Investigating brain metabolism in multiple sclerosis to examine mechanisms of injury and disability using magnetic resonance spectroscopy

The work presented in this thesis investigates the use of proton magnetic resonance spectroscopy (1H-MRS) to examine metabolic markers of brain injury in clinically isolated syndrome (CIS) and secondary progressive multiple sclerosis (SPMS); and their relationship to both cross-sectional and longitudinal measures of physical and cognitive disability. Metabolic markers of brain injury were measured to examine: (1) the cross-sectional and longitudinal relationships with clinical disability in SPMS; (2) the natural history of metabolites over 96-weeks in SPMS; (3) drug-specific mechanisms of action in a phase 2b multi-arm trial in SPMS; (4) associations with MRI markers of axonal, myelin injury and regional atrophy; and (5) the association between early metabolic changes and long-term disability in a 15-year follow-up cohort with CIS. CIS represents the first clinical attack in relapse onset multiple sclerosis (MS) and in a significant proportion of patients leads to moderate-severe long term disability including progression to the secondary progressive form of the disease. Whilst CIS and early MS are driven by focal inflammatory demyelination, SPMS encompasses several candidate mechanisms that ultimately lead to neurodegeneration. Whilst there has been much work done on understanding the pathology in these two subtypes of MS, there is an ongoing need to further understand in vivo pathology and their relationship to long-term disability. I firstly examined a large cross-sectional cohort from the Multiple Sclerosis – Secondary progressive Multi-Arm Randomisation Trial (MS-SMART, NCT01910259). I demonstrated that total N-acetyl aspartate (tNAA) levels in normal appearing white matter was associated with upper limb function. Associations between metabolic markers of neuroaxonal integrity, astrogliosis, membrane turnover and information processing speed were also found. Using 1H-MRS to longitudinally explore the largest ever reported cohort with SPMS, I confirmed that tNAA is associated with upper limb function at baseline and 96-weeks. I also identified changes in membrane turnover and cellularity (reflected by total choline) in grey and white matter; and identified riluzole as reaching its therapeutic target, but failing to have an impact on decreasing brain atrophy. I then examined which MRI measures are associated with clinical disability over 96-weeks in SPMS. Incorporating MR measures of axonal injury, myelin damage, regional atrophy and lesion load, I demonstrated that cortical grey matter and spinal cord atrophy; and decreased normal appearing white matter tNAA were the MRI measures associated with decreased upper limb function at 96-weeks. Furthermore, spinal cord atrophy was also the only MRI measure associated with a change in upper limb and ambulatory function over 96-weeks. White matter lesion load and tNAA in normal appearing white matter were the markers associated with longitudinal performance on measures of information processing speed in SPMS. Examining long term outcomes from a cohort with CIS, I demonstrated that early changes in neuroaxonal integrity and mitochondrial function (as reflected by tNAA) in normal appearing white matter were associated with moderate-severe disability at 15-years