Serum neurofilament light protein predicts clinical outcome in traumatic brain injury

Pashtun Shahim, Magnus Gren, Victor Liman, Ulf Andreasson, Niklas Norgren, Yelverton Tegner, Niklas Mattsson, Niels Andreasen, Martin Öst, Henrik Zetterberg, Bengt Nellgård, Kaj Blennow, Pashtun Shahim, Magnus Gren, Victor Liman, Ulf Andreasson, Niklas Norgren, Yelverton Tegner, Niklas Mattsson, Niels Andreasen, Martin Öst, Henrik Zetterberg, Bengt Nellgård, Kaj Blennow

Abstract

Axonal white matter injury is believed to be a major determinant of adverse outcomes following traumatic brain injury (TBI). We hypothesized that measurement of neurofilament light protein (NF-L), a protein found in long white-matter axons, in blood samples, may serve as a suitable biomarker for neuronal damage in TBI patients. To test our hypotheses, we designed a study in two parts: i) we developed an immunoassay based on Single molecule array technology for quantification of NF-L in blood, and ii) in a proof-of-concept study, we tested our newly developed method on serial serum samples from severe TBI (sTBI) patients (n = 72) and controls (n = 35). We also compared the diagnostic and prognostic utility of NF-L with the established blood biomarker S100B. NF-L levels were markedly increased in sTBI patients compared with controls. NF-L at admission yielded an AUC of 0.99 to detect TBI versus controls (AUC 0.96 for S100B), and increased to 1.00 at day 12 (0.65 for S100B). Importantly, initial NF-L levels predicted poor 12-month clinical outcome. In contrast, S100B was not related to outcome. Taken together, our data suggests that measurement of serum NF-L may be useful to assess the severity of neuronal injury following sTBI.

Conflict of interest statement

B.N., M.G., M.Ö., N.M., N.A., P.S., U.A., Y.T. and V.L. report no disclosures. N.N. is employed by UmanDiagnostics. H.Z. and K.B. are co-founders of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg, Sweden.

Figures

Figure 1. Temporal profile of the biomarkers…
Figure 1. Temporal profile of the biomarkers in severe traumatic brain injury.
(a) NF-L levels at admission and latter sampling time points (days 1–12) were increased in patients with TBI as compared to controls (***p < 0.001, all). (b) NF-L measured in ventricular cerebrospinal fluid from the patients who underwent ventriculostomy show similar releasing dynamics as in serum. S100B levels at day 0 (admission), day 1, day 2, day 3, day 4 (***p < 0.001, all), day 6 (*p < 0.05) were increased in sTBI patients compared with controls, and levels measured at latter time points were not statistically different from the control group (c). Values are presented as median; error bars indicate interquartile range.
Figure 2. Diagnostic accuracy of the biomarkers…
Figure 2. Diagnostic accuracy of the biomarkers for severe traumatic brain injury.
Area under the receiver operating characteristic curve (AUC) for NF-L (a) and S100B (b) concentrations at admission, and days 1–12 post-TBI versus control group. (c) shows the ROC curve for NF-L and S100B in survivors versus non-survivors. (d) shows the ROC curve for NF-L and S100B in favorable versus unfavorable outcome group. AUC for NF-L and S100B were 0.70 and 0.65 in survivors versus non-survivors; 0.71 and 0.60 in favorable versus unfavorable outcome, respectively.
Figure 3. Serum NF-L and S100B in…
Figure 3. Serum NF-L and S100B in non-survivors versus survivors of severe traumatic brain injury.
NF-L (a) and S100B (b) in serum samples obtained at 24 hours after injury. NF-L (c) and S100B (d) levels in serum samples obtained over the period of 1–12 days after injury (d). Values are presented as median; error bars indicate interquartile range.
Figure 4. NF-L is predictive of overall…
Figure 4. NF-L is predictive of overall clinical outcome 12 months after injury in severe traumatic brain injury.
Serum NF-L samples (a) obtained at initial 24 hours after injury significantly differed between the Glasgow Outcome Scale (GOS) categories (GOS 1 versus. GOS 2–5; *** p < 0.0001). (b) There was no significant difference in the levels of S100B and different GOS categories when corrected for multiple group comparisons. No patients were in a persistent vegetative state (GOS score of 2). (c) Serum NF-L levels during the initial 24 hours of sampling were significantly higher in patients with unfavorable outcome versus favorable. (d) There was no significant difference in the levels of S100B between patients with unfavorable versus favorable outcome. Values are presented as median; error bars indicate interquartile range.

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