Accurate diagnosis for mild traumatic brain injury (mTBI) remains challenging, as prognosis and return-to-play/work decisions are based largely on patient reports. Numerous investigations have identified and characterized cellular factors in the blood as potential biomarkers for TBI, in the hope that these factors may be used to gauge the severity of brain injury. None of these potential biomarkers have advanced to use in the clinical setting. Some of the most extensively studied blood biomarkers for TBI include S100β, neuron-specific enolase, glial fibrillary acidic protein, and Tau. Understanding the biological function of each of these factors may be imperative to achieve progress in the field. We address the basic question: what are we measuring? This review will discuss blood biomarkers in terms of cellular origin, normal and pathological function, and possible reasons for increased blood levels. Considerations in the selection, evaluation, and validation of potential biomarkers will also be addressed, along with mechanisms that allow brain-derived proteins to enter the bloodstream after TBI. Lastly, we will highlight perspectives and implications for repetitive neurotrauma in the field of blood biomarkers for brain injury.

IMPORTANCE An increased understanding of the relationship between subconcussive head impacts and near point of convergence (NPC) ocular-motor function may be useful in delineating traumatic brain injury.OBJECTIVE To investigate whether repetitive subconcussive head impacts during preseason football practice cause changes in NPC. DESIGN, SETTING, AND PARTICIPANTSThis prospective, observational study of 29 National Collegiate Athletic Association Division I football players included baseline and preseason practices (1 noncontact and 4 contact), and postseason follow-up and outcome measures were obtained for each time. An accelerometer-embedded mouthguard measured head impact kinematics. Based on the sum of head impacts from all 5 practices, players were categorized into lower (n = 7) or higher (n = 22) impact groups.EXPOSURES Players participated in regular practices, and all head impacts greater than 10g from the 5 practices were recorded using the i1Biometerics Vector mouthguard (i1 Biometrics Inc). MAIN OUTCOMES AND MEASURES Near point of convergence measures and symptom scores.RESULTS A total of 1193 head impacts were recorded from 5 training camp practices in the 29 collegiate football players; 22 were categorized into the higher-impact group and 7 into the lower-impact group. There were significant differences in head impact kinematics between lower-and higher-impact groups (number of impacts, 6 vs 41 [lower impact minus higher impact = 35; 95% CI, 21-51; P < .001]; linear acceleration, 99g vs 1112g [lower impact minus higher impact= 1013; 95% CI, 621 -1578; P < .001]; angular acceleration, 7589 radian/s 2 vs 65 016 radian/s 2 [lower impact minus higher impact= 57 427; 95% CI , 31 123-80 498; P < .001], respectively). The trajectory and cumulative burden of subconcussive impacts on NPC differed by group (F for group × linear trend 1, 238 = 12.14, P < .001 and F for group × quadratic trend 1, 238 = 12.97, P < .001). In the higher-impact group, there was a linear increase in NPC over time (B for linear trend, unstandardized coefficient [SE]: 0.76 [0.12], P < .001) that plateaued and resolved by postseason follow-up (B for quadratic trend [SE]: −0.06 [0.008], P < .001). In the lower-impact group, there was no change in NPC over time. Group differences were first observed after the first contact practice and remained until the final full-gear practice. No group differences were observed postseason follow-up. There were no differences in symptom scores between groups over time. CONCLUSIONS AND RELEVANCEAlthough asymptomatic, these data suggest that repetitive subconcussive head impacts were associated with changes in NPC. The increase in NPC highlights the vulnerability and slow recovery of the ocular-motor system following subconcussive head impacts. Changes in NPC may become a useful clinical tool in deciphering brain injury severity.

This study intended to examine effects of repetitive sub-concussive head impacts on ocular near point of convergence (NPC). 20 healthy young adult soccer players were assigned to either a heading or control group. Heading subjects completed 10 headers of soccer balls projected at a speed of 11.2?m/s. Control subjects did not perform heading. Linear head acceleration was measured with a triaxial accelerometer. The NPC assessment was performed at pre-, 0?h post-, and 24?h post-heading. During the NPC assessment participants were seated and a visual target was moved towards the eyes at 1cm/sec. The participant signaled when he/she experienced diplopia or deviation of the eye was observed, and the distance was recorded. The assessment was repeated twice and average NPC scores were used for further analysis. Soccer heading induced mean group head accelerations of 14.49?5.4?g. Mild head impacts led to an increased NPC distance, which was supported by a significant Group x Time interaction. In the heading group, 0?h post- and 24?h post-heading NPC scores were significantly receded compared to baseline. Conversely, NPC scores for the control group showed no difference over time. Our findings indicate that mild frontal head impacts affekt NPC for a minimum of 24?h-post heading, suggesting that oculomotor processes are disrupted, at least transiently, by repetitive mild head impact.

The current study investigates whether repetitive subconcussive impacts cause changes in plasma S100β levels, and also tests the associations between S100β changes and frequency/magnitude of impacts sustained. This prospective study of 22 Division-I collegiate football players included baseline and pre-season practices (one helmet-only and four full-gear). Blood samples were obtained and assessed for S100β levels at baseline and pre- to post-practices; symptom scores were assessed at each time-point. An accelerometer-embedded mouthguard was employed to measure the number of impacts (hits), peak linear acceleration (PLA), and peak rotational acceleration (PRA). Because we observed a distinct gap in impact exposure (hits, PLA, and PRA), players were clustered into lower (n = 7) or higher (n = 15) impact groups based on the sum of impact kinematics from all five practices. S100β levels significantly changed across the study duration. Although S100β levels remained stable from baseline to all pre-practice values, statistically significant acute increases in S100β levels were observed in all post-practice measures compared with the respective pre-practice values (range: 133-246% in the overall sample). Greater number of hits, sum of PLA, and sum of PRA were significantly associated with greater acute increases in S100β levels. There were significant differences in head impact kinematics between lower and higher impact groups (hits, 6 vs. 43 [M - M = 35, p < 0.001]; PLA, 99.4 vs. 1148.5 g [M - M = 1049.1, p < 0.001]; PRA, 7589 vs. 68,259 rad/s [M - M = 60,670, p < 0.001]). Players in the higher impact group showed consistently greater increases in plasma S100β levels, but not symptom scores, at each post-practice than the lower impact group. Collectively, these data suggest that although players continued to play without noticeable change in symptoms, a brain-enriched serological factor suggests an acute burden from head impacts. Assessing the effects of repetitive subconcussive head impacts on acute changes in S100β levels may be a clinically useful blood biomarker in tracking real-time acute brain damage in collegiate football players.

The purpose of the study was to examine an association of repetitive subconcussive head impacts with changes in plasma neurofilament light (NF-L) levels following 10 bouts of controlled soccer heading. In this randomized control trial, 37 healthy adult soccer players were randomly assigned into either a heading (n = 19) or kicking-control group (n = 18). The heading group executed 10 headers with soccer balls projected at a velocity of 25 mph over 10 min. Plasma samples were obtained at pre-heading baseline, 0 h, 2 h, and 24 h post-heading. The kicking-control group followed the same protocol with 10 kicks. Plasma NF-L was measured using ultrasensitive single-molecule array technology. Data from 34 subjects were eligible for analysis (heading n = 18 and kicking n = 16). Ten subconcussive head impacts induced a gradual increase in plasma NF-L expression for the heading group (β = 0.0297, standard error [SE] = 0.01, p = 0.0049), whereas there was no significant time effect for the kicking-control group. A follow-up analysis revealed that a significant difference appeared at 24 h post-heading (3.68 ± 0.30 pg/mL) compared with pre-heading (3.12 ± 0.29 pg/mL, p = 0.0013; Cohen's d = 1.898). At the 24 h post-heading time-point, the plasma NF-L level for the heading group was significantly higher than that of the kicking-control group with an estimated mean difference of 0.66 pg/mL (SE = 0.22, p = 0.0025). The data suggest that the increased level of plasma NF-L was driven by repetitive subconcussive head impacts and required longer than 2 h after the head impacts for the increase to be detected. Plasma NF-L levels may serve as an objective marker to monitor acute axonal burden from subconcussive head impacts.

ObjectiveEnhancing structural and functional integrity of mitochondria is an emerging therapeutic option against endothelial dysfunction. In this study, we sought to investigate the effect of fluid shear stress on mitochondrial biogenesis and mitochondrial respiratory function in endothelial cells (ECs) using in vitro and in vivo complementary studies.Methods and ResultsHuman aortic- or umbilical vein-derived ECs were exposed to laminar shear stress (20 dyne/cm2) for various durations using a cone-and-plate shear apparatus. We observed significant increases in the expression of key genes related to mitochondrial biogenesis and mitochondrial quality control as well as mtDNA content and mitochondrial mass under the shear stress conditions. Mitochondrial respiratory function was enhanced when cells were intermittently exposed to laminar shear stress for 72 hrs. Also, shear-exposed cells showed diminished glycolysis and decreased mitochondrial membrane potential (ΔΨm). Likewise, in in vivo experiments, mice that were subjected to a voluntary wheel running exercise for 5 weeks showed significantly higher mitochondrial content determined by en face staining in the conduit (greater and lesser curvature of the aortic arch and thoracic aorta) and muscle feed (femoral artery) arteries compared to the sedentary control mice. Interestingly, however, the mitochondrial biogenesis was not observed in the mesenteric artery. This region-specific adaptation is likely due to the differential blood flow redistribution during exercise in the different vessel beds.ConclusionTaken together, our findings suggest that exercise enhances mitochondrial biogenesis in vascular endothelium through a shear stress-dependent mechanism. Our findings may suggest a novel mitochondrial pathway by which a chronic exercise may be beneficial for vascular function.

Specific clinical tests should be used after a head and neck pathomechanical event to differentiate between symptoms due to a concussion and cervical injury. Continued research on the clinical utility of the 5 identified cervicogenic tests is also recommended.

Current thinking views mild head impact (i.e., subconcussion) as an underrecognized phenomenon that has the ability to cause significant current and future detrimental neurological effects. Repeated mild impacts to the head, however, often display no observable behavioral deficits based on standard clinical tests, which may lack sensitivity. The current study investigates the effects of subconcussive impacts from soccer heading with innovative measures of vestibular function and walking stability in a pre-0-2 h, post-24 h post-heading repeated measures design. The heading group (n = 10) executed 10 headers with soccer balls projected at a velocity of 25 mph (11.2 m/sec) over 10 min. Subjects were evaluated 24 h before, immediately after, and 24 h after soccer heading with: the modified Balance Error Scoring System (mBESS); a walking stability task with visual feedback of trunk movement; and galvanic vestibular stimulation (GVS) while standing with eyes closed on foam. A control group (n = 10) followed the same protocol with no heading. The results showed significant decrease in trunk angle, leg angle gain, and center of mass gain relative to GVS for the heading group compared with controls. Medial-lateral trunk orientation displacement and velocity during treadmill walking increased immediately after mild head impact for the heading group compared with controls. Controls showed an improvement in mBESS scores over time, indicating a learning effect, which was not observed with the heading group. These results suggest that mild head impact leads to a transient dysfunction in vestibular processing, which deters walking stability during task performance.