Kian Merchant-Borna

Persistent, long-term cerebral white matter changes after sports-related repetitive head impacts

Introduction Repetitive head impacts (RHI) sustained in contact sports are thought to be necessary for the long-term development of chronic traumatic encephalopathy (CTE). Our objectives were to: 1) characterize the magnitude and persistence of RHI-induced white matter (WM) changes; 2) determine their relationship to kinematic measures of RHI; and 3) explore their clinical relevance. Methods Prospective, observational study of 10 Division III college football players and 5 non-athlete controls during the 2011-12 season. All subjects underwent diffusion tensor imaging (DTI), physiologic, cognitive, and balance testing at pre-season (Time 1), post-season (Time 2), and after 6-months of no-contact rest (Time 3). Head impact measures were recorded using helmet-mounted accelerometers. The percentage of whole-brain WM voxels with significant changes in fractional anisotropy (FA) and mean diffusivity (MD) from Time 1 to 2, and Time 1 to 3 was determined for each subject and correlated to head impacts and clinical measures. Results Total head impacts for the season ranged from 431–1,850. No athlete suffered a clinically evident concussion. Compared to controls, athletes experienced greater changes in FA and MD from Time 1 to 2 as well as Time 1 to 3; most differences at Time 2 persisted to Time 3. Among athletes, the percentage of voxels with decreased FA from Time 1 to 2 was positively correlated with several helmet impact measures. The persistence of WM changes from Time 1 to 3 was also associated with changes in serum ApoA1 and S100B autoantibodies. WM changes were not consistently associated with cognition or balance. Conclusions A single football season of RHIs without clinically-evident concussion resulted in WM changes that correlated with multiple helmet impact measures and persisted following 6 months of no-contact rest. This lack of WM recovery could potentially contribute to cumulative WM changes with subsequent RHI exposures.

Significance of ubiquitin carboxy-terminal hydrolase L1 elevations in athletes after sub-concussive head hits

The impact of sub-concussive head hits (sub-CHIs) has been recently investigated in American football players, a population at risk for varying degrees of post-traumatic sequelae. Results show how sub-CHIs in athletes translate in serum as the appearance of reporters of blood-brain barrier disruption (BBBD), how the number and severity of sub-CHIs correlate with elevations of putative markers of brain injury is unknown. Serum brain injury markers such as UCH-L1 depend on BBBD. We investigated the effects of sub-CHIs in collegiate football players on markers of BBBD, markers of cerebrospinal fluid leakage (serum beta 2-transferrin) and markers of brain damage. Emergency room patients admitted for a clinically-diagnosed mild traumatic brain injury (mTBI) were used as positive controls. Healthy volunteers were used as negative controls. Specifically this study was designed to determine the use of UCH-L1 as an aid in the diagnosis of sub-concussive head injury in athletes. The extent and intensity of head impacts and serum values of S100B, UCH-L1, and beta-2 transferrin were measured pre- and post-game from 15 college football players who did not experience a concussion after a game. S100B was elevated in players experiencing the most sub-CHIs; UCH-L1 levels were also elevated but did not correlate with S100B or sub-CHIs. Beta-2 transferrin levels remained unchanged. No correlation between UCH-L1 levels and mTBI were measured in patients. Low levels of S100B were able to rule out mTBI and high S100B levels correlated with TBI severity. UCH-L1 did not display any interpretable change in football players or in individuals with mild TBI. The significance of UCH-L1 changes in sub-concussions or mTBI needs to be further elucidated.

Variations in the Nature of Behavioral Experience Can Differentially Alter the Consequences of Developmental Exposures to Lead, Prenatal Stress, and the Combination

Behavioral experience (BE) can critically influence later behavior and brain function, but the central nervous system (CNS) consequences of most developmental neurotoxicants are examined in the absence of any such context. We previously demonstrated marked differences in neurotransmitter changes produced by developmental lead (Pb) exposure ± prenatal stress (PS) depending upon whether or not rats had been given BE (Cory-Slechta, D. A., Virgolini, M. B., Rossi-George, A., Weston, D., and Thiruchelvam, M. (2009). The current study examined the hypothesis that the nature of the BE itself would be a critical determinant of outcome in mice that had been continually exposed to 0 or 100 ppm Pb acetate in drinking water alone or in combination with prenatal restraint stress. Half of the offspring in each of the four resulting groups/gender were exposed to positively reinforced (food-rewarded Fixed Interval schedule-controlled behavior) or negatively reinforced (inescapable forced swim) BE. Brain monoamines and amino acids differed significantly in relation to BE, even in control animals, as did the trajectory of effects of Pb ± PS, particularly in frontal cortex, hippocampus (both genders), and midbrain (males). In males, Pb ± PS-related changes in neurotransmitters correlated with behavioral performance. These findings suggest that CNS consequences of developmental toxicants studied in the absence of a broader spectrum of BEs may not necessarily be predictive of human outcomes. Evaluating the role of specific BEs as a modulator of neurodevelopmental insults offers the opportunity to determine what specific BEs may ameliorate the associated impacts and can assist in establishing underlying neurobiological mechanisms.

Subject-Specific Increases in Serum S-100B Distinguish Sports-Related Concussion from Sports-Related Exertion

Background The on-field diagnosis of sports-related concussion (SRC) is complicated by the lack of an accurate and objective marker of brain injury. Purpose To compare subject-specific changes in the astroglial protein, S100B, before and after SRC among collegiate and semi-professional contact sport athletes, and compare these changes to differences in S100B before and after non-contact exertion. Study Design Longitudinal cohort study. Methods From 2009–2011, we performed a prospective study of athletes from Munich, Germany, and Rochester, New York, USA. Serum S100B was measured in all SRC athletes at pre-season baseline, within 3 hours of injury, and at days 2, 3 and 7 post-SRC. Among a subset of athletes, S100B was measured after non-contact exertion but before injury. All samples were collected identically and analyzed using an automated electrochemiluminescent assay to quantify serum S100B levels. Results Forty-six athletes (30 Munich, 16 Rochester) underwent baseline testing. Thirty underwent additional post-exertion S100B testing. Twenty-two athletes (16 Rochester, 6 Munich) sustained a SRC, and 17 had S100B testing within 3 hours post-injury. The mean 3-hour post-SRC S100B was significantly higher than pre-season baseline (0.099±0.008 µg/L vs. 0.058±0.006 µg/L, p = 0.0002). Mean post-exertion S100B was not significantly different than the preseason baseline. S100B levels at post-injury days 2, 3 and 7 were significantly lower than the 3-hour level, and not different than baseline. Both the absolute change and proportional increase in S100B 3-hour post-injury were accurate discriminators of SRC from non-contact exertion without SRC (AUC 0.772 and 0.904, respectively). A 3-hour post-concussion S100B >0.122 µg/L and a proportional S100B increase of >45.9% over baseline were both 96.7% specific for SRC. Conclusions Relative and absolute increases in serum S100B can accurately distinguish SRC from sports-related exertion, and may be a useful adjunct to the diagnosis of SRC.

Acute plasma tau relates to prolonged return to play after concussion

Objective: To determine whether tau changes after sport-related concussion (SRC) relate to return to play (RTP). Methods: Collegiate athletes underwent preseason plasma sampling and cognitive testing and were followed. After a SRC (n = 46), athletes and controls (n = 37) had sampling at 6 hours, and at 24 hours, 72 hours, and 7 days after SRC. A sample of 21 nonathlete controls were compared at baseline. SRC athletes were grouped by long (>10 days, n = 23) and short (≤10 days, n = 18) RTP. Total tau was measured using an ultrasensitive immunoassay. Results: Both SRC and athlete controls had significantly higher mean tau at baseline compared to nonathlete healthy controls (F101,3 = 19.644, p < 0.01). Compared to SRC athletes with short RTP, those with long RTP had higher tau concentrations overall, after controlling for sex (F39,1 = 3.59, p = 0.022), compared to long RTP athletes, at 6 (p < 0.01), 24 (p < 0.01), and 72 hours (p = 0.02). Receiver operator characteristic analyses showed that higher plasma tau 6 hours post-SRC was a significant predictor of RTP >10 days (area under the curve 0.81; 95% confidence interval 0.62–0.97, p = 0.01). Conclusions: Elevated plasma tau concentration within 6 hours following a SRC was related to having a prolonged RTP, suggesting that tau levels may help inform RTP.

Characterization of Inhalation Exposure to Jet Fuel among U.S. Air Force Personnel

BACKGROUND Jet propulsion fuel-8 (JP-8) is the primary jet fuel used by the US military, collectively consuming ~2.5 billion gallons annually. Previous reports suggest that JP-8 is potentially toxic to the immune, respiratory, and nervous systems. The objectives of this study were to evaluate inhalation exposure to JP-8 constituents among active duty United States Air Force (USAF) personnel while performing job-related tasks, identify significant predictors of inhalation exposure to JP-8, and evaluate the extent to which surrogate exposure classifications were predictive of measured JP-8 exposures. METHODS Seventy-three full-time USAF personnel from three different air force bases were monitored during four consecutive workdays where personal air samples were collected and analyzed for benzene, ethylbenzene, toluene, xylenes, total hydrocarbons (THC), and naphthalene. The participants were categorized a priori into high- and low-exposure groups, based on their exposure to JP-8 during their typical workday. Additional JP-8 exposure categories included job title groups and self-reported exposure to JP-8. Linear mixed-effects models were used to evaluate predictors of personal air concentrations. RESULTS The concentrations of THC in air were significantly different between a priori exposure groups (2.6 mg m(-3) in high group versus 0.5 mg m(-3) in low, P < 0.0001), with similar differences observed for other analytes in air. Naphthalene was strongly correlated with THC (r = 0.82, P < 0.0001) and both were positively correlated with the relative humidity of the work environment. Exposures to THC and naphthalene varied significantly by job categories based on USAF specialty codes and were highest among personnel working in fuel distribution/maintenance, though self-reported exposure to JP-8 was an even stronger predictor of measured exposure in models that explained 72% (THC) and 67% (naphthalene) of between-worker variability. In fact, both self-report JP-8 exposure and a priori exposure groups explained more between-worker variability than job categories. CONCLUSIONS Personal exposure to JP-8 varied by job and was positively associated with the relative humidity. However, self-reported exposure to JP-8 was an even stronger predictor of measured exposure than job title categories, suggesting that self-reported JP-8 exposure is a valid surrogate metric of exposure when personal air measurements are not available.

Genome-Wide Changes in Peripheral Gene Expression following Sports-Related Concussion

We conducted a prospective study to identify genome-wide changes in peripheral gene expression before and after sports-related concussion (SRC). A total of 253 collegiate contact athletes underwent collection of peripheral blood mononuclear cells (PBMCs) before the sport season (baseline). Sixteen athletes who subsequently developed an SRC, along with 16 non-concussed teammate controls, underwent repeat collection of PBMCs within 6 h of injury (acutely). Concussed athletes underwent additional sample collection at 7 days post-injury (sub-acutely). Messenger RNA (mRNA) expression at baseline was compared with mRNA expression acutely and sub-acutely post-SRC. To estimate the contribution of physical exertion to gene changes, baseline samples from athletes who subsequently developed an SRC were compared with samples from uninjured teammate controls collected at the acute time-point. Clinical outcome was determined by changes in post-concussive symptoms, postural stability, and cognition from baseline to the sub-acute time-point. SRC athletes had significant changes in mRNA expression at both the acute and sub-acute time-points. There were no significant expression changes among controls. Acute transcriptional changes centered on interleukins 6 and 12, toll-like receptor 4, and NF-κB. Sub-acute gene expression changes centered on NF-κB, follicle stimulating hormone, chorionic gonadotropin, and protein kinase catalytic subunit. All SRC athletes were clinically back to baseline by Day 7. In conclusion, acute post-SRC transcriptional changes reflect regulation of the innate immune response and the transition to adaptive immunity. By 7 days, transcriptional activity is centered on regulating the hypothalamic-pituitary-adrenal axis. Future efforts to compare expressional changes in fully recovered athletes with those who do not recover from SRC could suggest putative targets for therapeutic intervention.

Evaluation of Nintendo Wii Balance Board as a Tool for Measuring Postural Stability After Sport-Related Concussion.

CONTEXT Recent changes to postconcussion guidelines indicate that postural-stability assessment may augment traditional neurocognitive testing when making return-to-participation decisions. The Balance Error Scoring System (BESS) has been proposed as 1 measure of balance assessment. A new, freely available software program to accompany the Nintendo Wii Balance Board (WBB) system has recently been developed but has not been tested in concussed patients. OBJECTIVE To evaluate the feasibility of using the WBB to assess postural stability across 3 time points (baseline and postconcussion days 3 and 7) and to assess concurrent and convergent validity of the WBB with other traditional measures (BESS and Immediate Post-Concussion Assessment and Cognitive Test [ImPACT] battery) of assessing concussion recovery. DESIGN Cohort study. SETTING Athletic training room and collegiate sports arena. PATIENTS OR OTHER PARTICIPANTS We collected preseason baseline data from 403 National Collegiate Athletic Association Division I and III student-athletes participating in contact sports and studied 19 participants (age = 19.2 ± 1.2 years, height = 177.7 ± 8.0 cm, mass = 75.3 ± 16.6 kg, time from baseline to day 3 postconcussion = 27.1 ± 36.6 weeks) who sustained concussions. MAIN OUTCOME MEASURE(S) We assessed balance using single-legged and double-legged stances for both the BESS and WBB, focusing on the double-legged, eyes-closed stance for the WBB, and used ImPACT to assess neurocognition at 3 time points. Descriptive statistics were used to characterize the sample. Mean differences and Spearman rank correlation coefficients were used to determine differences within and between metrics over the 3 time points. Individual-level changes over time were also assessed graphically. RESULTS The WBB demonstrated mean changes between baseline and day 3 postconcussion and between days 3 and 7 postconcussion. It was correlated with the BESS and ImPACT for several measures and identified 2 cases of abnormal balance postconcussion that would not have been identified via the BESS. CONCLUSIONS When accompanied by the appropriate analytic software, the WBB may be an alternative for assessing postural stability in concussed student-athletes and may provide additional information to that obtained via the BESS and ImPACT. However, verification among independent samples is required.

Plasma metabolomic biomarkers accurately classify acute mild traumatic brain injury from controls

Past and recent attempts at devising objective biomarkers for traumatic brain injury (TBI) in both blood and cerebrospinal fluid have focused on abundance measures of time-dependent proteins. Similar independent determinants would be most welcome in diagnosing the most common form of TBI, mild TBI (mTBI), which remains difficult to define and confirm based solely on clinical criteria. There are currently no consensus diagnostic measures that objectively define individuals as having sustained an acute mTBI. Plasma metabolomic analyses have recently evolved to offer an alternative to proteomic analyses, offering an orthogonal diagnostic measure to what is currently available. The purpose of this study was to determine whether a developed set of metabolomic biomarkers is able to objectively classify college athletes sustaining mTBI from non-injured teammates, within 6 hours of trauma and whether such a biomarker panel could be effectively applied to an independent cohort of TBI and control subjects. A 6-metabolite panel was developed from biomarkers that had their identities confirmed using tandem mass spectrometry (MS/MS) in our Athlete cohort. These biomarkers were defined at ≤6 hours following mTBI and objectively classified mTBI athletes from teammate controls, and provided similar classification of these groups at the 2, 3, and 7 days post-mTBI. The same 6-metabolite panel, when applied to a separate, independent cohort provided statistically similar results despite major differences between the two cohorts. Our confirmed plasma biomarker panel objectively classifies acute mTBI cases from controls within 6 hours of injury in our two independent cohorts. While encouraged by our initial results, we expect future studies to expand on these initial observations.

Potential Metabolomic Linkage in Blood between Parkinson’s Disease and Traumatic Brain Injury

The etiologic basis for sporadic forms of neurodegenerative diseases has been elusive but likely represents the product of genetic predisposition and various environmental factors. Specific gene-environment interactions have become more salient owing, in part, to the elucidation of epigenetic mechanisms and their impact on health and disease. The linkage between traumatic brain injury (TBI) and Parkinson’s disease (PD) is one such association that currently lacks a mechanistic basis. Herein, we present preliminary blood-based metabolomic evidence in support of potential association between TBI and PD. Using untargeted and targeted high-performance liquid chromatography-mass spectrometry we identified metabolomic biomarker profiles in a cohort of symptomatic mild TBI (mTBI) subjects (n = 75) 3–12 months following injury (subacute) and TBI controls (n = 20), and a PD cohort with known PD (n = 20) or PD dementia (PDD) (n = 20) and PD controls (n = 20). Surprisingly, blood glutamic acid levels in both the subacute mTBI (increased) and PD/PDD (decreased) groups were notably altered from control levels. The observed changes in blood glutamic acid levels in mTBI and PD/PDD are discussed in relation to other metabolite profiling studies. Should our preliminary results be replicated in comparable metabolomic investigations of TBI and PD cohorts, they may contribute to an “excitotoxic” linkage between TBI and PD/PDD.