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

Abstract

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 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.

Figure 1. Biomarker concentrations across TBI severities at enrollment

(A–D) Serum concentrations of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin C-terminal hydrolase-L1 (UCH-L1) across traumatic brain injury (TBI) severities at a median of 7 months after TBI. Boxplots show the median and interquartile range. The p values are adjusted for multiple comparisons with the Holm-Bonferroni method.

Figure 2. Time course of the blood biomarkers

(A–D) Time course of serum neurofilament light (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin C-terminal hydrolase-L1 (UCH-L1) across traumatic brain injury (TBI) severities. Error bars indicate SEM. The y-axes are log-transformed (log 10) for better visual clarity. The x-axes show the sampling time points after TBI.

Figure 3. Diagnostic utility of blood biomarkers over time

Plots show the diagnostic utility (area under the receiver operating characteristics curve [AUROC]) of serum neurofilament light (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin C-terminal hydrolase-L1 (UCH-L1) in distinguishing patients with traumatic brain injury from controls. Error bars indicate 95% confidence interval.

Figure 4. Association between blood biomarkers and functional outcome at enrollment

(A–D) Association between concentrations of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin C-terminal hydrolase-L1(UCH-L1) at enrollment and Glasgow Outcome Scale–Extended (GOS-E) assessed cross-sectionally. The x-axes show the log-transformed values for visual clarity. The ß estimates and p values are from linear regression models, covaried for age, education, and sex.

Figure 5. Association between blood biomarkers and GM and WM volumes at enrollment

(A–H) Association between serum concentrations of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin C-terminal hydrolase-L1 (UCH-L1) and gray matter (GM) and white matter (WM) volumes (all patients with traumatic brain injury). The ß estimates and p values are from regression models, covaried for age, education, sex, and total intracranial volume. Associations were also assessed with the univariate Spearman rank correlation (ρ). Brain regions were normalized to total intracranial volume before analysis with ρ.

Figure 6. Serum biomarkers at enrollment in relation to DTI fractional anisotropy

(A–D) Relationship between serum neurofilament light (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin C-terminal hydrolase-L1 (UCH-L1) measured at enrollment and diffusion tensor imaging (DTI) fractional anisotropy (FA) for corpus callosum (CC) integrity measured at enrollment. The ß estimates and p values are from regression models, covaried for age, education, and sex. We also assessed the relationship with univariate the Spearman rank correlation (ρ).