The slope of contrast-agent intensity in each voxel was calculated, with negative slopes reflecting contrast-agent washout from blood vessels, near zero slopes corresponding to BBB-protected brain tissue, and positive slopes reflecting contrast-agent accumulation due to BBB breakdown. The 95th percentile of all slopes in the control group (0.02) was defined as the threshold corresponding to high permeability. Automatic gaussian clustering of the percentage of suprathreshold voxels in each individual revealed 2 significantly different subpopulations (Mann-Whitney U test, P < .001): a group with low percentages, consisting of 11 control athletes and 9 players, and a group with high percentages, consisting of 6 football players and 1 control athlete.
Representative maps of suprathreshold voxels (slope >0.02, see color bar). The players in the pathological-BBB group presented focal BBB lesions in different cortical regions including the temporal (player 4), frontal (player 5), and parietal (player 6) lobes. Both gray and white matter were involved.
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Weissberg I, Veksler R, Kamintsky L, et al. Imaging Blood-Brain Barrier Dysfunction in Football Players. JAMA Neurol. 2014;71(11):1453–1455. doi:10.1001/jamaneurol.2014.2682
Copyright 2014 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
There has been an increasing awareness of the long-term neuropsychiatric pathologies associated with repeated mild traumatic brain injury (mTBI) and specifically sports-related concussive and subconcussive head impacts.1 While mTBI had been associated with diffusion tensor imaging evidence of diffusivity changes in soccer,2 American football, and hockey players,3 the mechanisms underlying the development of post-mTBI neurodegenerative complications are poorly understood.
Accumulating evidence points to vascular pathology and dysfunction of the blood-brain barrier (BBB) as a potential link between severe TBI and neurodegeneration.4 Moreover, participation in American football has been associated with changes in blood proteins reflecting BBB leakage.5 Thus, here we set out to visualize the extent and location of BBB dysfunction in football players using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).
Sixteen male amateur football players (mean [SD] age, 26.53 [3.3] years) and 13 male track and field athlete control participants (mean [SD] age, 28.54 [2.2] years) were recruited during the 2013/2014 season of American football in Israel. Exclusion criteria included previous psychiatric/neurological disorders. The study was approved by the Soroka University Medical Center Helsinki institutional review board, and all participants gave written informed consent.
After at least 2 months of training and competing, all participants underwent DCE-MRI (3.0T Philips Ingenia), and BBB permeability maps were created for each individual.6 In brief, a linear fit was used to calculate the slope of contrast agent concentration in each voxel over time. As positive slopes reflect contrast-agent accumulation due to BBB dysfunction, a threshold for high permeability was defined as the 95th percentile of all slopes in the control group. The percentage of brain volume with suprathreshold voxels was used as a measure of overall BBB pathology in each individual. A gaussian mixture model was applied to automatically cluster all participants into 2 BBB integrity–based groups.
History, symptoms, and cognitive function were evaluated using the National Football League Sideline Concussion Assessment Tool and the Standardized Assessment of Concussion (http://www.nflevolution.com). Comparisons between groups were performed using the Mann-Whitney U test. Data analysis was performed in Matlab 2013 and results are shown as mean (SD).
Following the exclusion of 1 player and 1 control participant owing to motion artifacts, gaussian mixture model clustering divided participants into 2 groups (P < .001): an intact-BBB group (mean [SD] suprathreshold voxels, 3.86% [2.2%]; n = 20) with 9 football players and 11 control participants and a pathological-BBB group (mean [SD] suprathreshold voxels, 16.29% [2.74%]; n = 7), of whom 6 were players (Figure 1). In the pathological group, high-BBB permeability was found in both gray and white matter of the cerebral cortex, with focal BBB lesions located in the base of temporal (n = 4), frontal (n = 5), parietal (n = 6), and occipital (n = 3) lobes (Figure 2). No significant differences in self-reported concussions were found between players (mean [SD], 1 [1.75]) and control participants (mean [SD], 1 [1.88]) nor between the intact-BBB (mean [SD], 0.93 [2.4]) and pathological-BBB (mean [SD], 1.16 [2.4]) groups. Similarly, comparisons of Sideline Concussion Assessment Tool and the Standardized Assessment of Concussion scores revealed no significant differences.
In this study, DCE-MRI was able to reveal BBB pathology in 40% of the examined football players and 8.3% of the control athletes, with football players comprising 85.7% of the pathological-BBB group. While indirect evidence of BBB permeability in football players was previously inferred by relative changes in serum protein levels,5 DCE-MRI enabled direct mapping of BBB lesions and quantitative assessment of overall BBB dysfunction. Although no correlation was found between BBB pathology and concussion history, possibly owing to BBB damage associated with repeated subconcussive impacts or unreported concussions, our results do associate football with an increased risk for BBB pathology. Limitations of this study include a relatively small sample size and lack of long-term follow-up.
Further research is warranted toward understanding the natural course of BBB dysfunction in mTBI, establishing BBB imaging as a reliable diagnostic tool, and potentially targeting the BBB for the prevention of post-mTBI complications.
Corresponding Author: Alon Friedman, MD, PhD, Department of Medical Neuroscience, Dalhousie University, 5850 College St, PO Box 15000, Halifax, NS B3H 4R2, Canada (email@example.com).
Author Contributions: Drs Shelef and Friedman had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Messrs Weissberg and Veksler served as co-first authors, each with equal contribution to the manuscript.
Study concept and design: Weissberg, Milikovsky, Friedman.
Acquisition, analysis, or interpretation of data: Weissberg, Veksler, Kamintsky, Saar-Ashkenazy, Shelef.
Drafting of the manuscript: Weissberg, Veksler, Kamintsky, Saar-Ashkenazy, Milikovsky.
Critical revision of the manuscript for important intellectual content: Weissberg, Kamintsky, Shelef, Friedman.
Statistical analysis: Weissberg, Veksler, Kamintsky, Saar-Ashkenazy, Milikovsky.
Obtained funding: Friedman.
Administrative, technical, or material support: Kamintsky, Saar-Ashkenazy.
Study supervision: Shelef, Friedman.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by the European Union’s Seventh Framework Program (FP7/2007-2013; grant agreement 602102, EPITARGET, to Dr Friedman) and the Israel Science Foundation (grant 713/11 to Dr Friedman).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank the Negev Football (Black Swarm) team for their participation in this study and Hadar Shalev, MD, and Sharon Naparstek, MsC, of the Department of Psychiatry, Soroka University Medical Center, for their advice on the study design. They did not receive compensation for the contributions.
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