• Pashtun Shahim, Adam Politis, Andre van der Merwe, Brian Moore, Vindhya Ekanayake, Sara M Lippa, Yi-Yu Chou, Dzung L Pham, John A Butman, Ramon Diaz-Arrastia, Henrik Zetterberg, Kaj Blennow, Jessica M Gill, David L Brody, and Leighton Chan.
• From the NIH (P.S., A.P., S.M.L., Y.-Y.C., D.L.P., J.A.B., J.M.G., D.L.B., L.C.); Center for Neuroscience and Regenerative Medicine (P.S., A.v.d.M., B.M., V.E., Y.-Y.C., D.L.P., J.A.B., J.M.G., D.L.B., L.C.); The Henry M. Jackson Foundation for the Advancement of Military Medicine (P.S., A.v.d.M., B.M., V.E., D.L.B.), Bethesda, MD; Department of Psychiatry and Neurochemistry (P.S., H.Z., K.B.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg; Clinical Neurochemistry Laboratory (P.S., H.Z., K.B.), Sahlgrenska University Hospital, Mölndal, Sweden; National Intrepid Center of Excellence (S.M.L.) and Defense and Veterans Brain Injury Center (S.M.L.), Walter Reed National Military Medical Center, Bethesda, MD; Department of Neurology (R.D.-A.), University of Pennsylvania, Philadelphia; UK Dementia Research Institute at UCL (H.Z.); Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology, London, UK; and Uniformed Services University of the Health Sciences (D.L.B.), Bethesda, MD. pashtun-poh.shahim@nih.gov.
• Neurology. 2020 Aug 11; 95 (6): e623-e636.

ObjectiveTo determine whether 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.MethodsPatients with TBI (n = 162) and controls (n = 68) were prospectively enrolled between 2011 and 2019. 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.ResultsAt enrollment, patients with TBI had increased serum NfL compared to controls (p < 0.0001). Serum NfL decreased over the course of 5 years but remained significantly elevated compared to controls. Serum NfL at 30 days distinguished patients with mild, moderate, and severe TBI from controls with an area under the receiver-operating characteristic curve (AUROC) of 0.84, 0.92, and 0.92, respectively. At enrollment, serum GFAP was elevated in patients with TBI compared to controls (p < 0.001). GFAP showed a biphasic release in serum, with levels decreasing during the first 6 months of injury but increasing over the subsequent study visits. The highest AUROC for GFAP was measured at 30 days, distinguishing patients with moderate and severe TBI from controls (both 0.89). Serum tau and UCH-L1 showed weak associations with 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.ConclusionsSerum NfL shows greater diagnostic and prognostic utility than GFAP, tau, and UCH-L1 for subacute and chronic TBI.Classification Of EvidenceThis study provides Class III evidence that serum NfL distinguishes patients with mild TBI from healthy controls.© 2020 American Academy of Neurology.

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