Imaging Cognitive Network Dysfunction in Multiple Sclerosis Patients with Relapse-Onset Clinical Phenotypes

Cognitive impairment strongly affects people with multiple sclerosis (MS). It comprises multifactorial symptoms and no consistent treatments are available to date. Although cognitive impairment has been observed in all stages of the disease, the majority of studies mainly focused on a specific clinical phenotype (primarily relapsing-remitting MS) or did not differentiate between MS subtypes. Advanced magnetic resonance imaging (MRI) techniques are providing useful measures of functional and structural abnormalities in patients with MS, allowing to overcome the limits of conventional MRI. This thesis wished to improve the understanding of the mechanisms responsible for the accumulation of cognitive dysfunction in patients with relapse-onset MS by combining different advanced structural and functional MRI techniques. First, we applied functional MRI (fMRI) to assess brain functional reorganization in relation to different cognitive tasks (face encoding and N-back) in patients with the main relapse-onset clinical phenotypes. We also explored the relationship between functional network alterations and clinical, cognitive, behavioural and structural MRI measures of disease-related damage. Our results provide new evidence for the debate about adaptive/maladaptive functional reorganization in MS, specifically in relation to the clinical and cognitive characteristics of MS phenotypes. Second, the investigation of resting state default mode network (DMN) functional connectivity enabled us to highlight that different modulations of DMN recruitment lead to different clinical profiles and manifestations. Moreover, functional connectivity of specific DMN areas (hippocampi) was found to be central for the assessment of important cognition-related aspects, such as depression. Finally, by applying voxel-wise MRI methods (VBM and TBSS) we explored the extent and distribution of brain GM atrophy and WM microstructural alterations in adult MS patients according to their age of disease onset, and we made some assumptions about the possible presence of pathophysiological mechanisms related to age of MS onset, that suggests a preserved reserve for structural plasticity that could modulate the structural and functional brain organization, in order to preserve or slow-down MS-related dysfunction. To conclude, the application of advanced MRI techniques allowed us to improve our knowledge on neuropsychological features in patients with relapse-onset MS.