Jane McDevitt

Apolipoprotein E Genotype and Concussion in College Athletes

Objective:To evaluate the association between apolipoprotein E (APOE) polymorphisms (E2, C/T Arg158Cys; E4, T/C Cys112Arg; and promoter, g-219t) and the history of concussion in college athletes. We hypothesized that carrying 1 or more APOE rare (or minor) allele assessed in this study would be associated with having a history of 1 or more concussions. Design:Multicenter cross-sectional study. Setting:University athletic facilities. Participants:One hundred ninety-six male football (n = 163) and female soccer (n = 33) college athletes volunteered. Interventions:Written concussion history questionnaire and saliva samples for genotyping. Main Outcome Measures:Self-reported history of a documented concussion and rare APOE genotype (E2, E4, promoter). Results:There was a significant association (Wald χ2 = 3.82; P = 0.05; odds ratio = 9.8) between carrying all APOE rare alleles and the history of a previous concussion. There was also a significant association (Wald χ2 = 3.96, P = 0.04, odds ratio = 8.4) between carrying the APOE promoter minor allele and experiencing 2 or more concussions. Conclusions:Carriers of all 3 APOE rare (or minor) alleles assessed in this study were nearly 10 times more likely to report a previous concussion and may be at a greater risk of concussion versus noncarriers. Promoter minor allele carriers were 8.4 times more likely to report multiple concussions and may be at a greater risk of multiple concussions versus noncarriers. Research involving larger samples of individuals with multiple concussions and carriers of multiple APOE rare alleles is warranted.

Concussive signs and symptoms following head impacts in collegiate athletes.

Objective: To evaluate the association between having a previously documented concussion and experiencing concussive signs and symptoms (S&S) following head impacts in collegiate athletes. Methods: Two hundred and one college male football (n = 168) and female womens soccer (n = 33) athletes participated in this retrospective case-control study. Athletes completed a questionnaire and reported if they had been diagnosed with concussion and if they experienced concussive S&S following a head impact during a game or practice in the previous year. Results: Almost 60% (89 of 152) of non-concussed athletes reported experiencing S&S following head impacts in the previous year compared to 80% (39 of 49) of concussed athletes. The Phi coefficient (r = 0.196, p = 0.005) results indicated a significant association between previous history of concussion and the occurrence of S&S following a head impact. Conclusions: A large percentage of non-concussed athletes are experiencing concussive S&S following head impacts during games and practices. Previously concussed athletes, however, report experiencing S&S more frequently following head impacts than their non-concussed counterparts. Although this study is subject to the limitations of a retrospective research design, these findings highlight the need for more diligent surveillance from clinicians, as many concussions are being missed.

Effect of soccer heading ball speed on S100B, sideline concussion assessments and head impact kinematics

Abstract Objective: To examine the effect of soccer heading ball speed on S-100B serum concentration, concussion sideline assessments and linear head impact acceleration. Methods: Sixteen division I soccer players participated in this pre-test post-test design study. Athletes performed five standing headers over a 10 minute period at 30 (n = 5), 40 (n = 5) or 50 (n = 6) miles per hour (mph) (randomized). S-100B serum concentration (ng mL−1) and sideline concussion assessments were measured prior to and post-heading. Peak resultant linear head acceleration (gravitational units; g) was measured during soccer heading. Results: No statistically significant interaction effects were identified between ball velocity groups over time on S100B (effect sizes ranged from 0.03–0.23) or concussion assessments tests. There was a non-significant increase (p = 0.06) in head impact acceleration from the 30 (30.6; SD = 6.2 g) to 50 mph (50.7; SD = 7.7 g) ball speed. Conclusions: In this controlled setting, an acute bout of soccer heading across various ball velocities did not affect S100B or concussion assessment test scores. These findings are preliminary, as the small sample size in each group may have played a role in the lack of significant findings.

Association between GRIN2A promoter polymorphism and recovery from concussion

Abstract Objective: To determine genetic variability within the N-methyl-D-aspartate receptor 2A sub-unit (GRIN2A) gene promoter and its association with concussion recovery time. The hypothesis tested was that there would be a difference in allele and/or genotype distribution between two groups of athletes with normal and prolonged recovery. Methods: DNA was extracted from saliva collected from a total of 87 athletes with a physician-diagnosed concussion. The (GT) variable number tandem repeats (VNTR) within the promoter region of GRIN2A was genotyped. The long (L) allele was an allele with ≥25 repeats and the short (S) allele was an allele with <25 repeats in the GT tract. Participants’ recovery time was followed prospectively and was categorized as normal (≤60 days) or prolonged (>60 days). Results: LL carriers were 6-times more likely to recover longer than 60 days following the concussive event (p = 0.0433) when compared to SS carriers. Additionally, L allele carriers were found more frequently in the prolonged recovery group (p = 0.048). Conclusion: Determining genetic influence on concussion recovery will aid in future development of genetic counselling. The clinical relevance of genotyping athletes could improve management of athletes who experience concussion injuries.

Neuronal structural protein polymorphism and concussion in college athletes

Objective: To examine the association between a neuronal structural protein polymorphism and the frequency and severity of concussions in college athletes. Methods: Forty-eight athletes with previous self-reported history of a concussion were matched with 48 controls that did not report a history of concussion. Each group was genotyped for neurofilament heavy (NEFH) polymorphism rs#165602 in this retrospective case-control study. Results: There was no significant association (χ2 = 0.487, p = 0.485) between carrying the NEFH rare allele and a history of one or more concussions due to small effect sizes. A Fishers exact test revealed no significant association (p = 1.00, ϕ = −0.03) between the presence of NEFH rare allele and a history of multiple concussions. The independent t-tests revealed no significant differences in duration of signs and symptoms (t = 1.41, p = 0.17, d = 0.48) or return to play (t = 0.23, p = 0.82, d = 0.08) between NEFH rare allele carrier and non-carriers. Conclusions: Among college athletes, carrying the rare allele assessed may not influence an athletes susceptibility to sustaining a concussion or return to play duration following a concussion.

Assessing subacute mild traumatic brain injury with a portable virtual reality balance device

Abstract Purpose: Balance impairment is a common sensorimotor symptom in mild traumatic brain injury (mTBI). We designed an affordable, portable virtual reality (VR)-based balance screening device (Virtual Environment TBI Screen [VETS]), which will be validated relative to the Neurocom Sensory Organization Test (SOT) to determine if it can replace commonly used postural assessments. Methods: This preliminary study examines healthy adults (n = 56) and adults with mTBI (n = 11). Participants performed six upright postural tasks on the VETS and the SOT. Analysis of variance was used to determine between-group differences. Pearson’s correlations were used to establish construct validity. Known-groups approach was used to establish classification accuracy. Results: The mTBI cohort performed significantly worse than the healthy cohort on the new device (p = 0.001). The new device has 91.0% accuracy and an ROC curve with a significant area-under-the-curve (AUC = 0.865, p < 0.001). Conditions with dynamic visual stimulation were the most sensitive to health status. The SOT had an 84.8% accuracy and AUC =0.703 (p = 0.034). Conclusions: The new VR-based device is a valid measure for detecting balance impairment following mTBI and can potentially replace more expensive and cumbersome equipment. Assessments that test visual-vestibular processing, such as VETS, increase sensitivity to mTBI-related balance deficits, which can be used to guide rehabilitation. Implications for rehabilitation Emerging technology using virtual reality can be economically integrated into the clinical setting for easy testing of postural control in neurologically impaired populations. Tailoring postural assessments to include tasks that rely on visual and vestibular integration will increase the accuracy of detecting balance impairment following mild traumatic brain injury.

Genetic variation in SLC17A7 promoter associated with response to sport-related concussions

Abstract Objective: To determine the association of the single nucleotide polymorphism (SNP) rs74174284 within SLC17A7 promoter with concussion severity or duration. Design: A between-subjects design was utilized. Methods: Saliva samples and concussion severity and duration data were collected from 40 athletes diagnosed with a sport-related concussion by a physician, utilizing a standardized concussion assessment protocol. DNA was extracted, estimated and genotyped. Results: An association was found between the dominant genetic model (CC vs GG + GC; p = 0.0179) and recovery, where those carrying the minor allele were 6.33-times more likely to experience prolonged recovery rates. Within the ImPACT assessment, those carrying the CC genotype (33.38 ± 10.15, p = 0.01) had worse motor speed scores upon initial assessment compared to both heterozygous (CG) and homozygous (GG) genotypes (41.59 ± 7.39). Conclusions: This study was the first to demonstrate an association between genetic polymorphism at rs7417284 SNP in the promoter region of the SLC17A7 gene and concussion severity and duration. Based upon these findings, rs74174284 is a potential predictive genetic marker for identifying athletes who are more susceptible for altered recovery times and worse motor speed ImPACT scores after sport-related concussion.

Sex Differences in Anthropometrics and Heading Kinematics Among Division I Soccer Athletes: A Pilot Study

Background: Soccer players head the ball repetitively throughout their careers; this is also a potential mechanism for a concussion. Although not all soccer headers result in a concussion, these subconcussive impacts may impart acceleration, deceleration, and rotational forces on the brain, leaving structural and functional deficits. Stronger neck musculature may reduce head-neck segment kinematics. Hypothesis: The relationship between anthropometrics and soccer heading kinematics will not differ between sexes. The relationship between anthropometrics and soccer heading kinematics will not differ between ball speeds. Study Design: Pilot, cross-sectional design. Level of Evidence: Level 3. Methods: Division I soccer athletes (5 male, 8 female) were assessed for head-neck anthropometric and neck strength measurements in 6 directions (ie, flexion, extension, right and left lateral flexions and rotations). Participants headed the ball 10 times (25 or 40 mph) while wearing an accelerometer secured to their head. Kinematic measurements (ie, linear acceleration and rotational velocity) were recorded at 2 ball speeds. Results: Sex differences were observed in neck girth (t = 5.09, P < 0.001), flexor and left lateral flexor strength (t = 3.006, P = 0.012 and t = 4.182, P = 0.002, respectively), and rotational velocity at both speeds (t = −2.628, P = 0.024 and t = −2.227, P = 0.048). Neck girth had negative correlations with both linear acceleration (r = −0.599, P = 0.031) and rotational velocity at both speeds (r = −0.551, P = 0.012 and r = −0.652, P = 0.016). Also, stronger muscle groups had lower linear accelerations at both speeds (P < 0.05). Conclusion: There was a significant relationship between anthropometrics and soccer heading kinematics for sex and ball speeds. Clinical Relevance: Neck girth and neck strength are factors that may limit head impact kinematics.

Supporting the Concept of Genetic Predisposition to Prolonged Recovery Following a Concussion

Objectives: During a concussion, mechanical forces cause neuron cell strain that initiates dysfunction through the indiscriminate movement of ions through protein channels. Receptors of extracellular glutamate exacerbate the Ca2+ ion influx, and prolong neuron dysfunction. Genetic variations in the NMDA NR2A subunits (i.e., NR2A & NR2B) are likely to modulate the severity and/or recovery from concussion. Therefore, we hypothesized that genetic variability (e.g., repeat polymorphism) within the GRIN2A (i.e., gene that produces the NR2A subunit) promoter region was associated with concussion recovery time. Methods: Fifty-one athletes with a diagnosed concussion from a hospital concussion program completed a standardized initial evaluation. Concussion injury characteristics, acute signs and symptoms followed by an objective screening, which included the vestibular ocular assessments, the BESS test, and an ImPACT exam were assessed. Enrolled participants provided salivary samples for isolation of DNA. The number of (GT) variable nucleotide tandem repeats (VNTR) within the promoter region (i.e., region of the gene involved in transcription) of GRIN2A was genotyped. The long (L) allele was defined as an allele with ≥ 25 dinucleotide repeats in the GT tract. The short (S) allele was defined as an allele with < 25 dinucleotide repeats in the GT tract. Based on the results of genetic analysis, participants were genotyped as LL homozygotes, SS homozygotes, or LS heterozygotes. Participants’ concussion recovery time was followed prospectively until the full return to play clearance date determined by the treating physician. Participant’s recovery time was categorized as normal (≤ 20 days) or prolonged (greater than 20 days). The DNA region surrounding position (-975 to -776) in the promoter of GRIN2A was amplified by PCR, and was analyzed by capillary electrophoresis. Fragment length polymorphism analysis was performed by measuring the migration time of a PCR product, and extrapolation to the known fragments in the DNA standard ladder using computer software. The number of GT dinucleotide repeats was calculated using the following equation: n(GT)=(L - 167)/2, where L is the length of the PCR fragment estimated in base pairs. Results: There was a significant association (x2 = 4.01, p = 0.045) between the GT VNTR (recessive model: LL versus SS + LS) and recovery, where the chance of prolonged recovery was 4.3 times greater (95% CI1.03-18.04) for homozygous carriers of the long allele. Conclusion: This was the first study to investigate and demonstrate the association of the (GT)n VNTR within GRIN2A with concussion recovery in athletes. Athletes carrying the long allele genotype were predisposed to prolonged recovery following a concussive injury. We believe that genetic influence on concussion recovery will aid in future development of genetic counseling in athletes and individuals exposed to concussive head impacts. The clinical relevance of genotyping athletes could help improve monitoring and management of athletes who experience concussion injuries.

Concussion Recovery Phase Affects Vestibular and Oculomotor Symptom Provocation

Vestibular and oculomotor testing is emerging as a valuable assessment in sport-related concussion (SRC). However, their usefulness for tracking recovery and guiding return-to-play decisions remains unclear. Therefore the purpose of this study was to evaluate their clinical usefulness for tracking SRC recovery. Vestibular and oculomotor assessments were used to measure symptom provocation in an acute group (n=21) concussed≤10 days, prolonged symptoms group (n=10) concussed ≥16 days (median=84 days), healthy group (n=58) no concussions in >6 months. Known-groups approach was used with three groups at three time points (initial, 2-week and 6-week follow-up). Provoked symptoms for Gaze-Stabilization (GST), Rapid Eye Horizontal (REH), Optokinetic Stimulation (OKS), Smooth-Pursuit Slow (SPS) and Fast (SPF) tests, total combined symptoms scores and near point convergence (NPC) distance were significantly greater at initial assessment in both injury groups compared to controls. Injury groups improved on the King-Devick test and combined symptom provocation scores across time. The acute group improved over time on REH and SPF tests, while the prolonged symptoms group improved on OKS. A regression model (REH, OKS, GST) was 90% accurate discriminating concussed from healthy. Vestibular and ocular motor tests give valuable insight during recovery. They can prove beneficial in concussion evaluation given the modest equipment, training and time requirements. The current study demonstrates that when combined, vestibular and oculomotor clinical tests aid in the detection of deficits following a SRC. Additionally, tests such as NPC, GST, REH, SPS, SPF OKS and KD provide valuable information to clinicians throughout the recovery process and may aid in return to play decisions.