White-matter lesions drive deep gray-matter atrophy in early multiple sclerosis: support from structural MRI

Background: In MS, the relationship between lesions within cerebral
white matter (WM) and atrophy within deep gray matter (GM) is
unclear. Objective: To investigate the spatial relationship between
WM lesions and deep GM atrophy. Methods: We performed a
cross-sectional structural magnetic resonance imaging (MRI) study
(3 Tesla) in 249 patients with clinically-isolated syndrome or
relapsing-remitting MS (Expanded Disability Status Scale score:
median, 1.0; range, 0-4) and in 49 healthy controls. Preprocessing
of T1-weighted and fluid-attenuated T2-weighted images resulted in
normalized GM images and WM lesion probability maps. We performed
two voxel-wise analyses: 1. We localized GM atrophy and confirmed
that it is most pronounced within deep GM; 2. We searched for a
spatial relationship between WM lesions and deep GM atrophy; to
this end we analyzed WM lesion probability maps by voxel-wise
multiple regression, including four variables derived from maxima
of regional deep GM atrophy (caudate and pulvinar, each left and
right). Results: Atrophy of each deep GM region was explained by
ipsilateral WM lesion probability, in the area most densely
connected to the respective deep GM region. Conclusion: We
demonstrated that WM lesions and deep GM atrophy are spatially
related. Our results are best compatible with the hypothesis that
WM lesions contribute to deep GM atrophy through axonal pathology.