Objective:To determine if neurofilament light (NfL), glial fibrillary acidic protein (GFAp), tau, and ubiquitin C-terminal hydrolase-L1 (UCH-L1) measured in serum relate to traumatic brain injury (TBI) diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) measures of traumatic axonal injury (TAI) in patients with TBI.Methods:Patients with TBI (n=162) and controls (n=68) were prospectively enrolled between 2009–2018. Of the 162 patients, 102 underwent repeated serum, functional outcome, brain MRI volumetry, and DTI assessments at 30, 90, and 180 days, and 1, 2, 3, 4, and 5 years after TBI.Results:At enrolment, patients with TBI had increased serum NfL compared to controls (p<0.0001). Serum NfL decreased over the course of five years, but remained significantly elevated compared to controls. Serum NfL at 30 days distinguished patients with mild, moderate, and severe TBI from controls with Area Under the Receiver-Operating Characteristic Curve (AUROC) of 0.84, 0.92, and 0.92, respectively. At enrolment, serum GFAp was elevated in TBI patients compared to controls (p<0.001). GFAp showed a biphasic release in serum, with levels decreasing during the first six months of injury, whereafter increased over the subsequent study visits. The highest AUROC for GFAp was measured at 30 days distinguishing moderate and severe TBI patients from controls (both 0.89). Serum tau and UCH-L1 showed weak associations to TBI severity and neuroimaging measures. Longitudinally, serum NfL was the only biomarker that was associated with the likely rate of MRI brain atrophy and DTI measures of progression of TAI.Conclusions:Serum NfL shows greater diagnostic and prognostic utility than GFAp, tau, and UCH-L1 for subacute and chronic TBI.Classification of Evidence:This study provides Class III evidence that serum NfL distinguishes patients with mild TBI from healthy controls.

Objective:To determine if serum neurofilament light (NfL) correlates with cerebrospinal fluid (CSF) NfL, TBI diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) estimates of traumatic axonal injury (TAI).Methods:Participants were prospectively enrolled in Sweden and the United States between 2011-2019. The Swedish cohort included 45 hockey players with acute concussion (AC) sampled at six days, 31 repetitive concussion (RC) with persistent post-concussive symptoms (PCS) assessed with paired CSF and serum (median, 1.3 years after concussion), 28 preseason controls, and 14 non-athletic controls. Our second cohort included 230 clinic-based participants (162 with TBI and 68 controls. Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n=30), 90 (n=48), and 180 (n=59) days, and 1 (n=84), 2 (n=57), 3 (n=46), 4 (n=38), and 5 (n=29) years after injury.Results:In athletes with paired specimens, CSF and serum NfL were correlated (r=0.71, p<0.0001). CSF and serum NfL distinguished players with PCS >1-year from PCS ≤1-year (Area Under the Receiver-Operating Characteristic Curve [AUROC], 0.81 and 0.80). The AUROC for PCS >1-year vs preseason controls were 0.97. In the clinic-based cohort, NfL at enrolment distinguished patients with mild vs moderate vs severe TBI (p<0.001 and p=0.048). Serum NfL decreased over the course of five years (ß=–0.09 log pg/mL, p<0.0001), but remained significantly elevated compared to controls. Serum NfL correlated with measures of functional outcome, MRI brain atrophy, and DTI estimates of TAI.Conclusions:Serum NfL shows promise as a biomarker for acute and repetitive sports-related concussion and patients with subacute and chronic TBI.Classification of Evidence:This study provides Class III evidence that increased concentrations of NfL distinguish TBI from controls.