An abnormal periventricular magnetization transfer ratio gradient occurs early in multiple sclerosis

Abstract

In established multiple sclerosis, tissue abnormality-as assessed using magnetization transfer ratio-increases close to the lateral ventricles. We aimed to determine whether or not (i) these changes are present from the earliest clinical stages of multiple sclerosis; (ii) they occur independent of white matter lesions; and (iii) they are associated with subsequent conversion to clinically definite multiple sclerosis and disability. Seventy-one subjects had MRI scanning a median of 4.6 months after a clinically isolated optic neuritis (49 females, mean age 33.5 years) and were followed up clinically 2 and 5 years later. Thirty-seven healthy controls (25 females, mean age 34.4 years) were also scanned. In normal-appearing white matter, magnetization transfer ratio gradients were measured 1-5 mm and 6-10 mm from the lateral ventricles. In control subjects, magnetization transfer ratio was highest adjacent to the ventricles and decreased with distance from them; in optic neuritis, normal-appearing white matter magnetization transfer ratio was lowest adjacent to the ventricles, increased over the first 5 mm, and then paralleled control values. The magnetization transfer ratio gradient over 1-5 mm differed significantly between the optic neuritis and control groups [+0.059 percentage units/mm (pu/mm) versus -0.033 pu/mm, P = 0.010], and was significantly steeper in those developing clinically definite multiple sclerosis within 2 years compared to those who did not (0.132 pu/mm versus 0.016 pu/mm, P = 0.020). In multivariate binary logistic regression the magnetization transfer ratio gradient was independently associated with the development of clinically definite multiple sclerosis within 2 years (magnetization transfer ratio gradient odds ratio 61.708, P = 0.023; presence of T lesions odds ratio 8.500, P = 0.071). At 5 years, lesional measures overtook magnetization transfer ratio gradients as significant predictors of conversion to multiple sclerosis. The magnetization transfer ratio gradient was not significantly affected by the presence of brain lesions [T lesions (P = 0.918), periventricular T lesions (P = 0.580) or gadolinium-enhancing T lesions (P = 0.724)]. The magnetization transfer ratio gradient also correlated with Expanded Disability Status Scale score 5 years later (Spearman r = 0.313, P = 0.027). An abnormal periventricular magnetization transfer ratio gradient occurs early in multiple sclerosis, is clinically relevant, and may arise from one or more mechanisms that are at least partly independent of lesion formation.

A surface‐in gradient of thalamic damage evolves in pediatric multiple sclerosis

“…Although we focused our pediatric MS imaging study on the thalamus, we suspect that this graded injury pattern may manifest more generally in periventricular structures of MS patients. Consistent with this are recent imaging studies in adult onset MS reporting an abnormal and graded pattern of periventricular MTR abnormality, with declining MTR levels observed in adjacent WM soon after the sentinel clinical event …”

“…Pathology studies of the subpial cortical injury describe demyelination, neuronal loss, microglial activation, and a relative paucity of inflammatory cells, as well as a pattern of damage that follows a "surface‐in" gradient . These observations are supported by recent magnetization transfer ratio (MTR) imaging studies in MS reporting a graded surface‐in abnormality starting at the brain–cerebrospinal fluid (CSF) interfaces of both the cortical surface and the ventricular surfaces . Together with the correlation between the severity of subpial cortical damage and the degree of meningeal inflammation, these findings have raised the hypothesis that soluble factors, potentially released by immune cells in the meninges, diffuse into the CSF and into the superficial brain layers such as the subpial cortical tissue, contributing to the observed gradient of pathological changes …”

“…There have been no tissue‐based studies directly assessing whether the thalamus exhibits a gradient of injury. As noted above, MTR imaging studies in adult onset MS have reported a graded surface‐in abnormality both at the cortical surface and at the ventricular surface, which would be expected to include thalamic structures …”

B cell rich meningeal inflammation associates with increased spinal cord pathology in multiple sclerosis

“…These findings suggest that immune-mediated damage arising from the overlying meninges is only one component of the pathogenetic mechanisms, and that other local and distal indirect contributions from cells in the parenchyma also contribute to lesion development and expansion. Our data also shows that it is not only subpial grey matter lesions which can topographically associate with meningeal inflammation and supports previous neuroimaging descriptions of gradients of white, as well as GM pathology, greatest near the brain's surfaces, in the central white and grey matter areas (8,41,51). It would be interesting to determine if gradients of spinal cord tissue damage exist in the subpial white matter or in the grey matter away from the central canal.…”

Periventricular magnetisation transfer ratio abnormalities in multiple sclerosis improve after alemtuzumab

“…Consistent with these histopathological findings, tissue abnormality, as assessed by magnetisation transfer ratio (MTR) in vivo, increases towards the cortical surfaces in all clinical stages of relapse-onset MS. 9 We have recently shown similar gradients in MTR abnormality around the ventricles in relapse-onset MS. 10 Both cortical and periventricular gradients are evident soon after a clinically-isolated syndrome 11,12 and are more marked in SPMS compared to RRMS. 9,10 The processes underlying abnormal cortical and periventricular MTR gradients remain unknown, but one possibility is that they are both linked with meningeal inflammation, perhaps through a CSF-mediated factor.…”