Blood-brain barrier disruption in sports-related traumatic encephalopathy syndrome
Cerebrovascular disruption has been implicated in the pathophysiology of head trauma and chronic traumatic encephalopathy (CTE).  However, the long-term consequences of repetitive head trauma on blood–brain barrier (BBB) integrity and its link to cognitive function remains unknown. Here, using dynamic contrast enhanced MRI (DCE-MRI), we show that BBB disruption can be detected years after combat and collision sports athletes (n = 47) have retired from their respective sports. A subgroup of individuals (n = 17) with extensive BBB disruption displayed worse cognitive decline compared to those with less extensive disruption. While commonly used systemic biomarkers of central nervous system injury and neurodegeneration were of limited utility, we did observe a greater systemic inflammatory burden with a higher proportion of circulating monocytes that was significantly associated with cognitive decline in retired athletes. Transcriptomic analysis of these peripheral immune cells revealed dysregulation of the complement system and vascular developmental pathways. Altered expression of complement receptors including C5AR1, ITGAM, ITGB2 and CD59, a potent inhibitor of the membrane attack complex (MAC), was associated with BBB disruption and cognitive decline. Post-mortem tissue from confirmed cases of CTE showed MAC deposition around cerebral blood vessels. Finally, bioinformatic analysis of single nucleus RNA sequencing data from post-mortem CTE cases revealed microglia-endothelial crosstalk which may mediate complement dysregulation. Together, our data suggest that sustained systemic inflammation and persistent BBB disruption is associated with the long-term outcome of repetitive head trauma. Overall design: RNA-seq profiling of peripheral blood mononuclear cells from retired athletes with a history of repetitive head trauma as well as controls from a non-contact sporting background