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.