Abstract
INTRODUCTION: Mild traumatic brain injury (mTBI), or concussion, is a substantial health problem, with up to 15% of patients experiencing persisting symptoms. Identifying patients at risk for a poor outcome or protracted recovery remains challenging. Axonal damage caused by rotational forces is now recognized as an important consequence of injury. Moreover, serum measurement of the neurofilament light (NfL) protein has emerged as a potentially promising biomarker of injury. METHODS: A gyrencephalic, porcine model of head rotational acceleration scaled to human mTBI was performed with survival of 48 hr (n = 2), 72 hr (n = 6) and 14 days (n = 4) and compared with shams at 72 hr (n = 1) and 14 days (n = 1). Serum NfL was measured pre-injury and at 40 min, 1.5 hr, 3-4 hr, 8 hr, 18 hr, 24 hr, 2 days, 3 days and 14 days post-injury. Detailed neuropathological assessment was performed including staining for markers of cell death (Fluoro-Jade-C), axonal injury (amyloid precursor protein and NfL), and blood-brain barrier (BBB) disruption (fibrinogen). RESULTS: Significant elevations in serum-NfL were identified following mTBI, with a peak at 72hr post-injury. Moreover, increased serum-NfL was detectable out to 2 weeks post-injury. Subsequent quantitative histological examinations demonstrated that axonal pathology was the likely source of elevated serum-NfL. However, the extent of axonal pathology quantified via multiple markers did not correlate strongly with the extent of serum-NfL. Interestingly, the extent of BBB permeability offered more robust correlations with serum-NfL measured at multiple time points, suggesting BBB disruption is an important determinant of serum biomarker dynamics after mTBI. CONCLUSIONS: These data provide novel insights to the temporal course and pathological basis of serum NfL measurements that inform its utility as a biomarker in mTBI. The ability of NfL to measure underlying pathology will be critical for future clinical and translational research.
Published Version
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