- Title
- Advanced magnetic resonance spectroscopic techniques for neurometabolic profiling of multiple sclerosis
- Creator
- Al-iedani, Oun
- Resource Type
- thesis
- Date
- 2020
- Description
- Professional Doctorate - Doctor of Philosophy (PhD)
- Description
- Multiple sclerosis (MS) is an immune-mediated neuronal disorder in which inflammatory cells attack the myelin of the central nervous system, leading to varying extents of neuroaxonal injury, demyelination and gliosis by affecting both the brain and spinal cord. In the last few decades, conventional MRI techniques, sensitive at detecting MS plaques in the brain and spinal cord, have been the main imaging tool for diagnosis and on-going monitoring for MS pathology, reflecting inflammatory activity via T2 lesions and brain damage via atrophy measurements. However, MRI features of MS are not specific to its pathological substrates which contribute to the development of permanent disability. Presently, MRI is not able to quantify the damage in normal appearing white matter and has technical limitations in detecting and quantifying damage to grey matter. Also, the clinical manifestations of MS plaques in different anatomical locations such as spinal cord and optic nerves are variable. A non-invasive, advanced MR technique of one-dimensional (1D) magnetic resonance spectroscopy (H-MRS) is capable of exploring the metabolic alterations of the MS brain in relatively small volumes of interest. This has the potential to provide molecular biomarkers for early detection and to monitor disease progression of the MS brain. This technique may allow better understanding of the pathophysiology of symptoms and aid in the development of new treatments. In this thesis, the diurnal stability and long-term repeatability and reliability of in-vitro and in-vivo measurements at 3 Tesla have been investigated to prove the validity of H-MRS technique in clinical settings. This study demonstrates the stability of neurometabolite levels in longitudinal studies (over extended periods of time) and the reliable detection and distinction of neurometabolites between healthy controls (HCs) and MS patients. The findings of the study showed H-MRS is reliable and had minimal diurnal variations. Disease modifying therapies (DMT) for multiple sclerosis treatment were deemed vital to understand the underlying pathology resulting in disease progression and therefore assist in developing new meaningful imaging biomarkers to evaluate the clinical efficacy of treatment radiologically. Few studies have used 1D H-MRS to monitor the response to DMT in relapsing-remitting MS (RRMS) and to assess if immunomodulatory therapies can reverse or prevent the progression of neuronal injury. Dimethyl fumarate (DMF), an oral DMT for MS, displays anti-oxidative properties, thought to be via modulation of glutathione (GSH). A longitudinal study was designed to evaluate the impact of DMF treatment longitudinally over 24 months (five time points) on hippocampal neurometabolites in RRMS patients using single voxel 1D H-MRS techniques at short TE and 3T. This study showed that cross-sectional analysis confirmed the importance of hippocampal NAA and increase in myo-inositol as indicators of axonal loss and gliosis in RRMS cohort compared to HCs. This study also showed that DMF treatment may impact on hippocampal metabolism, specifically GSH levels, which supports its assumed anti-oxidant mode of action, resulting in an anti-inflammatory effect in the MS brain following DMF treatment. This study is the first to illustrate a change in hippocampal metabolism associated with the onset of treatment with DMF in RRMS patients. This thesis also investigated the impact of DMF treatment on the pre-frontal cortex (PFC) and posterior cingulate gyrus (PCG) metabolic profiles at pre- and post-treatment onset at four time points using 1D H-MRS technique. The correlation between brain metabolites and severity of clinical and neuropsychological symptoms were analysed at three time points at baseline, 12 and 24 months following the initiation of DMF treatment in the regions responsible for cognitive functioning; PFC and PCG. This study showed significant cross-sectional reductions in N-acetylaspartate (NAA) in PFC and PCG and increase in PFC tCho in RRMS cohort compared to HCs. DMF treatment showed the mean NAA levels in PFC and PCG were altered significantly over the 24-month treatment period, but stabilised and didn’t significantly change between 1st and 2nd year of treatment. This study demonstrated that 1D H-MRS is a sensitive marker of disease activity with several metabolites correlating with clinical parameters, but also capable to detect a treatment effects prior to volumetric change. This study suggested that PCG and PFC regions may be sensitive to the progression of clinical and cognitive disabilities of MS patients and may play an important role in monitoring cognitive performance. Injectable DMTs (interferon and glatiramer acetate) as well as oral DMTs (fingolimod and DMF) have not only shown the reduction of relapse rate and T2 lesion load but also brain atrophy, which seems to be related to long term disease on disability. Additionally, the efficacy of these DMTs have also been evaluated using 1D H-MRS methods in a cross-sectional fashion. This study is the first in-vivo investigation of the impact of these treatments on the hippocampus, PFC and PCG metabolism in RRMS patients. RRMS patients, on therapy for a minimum of 6 months, with no new clinical symptoms or change in their disability status in the last 6 months were included in the study. This study also established the association between clinical symptoms in MS patients especially cognitive function and neurometabolites as well as volumetric changes. We also confirmed the importance of NAA and myo-inositol (m-Ins) as indicators of axonal loss and gliosis. This study demonstrated hippocampal metabolic correlation with memory, disability scale and TARCS; PCG with memory, CSF volume and TARCS; while PFC metabolites correlated with attention, depression and anxiety. The cross-sectional nature of our findings warrants longitudinal investigations to further clarify clinical effects of fingolimod and injectables, and to determine associations between hippocampus, PFC and PCG metabolic levels and treatment efficacy. Clinically, three-dimensional magnetic resonance spectroscopic imaging (3D MRSI) is more suitable than single voxel method due to the former’s ability to obtain important metabolic information with extended brain coverage. This thesis investigated the performance of fast MRSI techniques at short TE and 3T, using LASER sequence with adiabatic gradient-offset independent adiabaticity wideband pulse (GOIA-W)[16,4]. This fast MRSI techniques coupled with tissue segmentation of the brain were used to identify neurometabolic differences in normal appearing white matter (NAWM) and white matter lesions (WML) of RRMS patients compared to age and sex-matched HCs. This study used a novel post-processing analysis pipeline and three binary support vector machine (SVM) classification that allowed individual small voxel analysis to demonstrate true nature of NAWM and WML and distinguish tissue types. Our findings of significant changes in NAWM and more so in WML of MS patients compared with healthy voxels using spiral 3D MRSI indicates that the metabolic abnormalities (reduced NAA and increased m-Ins) in RRMS are associated with a gradual loss of axonal integrity and astrogliosis in white matter. This study demonstrates the benefit of MRSI in evaluating MS neurometabolic changes in damaged NAWM. SVM of MRSI data in the MS brain may be suited for clinical monitoring and progression of MS patients.
- Subject
- multiple sclerosis; MRS; MRSI; fast MRSI; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1414080
- Identifier
- uon:36699
- Rights
- Copyright 2020 Oun Al-iedani
- Language
- eng
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