Grey matter pathology in multiple sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. MS has traditionally been considered a disease affecting the well myelinated white matter areas. Recent insights into axonal pathology in MS raised the attention to the significance of grey matter lesions, which have not been well characterised yet. Thus, the aim of our study was to delineate the fundamental histopathological aspects of MS lesions in the grey matter.Our work identified extensive cortical demyelination associated with marginal inflammation in autopsy brain tissue of patients with chronic MS. In addition, we found evidence for T-cell/macrophage-mediated active inflammatory demyelination in cortex in biopsy brain tissue of patients with early MS. A direct comparison of the inflammatory activity in white matter and cortical lesions of the same patients revealed that the density and composition of T-lymphocytes was similar in early grey and white matter lesions. Foamy macrophages were, however, essentially absent; the blood brain barrier appeared intact, acute axonal injury was less in the cortical in contrast to the white matter lesions. While acute neuronal injury was apparent in a proportion of early lesions, neurons with synaptic boutons were well preserved in the chronic grey matter plaques.We examined the frequency and extent of remyelination in cortical and white matter lesions of patients with chronic MS. Cortical remyelination was identified light microscopically by the presence of irregularly arranged and less densely packed myelin sheaths, and confirmed by electron microscopy. A direct comparison of the extent of remyelination in white matter and cortical lesions of the same patients revealed that remyelination of cortical lesions was consistently more extensive. In addition, g-ratios of fibers in the normal appearing cortex yielded values consistent with remyelination.Preserved neuronal cell bodies and synaptic boutons as well as the extensive remyelination in chronic MS cortex suggested efficient repair and adaptive mechanisms that may take place in the grey matter during the course of MS. Therefore, the density, topography and morphology of synapses were investigated in the cerebellar dentate nucleus and in the nuclei of the pons by light and electron microscopy. There was a substantial loss of axosomatic synaptic contacts in the dentate nucleus in all MS patients examined. Synapses on the stem and peripheral dendrites, however, appeared well preserved. Subpopulations of neurons were affected to a variable degree. Dissociation of boutons from the soma membrane occurred irrespective of the lesional border; moreover, it could be found in sections, where no demyelinated lesions were recognised. In the pontine nuclei the density of synapses appeared largely preserved. The structural changes observed suggested the mechanisms that may be involved: (i) synaptic stripping that has been shown in various experimental models to be selective and reversible, (ii) autophagy and lysosomal degradation of synaptic elements and subsequent transport of residual bodies in intact axons, which has been shown during ontogenetic development to be a mode of reorganisation of synaptic contacts.Our data imply that inflammatory demyelination occurs in cortex even in early MS. Cortical de- and remyelination are frequent and the propensity to remyelinate is high in cortical MS lesions. Remodelling of synaptic contacts may take place even in late stages of the disease. Further studies are required to determine the conditions under which regeneration can be elicited and supported, thus providing functional improvement of patients suffering from MS.