IN VIVO DIFFUSION WEIGHTED MAGNETIC RESONANCE SPECTROSCOPY IN MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is a complex CNS disease in which inflammation, demyelination and neuroaxonal degeneration are concurrent processes. MS therapies developed to date are directed at the immune-mediated, inflammatory destruction of myelin – axonal degeneration is ongoing and not specifically targeted. In vivo techniques to measure axonal degeneration could be useful in developing neuroprotective agents. This dissertation explores the capacity of diffusion weighted spectroscopy (DWS) for measuring axonopathy in patients in vivo. DWS is a magnetic resonance technique that measures the diffusivity of metabolites, such as N-acetyl aspartate (NAA), in vivo, allowing compartment specific assessment of disease-related changes. Here we developed and optimized the DWS technique for use with patients on clinical scanners so that we could study NAA diffusivity in MS patients. In order to establish reliability parameters for DWS, comprehensive DWS data sets of the human corpus callosum were acquired and the inter- and intra-subject variability of empirical and modeled diffusion properties of NAA was investigated. Reproducibility analysis and power calculations demonstrated that a difference of 10% in NAA diffusivity could be detected with group sizes as small as 21 patients at 3T with a sequence that runs in under 20 minutes Cross-sectional study of MS patients and healthy controls revealed lower diffusion of NAA parallel to the long axis of axons in the corpus callosum of patients. This result demonstrated that, by detecting reduced diffusion of NAA parallel to axons in white matter, DWS may be capable of distinguishing axonal disruption in MS in the setting of increased parallel diffusion of water, which is commonly observed in MS but pathologically nonspecific. A longitudinal study of DWS in patients with stable and active disease replicated the previous cross-sectional findings and found that active MS patients had lower NAA parallel diffusivity at 6 months while stable patients remained constant. Additionally, water diffusion and volumetric measures did not detect changes in active MS patients during this period. As NAA diffusivity measurements reflect specifically on the intra-axonal space, these data suggest that NAA diffusivity is a read-out of axonal health in a background of multiple pathological processes in MS