A gradient in cortical pathology in multiple sclerosis by in vivo quantitative 7 T imaging

Mainero et al. use 7 Tesla MR quantitative T-2* imaging to map intracortical laminar pathology in patients with multiple sclerosis. A gradient of cortical pathology is seen across disease stages in association with worsening disability, suggesting that a pathological process driven from the pial surface contributes to disease progression.We used a surface-based analysis of T-2* relaxation rates at 7 T magnetic resonance imaging, which allows sampling quantitative T-2* throughout the cortical width, to map in vivo the spatial distribution of intracortical pathology in multiple sclerosis. Ultra-high resolution quantitative T-2* maps were obtained in 10 subjects with clinically isolated syndrome/early multiple sclerosis (a parts per thousand currency sign3 years disease duration), 18 subjects with relapsing-remitting multiple sclerosis (a parts per thousand yen4 years disease duration), 13 subjects with secondary progressive multiple sclerosis, and in 17 age-matched healthy controls. Quantitative T-2* maps were registered to anatomical cortical surfaces for sampling T-2* at 25%, 50% and 75% depth from the pial surface. Differences in laminar quantitative T-2* between each patient group and controls were assessed using general linear model (P < 0.05 corrected for multiple comparisons). In all 41 multiple sclerosis cases, we tested for associations between laminar quantitative T-2*, neurological disability, Multiple Sclerosis Severity Score, cortical thickness, and white matter lesions. In patients, we measured, T-2* in intracortical lesions and in the intracortical portion of leukocortical lesions visually detected on 7 T scans. Cortical lesional T-2* was compared with patients' normal-appearing cortical grey matter T-2* (paired t-test) and with mean cortical T-2* in controls (linear regression using age as nuisance factor). Subjects with multiple sclerosis exhibited relative to controls, independent from cortical thickness, significantly increased T-2*, consistent with cortical myelin and iron loss. In early disease, T-2* changes were focal and mainly confined at 25% depth, and in cortical sulci. In later disease stages T-2* changes involved deeper cortical laminae, multiple cortical areas and gyri. In patients, T-2* in intracortical and leukocortical lesions was increased compared with normal-appearing cortical grey matter (P < 10(-10) and P < 10(-7)), and mean cortical T-2* in controls (P < 10(-5) and P < 10(-6)). In secondary progressive multiple sclerosis, T-2* in normal-appearing cortical grey matter was significantly increased relative to controls (P < 0.001). Laminar T-2* changes may, thus, result from cortical pathology within and outside focal cortical lesions. Neurological disability and Multiple Sclerosis Severity Score correlated each with the degree of laminar quantitative T-2* changes, independently from white matter lesions, the greatest association being at 25% depth, while they did not correlate with cortical thickness and volume. These findings demonstrate a gradient in the expression of cortical pathology throughout stages of multiple sclerosis, which was associated with worse disability and provides in vivo evidence for the existence of a cortical pathological process driven from the pial surface.