT, NJA, MAL, CAH, DMG, MRZ and MKM. All authors were involved in the analysis and interpretation of the data. LP drafted the manuscript and all authors were involved in critical revision of the manuscript for important intellectual content. Statistical analysis was conducted by LP. Funding was obtained by LP. Administrative, technical or material support was provided by LP, PAG, MRZ and MKM. The study was supervised by LP, JR, PAG, CFB, CNT, NJA, MAL, CAH, DMG, MRZ and MKM. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding This study was supported by Award Number R01NS057676 (LP, Principal Investigator) from the National Institute of Neurological Disorders and Stroke.

  • Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health. Dissemination of results to participants is not possible/applicable.

  • Competing interests LP is an unpaid scientific consultant for Banyan Biomarkers, but receives no stocks or royalties from the company and will not benefit financially from this publication. RDW and LML receive contract research funding from Banyan Biomarkers. They do not receive stocks or royalties from the company and will not benefit financially from this publication.

  • Ethics approval This study was approved by the respective IRBs of each institution (Orlando Regional Medical Center IRB, Arnold Palmer Hospital for Children IRB and Children’s Hospital of Philadelphia IRB).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are not available for sharing at this time.