Pathological differences between white and grey matter multiple sclerosis lesions

Abstract

Multiple sclerosis (MS) is a debilitating disease characterized by demyelination of the central nervous system (CNS), resulting in widespread formation of white matter lesions (WMLs) and grey matter lesions (GMLs). WMLs are pathologically characterized by the presence of immune cells that infiltrate the CNS, whereas these immune cells are barely present in GMLs. This striking pathological difference between WMLs and GMLs raises questions about the underlying mechanism. It is known that infiltrating leukocytes contribute to the generation of WMLs; however, since GMLs show a paucity of infiltrating immune cells, their importance in GML formation remains to be determined. Here, we review pathological characteristics of WMLs and GMLs, and suggest some possible explanations for the observed pathological differences. In our view, cellular and molecular characteristics of WM and GM, and local differences within WMLs and GMLs (in particular, in glial cell populations and the molecules they express), determine the pathway to demyelination. Further understanding of GML pathogenesis, considered to contribute to chronic MS, may have a direct impact on the development of novel therapeutic targets to counteract this progressive neurological disorder.

Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis

“…Peculiar pathological patterns of white matter lesions are infiltration of immune cells (lymphocytes, macrophages, and microglia), Ig and complement deposition, ODC death, demyelination, axonal loss, and astrogliosis. Their occurrences in a white matter lesion depend on the lesion’s activity and pathologic profile [2,6,7,8]. Gray matter lesions have been associated with clinical disability and cognitive impairment [8,9,10].…”

“…Their occurrences in a white matter lesion depend on the lesion’s activity and pathologic profile [2,6,7,8]. Gray matter lesions have been associated with clinical disability and cognitive impairment [8,9,10]. They are characterized by an intact blood-brain barrier (BBB), the absence of lymphocyte infiltration, antibody deposits, and complements, therefore, grey matter lesions are considered mainly “non-inflammatory” [8,9,11,12,13].…”

“…Gray matter lesions have been associated with clinical disability and cognitive impairment [8,9,10]. They are characterized by an intact blood-brain barrier (BBB), the absence of lymphocyte infiltration, antibody deposits, and complements, therefore, grey matter lesions are considered mainly “non-inflammatory” [8,9,11,12,13]. Several reports suggest that both inflammatory and neurodegenerative processes contribute to the pathology of grey matter but their relationship is unexplained.…”

“…Extensive neuroimaging, immunohistochemical [8] and pathological studies are searching for the answers about whether the gray and white matter lesions are affected by the same mechanism. One hypothesis presumes retrograde degeneration secondary to the white matter lesion, but there are evidences of demyelination-independent grey matter damages in experimental autoimmune encephalomyelitis (EAE)/MS [9,14].…”

The link of inflammation and neurodegeneration in progressive multiple sclerosis

“…-Cortical and deep grey matter demyelination is very common in MS and exceeds white matter demyelination. However, little is known about its dynamics because lesion load measures have been difficult both by MRI and by histopathology [26][27][28]. In PMS strips or bands of subpial cortical demyelination, which differ in appearance from intracortical and leukocortical focal lesions ones, are by far the biggest contributors to total cortical lesion load, and do not occur in other inflammatory or non-inflammatory human CNS diseases.…”