- Title
- Diffusion tensor tractography evaluation for white matter damage in MS patients
- Creator
- Alshehri, Abdulaziz
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2023
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Multiple sclerosis (MS) is an idiopathic, acquired neurological disorder described by complex patterns of demyelination and axonal loss in the central nervous system (CNS). Symptoms include among others chronic fatigue, loss of motor control, and cognitive deficits. Clinical imaging outcomes such as lesion load and atrophy have limitations in diagnosing and tracking treatment response in MS, often have varying correlations with the symptoms of MS, and lack insight into pathological processes. Diffusion-weighted imaging (DWI) is a promising neuroimaging technique that can provide insights into the microstructural changes in MS. This thesis investigates the utility of DWI techniques, specifically the use of diffusion tensor imaging (DTI), fibre orientation distributions (FODs), and tractography, by exploring their relationships with clinical parameters and the effects of disease-modifying therapies (DMTs) in patients with a relapsing-remitting disease course. This thesis contains chapters of published, presented, and submitted works that contribute to understanding WM microstructure and its relationship with MS pathology and clinical outcomes. DTI is a method of measuring water flow in the brain, fitting a tensor model described by the nature of a molecule’s polarization and relaxation in a pulsed magnetic field. Because water mobility is highly sensitive to the surrounding cellular environment, it is thought that DTI can provide a more sensitive measure of pathology and better identify WM microstructure than traditional MRI, such as structural T1-weighted imaging. FODs are a recent extension of understanding multiple spherical harmonics of water flow in the brain. These FODs allow higher resolution of diffusivity in areas of crossing WM and are thought to better circumscribe pathological tissue than DTI. In combination with tractography, a method of reconstructing WM fibres, FODs can allow insight into the underlying cellular pathologies of MS. This thesis compared DTI metrics between people with relapsing-remitting MS (pw-RRMS) and healthy controls (HCs) and examined their correlations with clinical parameters and volumetric measures. Significant alterations in diffusivity and fractional anisotropy (FA) in total brain white matter (TBWM) were found in pw-RRMS when compared to HCs, and moderate correlations were found between these DTI measures and disability status and cognitive domains. It investigated the sensitivity of DTI to microstructural changes in pw-RRMS and the effects of different DMTs on DTI parameters in normal-appearing white matter (NAWM) and white matter lesions (WML) over time. It showed correlations between diffusion metrics and cognitive domains, suggesting the potential of DTI in evaluating treatment efficacy and disease progression. By examining the microstructural integrity of cortico-thalamic-striatal (CTS) tracts, the thesis found significant differences between pw-RRMS with HCs, and significant correlations of these changes with fatigue and disability over time. Utilizing FODs and tractography, it focused on assessing white matter microstructure at a network level in pw-RRMS over two years and their correlation with clinical parameters. It revealed widespread reductions in fibre density in specific brain regions of pw-RRMS compared to HCs and highlighted potential remyelination in a thalamocortical network during disease-modifying treatments. The findings from this thesis contribute to a deeper understanding of the microstructural changes in MS and their clinical implications. Both DTI and FODs combined with tractography have demonstrated correlations with clinical symptoms, cognitive function, and treatment response, suggesting their potential as valuable markers for assessing disease severity and treatment outcomes in MS. The utilization of advanced imaging techniques and analysis tools in this thesis provides insights into the underlying pathophysiology and supports the development of long-term treatment strategies for MS. This thesis consists of many chapters for some published/submitted or under review papers that include: Chapter 2 aims to contrast DTI metrics in people with relapsing-remitting MS (pw-RRMS) and healthy controls (HCs) and study the links between these metrics, clinical parameters, and volumetric measures. This study showed that diffusivity increased, and FA decreased for total brain white matter (TBWM) in pw-RRMS. Mean and radial diffusivity in TBWM and axial diffusivity in WML moderately correlated with disability status. Volumetric segmentation indicated a decrease in total brain volume, grey and white matter, accompanied by an increase in cerebrospinal fluid in pw-RRMS. DTI parameters in this study showed moderate correlation with cognitive domains, contrasting with white matter-related volumetric measurements in pw-RRMS, demonstrating the usefulness of DTI for assessing clinical features of MS. Chapter 3 evaluates the sensitivity of DTI in detecting microstructural changes in the white matter of pw-RRMS that result in progressive disability, since the role of diffusion in assessing the effectiveness of various therapies requires further research. This pioneering study compares the longitudinal effects of different DMTs on DTI metrics in pw-RRMS in NAWM and WML with HCs. Findings showed dissimilarities in most clinical parameters between pw-RRMS and HCs in both instances of observation. However, no significant differences in average changes over time were observed in any diffusion metrics between treatment groups in either tissue type. Diffusion metrics in NAWM and WML negatively correlated with most cognitive domains, whereas FA positively correlated at the initial measurement but only for NAWM at follow-up and negatively with disability over time. Chapter 4 delves into the microstructural integrity of cortico-thalamic-striatal (CTS) tracts and their correlation with fatigue and disability over time, using DTI measures in NAWM and WML selected nine tracts-of-interest (TOIs). The key finding is the significant difference in most diffusion metrics in TOIs in pw-RRMS versus HCs at baseline and 2-year follow-up (2-YFU). Notably, there was a significant decrease in WML diffusivities and an increase in FA over the follow-up period in most TOIs. Nonetheless, in this clinically stable cohort, DTI parameters remained unchanged in NAWM tracts over time, indicating potential repair of damaged MS tracts. This may serve as an outcome measure in future remyelination clinical trials. Chapter 5 studies white matter (WM) microstructure at a network level in a group of clinically stable, treated RRMS patients over two years and contrasts this network with matched HCs. Also, it explores the connection between changes in WM microstructure during treatment and clinical parameters in pw-RRMS. This study seeks to connect multiple sclerosis research with network neuroscience by quantifying network-level differences. This research points out extensive network reductions in fibre density in pw-RRMS at baseline compared to HCs, occurring in the frontal, parietal, and temporal regions. This network increased in size and connectivity at the 2-YFU, comprising similar regions as the baseline differences. Pw-RRMS exhibited lower fibre density at baseline in a thalamocortical network than 2-YFU, suggesting that remyelination may have occurred in this network over time. Chapter 6 concludes the main findings of this research and provides recommendations for future work.
- Subject
- multiple sclerosis (MS); diffusion tensor imaging (DTI); white matter; clinical parameters; tractography; Cortico-thalamic-striatal (CTS); fatigue; disability; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1493041
- Identifier
- uon:53468
- Rights
- Copyright 2023 Abdulaziz Alshehri
- Language
- eng
- Full Text
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