Optimisation, evaluation and application of cerebrovascular reactivity measurement using magnetic resonance imaging in patients with cerebral small vessel disease
Creators: name: Sleight, Emilie
Publisher: name: The University of Edinburgh
Year: 2023
Subjects: Small vessel disease
Cerebrovascular reactivity
MRI
Blood oxygen level dependent

description: Small vessel disease (SVD) is a common cause of strokes and dementia. Currently, there are no treatments; therefore, developing and validating early biomarkers of disease progression and treatment response is important for future drug trials. Though SVD pathogenesis is not well understood, findings from previous studies suggest that blood-brain barrier dysfunction and impaired cerebrovascular reactivity (CVR) contribute to the disease. The latter can be measured in vivo using a vasoactive stimulus in parallel with magnetic resonance imaging (MRI) techniques sensitive to blood flow, such as blood oxygen level dependent (BOLD) contrast, and has frequently been assessed in patients with steno-occlusive diseases. However, it is unclear if the technique is reliable when investigating cerebrovascular health in deep structures of the brain where SVD is prevalent. Therefore, this thesis aimed to assess and optimise the reliability of CVR measurements and deepen our understanding of its role in SVD pathogenesis. A systematic review was performed to provide a detailed overview of CVR MRI methodologies and clinical applications, including SVD, present in the literature, which identified several acquisition and analysis methods, a need for greater standardisation and lack of data on reliability. Specifically in SVD research, there was limited application of CVR MRI in SVD populations, little optimisation and reliability assessment of CVR in deep brain structures relevant to SVD, such as in white and subcortical grey matter. Following those findings, the effects of voxel- and region-based analysis approaches on reliability of CVR estimates were investigated using simulations and test-retest data from healthy volunteers. Voxel-based CVR magnitude estimates in tissues with high noise levels were prone to bias, whereas biases in region-based estimates were independent of noise level, but consistently underestimated CVR magnitude relative to the ground-truth mean. Furthermore, the test-retest study confirmed the repeatability of CVR estimates from a BOLD-CVR experiment with fixed inhaled stimulus, although a systematic, but small, bias was detected due to habituation to the gas challenge. The data from healthy volunteers were further used to conduct a proof-of-concept and investigate the feasibility of extracting cerebral pulsatility from BOLD-CVR data. Small-to-moderate correlations with pulsatility from phase-contrast MRI were found depending on the regions considered. CVR pulsatility was also computed in a small cohort of SVD patients: it was higher than in healthy volunteers, but no associations were found with SVD burden. It was concluded that further optimisation and validation of the technique is needed before being suitable for clinical research. Following the optimisation of the CVR MRI technique, relationships between CVR and SVD neuroimaging features, cognition, stroke severity and outcome were investigated cross-sectionally and longitudinally in a cohort of patients with mild stroke. In the cross-sectional analysis, CVR impairment in normal-appearing and damaged tissues was associated with worse SVD burden and cognition deficit. Furthermore, the longitudinal analysis showed that baseline CVR impairment predicted worsening of white matter hyperintensity and perivascular space volumes after one year. In conclusion, assessment of CVR in the brain and its deeper structures was successfully conducted in healthy volunteers and patients with SVD using MRI. However, this required appropriate optimisation of processing strategy as the latter can affect accuracy of CVR parameters and inter-study comparability. Importantly, applying the technique in a cohort of SVD patients led to the findings that CVR impairment was related to worse SVD burden and is a potential marker of SVD severity and progression.