It is abundantly clear that there is extensive gray matter pathology occurring in multiple sclerosis. While attention to gray matter pathology was initially limited to studies of autopsy specimens and biopsies, the development of new MRI techniques has allowed assessment of gray matter pathology in vivo. Current MRI techniques allow the direct visualization of gray matter demyelinating lesions, the quantification of diffuse damage to normal appearing gray matter, and the direct measurement of gray matter atrophy. Gray matter demyelination (both focal and diffuse) and gray matter atrophy are found in the very earliest stages of multiple sclerosis and are progressive over time. Accumulation of gray matter damage has substantial impact on the lives of multiple sclerosis patients; a growing body of the literature demonstrates correlations between gray matter pathology and various measures of both clinical disability and cognitive impairment. The effect of disease modifying therapies on the rate accumulation of gray matter pathology in MS has been investigated. This review focuses on the neuroimaging of gray matter pathology in MS, the effect of the accumulation of gray matter pathology on clinical and cognitive disability, and the effect of disease-modifying agents on various measures of gray matter damage. 1. Background Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS); focal areas of white matter demyelination have long been considered the key feature of MS [1]. Despite this belief that MS is primarily a white matter disease, early pathologic studies had reported focal areas of cortical demyelination in MS patients [2, 3]. In 1962, Brownell and Hughes [4] showed that, in MS, cortical demyelinating lesions represented up to 26% of the total number of cerebral plaques. Despite these early indications of the cortical pathology occurring in MS, in general very little attention was paid to cortical pathology. It is likely that this was due to both the difficulty in identifying cortical lesions at autopsy via conventional histochemical techniques and the marked conspicuity of inflammatory lesions in the white matter [5]. This focus on white matter demyelination rather than cortical pathology was initially compounded with the advent of MRI: conventional MRI techniques for imaging MS identify a majority of focal white matter lesions but are very insensitive for the detection of cortical MS lesions [6]. Despite initial focus on white matter demyelination, there has been increasing focus on the gray matter
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