Genetic Variants and Persistent Impairment Following Mild Traumatic Brain Injury: A Systematic Review.

OBJECTIVE: The purpose of this review is to systematically assess primary research publications on known genetic variants, which modify the risk for symptoms or dysfunction persisting 30 days or more following mild traumatic brain injury (mTBI). SUMMARY OF REVIEW: A search of PubMed and Embase from inception through June 2022 identified 42 studies that associated genetic variants with the presence of symptoms or cognitive dysfunction 30 days or more following mTBI. Risk of bias was assessed for each publication using the Newcastle Ottawa Scale (NOS). Fifteen of the 22 studies evaluating apolipoprotein E ( APOE ) ɛ4 concluded that it was associated with worse outcomes and 4 of the 8 studies investigating the brain-derived neurotrophic factor ( BDNF ) reported the Val66Met allele was associated with poorer outcomes. The review also identified 12 studies associating 28 additional variants with mTBI outcomes. Of these, 8 references associated specific variants with poorer outcomes. Aside from analyses comparing carriers and noncarriers of APOE ɛ4 and BDNF Val66Met, most of the reviewed studies were too dissimilar, particularly in terms of specific outcome measures but also in genes examined, to allow for direct comparisons of their findings. Moreover, these investigations were observational and subject to varying degrees of bias. CONCLUSIONS: The most consistent finding across articles was that APOE ɛ4 is associated with persistent post-mTBI impairment (symptoms or cognitive dysfunction) more than 30 days after mTBI. The sparsity of other well-established and consistent findings in the mTBI literature should motivate larger, prospective studies, which characterize the risk for persistent impairment with standardized outcomes in mTBI posed by other genetic variants influencing mTBI recovery.

Neurometabolic alterations in children and adolescents with functional neurological disorder.

OBJECTIVES: In vivo magnetic resonance spectroscopy (MRS) was used to investigate neurometabolic homeostasis in children with functional neurological disorder (FND) in three regions of interest: supplementary motor area (SMA), anterior default mode network (aDMN), and posterior default mode network (dDMN). Metabolites assessed included N-acetyl aspartate (NAA), a marker of neuron function; myo-inositol (mI), a glial-cell marker; choline (Cho), a membrane marker; glutamate plus glutamine (Glx), a marker of excitatory neurotransmission; γ-aminobutyric acid (GABA), a marker of inhibitor neurotransmission; and creatine (Cr), an energy marker. The relationship between excitatory (glutamate and glutamine) and inhibitory (GABA) neurotransmitter (E/I) balance was also examined. METHODS: MRS data were acquired for 32 children with mixed FND (25 girls, 7 boys, aged 10.00 to 16.08 years) and 41 healthy controls of similar age using both short echo point-resolved spectroscopy (PRESS) and Mescher-Garwood point-resolved spectroscopy (MEGAPRESS) sequences in the three regions of interest. RESULTS: In the SMA, children with FND had lower NAA/Cr, mI/Cr (trend level), and GABA/Cr ratios. In the aDMN, no group differences in metabolite ratios were found. In the pDMN, children with FND had lower NAA/Cr and mI/Cr (trend level) ratios. While no group differences in E/I balance were found (FND vs. controls), E/I balance in the aDMN was lower in children with functional seizures-a subgroup within the FND group. Pearson correlations found that increased arousal (indexed by higher heart rate) was associated with lower mI/Cr in the SMA and pDMN. CONCLUSIONS: Our findings of multiple differences in neurometabolites in children with FND suggest dysfunction on multiple levels of the biological system: the neuron (lower NAA), the glial cell (lower mI), and inhibitory neurotransmission (lower GABA), as well as dysfunction in energy regulation in the subgroup with functional seizures.

Age of first exposure to soccer heading: Associations with cognitive, clinical, and imaging outcomes in the Einstein Soccer Study.

Introduction: The objective of this study is to assess the role of age at first exposure (AFE) to soccer heading as a predictor of known adverse associations of recent and longer-term heading with brain microstructure, cognitive, and behavioral features among adult amateur soccer players. Methods: The sample included 276 active amateur soccer players (196 male and 81 female) aged 18-53 years old. AFE to soccer heading was treated as a binary variable, dichotomized at ≤ 10 years vs. >10 years old, based on a recently promulgated US Soccer policy, which bans heading for athletes ages 10 and under. Results: We found that soccer players who began heading at age 10 or younger performed better on tests of working memory (p = 0.03) and verbal learning (p = 0.02), while accounting for duration of heading exposure, education, sex, and verbal intelligence. No difference in brain microstructure or behavioral measures was observed between the two exposure groups. Discussion: The findings indicate that, among adult amateur soccer players, AFE to heading before age 10 compared to later start of heading, is not associated with adverse outcomes, and may be associated with better cognitive performance in young adulthood. Cumulative heading exposure across the lifespan, rather than early life exposure, may drive risk for adverse effects and should be the focus of future longitudinal studies to inform approaches to enhance player safety.

Associations Between Neurochemistry and Gait Performance Following Concussion in Collegiate Athletes.

OBJECTIVE: To evaluate the strength of associations between single-task and dual-task gait measures and posterior cingulate gyrus (PCG) neurochemicals in acutely concussed collegiate athletes. SETTING: Participants were recruited from an NCAA Division 1 University. PARTICIPANTS: Nineteen collegiate athletes acutely (<4 days) following sports-related concussion. DESIGN: We acquired magnetic resonance spectroscopy (MRS) in the PCG and gait performance measurements in the participants, acutely following concussion. Linear mixed-effects models were constructed to measure the effect of gait performance, in the single- and dual-task settings, and sex on the 6 neurochemicals quantified with MRS in mmol. Correlation coefficients were also calculated to determine the direction and strength of the relationship between MRS neurochemicals and gait performance, postconcussion symptom score, and number of previous concussions. MAIN MEASURES: Average gait speed, average cadence, N-acetyl aspartate, choline, myo-inositol, glutathione, glutamate plus glutamine, and creatine. RESULTS: Single-task gait speed (P = .0056) and cadence (P = .0065) had significant effects on myo-inositol concentrations in the PCG, independent of sex, in concussed collegiate athletes. Single-task cadence (P = .047) also had a significant effect on glutathione in the PCG. No significant effects were observed between dual-task gait performance and PCG neurochemistry. CONCLUSIONS: These findings indicate that increased concentrations of neuroinflammatory markers in the PCG are associated with slower single-task gait performance within 4 days of sports-related concussion.

Chronic traumatic encephalopathy: neuroimaging biomarkers.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with repetitive head impact exposure, such as that resulting from sports-related concussive and subconcussive brain trauma. Currently, the only way to diagnose CTE is by using neuropathologic markers obtained postmortem. To diagnose CTE earlier, so that possible treatment interventions may be employed, there is a need to develop noninvasive in vivo biomarkers of CTE. Neuroimaging provides promising biomarkers for the diagnosis of CTE and may also help elucidate pathophysiologic changes that occur with chronic sports-related brain injury. To describe the use of neuroimaging as presumed biomarkers of CTE, this chapter focuses on only those studies that report the chronic stages of sports-related brain injury, as opposed to previous chapters that described neuroimaging in the context of acute and subacute injury. Studies using positron emission tomography and magnetic resonance imaging and spectroscopy will be discussed for contact/collision sports such as American football, boxing, mixed martial arts, rugby, and soccer, in which repetitive head impacts are common.