Chronic Dysregulation of the Cerebrovasculature in a Mouse Model of Repetitive Mild Traumatic Brain Injury

Lynch, Cillian Eamonn (2019). Chronic Dysregulation of the Cerebrovasculature in a Mouse Model of Repetitive Mild Traumatic Brain Injury. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000e882

Abstract

There are over 2 million reports of Traumatic Brain Injury (TBI) every year in the United States alone, the majority of which are classified as a mild head injury. Incidences of mild TBI (mTBI), the kind of which are sustained most routinely by contact sports athletes, active military personnel, are now well accepted as being a risk factor for development of chronic neurodegenerative disorders such as Chronic Traumatic Encephalopathy (CTE).

To date, the diagnosis of CTE has been based on post-mortem neuropathological assessment of brain tissue, precluding the possibility of prophylactic or interventional therapy in human patients presenting with symptomatology too ambiguous for antemortem diagnosis, and ergo, appropriate clinical trial stratification.

Recently, it has been reported that military personnel and players of contact sports experiencing repetitive m-TBI (r-mTBI), as well as individuals suffering from chronic TBI-related illness, demonstrate a deficit in Cerebral Vascular Reactivity (CVR). This physiological impairment is non-invasively detected following repeat mTBI, and seen to be sustained at chronic time-points post-injury in both r-mTBI and moderate to severe TBI patients alike, implicating CVR detriment as an endophenotypic biomarker and possible in vivo diagnostic of TBI-related neuropathogenesis, and Traumatic Cerebral Vascular Injury (TCVI).

In this thesis, I developed and validated a preclinical in vivo imaging setup to examine CVR in our CTE-like neuropathology exhibiting mouse model of r-mTBI, with an aim to characterizing the evolving pathobiology of TCVI and concurrent euro behavioral impairment, and their correlation to perturbed CVR. I demonstrated recapitulation of the CVR deficit seen in the human population in our animal model, alongside sustained memory and learning impairment, and signs of an underlying response of the cerebral vasculature to injury. These finding implicate measurement of CVR as a valid preclinical diagnostic, and the treatment of TCVI as a compelling parallel pathological target in r-mTBI.