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

Eszter Tóth,András Király,Péter Faragó,Gergõ Csete,Zsigmond T Kincses,László Vécsei,Krisztina Bencsik,Tamás Spisák,Nikoletta Szabó

doi:10.3389/fnana.2017.00023

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.

Highlights

Multiple sclerosis is an inflammatory, demyelinating, neurodegenerative disease of the central nervous system
The lesions were distributed across widespread white matter regions, but the lesion probability was highest in the periventricular white matter (Figure 1 first row)
The SIENAX analysis revealed reduction in total brain volume, total white matter, and total gray matter volume in the multiple sclerosis patients compared to controls

Summary

Introduction

Multiple sclerosis is an inflammatory, demyelinating, neurodegenerative disease of the central nervous system. Besides the white matter lesions, which are the diagnostic cornerstones of the disease, increasing attention is being paid to gray matter atrophy, which has recently become a tool for the follow-up of the therapeutic efficacy (Kincses et al, 2014; De Stefano et al, 2016). The demyelination in the gray matter is comparable in extent to that in the white matter (Gilmore et al, 2009). Ex-vivo studies have shown that the demyelination is mainly subpial (Type III lesions) and presents in the form of ribbons, often affecting several adjacent gyri. This kind of cortical demyelination proved to be associated with meningeal inflammation. Earlier studies found that a non-targeted general immunopathological response arising from this meningeal inflammation and mediated by the cerebrospinal fluid is responsible for the cortical pathology (Magliozzi et al, 2010; Lisak et al, 2012)

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