Time course and diagnostic utility of NfL, tau, GFAp, and UCH-L1 in subacute and chronic TBI

Objective: To 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. Methods: Patients 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. Results: At
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 bio-marker 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.