Multimodal Neuroimaging Signatures of Disease Characterization and Correlation in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic neurological disorder characterised by complex patterns of demyelination and axonal loss in the central nervous system (CNS). Symptoms include, but are not limited to, chronic fatigue, anxiety, depression, disability, and cognitive decline. Conventional magnetic resonance imaging (MRI) is the gold standard of clinical imaging for diagnosis, monitoring and evaluation of treatment. However, current clinical imaging techniques have limitations with regards to investigating pathological processes and finding correlations between disease progression and symptoms of MS. Advanced multimodal neuroimaging can provide insight into the molecular, metabolic, and microstructural levels of changes in the brains of people with MS (pwMS). This thesis covers the utility of multimodal MR neuroimaging signatures in MS, and explores the associations between these unique MRI metrics and clinically relevant measures of disease severity and progression in MS. It includes chapters of published, presented, and submitted work that have contributed to a deeper understanding of the molecular, metabolic, and microstructural changes in MS and their clinical relevance. The chapters proceed as follows: Chapter 1 presents a thorough exploration of MS, focusing on its pathophysiology, phenotypic classifications, symptoms, diagnostic processes, and treatment options. It highlights the role of MRI as the principal imaging technique for detecting and monitoring MS, emphasizing its efficacy and utility. The chapter focuses on some advanced MRI methods that been used in this thesis to uncover the underlying pathophysiological mechanisms responsible for MS symptoms. By correlating observable MRI changes with the symptoms experienced by pwMS, these advanced techniques provide valuable insights into how specific lesions or brain regions and neurodegenerative processes contribute to the diverse neurological symptoms observed in MS. This connection aids clinicians and researchers in better understanding and addressing the complexities of the disease. Chapter 2 provides a comprehensive review of a range of advanced myelin-sensitive MRI-based techniques that have been developed for the quantification of myelin in the brains of pwMS. These techniques include relaxometry metrics, ultra-short echo-time (UTE) imaging, magnetization transfer imaging (MTI), and quantitative susceptibility mapping (QSM) metrics. This chapter also discusses the histological methods that have been used to validate MR myelin imaging metrics and considers how these metrics might be applied in clinical settings. Furthermore, this chapter highlights the importance of MR myelin imaging for monitoring MS disease progression and for evaluating the effectiveness of new therapeutic strategies that focus on myelin repair. Chapter 3 evaluates amide proton transfer weighted (APTw) imaging in the brain of people with relapsing-remitting MS (pw-RRMS). APTw is a novel MR molecular imaging technique that is based on chemical exchange saturation transfer (CEST), which indirectly detects selected metabolites while also providing morphological images. APTw measures the exchange of protons between amide groups (associated with peptides and proteins) and water. This first study in pw-RRMS evaluates the ability of APTw signals to differentiate between T1w isointense lesions and their contralateral normal appearing white matter (cNAWM), and T1w hypointense lesions (also known as ‘black hole’ lesions) and their cNAWM. Our results indicate that APTw imaging has the potential to provide essential complementary molecular information about MS lesions and pathology in a non-invasive manner. Chapter 4 explores changes in brain iron deposition in pw-RRMS in comparison with that of healthy controls (HCs), with a particular focus on regions linked to the fear circuit. The study evaluated the relationship between iron deposition in these areas as determined using QSM and clinical measurements. Our research revealed that QSM signals indicating iron deposition were significantly higher in pw-RRMS than in HCs. In particular, caudate, putamen, and medial prefrontal cortex (mPFC) showed the greatest increases. These three regions along with anterior cingulate cortex (ACC) are strongly associated with severity of fatigue in pw-RRMS. Chapter 5 investigates neurometabolic abnormalities within the frontal and parietal regions of three types of tissue - normal-appearing grey matter (NAGM), normal-appearing white matter (NAWM), and white matter lesions (WML) - using in vivo multi-voxel magnetic resonance spectroscopic imaging (MRSI) to acquire data from both pw-RRMS and HCs. Specifically, we measure the ratios of glutamate (Glu), glutamine+glutamate (Glx), glutathione (GSH), myo-inositol (Ins), and total N-acetylaspartate (tNAA) in relation to total creatine (tCr) in the above tissues with the aim was of identifying neurometabolic alteration signatures which could then be correlated with clinical measurements. Glu and Glx ratios in pw-RRMS were higher than in HCs for all tissue types. For pw-RRMS, Glu and Glx ratios in frontal regions were significantly higher than in parietal regions in both NAWM and WML, which seems to indicate that frontal regions have an increased susceptibility to MS progression. GSH and Ins ratios in the parietal regions were higher than in the frontal regions of pw-RRMS across all tissue types, with the differences also being significant. Meanwhile, tNAA ratios in the frontal regions of NAGM and NAWM were significantly lower than those in the parietal regions for pw-RRMS. We found significant positive correlations between Glu ratios in frontal WML and anxiety scores, and significant positive correlations between GSH ratios in parietal NAGM and fatigue scores. We also found significant negative correlations between tNAA ratios in both frontal and parietal NAWM and WML regions and disability scores. Chapter 6 summarises the key findings of this research and proposes avenues for future exploration. Additionally, this chapter identifies limitations of the current study and suggests recommendations for further investigation to build upon this work.