Comparative Assessment of the Prognostic Value of Biomarkers in Traumatic Brain Injury Reveals an Independent Role for Serum Levels of Neurofilament Light

Abstract

Traumatic brain injury (TBI) is a common cause of death and disability, worldwide. Early determination of injury severity is essential to improve care. Neurofilament light (NF-L) has been introduced as a marker of neuroaxonal injury in neuroinflammatory/-degenerative diseases. In this study we determined the predictive power of serum (s-) and cerebrospinal fluid (CSF-) NF-L levels towards outcome, and explored their potential correlation to diffuse axonal injury (DAI). A total of 182 patients suffering from TBI admitted to the neurointensive care unit at a level 1 trauma center were included. S-NF-L levels were acquired, together with S100B and neuron-specific enolase (NSE). CSF-NF-L was measured in a subcohort (n = 84) with ventriculostomies. Clinical and neuro-radiological parameters, including computerized tomography (CT) and magnetic resonance imaging, were included in the analyses. Outcome was assessed 6 to 12 months after injury using the Glasgow Outcome Score (1-5). In univariate proportional odds analyses mean s-NF-L, -S100B and -NSE levels presented a pseudo-R2 Nagelkerke of 0.062, 0.214 and 0.074 in correlation to outcome, respectively. In a multivariate analysis, in addition to a model including core parameters (pseudo-R2 0.33 towards outcome; Age, Glasgow Coma Scale, pupil response, Stockholm CT score, abbreviated injury severity score, S100B), S-NF-L yielded an extra 0.023 pseudo-R2 and a significantly better model (p = 0.006) No correlation between DAI or CT assessed-intracranial damage and NF-L was found. Our study thus demonstrates that S-NF-L correlates to TBI outcome, even if used in models with S100B, indicating an independent contribution to the prediction, perhaps by reflecting different pathophysiological processes, not possible to monitor using conventional neuroradiology. Although we did not find a predictive value of NF-L for DAI, this cannot be completely excluded. We suggest further studies, with volume quantification of axonal injury, and a prolonged sampling time, in order to better determine the connection between NF-L and DAI.

Fig 1. Characteristics of serum NF-L samples.

Histograms illustrating the number of s-NF-L samples per patient (A) and the distribution over time after trauma (B). C illustrates the s-NF-L levels over time (one dot per sample), with a red line representing the locally weighted scatterplot smoothing (LOWESS), a nonlinear regression of data points. D illustrates the s-NF-L levels over time after trauma using boxplots.

Fig 2. Serum NF-L levels by patient.

Every line (separate color) represents an individual patient. Generally, even if there were differences in concentration between patients they were limited over time for the individual patient.

Fig 3. Both serum-S100B and –NF-L correlate to TBI outcome.

Serum levels of S100B (A) and NF-L (B) (x-axis, respectively) vs Glasgow Outcome Score (GOS) (y-axis, left) shown using conditional density plots. The red line represents the data distribution. Outcome proportions are illustrated, summing to one (y-axis right).

Fig 4. Correlations between CSF and serum samples of NF-L are illustrated.

One color represents one patient (A). The mean CSF and serum samples were calculated and correlated (B).

Fig 5. The within patient changes of serum (A) and CSF (B)-NF-L illustrated using histograms of logged data.

The differences over time for each patient were low, with a majority of patients not diverging more than 3.2 ng/L in serum (Fig 5A) and more than 10 ng/L in CSF (Fig 5B).