Gray Matter Involvement in Multiple Sclerosis: A New Window into Pathogenesis

Multiple sclerosis (MS) has long been regarded as an immune-mediated multifocal disease involving mainly white matter tracts of the central nervous system. For more than a century, disruption of the blood-brain barrier, transendothelial migration of activated leukocytes, and destruction of the myelin-oligodendrocyte complex have formed the main focus of research on the pathogenesis of MS. However, recent neuropathological studies, along with implementation of modern neuroimaging techniques, particularly magnetic resonance imaging (MRI) fluid-attenuated inversion recovery (FLAIR), positron emission tomography, and magnetization transfer, have changed our view of MS from one of a primarily white matter disease to one of a whole-brain disease with significant brain atrophy and involvement of cortical and subcortical gray matter. The measurement of brain atrophy is a new, promising technique that shows a close relationship to cognitive impairment and physical disability and may serve as a marker of disease progression. Increasing whole-brain atrophy has been demonstrated to develop early in the course of MS. The pathogenesis of such progressive brain atrophy in MS patients and the relative contributions of gray and white matter atrophy remain largely unknown. Recent neuroimaging studies have indicated that neuronal degeneration and volume loss occur in the deep gray matter nuclei of patients with MS. Cifelli et al performed a detailed study on thalamic neurodegeneration using volumetric MRI and magnetic resonance spectroscopy in vivo and postmortem neuropathologic examinations to estimate thalamic neuronal loss. The authors found significant thalamic neurodegeneration, metabolite depletion, and volume loss, including a 22% reduction in neuronal density and a 21% decrease in volume compared to normal controls. Another study, by Bermel et al, using a 3-dimensional MRI procedure reconstructed and compared caudate nuclei with age-matched healthy controls and found a 19% reduction in caudate volume occurring selectively in patients with MS. Neurodegeneration in gray matter is associated with the apoptotic loss of neurons and the development of transected axons and dendrites. The pathogenesis of gray matter injury in MS patients remains largely unknown, but both direct (inflammation and neurotoxicity) and indirect (diaschisis and Wallerian degeneration) mechanisms of injury appear to contribute. Neuroimaging studies have also demonstrated another interesting aspect of gray matter pathology in MS patients: hypointensity on T2-weighted images in the brain stem, basal ganglia, thalamus, and cerebral cortex, which probably reflects pathologic iron deposition. Bakshi and colleagues have shown that gray matter T2 hypointensity is common in MS and is related to disease course, physical disability, MRI lesion load, and brain atrophy. In this issue of the Journal of Neuroimaging, Fabiano et al approach the subject area from a different angle, using diffusion-weighted MRI, and report that patients with MS have increased thalamic water diffusion that is partly associated with clinical course, lesion load, and whole-brain atrophy. The authors applied diffusionweighted MRI to patients with clinically definite MS and healthy controls and determined thalamic apparent diffusion coefficients (ADCs), whole-brain atrophy (brain parenchymal fraction), FLAIR hyperintense lesion volume, and clinical course. Increased ADCs in the thalamus were found to be associated with whole-brain atrophy. The results of this study lend more support to the concept of a shared contribution of gray and white matter injury to the pathogenesis of MS.