Evidence of progressive tissue loss in the core of chronic MS lesions: A longitudinal DTI study

Abstract

Objective: Using diffusion tensor imaging (DTI), we examined chronic stable MS lesions, peri-lesional white matter (PLWM) and normal appearing white matter (NAWM) in patients with relapsing-remitting multiple sclerosis (RRMS) for evidence of progressive tissue destruction and evaluated whether diffusivity change is associated with conventional MRI parameters and clinical findings.

Method: Pre- and post-gadolinium T1, T2 and DTI images were acquired from 55 consecutive RRMS patients at baseline and 42.3 ± 9.7 months later. Chronic stable T2 lesions of sufficient size were identified in 43 patients (total of 134 lesions). Diffusivity parameters such as axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD) and fractional anisotropy (FA) were compared at baseline and follow-up. MRI was also performed in 20 normal subjects of similar age and gender.

Results: Within the core of chronic MS lesions the diffusion of water molecules significantly increased over the follow-up period, while in NAWM all diffusivity indices remained stable. Since increase of AD and RD in lesional core was highly concordant, indicating isotropic nature of diffusivity change, and considering potential effect of crossing fibers on directionally-selective indices, only MD, a directionally-independent measure, was used for further analysis. The significant increase of MD in the lesion core during the follow-up period (1.29 ± 0.19 μm²/ms and 1.34 ± 0.20 μm²/ms at baseline and follow-up respectively, P < 0.0001) was independent of age or disease duration, total brain lesion volume or new lesion activity, lesion size or location and baseline tissue damage (T1 hypointensity). Change of MD in the lesion core, however, was associated with progressive brain atrophy (r = 0.47, P = 0.002). A significant gender difference was also observed: the MD change in male patients was almost twice that of female patients (0.030 ± 0.04 μm²/ms and 0.058 ± 0.03 μm²/ms in female and male respectively, P = 0.01). Sub-analysis of lesions with lesion-free surrounding revealed the largest MD increase in the lesion core, while MD progression gradually declined towards PLWM. MD in NAWM remained stable over the follow-up period.

Conclusion: The significant increase of isotropic water diffusion in the core of chronic stable MS lesions likely reflects gradual, self-sustained tissue destruction in demyelinated white matter that is more aggressive in males.

Keywords: Chronic demyelination; Diffusion; Lesions; Multiple sclerosis.

Fig. 1

Lesion and NAWM ROIs. A. Examples of lesion position adjustment (lesion shifting outwards). Red contour: baseline lesion, green contour: follow-up lesion displayed on follow-up T2 FLAIR image. B. Example of 4 ROIs used for NAWM. C. Segmentation of lesional and perilesional white matter displayed on baseline T2 FLAIR image. Red colour represents lesion core, green colour represents lesion “rim” and PLWM shells are yellow and magenta. D. Example of removing CSF contamination from PLWM displayed on baseline T2 FLAIR image. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Correlation between AD and RD changes in individual lesions.

Fig. 3

Change of MD in individual patients during follow-up period.

Fig. 4

Effect of brain atrophy and gender on lesional diffusivity change: A. Association between increase of lateral ventricular volume and lesional MD change B. Change in lesional MD in male and female groups.

Fig. 5

Sub-analysis of lesional and peri-lesional white matter. A. Baseline MD in lesion core, lesion rim, PLWM, NAWM and normal controls (vertical scale-μm²/ms, error bar ± 2SE). B. MD progression in lesion core, lesion rim, PLWM and NAWM. (vertical scale-μm²/ms, error bar ± 2SE). Horizontal bars represent statistically significant difference (P < 0.05).