MRI Analysis of White Matter Myelin Water Content in Multiple Sclerosis: A Novel Approach Applied to Finding Correlates of Cortical Thinning.

Michael Dayan,Ashish Raj,Elizabeth Monohan,Eve M Locastro,Sneha Pandya,Tim Vartanian,Susan A Gauthier,Thanh D Nguyen,Sandra M Hurtado Rúa,Kyoko Fujimoto

doi:10.3389/fnins.2017.00284

Abstract

A novel lesion-mask free method based on a gamma mixture model was applied to myelin water fraction (MWF) maps to estimate the association between cortical thickness and myelin content, and how it differs between relapsing-remitting (RRMS) and secondary-progressive multiple sclerosis (SPMS) groups (135 and 23 patients, respectively). It was compared to an approach based on lesion masks. The gamma mixture distribution of whole brain, white matter (WM) MWF was characterized with three variables: the mode (most frequent value) m1 of the gamma component shown to relate to lesion, the mode m2 of the component shown to be associated with normal appearing (NA) WM, and the mixing ratio (λ) between the two distributions. The lesion-mask approach relied on the mean MWF within lesion and within NAWM. A multivariate regression analysis was carried out to find the best predictors of cortical thickness for each group and for each approach. The gamma-mixture method was shown to outperform the lesion-mask approach in terms of adjusted R2, both for the RRMS and SPMS groups. The predictors of the final gamma-mixture models were found to be m1 (β = 1.56, p < 0.005), λ (β = −0.30, p < 0.0005) and age (β = −0.0031, p < 0.005) for the RRMS group (adjusted R2 = 0.16), and m2 (β = 4.72, p < 0.0005) for the SPMS group (adjusted R2 = 0.45). Further, a DICE coefficient analysis demonstrated that the lesion mask had more overlap to an ROI associated with m1, than to an ROI associated with m2 (p < 0.00001), and vice versa for the NAWM mask (p < 0.00001). These results suggest that during the relapsing phase, focal WM damage is associated with cortical thinning, yet in SPMS patients, global WM deterioration has a much stronger influence on secondary degeneration. Through these findings, we demonstrate the potential contribution of myelin loss on neuronal degeneration at different disease stages and the usefulness of our statistical reduction technique which is not affected by the typical bias associated with approaches based on lesion masks.

Highlights

The mechanisms of cortical atrophy in multiple sclerosis (MS) are poorly understood
Multiple Metrics Measured in a Large Cohort of RRMS and secondary-progressive multiple sclerosis (SPMS) Patients
A change in m1 is assumed to result from focal demyelination, likely predominantly found within lesions and dirty white matter (WM). These results suggest that a small contribution of secondary degeneration is related to focal WM myelin injury and other sources not included in our model such as normal aging and primary disease related gray matter (GM) pathology (i.e., GM lesions Seewann et al, 2011), may drive the decrease in cortical thickness

Summary

Introduction

The mechanisms of cortical atrophy in multiple sclerosis (MS) are poorly understood. Lesions are the most visible radiological aspect of the disease, used for both diagnosis (Polman et al, 2011) and clinical trials (Polman et al, 2006; Kappos et al, 2007; Mikol et al, 2008), disability has been shown to have a stronger correlation with gray matter (GM) cortical atrophy compared to WM measurements (Ramasamy et al, 2009; Calabrese et al, 2010, 2011; Narayana et al, 2013). It is of particular interest to explore the mechanisms driving cortical thinning. We hypothesize that the relationship between WM demyelination and cortical thinning is different among these two disease stages

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