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

Abstract

We used a surface-based analysis of T2∗ relaxation rates at 7 T magnetic resonance imaging, which allows sampling quantitative T2∗ throughout the cortical width, to map in vivo the spatial distribution of intracortical pathology in multiple sclerosis. Ultra-high resolution quantitative T2∗ maps were obtained in 10 subjects with clinically isolated syndrome/early multiple sclerosis (≤3 years disease duration), 18 subjects with relapsing-remitting multiple sclerosis (4 years disease duration), 13 subjects with secondary progressive multiple sclerosis, and in 17 age-matched healthy controls. Quantitative T2∗ maps were registered to anatomical cortical surfaces for sampling T2∗ at 25%, 50% and 75% depth from the pial surface. Differences in laminar quantitative T2∗ 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 T2∗, neurological disability, Multiple Sclerosis Severity Score, cortical thickness, and white matter lesions. In patients, we measured, T2∗ in intracortical lesions and in the intracortical portion of leukocortical lesions visually detected on 7 T scans. Cortical lesional T2∗ was compared with patients' normal-appearing cortical grey matter T2∗ (paired t-test) and with mean cortical T2∗ in controls (linear regression using age as nuisance factor). Subjects with multiple sclerosis exhibited relative to controls, independent from cortical thickness, significantly increased T2∗, consistent with cortical myelin and iron loss. In early disease, T2∗ changes were focal and mainly confined at 25% depth, and in cortical sulci. In later disease stages T2∗ changes involved deeper cortical laminae, multiple cortical areas and gyri. In patients, T2∗ in intracortical and leukocortical lesions was increased compared with normal-appearing cortical grey matter (P < 10-10 and P < 10-7), and mean cortical T2∗ in controls (P < 10-5 and P < 10-6). In secondary progressive multiple sclerosis, T2∗ in normal-appearing cortical grey matter was significantly increased relative to controls (P < 0.001). Laminar T2∗ 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 T2∗ 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.