Abstract
Multiple Sclerosis (MS) is a major cause of neurological disability, which increases predominantly during disease progression as a result of cortical and grey matter structures involvement. The gradual accumulation of disability characteristic of the disease seems to also result from a different set of mechanisms, including in particular immune reactions confined to the Central Nervous System such as: (a) B-cell dysregulation, (b) CD8+ T cells causing demyelination or axonal/neuronal damage, and (c) microglial cell activation associated with neuritic transection found in cortical demyelinating lesions. Other potential drivers of neurodegeneration are generation of oxygen and nitrogen reactive species, and mitochondrial damage, inducing impaired energy production, and intra-axonal accumulation of Ca2+, which in turn activates a variety of catabolic enzymes ultimately leading to progressive proteolytic degradation of cytoskeleton proteins. Loss of axon energy provided by oligodendrocytes determines further axonal degeneration and neuronal loss. Clearly, these different mechanisms are not mutually exclusive and could act in combination. Given the multifactorial pathophysiology of progressive MS, many potential therapeutic targets could be investigated in the future. This remains however, an objective that has yet to be undertaken.
Highlights
Multiple Sclerosis (MS) is a chronic inflammatory disease of the Central Nervous System (CNS)leading to demyelination and diffuse neurodegeneration in both brain and spinal cord grey and white matter of the brain and spinal cord [1,2]
Even though MS was considered early on to be a demyelinating disease of CNS white matter mediated by inflammation, the possibility has been raised in recent years that cortical and deep grey matter demyelination may exceed that of white-matter demyelination, with both postmortem and in vivo studies revealing presence of extensive lesions in grey matter (GM) structures [8,17,18]
Astrocytes as part of the immune system could contribute to disease progression through several mechanisms. They can directly affect cell entry to the CNS, via de the BBB, by regulating expression of adhesion molecules, vascular adhesion-molecule-1 (VCAM-1), and intercellular adhesion-molecule-1 (ICAM-1), that bind to lymphocyte receptors very late antigen-4 (VLA4), and lymphocyte function-associated antigen-1 (LFA-1), respectively [116,117]
Summary
Multiple Sclerosis (MS) is a chronic inflammatory disease of the Central Nervous System (CNS). Biomedicines 2019, 7, 14 compartmentalized pathological processes within the brain mediated mainly by resident CNS cells Evidence of this comes from MRI showing decreased gadolinium (Gd) enhancement in CNS lesions found in progressive MS patients, indicating reduced BBB breakdown and less movement of immune cells into the CNS. Whether inflammation and neurodegeneration are primary or secondary processes, and how they interact during the course of disease remains unclear Another major pathological substrate of progressive MS is cortical demyelination. In progressive MS lesions diffuse pathology is present in normal appearing white and grey matter, reflected by diffuse axonal injury with profound microglia activation within a background of a global inflammation of the entire brain and the meninges [13]. This review discusses present knowledge on grey matter involvement in progressive MS, as well as the putative mechanisms that can determine the processes of neurodegeneration and neuronal death
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