FUNCTIONAL AND STRUCTURAL MRI CORRELATES OF COGNITIVE DYSFUNCTION IN PEDIATRIC MS AND A COMPARISON OF COGNITIVE RESILIENCE WITH ADULT-ONSET MS

During my PhD, I focused on the study of the MRI substrates of cognition in pediatric-onset (PO) multiple sclerosis (MS) patients and on the validation of a novel paper-pencil cognitive test, the Consecutive-letter Substitution Test (CST), to assess information processing speed (IPS). By applying unsupervised machine learning, we identified three cognitive phenotypes in pediatric MS patients: normal functioning, mild verbal memory and semantic fluency deficits, and global impairment, each associated with different clinical features, as well as structural and functional MRI abnormalities. In a longitudinal setting, I tested the association between consolidated resilience, inter-network functional connectivity changes and cognitive decline in different age groups of MS patients. Results showed that the protective role of consolidated resilience on cognition was mediated by inter-network connectivity of the frontoparietal network (FPN) in pediatric MS patients and by the inter-network connectivity of the salience and executive networks in adult MS patients. These findings suggest that the association between higher consolidated resilience and better cognitive outcomes in MS patients is moderated by specific RS FC patterns between cognitive networks, that change with age. Using DTI, we explored the maturational processes of the superficial white matter (SWM) in POMS and identified widespread reductions in myelination level compared to age-expected values, also demonstrated their association with IPS and visuospatial abilities. Increased cortical thinning and decreased cortical volume were found across the entire cortical mantle. Finally, we provided preliminary evidence of the validity and reliability of the CST, an IPS test that, compared to the Symbol Digit Modalities Test (SDMT), aims to be less influenced by visual scanning abilities and visuospatial memory. The CST showed strong convergent validity with measures of working memory, attention and IPS. It provided a more focused measure of cognitive speed compared to the SDMT, which was also influenced by verbal memory and verbal fluency abilities . In conclusion, in this PhD project we used conventional and advanced neuroimaging techniques to elucidate the substrates of cognitive decline in POMS, and introduced the CST, a reliable test for assessing IPS.