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.

Is the Relationship between Cortical and White Matter Pathologic Changes in Multiple Sclerosis Spatially Specific? A Multimodal 7-T and 3-T MR Imaging Study with Surface and Tract-based Analysis

“…Studies about histopathologic and MR imaging correlations reported increased (ie, longer) T2* in WM and cortical MS lesions, which corresponded to decreased myelin and iron content (20,21). We recently demonstrated, in a heterogeneous MS cohort, that quantitative T2* was increased at different cortical depths throughout stages of MS relative to healthy control participants, and proved to be a marker of neurologic disability more sensitive than cortical tissue loss (22).…”

“…Eight patients were excluded because of lack of DTI data, one patient because of the presence of tumor-like lesion, and two patients because of motion artifacts during MR imaging. Thirty-four MS patients (23 women), a subset of a previously published cohort that included 41 patients with MS (22), and included cases with clinically isolated association between WM and gray matter degeneration in MS; however, the spatial specificity of this association was not investigated (12)(13)(14)(15).…”

“…Intracortical quantitative T2* maps (in milliseconds) were estimated from 7-T fast low-angle shot multiecho T2* images in each patient and registered onto the corresponding 3 T cortical surfaces as previously detailed (18,19,22). Quantitative T2* was sampled at 25%, 50%, and 75% depth from the pial surface (0% depth) to the gray matter-WM boundary (100% depth) over the entire surface and within regions of interest for each hemisphere (the tract cortical projection area will be further described in this article).…”

Spatial Correlation of Pathology and Perfusion Changes within the Cortex and White Matter in Multiple Sclerosis

“…Steenwijk et al 9 reported a stronger relationship between cGM atrophy and WM tract pathology in RRMS compared to SPMS patients, concluding that the association between NAWM and cGM becomes increasingly independent with disease progression. The assertion that cGM and WM progression is either dependent or partly independent is supported by histopathological and radiological series demonstrating the role of meningeal mediated processes in both cortical and leucocortical lesion but not WM T2h-l development 10, 11 .…”

Laminar cortical damage in multiple sclerosis

“…Novel pulse sequences such as double inversion recovery and phase-sensitive inversion recovery, but also higher spatial resolution, through application of ultrahigh field scanners operating at 7 T, can be used for this purpose. In this issue of Brain, Mainero and colleagues used a high-resolution T 2 *-weighted magnetic resonance sequence to examine quantitative differences across cortical layers through the use of quantitative T 2 * (the inverse of the T 2 * relaxation rate) from a multi-echo gradient-echo pulse sequence (Mainero et al, 2015). The in-plane resolution (0.25 mm) allowed the investigators to examine signal intensity and T 2 *-relaxation rates at 25%, 50% and 75% depths of the cortical mantle inward from the pial surface based on segmentation of anatomical magnetic resonance images.…”