Time is myelin: early cortical myelin repair prevents atrophy and clinical progression in multiple sclerosis

Abstract

Cortical myelin loss and repair in multiple sclerosis (MS) have been explored in neuropathological studies, but the impact of these processes on neurodegeneration and the irreversible clinical progression of the disease remains unknown. Here, we evaluated in vivo cortical demyelination and remyelination in a large cohort of people with all clinical phenotypes of MS followed up for 5 years using magnetization transfer imaging (MTI), a technique that has been shown to be sensitive to myelin content changes in the cortex. We investigated 140 people with MS (37 clinically isolated syndrome, 71 relapsing-MS, 32 progressive-MS), who were clinically assessed at baseline and after 5 years and, along with 84 healthy controls, underwent a 3 T-MRI protocol including MTI at baseline and after 1 year. Changes in cortical volume over the radiological follow-up were computed with a Jacobian integration method. Magnetization transfer ratio was employed to calculate for each patient an index of cortical demyelination at baseline and of dynamic cortical demyelination and remyelination over the follow-up period. The three indices of cortical myelin content change were heterogeneous across patients but did not significantly differ across clinical phenotypes or treatment groups. Cortical remyelination, which tended to fail in the regions closer to CSF (-11%, P < 0.001), was extensive in half of the cohort and occurred independently of age, disease duration and clinical phenotype. Higher indices of cortical dynamic demyelination (β = 0.23, P = 0.024) and lower indices of cortical remyelination (β = -0.18, P = 0.03) were significantly associated with greater cortical atrophy after 1 year, independently of age and MS phenotype. While the extent of cortical demyelination predicted a higher probability of clinical progression after 5 years in the entire cohort [odds ratio (OR) = 1.2; P = 0.043], the impact of cortical remyelination in reducing the risk of accumulating clinical disability after 5 years was significant only in the subgroup of patients with shorter disease duration and limited extent of demyelination in cortical regions (OR = 0.86, P = 0.015, area under the curve = 0.93). In this subgroup, a 30% increase in cortical remyelination nearly halved the risk of clinical progression at 5 years, independently of clinical relapses. Overall, our results highlight the critical role of cortical myelin dynamics in the cascade of events leading to neurodegeneration and to the subsequent accumulation of irreversible disability in MS. Our findings suggest that early-stage myelin repair compensating for cortical myelin loss has the potential to prevent neuro-axonal loss and its long-term irreversible clinical consequences in people with MS.

Keywords: imaging; multiple sclerosis; myelin; neurodegeneration; neuroprotection; remyelination.

Figure 1

Simplified method flow chart. (A) Cross-sectional grey matter (GM) volume, magnetization transfer ratio (MTR) maps and distance maps were created in native space in all subjects and then normalized to standard space, passing through the half-way space in patients. In half-way space, T1-weighted images were used to calculate cortical GM atrophy using the Jacobian integration method. (B) Definition of a threshold (THR) to identify cortical demyelinated voxels in people with multiple sclerosis (pwMS) compared to healthy controls (HCs). Regions of significant group differences between MTR maps of people with MS and HCs were identified through voxel-wise non-parametric permutation-based t-test. For each centre, from these regions of significant difference, mean MTR in people with MS and HCs were extracted and used to calculate a relative percentage difference, which was defined as the threshold for cortical demyelination. (C) Classification of cortical demyelinated voxels in people with MS. We calculated the relative difference between the MTR value of any given cortical voxel in people with MS and the average MTR value of all voxels in HCs localized at the same distance as the given voxel from the external CSF. If this difference was greater than the previously calculated threshold, that cortical voxel was classified as ‘demyelinated’, otherwise as ‘normally myelinated’. As a result, we generated a map of cortical demyelination for each patient at each time point.

Figure 2

Magnetization transfer ratio-based myelin content maps. (A and B) Cortical voxels in patients classified as demyelinated compared with healthy controls at baseline and follow-up are highlighted in red. (C) Cortical voxels classified as dynamically demyelinated (i.e. voxels classified as normally myelinated at baseline and demyelinated at follow-up) are highlighted in blue, while cortical voxels classified as remyelinated (i.e. voxels classified as demyelinated at baseline which recovered a normal magnetization transfer ratio signal at follow-up) are displayed in green.

Figure 3

The three indices of cortical myelin content change are largely heterogeneous across patients and affected by the distance from CSF. (A) Cortical myelin content change is represented by a bar plot in which each bar represents the cortex of a single patient: cortical voxels classified as demyelinated at baseline and follow-up are highlighted in red; cortical voxels classified as remyelinated are in green; and cortical voxels classified as dynamically demyelinated are in blue. Bars are sorted based on demyelination at baseline. B–D show the differences between the inner and outer cortex in the extent of cortical demyelination (B), dynamic demyelination (C) and remyelination (D).

Figure 4

Association between the indices of cortical myelin content change and cortical atrophy development over 1 year. (A) Predicted cortical grey matter (GM) atrophy according to the extent of cortical remyelination: a greater extent of cortical remyelination predicts lower cortical atrophy over 1 year. (B) Predicted cortical GM atrophy according to the extent of cortical dynamic demyelination: a greater extent of cortical dynamic demyelination predicts greater cortical atrophy over 1 year.

Figure 5

Association between the index of cortical remyelination and the probability of clinical progression after 5 years. (A) Predicted probabilities of clinical progression in the multiple sclerosis (MS) cohort characterized by a limited extent of cortical demyelination at baseline and a disease duration shorter than 5 years. (B) Predicted probabilities of clinical progression in the MS cohort characterized by an extent of cortical demyelination at baseline greater than 8.5% or a disease duration longer than 5 years.