- Title
- Understanding Multiple Sclerosis related fatigue using neuroimaging
- Creator
- Arm, Jameen
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2021
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Fatigue is the most common symptom in patients with multiple sclerosis (MS). It affects 70% of MS patients and is closely linked to their perceived general health, mental well-being and overall quality of life. Fatigue has a significant social impact and economic burden on MS sufferers. Although many theories for the origin of fatigue have been proposed, the exact mechanism of how this symptom originates is poorly understood. The evidence so far demonstrates that fatigue may be related to immune-related processes such as acute/chronic inflammation, immune-mediated neurodegeneration/alterations of endocrine functions and non-immune mediated disturbances and factors, namely sleep disturbances, depression, cognitive alterations, chronic infections, and adverse effects of disease modulating therapies. Clinically, it is essential to manage fatigue effectively to minimise its impact on a patient's mental and physical well-being. However, managing fatigue is challenging for neurologists as it overlaps with other symptoms and most importantly, the tools used to evaluate fatigue only provide a subjective assessment. Objective evaluation is critical for developing comprehensive treatment approaches and understanding the pathophysiological mechanisms. Magnetic Resonance Imaging (MRI), primarily a structural imaging technique, has been the workhorse for neurologists to diagnose and monitor the primary disease and manage disease progression in MS. Fatigue has also been studied using MRI, more recently with advanced quantitative methods such as functional MRI and diffusion tensor imaging or DTI, to derive the functional and microstructural correlates linked to this symptom. Fatigued patients displayed both hyper/hypoactive regions and abnormal neural networks in some regional brain structures, predominantly frontal lobe, striatum and basal ganglia, in these studies, yet the pathophysiological mechanism remains elusive. The metabolic underpinning of MS-related fatigue is not fully known. Among all the methods on the study of metabolism, magnetic resonance spectroscopy (MRS) allows the interrogation of metabolic profiling or biochemical fingerprints of different pathological states in vivo. It thus has the potential to be used in understanding fatigue. Earlier studies using one dimensional MRS to investigate the metabolic nature of MS-related fatigue show the changes in major neurochemical in the brain, N-acetyl aspartate. The major challenge however with the one-dimensional technique is separating the signal from various metabolites due to their inherent peak overlap. In this thesis, two distinct MRS methods were used to overcome the issue of peak overlap that enabled not just separating the signals but identifying several new neurochemicals related to MS fatigue that could not be detected in earlier MRS studies. Firstly, two dimensional localised correlation spectroscopy (2D L-COSY) was chosen because of its ability to detect multiple metabolites simultaneously, including those that are in low concentrations, without ambiguity. My initial experiments to investigate this technique's repeatability and diurnal effects demonstrate that 2D L-COSY is a reliable MRS method for in vivo applications. However, the time of the day this method is applied is crucial. The time of the day must be considered while interpreting the results because of the variability in the peak detection. Following this, in a cross-sectional study, the application of 2D L-COSY on a group of relapse remitting MS (RRMS) patients with severe fatigue revealed close associations between overall fatigue score and specific neurochemicals such as glutathione glycerophosphocholine and fucose in the posterior cingulate cortex. This pioneering study provides the first in vivo evidence of the involvement of the multiple metabolites in MS-related fatigue. Fatigue is an evolving symptom and as such, understanding its changing nature over time is equally important. This is an essential component in developing effective pharmaceutical therapies. In my longitudinal study, a significant reduction in fatigue levels was noted in RRMS patients along with a change in many metabolites but mainly for glutathione, glucose and glutamine/glutamate pool as well as NAA over two years following disease modulating therapy. The findings from this study confirmed the evolving nature of MS fatigue and the potential of 2D L-COSY in studying this symptom. Contrary to the evidence that some disease modulating therapies worsen fatigue symptoms, this study proved that treatment with dimethyl fumarate did have a positive effect in improving fatigue. Secondly, I used the spectral editing technique, MEGA-PRESS, to investigate the link between the inhibitory/excitatory neurotransmitters (Ɣ-aminobutyric acid (GABA) and glutamine/glutamate pool from two specific cortical locations (prefrontal and sensorimotor) in a group of RRMS patients. The reduction in GABA levels in fatigued patients compared to healthy subjects illustrates dysfunction in the GABAergic pathway. For the first time, this study established the inverse correlation between fatigue and GABA levels in MS fatigue. In summary, the neurochemical mechanism of MS fatigue has been explored using advanced MRS methods in this thesis. Firstly, the evidence from this study confirms the complex and intricate nature of MS fatigue and that studying metabolic behaviour will undoubtedly enrich our understanding of the pathophysiological mechanism behind this debilitating symptom. Secondly, advanced MRS methods have tremendous potential in unravelling the biochemical underpinnings of symptoms, especially in a heterogeneous neurological condition like MS. The results obtained in this thesis provides an in-depth view of the metabolic nature of fatigue in MS and form a foundation for large clinical and pharmaceutical trials.
- Subject
- Multiple Sclerosis; fatigue; neuroimaging; quality of life; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1468491
- Identifier
- uon:48056
- Rights
- Copyright 2021 Jameen Arm
- Language
- eng
- Full Text
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| View Details Download | ATTACHMENT01 | Thesis | 6 MB | Adobe Acrobat PDF | View Details Download | ||
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