Remyelination varies between and within lesions in multiple sclerosis following bexarotene.

OBJECTIVE: In multiple sclerosis chronic demyelination is associated with axonal loss, and ultimately contributes to irreversible progressive disability. Enhancing remyelination may slow, or even reverse, disability. We recently trialled bexarotene versus placebo in 49 people with multiple sclerosis. While the primary MRI outcome was negative, there was converging neurophysiological and MRI evidence of efficacy. Multiple factors influence lesion remyelination. In this study we undertook a systematic exploratory analysis to determine whether treatment response - measured by change in magnetisation transfer ratio - is influenced by location (tissue type and proximity to CSF) or the degree of abnormality (using baseline magnetisation transfer ratio and T1 values). METHODS: We examined treatment effects at the whole lesion level, the lesion component level (core, rim and perilesional tissues) and at the individual lesion voxel level. RESULTS: At the whole lesion level, significant treatment effects were seen in GM but not WM lesions. Voxel-level analyses detected significant treatment effects in WM lesion voxels with the lowest baseline MTR, and uncovered gradients of treatment effect in both WM and CGM lesional voxels, suggesting that treatment effects were lower near CSF spaces. Finally, larger treatment effects were seen in the outer and surrounding components of GM lesions compared to inner cores. INTERPRETATION: Remyelination varies markedly within and between lesions. The greater remyelinating effect in GM lesions is congruent with neuropathological observations. For future remyelination trials, whole GM lesion measures require less complex post-processing compared to WM lesions (which require voxel level analyses) and markedly reduce sample sizes.

Magnetisation transfer ratio abnormalities in primary and secondary progressive multiple sclerosis.

BACKGROUND: In relapse-onset multiple sclerosis (MS), tissue abnormality - as assessed with magnetisation transfer ratio (MTR) imaging - is greater in the outer cortical and inner periventricular layers. The cause of this remains unknown but meningeal inflammation has been implicated, particularly lymphoid follicles, which are seen in secondary progressive (SP) but not primary progressive (PP) MS. Cortical and periventricular MTR gradients might, therefore, differ in PPMS and SPMS if these follicles are responsible. OBJECTIVE: We assessed cortical and periventricular MTR gradients in PPMS, and compared gradients between people with PPMS and SPMS. METHODS: Using an optimised processing pipeline, periventricular normal-appearing white matter and cortical grey-matter MTR gradients were compared between 51 healthy controls and 63 people with progressive MS (28 PPMS, 35 SPMS). RESULTS: The periventricular gradient was significantly shallower in healthy controls (0.122 percentage units (pu)/band) compared to PPMS (0.952 pu/band, p < 0.0001) and SPMS (1.360 pu/band, p < 0.0001). The cortical gradient was also significantly shallower in healthy controls (-2.860 pu/band) compared to PPMS (-3.214 pu/band, p = 0.038) and SPMS (-3.328 pu/band, p = 0.016). CONCLUSION: Abnormal periventricular and cortical MTR gradients occur in both PPMS and SPMS, suggesting comparable underlying pathological processes.

Sensitivity of multi-shell NODDI to multiple sclerosis white matter changes: a pilot study.

Diffusion tensor imaging (DTI) is sensitive to white matter (WM) damage in multiple sclerosis (MS), not only in focal lesions but also in the normal-appearing WM (NAWM). However, DTI indices can also be affected by natural spatial variation in WM, as seen in crossing and dispersing white matter fibers. Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion-weighted imaging technique that provides distinct indices of fiber density and dispersion. We performed NODDI of lesion tissue and NAWM in five MS patients and five controls, comparing the technique with traditional DTI. Both DTI and NODDI identified tissue damage in NAWM and in lesions. NODDI was able to detect additional changes and it provided better contrast in MS-NAWM microstructure, because it distinguished orientation dispersion and fiber density better than DTI. We showed that NODDI is viable in MS patients and that it offers, compared with DTI parameters, improved sensitivity and possibly greater specificity to microstructure features such as neurite orientation.

Reconstructing contralateral fiber tracts: methodological aspects of cerebello-thalamocortical pathway reconstruction.

The identification of pathways connecting the cerebral cortex with subcortical structures is critical to understanding how large-scale brain networks operate. The cerebellum, for example, is known to project numerous axonal bundles to thecerebral cortex passing through the thalamus. This paper focuses on the technical details of cerebello-thalamo-cortical pathway reconstruction using advanced diffusion MRI techniques in humans in vivo. Pathways reconstructed using seed/target placement on super-resolution maps, created with track density imaging (TDI), were compared with those reconstructed by defining regions of interest (ROIs) on non-diffusion weighted images (b0). We observed that the reconstruction of the pathways was more anatomically accurate when using ROIs placed on TDI rather than on b0 maps, while inter-subject variability and reproducibility were similar between the two methods. Diffusion indices along pathways showed a position-dependent specificity that will need to be taken into consideration in future clinical investigations.