Mechanisms of spinal cord degeneration and repair in multiple sclerosis: A 3T MRI study of the spinal cord

The spinal cord is a clinically eloquent structure, commonly affected in multiple sclerosis (MS) and spinal neuroaxonal loss is an important cause of non-remitting, disability progression. Neuroaxonal loss in MS is likely to be multifactorial and caused by several disease pathways. In contrast, repair and adaptive mechanisms can ameliorate disability following clinical relapses. This thesis has explored some of these clinically relevant disease mechanisms by combining single-voxel proton spectroscopy (MRS) and Q-space imaging (QSI), two advanced MRI techniques, which have increased pathological specificity for neurodegeneration and myelin, and allow quantification of metabolites that reflect biological mechanisms, to study spinal neurodegeneration and repair in MS. In persons with early primary progressive MS (PPMS), spinal MRS and QSI exhibited increased sensitivity for detection of early disease changes than more conventional measures such as spinal cord atrophy and correlated with clinical disability measures suggesting these measures are functionally relevant. Region of interest analysis of the relationship between QSI indices in spinal white matter tracts and clinical scores which reflect the motor or sensory functions conveyed within those tracts, suggests a strong structure-function relationship exists between axonal integrity and disability. In persons with relapsing remitting MS (RRMS), with recent (within 4 weeks) symptoms suggestive of spinal cord relapse, serial imaging with spinal MRS and QSI over 6 months reflected clinical changes over that time. Specifically, rising spinal concentrations of total N-acetyl-aspartate (tNAA) and restriction of QSI-derived perpendicular diffusivity, which I hypothesise reflect, restoration of mitochondrial function and remyelination, respectively, underlie clinical recovery. Within the RRMS cohort, MRS and QSI measures at baseline were predictive of clinical outcomes at 6 months; elevated baseline spinal glutamate-glutamine (Glx), myo-inositol (Ins) and total creatine (tCr) concentrations and increased QSI-derived perpendicular diffusivity predicted poor outcomes and may reflect important mechanisms of disability progression such as; demyelination, neurodegeneration, astrogliosis and altered neuronal metabolism. Taken together the results suggest that mechanisms of disability following spinal cord relapse are complex and glutamate excitotoxicity, gliosis and axonal metabolic dysfunction may be important determinants of residual disability following relapses. This work suggests that newer, quantitative MRI techniques when applied to the spinal cord are sensitive markers of disease activity and progression and could be useful in monitoring therapies that aim to prevent neurodegeneration and enhance remyelination in MS