ADVANCED SUSCEPTIBILITY AND DIFFUSION WEIGHTED IMAGING IN THE DIAGNOSIS OF MULTIPLE SCLEROSIS: FROM RESEARCH TO CLINICAL APPLICATIONS

Rational and Objectives In 2015, the Institute of Medicine described the need to study the phenomenon of misdiagnosis as a “moral, professional, and public health imperative”. Despite the periodic updates of diagnostic criteria for MS, the risk of diagnosing as having MS patients with other disease involving the Central Nervous System (CNS) remains still not negligible. Indeed, diagnosis of MS may be straightforward, but a rapid and accurate diagnosis of MS can also be an issue, particularly due to the lack of specific biomarkers. Alongside developments that enabled earlier diagnosis of MS, the introduction of disease-modifying therapies (DMTs) for MS provided increasing evidence that earlier treatment is associated with better long-term outcomes. This evidence leads to an increasing pressure for the physician to make a diagnosis of MS as early as possible. This pressure, in turn, creates a tension between the benefits of an early MS diagnosis and the risk of an inaccurate diagnosis that may cause serious, sometimes life-threatening, health and financial consequences. Among MS mimics, migraine (alone or in combination with additional diagnoses) has been reported as the most common alternative diagnosis in patients misdiagnosed with MS (reported in 22% of misdiagnosed patients). Interestingly, in the patients with migraine, it was reported that often migraineurs symptoms mistaken for demyelinating attacks were incorrectly used to satisfy Dissemination in Time (DIT) criteria for MS. On the other side, migraine-associated white matter (WM) hyperintensity were often considered in the fulfilment of Dissemination in Space (DIS) imaging criteria for MS. Nevertheless, the differential diagnosis between MS and its mimics is not the only challenge. In a treatment era when also the only evidence of radiological disease activity in clinically stable patients may be the trigger to escalate MS therapy, the presence of comorbidities in a patient with MS introduces an extra challenge, represented by the need to distinguish whether a new T2 lesion is due to MS or to comorbidities. The high prevalence of small vessel disease (SVD)-related white matter hyperintensities in people over 50 years of migraine in general population including MS patients and the similar features shared with MS in conventional MRI sequences regardless of their different histopathological substrates, makes this issue not negligible. The identification of specific and sensitive biomarkers able to distinguishes MS from other diseases represent an unmet need. Several cerebrospinal fluid and serum biomarkers of MS have been studied, but no tests with high specificity and sensitivity are now available. Another issue is represented by the fact that many proposed biomarkers have only been explored in the context of cross-sectional studies, while their longitudinal evaluation is essential. As concerns MRI biomarkers, the “Central Vein Sign” inside WM lesions has been proposed as a very promising biomarker of inflammatory demyelination and, thus, may aid the diagnosis of MS and differentiation from its mimics. On the other hand, multi-compartments diffusion models have been demonstrated their potential in investigating tissue abnormalities inside MS lesions and Normal Appearing White Matter (NAWM), as demyelination, fibre loss and axonal degeneration. The work described in this thesis aimed at investigating the application of the Central Vein Sign detected on advanced susceptibility weighted images to differentiate MS from migraine and then, at applying the Central Vein Sign associated with advanced diffusion weighted images, to explore the impact of ageing and comorbidities on WM lesions architecture in MS. Overview of the Thesis • Chapter 2 includes a description of multiple sclerosis, with a final focus on MS mimics and their challenging differentiation from MS. • In the chapter 2 an overview of the state of the art of advanced susceptibility and diffusion weighted imaging methods used to investigate brain structure is provided, together with a summary of previous studies that used these techniques in MS. • In the chapter 3 the first study, aiming at investigating the performance of the Central Vein Sign (CVS) in the differential diagnosis between MS and migraine is described. • The chapter 4 illustrates the second study, exploring the performance of the CVS and spherical Mean Technique (SMT) model in differentiating MS lesions from white matter hyperintensities related to ageing, concomitant small vessel disease and migraine in a cohort of patients with MS. The chapters 3 and 4 contain sections including the background, aims, methods and discussion specific for each study.