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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Shoemaker, J. Kevin

Abstract

Dampening of pulsatile pressure waves within blood vessels is an essential feature of the arterial system. Vascular stiffening increases the speed and the pulsatile energy of the pressure wave, leaving low resistance organs like the brain vulnerable to microvascular mechanical damage. Due to access limitations, the effect of cerebrovascular stiffening on brain structure and neurological outcomes remains unknown. The purpose of this thesis was to assess the influence of vascular stiffening in peripheral arteries on white matter integrity (WMLv) (Chapter 2), obtain direct measures of cerebrovascular stiffness via phase contrast magnetic resonance imaging (PCMRI) (Chapter 3), and examine the impact of acute vasodilation on cerebrovascular stiffness (Chapter 4). We found that ischemic heart disease patients (IHD) had greater vascular stiffness compared with controls. However, IHD status did not influence WMLv. Regardless of vascular pathology, common carotid stiffness and ultrasound-based carotid-cerebral pulse wave transit times were associated with WMLv independently. Therefore, we applied PCMRI to the cerebral vessels to acquire direct measures of cerebrovascular stiffness in the internal carotid (ICA) and middle cerebral (MCA) arteries. Using cardiac-gated PCRMI, we collected blood flow velocity data at multiple segments of the ICA (icaPWV) and M1-M2 segment of the MCA (mcaPWV) to construct time–intensity curves and calculate PWV at temporal resolutions up to 25ms. We demonstrated that mcaPWV can detect vascular stiffening in a cross-section of young and older healthy individuals. Additionally, PWV increases from extracranial to intracranial segments, and this acceleration is amplified with age. We then measured peripheral and intracranial vascular stiffness in response to vasodilation using hypercapnia (HC; 6% CO2, 21% O2, balanced N2) and nitroglycerin (NTG; 0.4mg, sublingual) in healthy young adults. Vasodilation in the MCA increased PWV and characteristic impedance. Additionally, the preferential effect of HC on conduit and downstream vascular properties of cerebral vessels versus non-specific conduit vasodilation of NTG suggests that multiple mechanisms may contribute to cerebrovascular stiffening. This thesis provides a method to obtain direct measures of intracranial PWV and demonstrates the capacity for acute modification of cerebrovasculature stiffness. This work may advance future understanding of cerebrovascular changes, damage, and therapeutics in vulnerable populations.

Summary for Lay Audience

Dampening of the high-pressure flow in blood vessels is an essential feature of the arterial system. Stiffening of the vascular system, which occurs in aging and disease, increases the speed and pulsatile energy of the pressure wave. This renders low resistance organs like the brain susceptible to microvascular mechanical damage. Peripheral extracranial arterial stiffening is associated with cerebrovascular abnormalities. However, due to access challenges imposed by the skull, the influence of cerebrovascular stiffness on brain structure and neurological outcomes remains unknown. In that regard, this dissertation provides evidence that the speed of the pulse wave moving into the brain is associated with structural and functional impairments to cerebral white matter. Further, we introduce a novel application of magnetic resonance imaging that can be used to obtain direct measurements of cerebrovascular stiffness. Using this methodology, we found that the pulse wave accelerates when it moves into the brain, and this acceleration is amplified in aging arteries. Additionally, we applied laboratory and pharmacological techniques to acutely modify the cerebral vessel mechanics, which can alter the pulsatile properties of the blood pressure wave in the brain. This dissertation describes a method to obtain direct measures of intracranial pulse wave velocity while providing information on the capacity for acute modification of cerebrovascular stiffness. In the future, this work may lay the foundation for advancing our understanding of cerebrovascular damage, change, and therapeutics in vulnerable populations.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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