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Cortical mechanisms of disease progression in early multiple sclerosis


Multiple sclerosis (MS) is a demyelinating and neurodegenerative disorder of the central nervous system, and the leading non-traumatic cause of disability in young adults. Advances in immunohistochemistry have recently refocused the attention of MS research from a pathophysiologic paradigm of white matter (WM) disease to the neocortical gray matter (GM). Post-mortem findings show that subpial lesions, which mainly involve the outer layers of the cortex, are the most common type of cortical lesions (CLs), especially in late stage disease. The ex vivo observation that there is a gradient of demyelination through the cortical laminae, with the most dramatic changes seen within the iuxtameningeal cortical layers, supports the hypothesis of a primary pathogenic mechanism, driven from the pial surface, for cortical degeneration in MS. Recent neuropathological evidence that the cortex can be the site of demyelinating CLs near the time of disease onset, supports the presence of an early degenerative process that primarily targets the cortex, independent from WM lesions. The ability to characterize in vivo the development and evolution of subpial pathology and CLs from the earliest disease stages can provide more definitive evidence of their role in the pathogenesis and progression of MS. Magnetic resonance imaging (MRI) studies, although insensitive to subpial lesions, have demonstrated a variable degree of cortical involvement early in the disease. Our studies at ultra-high field 7 T MRI in MS show that T2* imaging detects more CLs and has greater sensitivity to subpial pathology than currently available clinical imaging methods. Using a surface-based laminar analysis of cortical T2* at a given depth from pial surface, we demonstrated in patients with MS subpial T2* increases across the cortex that may reflect subpial lesions described ex vivo, and that correlate with patients level of disability. Our data are supported by ex vivo- MR examinations of MS brains, which have shown the great sensitivity of T2* imaging to detect CLs in MS. Here, we propose a longitudinal study targeted to a very early MS population, and the use of accurate and clinically feasible acquisition and processing methods at 7 T and 3 T MRI to image and characterize cortical pathology in vivo. We hypothesize that CLs including subpial pathology can be an early event in MS, are independent from WM damage, and constitute a sensitive marker of an aggressive disease phenotype. A better understanding of the in vivo mechanisms of cortical disease progression from the earliest stages of MS would allow for more accurate indicators of different MS phenotypes. This in turn could be useful in directing future phenotype-genotype correlations, for evaluating the therapeutic response to specific treatment, and could potentially be the key to developing evidence-based guidelines for differentiating patients and selecting appropriate treatments, as well as facilitating development of novel therapeutic approaches.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.