Blood-Based Biomarkers for Improved Characterization of Traumatic Brain Injury: Recommendations from the 2024 National Institute for Neurological Disorders and Stroke Traumatic Brain Injury Classification and Nomenclature Initiative Blood-Based Biomarkers Working Group

Abstract

A 2022 report by the National Academies of Sciences, Engineering, and Medicine called for a Traumatic Brain Injury (TBI) Classification Workshop by the National Institutes of Health (NIH) to develop a more precise, evidence-based classification system. The workshop aimed to revise the Glasgow Coma Scale-based system by incorporating neuroimaging and validated blood biomarker tests. In December 2022, the National Institute for Neurological Disorders and Stroke formed six working groups of TBI experts to make recommendations for this revision. This report presents the findings and recommendations from the blood-based biomarker (BBM) working group, including feedback from the workshop and subsequent public review. The application of BBMs in a TBI classification system has potential to allow for a more adaptable and nuanced approach to triage, diagnosis, prognosis, and treatment. Current evidence supports the use of glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1, and S100B calcium-binding protein (S100B) to assist in reclassification of TBI at acute time points (0-24 h) primarily in emergency department settings, while neurofilament light chain (NfL), GFAP, and S100B have utility at subacute time points (1-30 days) in-hospital and intensive care unit settings. Blood levels of these biomarkers reflect the extent of structural brain injury in TBI and may be useful for describing the extent of structural brain injury in a classification system. While there is insufficient evidence to support a role for BBMs at chronic time points (>30 days), emerging evidence suggests that NfL and phosphorylated tau may have a potential future role in this regard. For inclusion in a revised TBI classification system, BBM assays must have appropriate age- and sex-specific reference ranges, be harmonized across platforms, and achieve high analytical precision, including accuracy, linearity, detection limits, selectivity, recovery, reproducibility, and stability. Improving transparency in BBM assay development can be achieved through large-scale data sharing of methods and results. Future research should focus on methods for promoting clinical adoption of BBM results, correlating BBMs with advanced neuroimaging, and on discovering new biomarkers for improved diagnosis and prognosis.

Keywords: S100B calcium-binding protein; brain biomarkers; concussion; glial fibrillary acidic protein; neurofilament light chain; traumatic brain injury; ubiquitin C-terminal hydrolase L1.