Author ORCID Identifier

https://orcid.org/0000-0002-1765-8867

Semester

Spring

Date of Graduation

2024

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Not Listed

Committee Chair

Candice Brown, Ph.D

Committee Co-Chair

Zachary M. Weil, Ph.D

Committee Member

James Simpkins, Ph.D

Committee Member

John Hollander, Ph.D

Committee Member

Werner Geldenhuys, Ph.D

Abstract

Traumatic brain injury (TBI) is a significant health concern across the United States as well as the broader globe, affecting millions of individuals on an annual basis. While most recover from their TBI and resume their lives normally, some subsets of TBI survivors continue to experience impairments and increased risk for future diseases like cardiovascular disease, stroke, and aging related disease like Alzheimer’s Disease or VCID.

TBI remains a fundamentally difficult neurological injury to pin down mechanistically, due to the variability in severity, timing, and age of patient, among other factors. One significant factor in the pathology has consistently been the post-injury function of the cerebrovasculature, and while it is known that TBI worsens cerebrovascular function, much of the general understanding of the mechanisms underlying this dysfunction remains uncovered. This dissertation attempts to uncover some of these mysteries by examining two previously understudied phenomena related to the effects of TBI on ischemic stroke and how prior cerebrovascular damage impacts TBI.

In Part 1, I investigated how TBI has widespread and persistent implications for ischemic stroke outcomes in mice, particularly related to the function of the cerebrovasculature. I determined TBI worsens these stroke outcomes, albeit differently in male and female mice. Additionally, the cerebrovascular dysfunction from even a mild TBI persists well beyond the acute timepoint, and has specific impacts on pericyte connectivity to the endothelium.

In Part 2, I investigated how prior chronic cerebral hypoperfusion led to cerebrovascular dysfunction that is often instrumental in worse TBI outcomes. Notably, combining this hypoperfusion with TBI often led to worse outcomes than the individual impairments alone. These outcomes are prevalent again regarding neurovascular health, as well as in metabolic pathways, both of which are potentially predictive of long-term health.

The data in this dissertation provides further context into the rapidly expanding field of cerebrovascular injury and gives potential for future research in the TBI field. The work conducted here show that there is the potential for prior vascular risk factors to play a significant role in TBI outcomes and emphasize the necessity of future studies to further focus on the mechanistic underpinnings of worsened TBI outcomes to more efficiently treat TBI and future cardio- and cerebrovascular disease.

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