Abstract
Across the neurotrauma field, biomarkers, particularly blood-based biomarkers, are paradigm shifting in the diagnosis and mechanistic understanding of traumatic brain injury (TBI). The review by Beard et al., in this issue of Journal of Neurotrauma entitled “Biofluid, Imaging, Physiological and Functional Biomarkers of Mild Traumatic Brain Injury and Subconcussive Head Impacts” summarizes the mild TBI and subconcussive head impact biomarkers across four main categories: biofluid, imaging, physiological, and functional. Within each section, the authors identify and discuss recent advancements and explores essential factors for integrating these biomarkers into clinical practice. For example, collective efforts of national and international consortiums have elucidated that serum GFAP and UCHL-1 levels within 12 h post-injury have a high sensitivity and negative predictive value for a positive head CT. 1 –3 This biofluid biomarker combination has recently received FDA clearance as a point of care whole blood application for an aid in diagnosis of TBI. 4 Within imaging biomarkers, magnetic resonance imaging (MRI) has proven to be a promising clinical tool for both diagnosis and prognosis of TBI across a range of severities and up to 1 year post-injury. 5 Although still in the early validation stages, diffusion tensor imaging may identify chronic abnormalities present in athletes or military personnel with repetitive subconcussive or low-level blast exposure. 6,7 Ocular performance physiological markers, specifically eye-tracking devices have received FDA clearance. Although these non-invasive tools are still in early discovery phase, they also have the potential to diagnose and identify ongoing symptoms of mild TBI. 8 –10 Across all four categories, the studies reviewed highlight a path in which productive collaboration between academic and industry research fields can ultimately lead to point-of-care FDA approval and realistic clinical implementation.
Interpretation of published literature on the topic of biomarkers, can be surprisingly challenging, particularly when comparing results across studies. While advances in the technology for the detection of biofluid and imaging biomarkers may allow for more efficient and sensitive methods, the field is beginning to be inundated with conflicting reports. This is in part due to variations in experimental design including: the time-point(s) selected post-injury, the specific biofluid matrix or imaging agent, the detection or imaging platform and variables that have yet to be defined. This is in addition to the many challenges in recruiting a representative patient cohort. A researcher may believe they are comparing apples to apples, however even the slightest difference in one of many factors can yield distinct results. This challenge is part of the reason why Journal of Neurotrauma has instituted “Transparency, Rigor and Reproducibility” statement requirements. All this to say, that for a traumatic brain injury that is defined in part by its heterogeneity, a lack in high level of standardization, may hinder the progress of utilization of biomarkers. Future work in the biomarker realm, like many aspects of TBI research in general, must emphasize consistency and transparency of experimental design and methods specifically through inclusion of common data elements. Comprehensive synthesis and critical review of these vast biomarker publications, as exemplified by Beard et al., are crucial to proper interpretation and implications of results. This becomes exponentially important as various biomarker technologies advance, and novel, innovative methods emerge.
A question on the minds of many in the field is whether we have all the biomarkers we need, and whether the most important path forward now is to understand them better. In our view, the answer is probably not. The biomarkers we have are good and getting better, but there is a lot of room for improvement given the vast complexity of the human brain, types of injury, and evolving pathophysiological responses to injury over time. As the field matures, we expect a focus on both discovery and rigor, with smaller initial studies leading quickly and in a well-organized fashion to larger multicenter validation studies and fully transparent reporting of results, both positive and negative.