Traumatic brain injury (TBI) is one the leading causes of mortality and morbidity affecting humanity, and a recognized risk factor for late-life neurodegenerative disorders. The absence of validated biomarkers in the neurotrauma field is a barrier to drug development in this area, and consequently there are currently no disease-modifying therapies that limit the burden of TBI. 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. Recent breakthroughs in pre-clinical models indicate that novel therapeutic interventions are effective in promoting resilience of injured axons and improving neurologic outcome after experimental TBI. Successful translation of such therapies will require prognostic biomarkers that can measure TAI in individual patients, as well as pharmacodynamic biomarkers to measure the 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 earlier stages in the neurodegenerative process. The recent ability to assay axonal proteins in peripheral blood has made it potentially feasible to assess TAI rapidly, inexpensively, and longitudinally. The goal of this project is to clinically validate the axonal protein neurofilament light chain (NfL) as a prognostic biomarker of TAI. The project consists of three aims: Aim 1. Reference intervals (RIs) for NfL will be determined according to Clinical Laboratory Standards Institute (CLSI) guidelines, using commercially available assays (Quanterix, LLC, Lexington, MA). Aim 2. NfL levels will be measured in existing serum samples from participants enrolled in a multi-center observational study (TRACK-TBI) who also have MRIs at 2 weeks and 6 months post injury. The relationship between NfL elevations and neuroimaging measures of TAI (DTI measure of FA at the 2-week scan) and axonal degeneration (white matter volume at 6 months after injury) will be assessed. Aim 3. The follow-up period will then be extended for a subset of TRACK-TBI participants from 1 year to 5 years after injury, to assess the relationship between persistent NfL elevations and neurodegeneration. The existing clinical, imaging, and biomarker data in these subjects will be leveraged to identify risk factors, comorbidities, and prognostic biomarkers of long-term TBI-associated degeneration.
University of Pennsylvania