Multiple sclerosis (MS) is a chronic inflammatory-demyelinating and neurodegenerative disease of the central nervous system that affects 400.000 people in US. Most patients (80-85%) experience a relapsingremitting (RR) course with episodes of neurological dysfunction followed by complete or partial remission. After variable time, almost half of these patients develop into the secondary progressive (SP) form, characterized by gradual, relapse-independent clinical progression. About 15 to 20% of patients, experience a primary progressive (PP) course characterized by a gradual worsening of neurological functions from the onset. Recent series of brain pathology studies have showed that PP- and SP-MS patients presented a pattern of extensive cortical demyelination and more diffuse injury of normal-appearing white matter while demyelinated white matter plaques represented the primary injury in RR-MS patients. In addition, although diffuse microscopic injury of the normal-appearing spinal cord (SC) tissue occurs in RR-MS, it is predominant in patients with progressive MS. Although the mechanisms underlying the accumulation of disability in progressive MS are still unclear, a major role seems to be played by 'occult' tissue damage.Therefore, we propose that (1) gray matter (GM) lesion count, sub-cortical GM magnetic field correlation (MFC) index and GM diffusion metrics will be more altered in patients with progressive MS than in RR-MS patients or healthy controls, reflecting more extensive GM lesional and microscopic damage; (2) GM MRI measures (lesions count, MFC index and diffusion levels) will predict brain volumes and neuropsychological performance ; (3) SC diffusion metrics will be more altered in patients with progressive MS than in RR-MS patients or healthy controls, reflecting more extensive microscopic damage and will be associated with SC volume and clinical measures. We will use novel MRI techniques such as double inversion recovery MRI, MFC MRI and diffusion kurtosis imaging to measure cortical lesions number, tissue accumulation of iron and microscopic, diffuse injury of cortical GM and cervical SC tissue.
The health relatedness of this project: (i) To identify comprehensive, sensitive and clinically relevant biomarkers of disease progression. (ii) To improve our understanding of the pathophysiology of neurodegeneration and identify new quantitative MRI metrics for treatment monitoring in progressive MS.
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