Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI)- a Longitudinal Biomarker Study

This longitudinal observational study is part of the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) initiative, a multi-institutional project designed to characterize the acute and longer-term clinical, neuroimaging, and blood biomarker features of TBI. TRACK-TBI enrolled TBI patients at 18 Level 1 Trauma Centers in the US, across the age and injury spectrum. This study will extend the follow-up period for TRACK-TBI participants. The extensive clinical, imaging, and biomarker data that has already been collected in these TRACK-TBI participants, in combination with the extended longitudinal data, will allow for the identification of risk factors, co-morbidities, and prognostic biomarkers of TBI. Consequently, the extension of study follow-up will help to determine negative neurological and psychological outcomes of individuals who experienced a TBI compared to healthy and orthopedic controls.

TBI is a complex disease process, in which diverse injury subtypes and multiple molecular mechanisms overlap. There is a need to identify and measure these subtypes, in order to develop precision medicine approaches where specific pathobiological processes are targeted by mechanistically appropriate therapies. The absence of validated biomarkers in the neurotrauma field is a barrier to drug development in this area, and there are currently no disease-modifying therapies that limit the burden of TBI. Biomarkers specific for injury mechanisms should be identified to select participants for clinical trials of targeted therapies (prognostic biomarkers), as well as to confirm target engagement and biological efficacy (pharmacodynamic biomarkers).

Traumatic axonal injury (TAI) is a common pathologic consequence of TBI, and underlies some of the most disabling consequences of injury, including cognitive and affective problems. TAI progresses for years after injury in a subset of patients, and is a key mechanism for long-term neurodegeneration after TBI. Recent breakthroughs in pre-clinical models indicate that novel therapeutic interventions, including strategies such as targeting the mitochondrial transition pore, or promoting axonal maintenance factors are effective in promoting resilience of injured axons and improving neurologic outcome after experimental TBI. Translation of such promising therapies into clinical trials will require prognostic biomarkers that can measure TAI in individual patients, so they can be selected for early phase studies of axon-protective therapies, as well pharmacodynamic biomarkers than can measure the biologic efficacy of such treatments. Currently, the best biomarker for TAI is fractional anisotropy (FA) and mean diffusivity (MD) of white matter tracts, measured using diffusion tensor imaging (DTI) MRI. This technique, while robust, is poorly suited for dynamic longitudinal assessments, and measures the end-result of axonal degeneration, rather than an early step in the neurodegenerative process. Recently, the ability to assay axonal proteins in peripheral blood has made it potentially feasible to assess of TAI rapidly, inexpensively, and longitudinally. The axonal protein that holds the most promise as a biomarker of axonal degeneration is neurofilament light chain (NF-L). This project aims to address the gaps in the existing literature regarding specific biomarkers for injury mechanisms and outcomes following TBI. Furthermore, it is likely that a sophisticated understanding of the subtypes and molecular mechanisms of TBI will be required to successfully develop therapies to treat these subtypes.