A Biomarker for Concussion: The Good, the Bad, and the Unknown

Abstract

Background Traumatic brain injury (TBI) is a significant cause of morbidity, mortality, and disability in the US, with >2.8 million patients presenting to the emergency department (ED) annually. However, the diagnosis of TBI is challenging and presents a number of difficulties, particularly at the mildest end of the spectrum: concussion. A number of groups have researched biomarkers to aid in the evaluation of TBI, and most recently in 2018 the Food and Drug Administration approved a new blood-based immunoassay biomarker using ubiquitin carboxyl hydrolase L1 and glial fibrillary acidic protein to aid in head computed tomography (CT) triage. Content This review clarifies the practical challenges in assessing and implementing a new blood biomarker. It then examines the clinical context and need, as well as the evidence used to validate this new immunoassay. Summary Concussion is a multifaceted diagnosis with a need for biomarkers to assist in diagnostic and prognostic assessment. Recent articles in the lay press have revealed misunderstanding about the function of this new test, expressing hopes that this biomarker serves patients at the mildest end of the spectrum and is useful for athletes and children. None of these assumptions are correct, as this biomarker has been evaluated in patients only at the moderate end of the spectrum and has been validated only in adults presenting to the ED who have already been triaged to receive head CT, not in athletes or children. The next steps for this assay should consider clinical work flow and clarifying its intended use, including integration with existing triage methods, and validating the assay for a broader population.

Do concussed and non-concussed head trauma individuals have similar symptoms? A retrospective chart review of chronic post-concussive symptomatology

“…Considering this, a need to incorporate more sensitive testing that can detect milder brain injuries, such as advanced imaging techniques or biomarker quantification, becomes evident. [14][15][16] Early detection and labeling of these sub-threshold mTBIs would help us to provide appropriate care and mitigate long-term consequences.…”

Behavioral and Cognitive Aspects of Concussion

“…Regarding diagnosis of TBI itself, none of these biomarkers has been sufficiently validated to justify its use as a diagnostic tool in the individual case. Key limitations to the individual diagnostic application include (1) a lack of “normative” values of these biomarker candidates in healthy (uninjured) people, (2) the fact that injuries outside the brain/central nervous system (eg, orthopedic trauma) can contribute to circulating plasma or serum concentrations, (3) a lack of standardization or availability of assays timed to expected biomarker elevations, and (4) variability in the definition of TBI 68,71,73 …”

“…Key limitations to the individual diagnostic application include (1) a lack of "normative" values of these biomarker candidates in healthy (uninjured) people, (2) the fact that injuries outside the brain/central nervous system (eg, orthopedic trauma) can contribute to circulating plasma or serum concentrations, (3) a lack of standardization or availability of assays timed to expected biomarker elevations, and (4) variability in the definition of TBI. 68,71,73 Regarding the prognostic value of biomarkers, S100B, GFAP, ubiquitin C-terminal hydroxylase, and neurofilament light chain have all been shown in some studies to predict outcome and recovery by using the Glasgow Outcome Scale, 71,74 although results have not been universally positive, and use in the individual case is not indicated. 75 The use of a multivariate panel of several biomarkers simultaneously may hold more promise.…”