Serial Sampling of Serum Protein Biomarkers for Monitoring Human Traumatic Brain Injury Dynamics: A Systematic Review

Abstract

Background: The proteins S100B, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and neurofilament light (NF-L) have been serially sampled in serum of patients suffering from traumatic brain injury (TBI) in order to assess injury severity and tissue fate. We review the current literature of serum level dynamics of these proteins following TBI and used the term "effective half-life" (t_1/2) in order to describe the "fall" rate in serum.

Materials and methods: Through searches on EMBASE, Medline, and Scopus, we looked for articles where these proteins had been serially sampled in serum in human TBI. We excluded animal studies, studies with only one presented sample and studies without neuroradiological examinations.

Results: Following screening (10,389 papers), n = 122 papers were included. The proteins S100B (n = 66) and NSE (n = 27) were the two most frequent biomarkers that were serially sampled. For S100B in severe TBI, a majority of studies indicate a t_1/2 of about 24 h, even if very early sampling in these patients reveals rapid decreases (1-2 h) though possibly of non-cerebral origin. In contrast, the t_1/2 for NSE is comparably longer, ranging from 48 to 72 h in severe TBI cases. The protein GFAP (n = 18) appears to have t_1/2 of about 24-48 h in severe TBI. The protein UCH-L1 (n = 9) presents a t_1/2 around 7 h in mild TBI and about 10 h in severe. Frequent sampling of these proteins revealed different trajectories with persisting high serum levels, or secondary peaks, in patients with unfavorable outcome or in patients developing secondary detrimental events. Finally, NF-L (n = 2) only increased in the few studies available, suggesting a serum availability of >10 days. To date, automated assays are available for S100B and NSE making them faster and more practical to use.

Conclusion: Serial sampling of brain-specific proteins in serum reveals different temporal trajectories that should be acknowledged. Proteins with shorter serum availability, like S100B, may be superior to proteins such as NF-L in detection of secondary harmful events when monitoring patients with TBI.

Keywords: S100B; biomarkers; glial fibrillary acidic protein; neurofilament light; neuron-specific enolase; serum; traumatic brain injury; ubiquitin carboxy-terminal hydrolase L1.

Figure 1

Illustrating the selection of articles with serial sampling of S100B.

Figure 2

Histograms of frequency of effective serum half-life in different studies. Histograms illustrating the aggregated effective serum half-lives as derived from the different studies including S100B (A), neuron-specific enolase (NSE) (B), glial fibrillary acidic protein (GFAP) (C), and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) (D). Studies with a sampling frequency of 24 h or shorter and a valid estimate of the effective serum half-life were included. The bin size is set to 10 h in order to easily visualize trends; a relatively short effective serum half-life for S100B and UCH-L1, while it was longer for NSE and GFAP. An effective serum half-life for neurofilament light could not be included as it was impossible to estimate from the available literature.

Figure 3

Protein kinetics following injury. Highlighting the estimated temporal profile from trauma if frequently sampled. Initially, there will be a major release of the protein from extracranial sources (gray line), in theory more so if it is present to a larger extent in tissue likely to be injured (i.e., S100B in adipose tissue), even if this contribution generally decreases rapidly. The cerebral contribution (blue line) will continue to increase in serum (for S100B up to 27 h), presumably due to influx from the injured brain. In case of ongoing injury development, the subsequent serum samples may have a prolonged decline or even continue to increase depending on the injury severity (red line). In case of a new injury development, secondary peaks have been shown (green line). While this pattern is most studied for S100B, it applies to some extent to all the biomarkers even if the time frames are different.

Figure 4

Protein kinetics for each protein in serum over time. Graph illustrating how the influence of an increasing effective half-life results in a serum sample in an uneventful traumatic brain injury (TBI) (without secondary deterioration) for ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) (red), S100B (black), neuron-specific enolase (NSE)/glial fibrillary acidic protein (GFAP) (blue), and neurofilament light (NF-L) (green). Biomarker concentration in serum on y-axis and time in hours on x-axis. Note that these are estimates based on the knowledge of S100B kinetics in serum, current literature makes it difficult to illustrate more accurate trajectories over time for the other proteins.