A Novel, Low-Cost Glaucoma Calculator to Identify Glaucoma Patients and Stratify Management.

Glaucoma is a leading cause of preventable blindness globally. Nearly, half of the patients who have glaucoma in the United States are unaware of their diagnosis, and this number is far greater in resource poor areas. The risk of progressive and irreversible loss of vision is decreased with an early diagnosis, and better access to treatment is vital to improve the visual outcome for patients. We therefore postulated that a minimally invasive, low-cost calculator used to predict the risk of glaucoma and inform the course of follow-up care will improve patient prognosis. We retrospectively examined data from 104 eyes of patients who underwent a complete ocular examination, visual field, and corneal pachymetry at Advanced Eye Care of New York (54 with glaucoma and 50 controls). Receiver operating curves (ROC) were utilized to determine the correct glaucoma classification rates of the Laroche glaucoma calculator (Range -3 to 18), a novel tool that combines age, intraocular pressure (IOP), and central corneal thickness (CCT) into a composite metric. Additionally, we compared the discriminatory power of this calculator to age, intraocular pressure (IOP), and central corneal thickness (CCT) separately. A score of greater than or equal to 6 on the Laroche glaucoma calculator (sensitivity 90.74%, specificity 64.00%, correct classification 77.88%) optimizes the accuracy of this tool. Compared to IOP (Area Under the Curve (AUC) = 0.72, chi2 = 4.21, p=0.04) and CCT (AUC = 0.53), chi2 24.72 p < 0.001), the Laroche glaucoma calculator (AUC = 0.81) was significantly better at discriminating against glaucoma patients vs. controls. These results demonstrate that the Laroche calculator is a novel, effective tool for identifying glaucoma, and it may provide a low-cost risk stratification tool, particularly in areas with limited resources.

Framing potential for adverse effects of repetitive subconcussive impacts in soccer in the context of athlete and non-athlete controls.

The benefits of athletic activity may be attenuated by sport-related head impacts, including soccer-related concussion and subconcussive events. The purpose of this study is to characterize the specific effects of soccer heading on white matter microstructure and cognitive function, independent of concussion, relative to non-athlete controls and relative to active athletes who are not involved in collision sports. 246 amateur soccer players, 72 non-contact/non-collision sports athletes and 110 healthy,non-athlete controls were included in the study, and underwent cognitive testing and 3T diffusion tensor imaging (DTI). Voxelwise linear regression, comparing soccer players and non-contact/non-collision sports athletes healthy,non-athlete controls, identified regions of abnormally low and high fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) in athlete participants. Generalized estimating equations were used to examine the effects of 2 week and 1 year heading exposure quartile on cognitive performance and on the volume of each high and each low DTI parameter. Athletes with no or lower exposure to repetitive heading exhibited greater expression of low RD, greater expression of high FA and better performance on tasks of attention, processing speed, verbal memory, and working memory compared to non-athletes. Soccer players with the highest exposure to repetitive head impacts, however, did not differ significantly from healthy, non-athletes on either micro-structural features or cognitive performance, findings not explained by concussion history or demographic factors. These results are consistent with the notion that beneficial effects of athletic conditioning or training on brain structure and function may be attenuated by exposure to repeated subconcussive head impacts.

Associations of Apolipoprotein E ε4 Genotype and Ball Heading With Verbal Memory in Amateur Soccer Players.

Importance: Emerging evidence suggests that long-term exposure to ball heading in soccer, the most popular sport in the world, confers risk for adverse cognitive outcomes. However, the extent to which the apolipoprotein E ε4 (APOE ε4) allele, a common risk factor for neurodegeneration, and ball heading are associated with cognition in soccer players remains unknown. Objective: To determine whether the APOE ε4 allele and 12-month ball heading exposure are associated with verbal memory in a cohort of adult amateur soccer players. Design, Settings, and Participants: A total of 379 amateur soccer players were enrolled in the longitudinal Einstein Soccer Study from November 11, 2013, through January 23, 2018. Selection criteria included participation in soccer for more than 5 years and for more than 6 months per year. Of the 379 individuals enrolled in the study, 355 were genotyped. Three players were excluded for reporting extreme levels of heading. Generalized estimating equation linear regression models were employed to combine data across visits for a cross-sectional analysis of the data. Exposures: At each study visit every 3 to 6 months, players completed the HeadCount 12-Month Questionnaire, a validated, computer-based questionnaire to estimate 12-month heading exposure that was categorized as low (quartiles 1 and 2), moderate (quartile 3), and high (quartile 4). Main Outcome and Measures: Verbal memory was assessed at each study visit using the International Shopping List Delayed Recall task from CogState. Results: A total of 352 soccer players (256 men and 96 women; median age, 23 years [interquartile range, 21-28 years]) across a total of 1204 visits were analyzed. High levels of heading were associated with worse verbal memory performance (ß = -0.59; 95% CI, -0.93 to -0.25; P = .001). There was no main association of APOE ε4 with verbal memory (ß = 0.09; 95% CI, -0.24 to 0.42; P = .58). However, there was a significant association of APOE ε4 and heading with performance on the ISRL task (χ2 = 7.22; P = .03 for overall interaction). In APOE ε4-positive players, poorer verbal memory associated with high vs low heading exposure was 4.1-fold greater (APOE ε4 negative, ß = -0.36; 95% CI, -0.75 to 0.03; APOE ε4 positive, ß = -1.49; 95% CI, -2.05 to -0.93), and poorer verbal memory associated with high vs moderate heading exposure was 8.5-fold greater (APOE ε4 negative, ß = -0.13; 95% CI, -0.54 to 0.29; APOE ε4 positive, ß = -1.11, 95% CI, -1.70 to -0.53) compared with that in APOE ε4-negative players. Conclusions and Relevance: This study suggests that the APOE ε4 allele is a risk factor for worse memory performance associated with higher heading exposure in the prior year, which highlights that assessing genetic risks may ultimately play a role in promoting safer soccer play.

BDNF Val66Met Positive Players Demonstrate Diffusion Tensor Imaging Consistent With Impaired Myelination Associated With High Levels of Soccer Heading: Indication of a Potential Gene-Environment Interaction Mechanism.

The purpose of this study was to examine the potential effect modifying role of the BDNF Val66Met polymorphism on the association of soccer heading with white matter microstructure. We studied 312 players enrolled in the ongoing Einstein Soccer Study, a longitudinal study of amateur soccer player in New York City and surrounding areas. At enrollment and 2 years later, total heading in the prior 12 months (12-mo.) was estimated using an established self-report instrument and diffusion tensor imaging (DTI) was performed. Generalized Estimating Equations (GEE) logistic regression models were employed to test effect modification by the BDNF Val66Met polymorphism on the association between 12-mo. heading exposure and DTI. We identified a significant interaction of 12-mo heading*BDNF Val66Met genotype on the presence of low Radial Diffusivity, a DTI marker associated with myelination. Only Met (+) players demonstrated significantly reduced odds of low RD [OR (95 % CI): -2.36 (-3.53, -1.19)] associated with the highest vs. lowest quartile of 12-mo heading exposure. BDNF Val66Met (+) soccer players with long-term exposure to high levels of heading exhibit less low Radial Diffusivity, suggesting impaired re-myelination may be a substrate of the previously reported association between heading and poor functional outcomes in soccer players.

The neurobiological effects of repetitive head impacts in collision sports.

It is now recognized that repetitive head impacts (RHI) in sport have the potential for long-term neurological impairments. In order to identify targets for intervention and/or pharmacological treatment, it is necessary to characterize the neurobiological mechanisms associated with RHI. This review aims to summarize animal and human studies that specifically address Blood Brain Barrier (BBB) dysfunction, abnormal neuro-metabolic and neuro-inflammatory processes as well as Tau aggregation associated with RHI in collision sports. Additionally, we examine the influence of physical activity and genetics on outcomes of RHI, discuss methodological considerations, and provide suggestions for future directions of this burgeoning area of research.

Comparing Region of Interest versus Voxel-Wise Diffusion Tensor Imaging Analytic Methods in Mild and Moderate Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Diffusion tensor imaging is a magnetic resonance imaging technique that is uniquely capable of detecting microstructural tissue damage in mild and moderate traumatic brain injuries (TBIs). To date, it remains unknown if two common analytic techniques, region of interest (ROI) versus voxel-wise (VW) analyses, detect injury in similar locations. The purpose of this systematic review and meta-analysis was to directly compare the regions of abnormality elucidated by each method. Twenty-seven ROI and 11 VW studies met our inclusion criteria. Our ROI meta-analysis identified 11 regions, including the splenium of the corpus callosum, where fractional anisotropy (FA) was significantly decreased in TBI patients, compared with controls. Likewise, we identified higher mean diffusivity/apparent diffusivity constant in the genu, body, and splenium of the corpus callosum. Alternatively, our VW analysis identified one region of high FA in the right superior longitudinal fasciculus and seven regions of low FA, with the two largest located in the corpus callosum. High mean diffusivity and high radial diffusivity, both in the right inferior longitudinal fasciculus, also was revealed by our VW analysis. Moreover, we have shown that the magnitude of damage in the corpus callosum revealed by ROI analysis (z = -3.15) is greater than that demonstrated by VW analysis (z = -1.41). Overall, this study indicates that both ROI and VW analytic methods are sensitive to low FA in the corpus callosum; however, the ROI method has more power to detect the full extent of tissue abnormality in the corpus callosum. More research utilizing standardized methods and reporting is essential to fully characterize the extent to which ROI and VW analyses can concordantly detect other locations of pathology in mild and moderate TBI patients.

MRI-defined White Matter Microstructural Alteration Associated with Soccer Heading Is More Extensive in Women than Men.

Purpose To examine the role of sex in abnormal white matter microstructure after soccer heading as identified by using the diffusion-tensor imaging (DTI) metric fractional anisotropy (FA). Materials and Methods In this prospective cross-sectional study, 98 individuals who were enrolled in a larger prospective study of amateur soccer players (from 2013 to 2016) were matched 1:1 for age and history of soccer heading in the prior 12 months. Among the subjects, 49 men (mean age, 25.7 years; range, 18-50 years) and 49 women (mean age, 25.8 years; range, 18-50 years) with median total soccer headings per year of 487 and 469, respectively, underwent 3.0-T DTI. Images were registered to the Johns Hopkins University template. A voxelwise linear regression was fitted for FA with terms for the number of headings during the previous 12 months and its interaction with sex after controlling for the following potential confounders: age, years of education, number of lifetime concussions, and handedness. In the resulting statistical maps, P < .01 indicated a statistically significant difference, with a threshold cluster size larger than 100 mm3. Results Among men, three regions were identified in which greater heading exposure was associated with lower FA; eight such regions were identified among women (>100 contiguous voxels, P < .01). In seven of the eight regions identified in women, the association between heading and FA was stronger in women than in men. There was no significant difference of heading with FA between the sexes for any region in which heading was associated with FA among men (P > .01, <100 contiguous voxels). Conclusion With similar exposure to heading, women exhibit more widespread evidence of microstructural white matter alteration than do men, suggesting preliminary support for a biologic divergence of brain response to repetitive trauma. © RSNA, 2018 Online supplemental material is available for this article.

Heading and unintentional head impacts have opposing associations with Patient Reported Outcomes in amateur soccer players.

The effects of soccer-related head impacts, beyond overt concussions, on Patient Reported Outcomes (PROs) have not been explored to date. Generalized estimating equations were employed to determine the association between soccer-related head impacts (headers in the prior 2 weeks, unintentional head impacts in the prior 2 weeks, headers in the prior 12 months and lifetime concussions) on PROs including depression, anxiety, sleep disturbance and sleep impairment. Compared to players with no unintentional head impacts in the prior 2 weeks, players with one unintentional exposure reported more symptoms of anxiety (p = 0.002) and players with 2+ exposures reported more symptoms of depression (p = 0.006) and anxiety (p < 0.001). In contrast, players in the 3rd Quartile of 12 mo. headers reported less anxiety (p = 0.001), sleep disturbance (p = 0.002) and sleep impairment (p < 0.001) compared to those in the 1st quartile. Unintentional head impacts are associated with worse PROs while more headers are paradoxically associated with better PROs.

In vivo effects of ketamine on glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder: Proof of concept.

We previously reported the rapid and robust clinical effects of ketamine versus saline infusions in a proof-of-concept crossover trial in unmedicated adults with obsessive-compulsive disorder (OCD). This study examined the concurrent neurochemical effects of ketamine versus saline infusions using proton magnetic resonance spectroscopy ((1)H MRS) during the clinical proof-of-concept crossover trial. Levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the excitatory neurochemicals glutamate+glutamine (Glx) were acquired in the medial prefrontal cortex (MPFC), a region implicated in OCD pathology. Seventeen unmedicated OCD adults received two intravenous infusions at least 1 week apart, one of saline and one of ketamine, while lying supine in a 3.0 T GE MR scanner. The order of each infusion pair was randomized. Levels of GABA and Glx were measured in the MPFC before, during, and after each infusion and normalized to water (W). A mixed effects model found that MPFC GABA/W significantly increased over time in the ketamine compared with the saline infusion. In contrast, there were no significant differences in Glx/W between the ketamine and saline infusions. Together with earlier evidence of low cortical GABA in OCD, our findings suggest that models of OCD pathology should consider the role of GABAergic abnormalities in OCD symptomatology.

Assessment of glutamate in striatal subregions in obsessive-compulsive disorder with proton magnetic resonance spectroscopy.

Glutamatergic signaling abnormalities in cortico-striatal circuits are hypothesized to lead to the repetitive thoughts and behaviors of obsessive-compulsive disorder (OCD). To test this hypothesis, studies have used proton magnetic resonance spectroscopy (1H MRS) to measure glutamatergic compounds in the striatum of individuals with OCD. However, no studies have used methods that could measure glutamate minimally contaminated by glutamine and γ-aminobutyric acid (GABA) in striatal subregions. Therefore, in this study, a proton MRS imaging (1H MRSI) technique with relatively high spatial resolution at 3.0 T was used to measure minimally contaminated glutamate levels in three striatal subregions (i.e., dorsal caudate, dorsal putamen, and ventral striatum) in 15 unmedicated adults with OCD and 16 matched healthy control subjects. No significant group differences in glutamate levels were found in any of the three striatal subregions. In contrast, a study in unmedicated pediatric OCD patients that measured glutamatergic compounds in the dorsal caudate by MRS at 1.5 T found significant elevations. Further studies are warranted to assess whether these discrepant MRS findings are due to differences in subject age or MRS methodology, or potentially are associated with glutamatergic gene variants implicated in OCD.