Although cMRI has improved dramatically our ability to diagnose MS and to monitor treatment efficacy, it provides only limited pieces of information about MS pathology in terms of both accuracy and specificity. This suggests that the cMRI should not be used to establish long-term prognosis of individual MS patients (treated or untreated) and that the ability of a given treatment to modify metrics derived from cMRI does not mean necessarily that the treatment will be able to modify favorably the clinical course of the disease. This limitation may be overcome by the application of nonconventional MRI techniques, which should be used to define new MRI markers of MS evolution. Ideally, these new MRI markers should be quantitative, provide information about the most destructive aspects of MS pathology, and be derived from (at least) the entire brain. None of the MRI techniques taken in isolation is able to provide a complete picture of the complexity of the MS process and this should call for the definition of aggregates of MRI quantities, thought to reflect different aspects of MS pathology, to improve our ability to monitor the disease (171,270). Moreover, metrics derived from MT MRI, DW MRI, and 1H-MRS should be increasingly used to monitor MS evolution, either natural or modified by treatment. At present, longitudinal natural history data collected in large samples of MS patients (especially in those at the earliest clinical stage of the disease) using these MR techniques are needed to gain additional insight into disease pathophysiology and to define the role of modern MR technologies in the assessment of MS. Finally, in the evaluation of the relationship between clinical and MRI markers of disease evolution, the presence and efficacy of functional cortical changes should also be considered.

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