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

Ronel Veksler, Udi Vazana, Yonatan Serlin, Ofer Prager, Jonathan Ofer, Nofar Shemen, Andrew M. Fisher, Olga Minaeva, Ning Hua, Rotem Saar-Ashkenazy, Itay Benou, Tammy Riklin-Raviv, Ellen Parker, Griffin Mumby, Lyna Kamintsky, Steven Beyea, Chris V. Bowen, Ilan Shelef, Eoin O'Keeffe, Matthew CampbellDaniela Kaufer, Lee E. Goldstein, Alon Friedman

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


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.

Original languageEnglish
Pages (from-to)1826-1842
Number of pages17
Issue number6
StatePublished - 1 Jun 2020


  • American football
  • blood-brain barrier
  • dynamic contrast-enhanced magnetic resonance imaging
  • repetitive mild traumatic brain injury
  • transcellular transport

ASJC Scopus subject areas

  • Clinical Neurology


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