P2-206: contribution of focal microvascular disruption to neuroinflammation and tau pathology in a mouse model of impact concussion and chronic traumatic encephalopathy

The mechanisms underlying the association between repetitive head impacts and CTE are unknown. Most of our knowledge on CTE comes from studies characterizing the disease in deceased former athletes and military veterans representing chronic effects of repetitive neurotrauma. Little is known about the changes that occur in the acute-subacute posttraumatic period that trigger CTE pathobiology. In the current study we combined human and murine neuropathological analyses, experimental animal modeling, in vivo and ex vivo imaging analyses of blood-brain barrier function, and biomechanical and computational simulations to investigate these questions. The key pathological hallmarks of the young postmortem athlete brains assessed in this study included traumatic microvascular injury with focal blood brain barrier (BBB) disruption, perivascular neuroinflammation, astrocytosis, axonopathy, and phosphorylated tau proteinopathy. Further investigation using a mouse model of lateral closed-head concussive impact injury revealed focal BBB disruption, infiltration of peripheral monocytes, neuroinflammation, axonopathy, and phosphorylated tau pathology within the area of impact. Most notably, findings from in vivo dynamic contrast-enhanced magnetic resonance imaging showed diagnostically detectable levels of serum protein extravasation that colocalized with impact pathologies within the impact area, and that could be verified ex vivo by gadolinium metallomic imaging mass spectrometry. No significant correlations were found between impact pathologies and transient neurobehavioral deficits recorded at the time of injury. Using computational modeling, we showed that cranial point loading and intracerebral shear stress were generated by impact injury, and that the onset of gross head motion occurred after the peak of high-amplitude shear stress in the brain. We conclude that traumatic microvascular injury leads to extravasation of plasma proteins that trigger focal neural inflammation and aggravate phosphorylated tau proteinopathy following closed-head impact injury. These findings suggest traumatic microvascular injury as a candidate mechanism linking closed-head impact to acute brain injury and chronic post-traumatic sequelae.