Gray Matter Atrophy Is Primarily Related to Demyelination of Lesions in Multiple Sclerosis: A Diffusion Tensor Imaging MRI Study

Abstract

Objective: Cortical pathology, periventricular demyelination, and lesion formation in multiple sclerosis (MS) are related (Hypothesis 1). Factors in the cerebrospinal fluid close to these compartments could possibly drive the parallel processes. Alternatively, the cortical atrophy could be caused by remote axonal transection (Hypothesis 2). Since MRI can differentiate between demyelination and axon loss, we used this imaging modality to investigate the correlation between the pattern of diffusion parameter changes in the periventricular- and deep white matter and the gray matter atrophy. Methods: High-resolution T1-weighted, FLAIR, and diffusion MRI images were acquired in 52 RRMS patients and 50 healthy, age-matched controls. We used EDSS to estimate the clinical disability. We used Tract Based Spatial Statistics to compare diffusion parameters (fractional anisotropy, mean, axial, and radial diffusivity) between groups. We evaluated global brain, white, and gray matter atrophy with SIENAX. Averaged, standard diffusion parameters were calculated in four compartment: periventricular lesioned and normal appearing white matter, non-periventricular lesioned and normal appearing white matter. PLS regression was used to identify which diffusion parameter and in which compartment best predicts the brain atrophy and clinical disability. Results: In our diffusion tensor imaging study compared to controls we found extensive alterations of fractional anisotropy, mean and radial diffusivity and smaller changes of axial diffusivity (maximal p > 0.0002) in patients that suggested demyelination in the lesioned and in the normal appearing white matter. We found significant reduction in total brain, total white, and gray matter (patients: 718.764 ± 14.968, 323.237 ± 7.246, 395.527 ± 8.050 cm³, controls: 791.772 ± 22.692, 355.350 ± 10.929, 436.422 ± 12.011 cm³; mean ± SE), (p < 0.015; p < 0.0001; p < 0.009; respectively) of patients compared to controls. The PLS analysis revealed a combination of demyelination-like diffusion parameters (higher mean and radial diffusivity in patients) in the lesions and in the non-lesioned periventricular white matter, which best predicted the gray matter atrophy (p < 0.001). Similarly, EDSS was best predicted by the radial diffusivity of the lesions and the non-lesioned periventricular white matter, but axial diffusivity of the periventricular lesions also contributed significantly (p < 0.0001). Interpretation: Our investigation showed that gray matter atrophy and white matter demyelination are related in MS but white matter axonal loss does not significantly contribute to the gray matter pathology.

Keywords: brain atrophy; demyelination; multiple sclerosis; normal-appearing white matter; periventricular white matter.

Figure 1

Extensive diffusion parameter changes and cortical atrophy were found in multiple sclerosis patients. The first row depicts the lesion probability map of the 52 patients. The colorbar represents the number of patients having a lesion in a particular localization. The lesion probability map was overlaid on the MNI152 standard brain. The z coordinates of the selected slices are shown below the images. The next section of the Figure depicts the results of the TBSS analysis. Significant differences in FA, MD, and axial and radial diffusivity between patients and controls in the white matter skeleton are shown in the consecutive rows. A blue color indicates decrease, and red-to-yellow colors an increase in the given diffusion parameters. A thickened version of the significant cluster is used for easier visualization (red-to-yellow or blue shades). Colorbars represent p-values (corrected for multiple correlation). Statistical images are overlaid on the FMRIB58_FA standard FA template and the z coordinates are shown below the images. The z-values under the significant corrected p-values (p < 0.05) are shown. Images are overlaid on the MNI152 standard brain and the z coordinates are shown under the images.

Figure 2

Normalized brain volumes of patients and controls. The error bars represent the standard errors.

Figure 3

Partial least squares loadings and VIP scores that describe the optimum contrast of the independent variables that predict the gray matter volume. From these loadings and VIP scores, it is conceivable the predominantly the diffusion parameters of the lesions and the non-lesioned periventricular white matter (PV-WM) drive the gray matter atrophy. Of the diffusion parameters, MD and RD, related most significantly to the gray matter atrophy. VIP scores are considered significant if higher than 1.

Figure 4

Partial least squares loadings and VIP scores that describe the optimum contrast of the independent variables that predict the disability (EDSS) of the patients. EDSS can be predicted most significantly from the RD and MD of the lesions and the periventricular non-lesioned white matter. A further contribution can be seen from the AD change in the periventricular lesions. VIP scores are considered significant if higher than 1.

Figure 5

Graphical Presentation: EDSS was best predicted by the radial diffusivity of the lesioned and non-lesioned periventricular white matter and also the axial diffusivity of the lesioned periventricular white matter (Part 1). The gray matter atrophy (marked with blue color) was best predicted by the combination of demyelination-like diffusion parameters (Hypothesis I.), in the lesions and in the non-lesioned periventricular white matter (marked with red color), but not by the axonloss-like diffusion parameters in the NAWM (Hypothesis II; lesions are marked with green color; Part 2).