Investigation of pathophysiological mechanisms in clinically isolated syndrome using advanced imaging techniques

This thesis concerns an observational study of patients recruited after their first episode of neurological symptoms suggestive of demyelination in the central nervous system and diagnosed either with clinically isolated syndrome or relapsing-remitting multiple sclerosis. In multiple sclerosis, brain tissues can exhibit extensive neuroaxonal microstructural and metabolic abnormalities, but little is known about their presence and significance at the time of the first demyelinating episode. I used a novel multi-parametric quantitative MRI approach, combining neurite orientation dispersion and density imaging (NODDI), which gives information about tissue microstructure, and 23Na MRI, which estimates total sodium concentration, a marker of metabolic dysfunction, in the brains of clinically isolated syndrome patients. I found microstructural and sodium homeostasis alterations in cortical areas of patients that showed clinical relevance. Within the diffuse axonal dispersion found in the normal-appearing white matter, the corpus callosum shared with lesions, signs of axonal damage and metabolic dysfunction, thus emerging as a possible target for early neuroprotective interventions. Structural cortical networks (SCNs) represent patterns of coordinated morphological modifications in cortical areas and they have shown pathophysiological changes in many brain disorders, including multiple sclerosis. I investigated alterations of SCNs at the individual level in this early cohort. Patients showed altered small-world topology, an efficient network organization combining dense local clustering with relatively few long-distance connections. These disruptions were worse for patients with higher lesion load and worse cognitive processing speed indicating that pathophysiological changes in the cortical morphology can influence clinical outcomes. Finally, I hypothesised that the patients in the cohort presenting with optic neuritis may have disturbances in neuropsychological functions related to visual processes. I found that cognitive visuospatial processing is affected after unilateral optic neuritis and improves over time with visual recovery, independently of the structural damage in the visual and central nervous system.