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DELAYED OUTCOMES OF IONIZING RADIATION ON COGNITIVE FUNCTION, NEUROIMAGING, AND THE CEREBROSPINAL FLUID PROTEOME

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title
DELAYED OUTCOMES OF IONIZING RADIATION ON COGNITIVE FUNCTION, NEUROIMAGING, AND THE CEREBROSPINAL FLUID PROTEOME
author
Johnson, Brendan Joseph
abstract
ABSTRACTBrendan J. Johnson, D.V.M. In the event of a nuclear accident or attack, thousands of people could receive high doses of total-body irradiation (TBI). Although retrospective analysis of atomic bomb and nuclear disaster survivors have been conducted, the long-term outcomes on the brain and cognitive function are conflicting. Radiation-induced brain injury (RIBI) is characterized by inflammation, vascular injury, and white matter (WM) injury, but the exact pathogenesis of this progressive injury is unknown. The goal of this work was to characterize the functional consequences of single, high-dose TBI in rhesus macaques (Macaca mulatta) and to identify pathways for therapeutic intervention. The multifaceted approach to assess RIBI in these animals included imaging, cerebrospinal fluid (CSF) and plasma analysis, and cognitive assessments and was conducted in four separate studies. In Chapter 2, we retrospectively evaluated T1-weighted and diffusion tensor imaging (DTI) MRI scans from over 159 rhesus macaques. Young, irradiated animals had lower relative WM than unirradiated controls. Furthermore, WM microstructure was altered by TBI with reduced WM maturation and myelin injury demonstrated using DTI. Chapter 3 consisted of two separate components. First, we developed the methodology to induce hypercapnia for use during MRI to evaluate cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). Next, we applied our methods to evaluate the effects of radiation on CBF and CVR in 75 male rhesus macaques. We documented a xvi predictable decline in CVR with age in unirradiated animals but did not detect an effect of radiation on either CBF or CVR. Moreover, analysis of microvessel density in the hippocampus and frontal lobe from banked brain tissues revealed no difference by irradiation status. In Chapter 4, we evaluated the CSF and plasma proteomes in 14 macaques 2-14 years after TBI (dose range: 4-8 Gy) compared with 16 unirradiated controls. Albumin and total protein analysis of CSF and plasma revealed no significant increase in blood-brain- barrier leakage in TBI animals. The CSF and plasma proteomes of irradiated animals were characterized by increased expression of inflammatory proteins, specifically acute-phase proteins, complement factors, and adhesion molecules. Chapter 5 focused on the ramifications of TBI on cognitive function. Fifteen animals successfully completed a task of problem-solving ability. Using this test, we were unable to identify differences in cognitive ability in irradiated animals 3-8 years after TBI. We documented behavioral differences between irradiated animals and unirradiated controls characterized by an increased willingness of irradiated animals to interact with the test. In conclusion, total-body irradiation results in systemic and local inflammation, myelin injury, and disorganization of WM years after exposure. Vascular injury likely contributes to RIBI in these animals, but our whole-brain imaging was unable to detect functional differences between irradiated and unirradiated groups. These findings suggest the RIBI in these animals may be detected using sensitive imaging modalities even in the absence of significant cognitive decline.
subject
Cerebrospinal Fluid
Cognition
Neuroimaging
Non-human primate
Radiation
contributor
Cline, Mark (advisor)
Andrews, Rachel (committee member)
Baxter, Mark (committee member)
Whitlow, Christopher (committee member)
date
2024-02-13T09:36:06Z (accessioned)
2024 (issued)
degree
Molecular Medicine and Translational Science (discipline)
embargo
2029-01-12 (terms)
2029-01-12 (liftdate)
identifier
http://hdl.handle.net/10339/102909 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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