Athough the definition has not always been consistent between circumstances or medical specialties, traumatic brain injury (TBI) is best defined as a non-degenerative, non-congenital insult to the brain from an external mechanical force, possibly leading to permanent or temporary impairment of cognitive, physical, and psychosocial functions, with an associated diminished or altered state of consciousness. There are approximately 2 million incidents of TBI in the US each year, and 5.3 million citizens live with chronic issues as a result. About half of all those who experience a TBI have some sort of short term disability. This is particularly true with mild TBI, where symptoms may be viewed subjectively. Failure to properly manage TBIcan result in long term cognitive, academic and mental health difficulties. Understanding how to better define, create prognosis and treat mild TBI has been the pursuit of many scientists. Recent advances in biomarkers have demonstrated some promise in helping clinicians manage mild TBI.
Recently Wang et al. (2018) reviewed the evidence for clinical utility for TBI biomarkers. Their review included protein biomarkers for neuronal cell body injury (UCH-L1, NSE), astroglial injury (GFAP, S100B), neuronal cell death (αII-spectrin breakdown products), axonal injury (NF proteins), white matter injury (MBP), post-injury neurodegeneration (total Tau and phospho-Tau), post-injury autoimmune response (brain antigen-targeting autoantibodies), and other emerging non-protein biomarkers. The FDA recently granted marketing approval to a test for TBI management that included GFAP and UHC-L1. Wang et al. (2018) noted that in multiple studies, both serum UCH-L1 and GFAP concentrations on the second day predicate the recovery and unfavorable outcome by distinguishing patients with Glasgow Outcome Scale (GOS) scores 1–3 (severe disability) from patients with GOS score 4–5 (low to moderate disability). The authors identified remaining issues to be addressed across the market for TBI biomarkers in order to reach full clinical validation, which include, but are not limited to:
- Assay platforms: Challenges remain in developing robust, accessible TBI assays that can provide results near or at the point of care.
- Assay standardization: Standardized assays with standard reference materials for the top TBI protein biomarkers candidates are not available and should be established.
- Potential Confounds: The effects of age (e.g. age range from newborn to 80-year-old) on baseline (normal control) and post-TBI CSF, serum, plasma and whole blood values for the top biomarker candidates should be established.
- Clinical usefulness validation of new biomarkers: As more researchers report on the discovery of ‘new’ TBI biomarkers, many of them use a very small sample size, and they often show simple group comparison as evidence and not how a clinician can use the information to manage the care of the patient
Children are special subset who require careful monitoring with mild TBI. In the US, 1 in 220 pediatric patients admitted to the emergency room is diagnosed with a TBI, resulting in an estimated annual incidence rate of about 144,000 pediatric TBI. Lugones, et al. (2018) undertook a systemic review of 21 studies that examined 14 different pediatric TBI biomarkers using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework to evaluate evidence. Of the 14 biomarkers analyzed, only two were thought to have good evidence. The authors concluded that glial fibrillary acidic protein (GFAP) appears to be promising for the prognosis and monitoring of mild pediatric TBI, whereas ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) appears more promising at mild pediatric TBI diagnosis. Overall they felt that there was little consistency on design and measurement tools between studies, and that more uniform research is needed in order to validate the use of blood biomarkers in pediatric TBI.
In conclusion, there are many new advances in TBI biomarkers on the horizon, and while some are close to establishing analytical and clinical validity, more research on clinical utility of these biomarkers is needed.
- Dawodu ST and Kishner S. “Traumatic Brain Injury (TBI) – Definition, Epidemiology, Pathophysiology: Overview, Epidemiology, Primary Injury.” Medscape, August 2017. Retrieved at https://emedicine.medscape.com/article/326510-overview
- Wang KK, Yang Z, Zhu T, Shi Y, Rubenstein R, Tyndall JA, Manley GT. An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Rev Mol Diagn. 2018 Feb;18(2):165-180.
- Lugones M, Parkin G, Bjelosevic S, Takagi M, Clarke C, Anderson V, Ignjatovic V. Blood biomarkers in paediatric mild traumatic brain injury: a systematic review. Neurosci Biobehav Rev. 2018 Apr;87:206-217.
- FDA Grants Marketing Authorization to Banyan Biomarkers for the First Diagnostic Blood Test for Traumatic Brain Injury. Retrieved from https://www.businesswire.com/news/home/20180214006251/en/FDA-Grants-Marketing-Authorization-Banyan-Biomarkers-Diagnostic