Blood biomarkers for mild traumatic brain injury: a selective review of unresolved issues

Abstract

Background: The use of blood biomarkers after mild traumatic brain injury (mTBI) has been widely studied. We have identified eight unresolved issues related to the use of five commonly investigated blood biomarkers: neurofilament light chain, ubiquitin carboxy-terminal hydrolase-L1, tau, S100B, and glial acidic fibrillary protein. We conducted a focused literature review of unresolved issues in three areas: mode of entry into and exit from the blood, kinetics of blood biomarkers in the blood, and predictive capacity of the blood biomarkers after mTBI.

Findings: Although a disruption of the blood brain barrier has been demonstrated in mild and severe traumatic brain injury, biomarkers can enter the blood through pathways that do not require a breach in this barrier. A definitive accounting for the pathways that biomarkers follow from the brain to the blood after mTBI has not been performed. Although preliminary investigations of blood biomarkers kinetics after TBI are available, our current knowledge is incomplete and definitive studies are needed. Optimal sampling times for biomarkers after mTBI have not been established. Kinetic models of blood biomarkers can be informative, but more precise estimates of kinetic parameters are needed. Confounding factors for blood biomarker levels have been identified, but corrections for these factors are not routinely made. Little evidence has emerged to date to suggest that blood biomarker levels correlate with clinical measures of mTBI severity. The significance of elevated biomarker levels thirty or more days following mTBI is uncertain. Blood biomarkers have shown a modest but not definitive ability to distinguish concussed from non-concussed subjects, to detect sub-concussive hits to the head, and to predict recovery from mTBI. Blood biomarkers have performed best at distinguishing CT scan positive from CT scan negative subjects after mTBI.

Keywords: Blood biomarkers; CT scan; Concussion; GFAP; Kinetics; Mild traumatic brain injury; NF-L; Return to sport; S100B; Tau; UCH-L1.

Fig. 1

Cluster trajectories for NF-L biomarker for concussed contact sport subjects formed two clusters C1 and C2. C1 (red line) showed a robust rise in NF-L after concussion whereas C2 (purple line) showed a modest elevation in NF-L not much different from the non-contact sport concussed, contact sport controls, and not-contact sport controls. C1 and C2 differed at all time points (p <0.05). Reproduced from [29] with permission. Original data from CARE study [30]

Fig. 2

T_max is the time at which the biomarker is at its highest level. The half-life is the time needed for the biomarker level to drop by 50% during the elimination phase. Accurate estimates of half-life can only be made after the absorption phase is complete. With delayed or continuing absorption of biomarker after mTBI estimates of half-life are difficult

Fig. 3

Calculated time-concentration curves for four blood biomarkers after mTBI based on a one-compartment pharmacokinetic model [74]. Each curve reflects a subject from the CARE dataset [31] who sustained a sports related concussion. Four blood biomarker levels were used to estimate the amount of biomarker released at impact and the pharmacokinetic model was used to generate the time-concentration curve based on Equation 3. Tests of modality suggested that biomarker levels were bi-modal [29]. Reproduced from [74] with permission