Background: Despite the use of new high efficacy therapies, complete disease remission is elusive in most people with multiple sclerosis (MS). This is particularly relevant for patients affected by aggressive MS, who deal with frequent relapses and accelerated accrual of irreversible disability. No evidence-based criteria exist to guide the choice on the best treatment approach in these patients. It is therefore urgent to collect data on available therapies for aggressive MS, analyzing their onset of action, the intensity of their immunosuppressive effects and their long-term clinical outcomes. Given that chronic, smoldering inflammation behind an intact blood-brain barrier has been identified as one of the most important drivers of disability progression, it is of fundamental importance to evaluate the impact of therapies on compartmentalized chronic neuroinflammation. This is particularly true for newer treatments, including hematopoietic stem cell transplantation (AHSCT), which is currently under investigation as a treatment strategy for aggressive MS. Aims: Against this background, the overarching aims of this thesis project were to: 1) Assess the clinical and MRI outcomes of patients with aggressive MS treated with different highly active immunotherapies 2) Investigate the impact of different highly active immunotherapies on chronic inflammation For the first aim of this project, we performed three different separate studies evaluating the impact of (i) AHSCT, (ii) alemtuzumab and (iii) ocrelizumab on clinical and MRI outcomes in patients presenting an aggressive form of MS. For the second aim, we performed a longitudinal prospective quantitative MRI study evaluating the impact of AHSCT and other highly active therapies on acute and chronic inflammation assessed with quantitative susceptibility mapping (QSM) in aggressive MS patients. Then, aiming at comprehensively detect the smoldering inflammatory component in MS lesions, we performed a combined quantitative MRI study investigating the relationship between axonal integrity, myelin content and iron deposition in the entire spectrum of MS lesions. Results: First, we showed that AHSCT prevented disability progression and inflammatory disease activity in most patients affected by relapsing-remitting MS and that these effects last for more than a decade. We also demonstrated that AHSCT significantly reduced the risk of relapses and MRI activity, allowing complete disease remission in a higher proportion of patients compared with alemtuzumab. Similar results were observed in patients treated with ocrelizumab, although we observed some evidence of persistent MRI activity in the first year of treatment. We showed that chronic smoldering inflammation, detected by QSM as paramagnetic rim lesions, is frequent in aggressive MS, being detectable in 80% of patients. Our preliminary results show that chronic active, paramagnetic rim lesions tend to persist over time, despite the use of highly active immunosuppression, including AHSCT. However, we found that some lesions exhibit changes in the intensity and the distribution of QSM signal over time, which could be related, at least in part, to highly active CNS penetrant drugs treatment used in these patients. Lastly, with a multimodal MRI approach we distinguished different types of MS lesions (hypo-isointense, homogeneous hyperintense, inhomogeneous hyperintense and paramagnetic rim), which were characterized by increasing degrees of axonal and myelin disruption. Discussion: Aggressive MS is characterized by a great amount of acute and chronic neuroinflammation, which can be detected and monitored in vivo by quantitative MRI. Among high efficacy immunotherapies, AHSCT has the potential to control neuroinflammation allowing long-lasting disease remission.