Slow blood-to-brain transport underlies enduring barrier dysfunction in American football players.

Repetitive mild traumatic brain injury in American football players has garnered increasing public attention following reports of chronic traumatic encephalopathy, a progressive tauopathy. While the mechanisms underlying repetitive mild traumatic brain injury-induced neurodegeneration are unknown and antemortem diagnostic tests are not available, neuropathology studies suggest a pathogenic role for microvascular injury, specifically blood-brain barrier dysfunction. Thus, our main objective was to demonstrate the effectiveness of a modified dynamic contrast-enhanced MRI approach we have developed to detect impairments in brain microvascular function. To this end, we scanned 42 adult male amateur American football players and a control group comprising 27 athletes practicing a non-contact sport and 26 non-athletes. MRI scans were also performed in 51 patients with brain pathologies involving the blood-brain barrier, namely malignant brain tumours, ischaemic stroke and haemorrhagic traumatic contusion. Based on data from prolonged scans, we generated maps that visualized the permeability value for each brain voxel. Our permeability maps revealed an increase in slow blood-to-brain transport in a subset of amateur American football players, but not in sex- and age-matched controls. The increase in permeability was region specific (white matter, midbrain peduncles, red nucleus, temporal cortex) and correlated with changes in white matter, which were confirmed by diffusion tensor imaging. Additionally, increased permeability persisted for months, as seen in players who were scanned both on- and off-season. Examination of patients with brain pathologies revealed that slow tracer accumulation characterizes areas surrounding the core of injury, which frequently shows fast blood-to-brain transport. Next, we verified our method in two rodent models: rats and mice subjected to repeated mild closed-head impact injury, and rats with vascular injury inflicted by photothrombosis. In both models, slow blood-to-brain transport was observed, which correlated with neuropathological changes. Lastly, computational simulations and direct imaging of the transport of Evans blue-albumin complex in brains of rats subjected to recurrent seizures or focal cerebrovascular injury suggest that increased cellular transport underlies the observed slow blood-to-brain transport. Taken together, our findings suggest dynamic contrast-enhanced-MRI can be used to diagnose specific microvascular pathology after traumatic brain injury and other brain pathologies.

Combining white matter diffusion and geometry for tract-specific alignment and variability analysis.

We present a framework for along-tract analysis of white matter (WM) fiber bundles based on diffusion tensor imaging (DTI) and tractography. We introduce the novel concept of fiber-flux density for modeling fiber tracts' geometry, and combine it with diffusion-based measures to define vector descriptors called Fiber-Flux Diffusion Density (FFDD). The proposed model captures informative features of WM tracts at both the microscopic (diffusion-related) and macroscopic (geometry-related) scales, thus enabling improved sensitivity to subtle structural abnormalities that are not reflected by either diffusion or geometrical properties alone. A key step in this framework is the construction of an FFDD dissimilarity measure for sub-voxel alignment of fiber bundles, based on the fast marching method (FMM). The obtained aligned WM tracts enable meaningful inter-subject comparisons and group-wise statistical analysis. Moreover, we show that the FMM alignment can be generalized in a straight forward manner to a single-shot co-alignment of multiple fiber bundles. The proposed alignment technique is shown to outperform a well-established, commonly used DTI registration algorithm. We demonstrate the FFDD framework on the Human Connectome Project (HCP) diffusion MRI dataset, as well as on two different datasets of contact sports players. We test our method using longitudinal scans of a basketball player diagnosed with a traumatic brain injury, showing compatibility with structural MRI findings. We further perform a group study comparing mid- and post-season scans of 13 active football players exposed to repetitive head trauma, to 17 non-player control (NPC) subjects. Results reveal statistically significant FFDD differences (p-values<0.05) between the groups, as well as increased abnormalities over time at spatially-consistent locations within several major fiber tracts of football players.