La combinazione di tecniche avanzate di risonanza magnetica e tomografia a emissione di positroni nell'esplorazione della rimielinizzazione nella sclerosi multipla

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with inflammatory and degenerative components affecting both the white (WM) and the grey matter (GM). The key neuropathological hallmarks of MS include demyelination, inflammation, astrocytic gliosis, and neurodegeneration, which is considered the main pathological substrate of clinical progression. Among these, myelin loss is considered the cornerstone of the pathophysiology of MS and the dynamics of myelin content change are thought to have a relevant impact on neurodegeneration and disability all along the course of the disease. Endogenous myelin repair is a physiological response to a demyelinating event and is mediated by population of adult brain resident progenitor cells which migrate into areas of demyelination and differentiate into actively myelinating oligodendrocytes. In experimental models a high variability in the extent of remyelination has been observed in MS patients, with myelin repair being widespread in few patients only, and sparse or ineffective in the others. Several factors have been suggested to influence the efficacy of this process and even in the same patient, a high heterogeneity may exist between different areas, suggesting the presence of local factors influencing the extent of remyelination. Although our knowledge concerning the biologic process of myelin repair has progressively increased over time, to date its clinical impact remains partly unknown. The exploration of myelin content change in MS patients in vivo has been challenging, due to the heterogeneity of the disease but also to the lack of appropriate methodologies to study the complex interplay between the pathological changes occurring both to the myelin sheet and to the neuroaxonal unit, particularly at the cortical level. Various methods have been proposed for this purpose, among which [11C]PIB-PET has been proved sensitive and specific in the evaluation of myelin content. However, the reduced spatial resolution, together with the fact that a reference region, represented by the cerebral cortex, is required for signal quantification, limit the application of this method to cortical grey matter. Among the various alternative techniques to the PET imaging, magnetization transfer ratio (MTR), an imaging metric sensitive to myelin content changes in MS, has been shown to be lower in cortical lesions than in normally myelinated cortex and has been successfully employed to generate maps sensitive to myelin loss in cortical grey matter. In this context, the aims of my PhD project were focused on the exploration of myelin repair, focusing primarily on the delineation of a method capable of producing patient-specific cortical maps of demyelination and remyelination using MTR. With these maps I had the chance to explore the spatial distribution of myelin repair and to evaluate the role of both cortical demyelination and remyelination in determining cortical atrophy and clinical progression, outlining though the supposed role of myelin repair in preventing neurodegeneration in MS.