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

Abstract

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.

Subconcussive brain vital signs changes predict head-impact exposure in ice hockey players

“… 23 Magnetic resonance imaging studies have demonstrated that players exposed to repetitive head impacts over the course of a season show significant abnormalities compared to controls over the same time period and that these abnormalities are related to the extent of exposure to head impacts. 4 , 5 , 24 …”

Identifying degenerative effects of repetitive head trauma with neuroimaging: a clinically-oriented review

“…It is unclear whether these structural white matter findings reflect neurodegenerative changes, especially in younger, asymptomatic participants. However, several studies document cerebrovascular pathophysiology associated with repetitive head trauma, including altered cerebral perfusion dynamics [ 64 , 94 – 97 ] and blood–brain-barrier dysfunction [ 98 , 99 ], which may produce white matter signal abnormalities on MRI. In CTE cases, more severe white matter rarefaction is associated with greater exposure to repetitive head trauma, severity of neurofibrillary tangle deposition, and likelihood of developing dementia [ 32 ].…”

Sex-Related Differences in Regional Blood–Brain Barrier Integrity in Non-Demented Elderly Subjects

“…Although the present study has a small number of participants, we think that it can play a role as an introductory study that can help determine the pathophysiology of AD or plan a drug treatment strategy in the future. Secondly, our DCE imaging acquisition time was only 10 min, which is relatively short compared to recent recommendations [ 26 , 27 ]. Slow subtle BBB leak could be better visualized using a modified DCE protocol with a longer acquisition time (>16 min) [ 26 ].…”

“…Secondly, our DCE imaging acquisition time was only 10 min, which is relatively short compared to recent recommendations [ 26 , 27 ]. Slow subtle BBB leak could be better visualized using a modified DCE protocol with a longer acquisition time (>16 min) [ 26 ]. However, in terms of clinical practice, 10 min appears to be the maximum acquisition time which limits motion in elderly patients.…”