Multiple sclerosis (MS) is an immune-mediated disease affecting central nervous system (CNS). Although MS is classically considered a white matter (WM) disease, the involvement of gray matter (GM) in the pathogenic process has been confirmed by pathology studies and MRI studies. Impairment of cognitive domains such as memory, mental processing speed, attention, and executive function can occur from the early stage of the disease and tends to worsen over time, despite stable physical symptoms. WM demyelination is moderately correlated with CI, suggesting that probably WM abnormalities alone cannot fully explain the extent of clinical symptoms in MS, including CI. Several MRI techniques have shown the involvement of GM in MS and the association between GM damage, physical disability, and CI. The aim of this review is to provide an overview of CI and GM damage assessed by structural brain MRI. 1. Introduction Multiple sclerosis (MS) is an immune-mediated disease affecting central nervous system (CNS), characterized by demyelination and axonal degeneration [1]. The etiology of MS is still unknown, although it is believed a complex interplay between genetic and environmental factors may have a role [2]. Although MS is classically considered a white matter (WM) disease, the involvement of gray matter (GM) in the pathogenic process has been confirmed by pathology studies [3, 4]. In the last years cognitive impairment (CI) has been recognized as an important feature of MS, affecting up to 65% of patients [5]. Impairment of cognitive domains such as memory, mental processing speed, attention, and executive function can occur from the early stage of the disease and tends to worsen over time, resulting in significant functional impairment at work and at home, despite minimal physical disability [6, 7]. It has been shown that WM demyelination is moderately correlated with CI, suggesting that probably WM abnormalities alone cannot fully explain the extent of clinical symptoms in MS, including CI [8, 9]. The definition of the pathogenic mechanism underlying the development of CI is crucial in order to identify novel biomarkers to monitor disease progression and therapy neuroprotective effect. Several MRI techniques have shown the involvement of GM in MS and the association between GM damage, physical disability, and CI [10–12]. The aim of this review is to provide an overview of CI and GM damage assessed by structural MRI. A review of functional imaging and its correlation with cognitive performance has not been included in the present paper. 2. Cognitive Impairment
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