Objective Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease of unknown etiology. Although the prevalent view regards a CD4+‐lymphocyte autoimmune reaction against myelin at the root of the disease, recent studies propose autoimmunity as a secondary reaction to idiopathic brain damage. To gain knowledge about this possibility we investigated the presence of axonal and myelinic morphological alterations, which could implicate imbalance of axon‐myelin units as primary event in MS pathogenesis. Methods Using high resolution imaging histological brain specimens from patients with MS and non‐neurological/non‐MS controls, we explored molecular changes underpinning imbalanced interaction between axon and myelin in normal appearing white matter (NAWM), a region characterized by normal myelination and absent inflammatory activity. Results In MS brains, we detected blister‐like swellings formed by myelin detachment from axons, which were substantially less frequently retrieved in non‐neurological/non‐MS controls. Swellings in MS NAWM presented altered glutamate receptor expression, myelin associated glycoprotein (MAG) distribution, and lipid biochemical composition of myelin sheaths. Changes in tethering protein expression, widening of nodes of Ranvier and altered distribution of sodium channels in nodal regions of otherwise normally myelinated axons were also present in MS NAWM. Finally, we demonstrate a significant increase, compared with controls, in citrullinated proteins in myelin of MS cases, pointing toward biochemical modifications that may amplify the immunogenicity of MS myelin. Interpretation Collectively, the impaired interaction of myelin and axons potentially leads to myelin disintegration. Conceptually, the ensuing release of (post‐translationally modified) myelin antigens may elicit a subsequent immune attack in MS. ANN NEUROL 2021;89:711–725

In patients with long-standing disease, neuronal and axonal pathology are the predominant pathological substrates of MRI-measured cortical volume in chronic MS.

Over the past decade, immunohistochemical studies have provided compelling evidence that gray matter (GM) pathology in multiple sclerosis (MS) is extensive. Until recently, this GM pathology was difficult to visualize using standard magnetic resonance imaging (MRI) techniques. However, with newly developed MRI sequences, it has become clear that GM damage is present from the earliest stages of the disease and accrues with disease progression. GM pathology is clinically relevant, as GM lesions and/or GM atrophy were shown to be associated with MS motor deficits and cognitive impairment. Recent autopsy studies demonstrated significant GM demyelination and microglia activation. However, extensive immune cell influx, complement activation and blood-brain barrier leakage, like in WM pathology, are far less prominent in the GM. Hence, so far, the cause of GM damage in MS remains unknown, although several plausible underlying pathogenic mechanisms have been proposed. This paper provides an overview of GM damage in MS with a focus on its topology and histopathology.

Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the CNS. Multiple sclerosis lesions include significant demyelination of the gray matter, which is thought to be a major contributor to both physical and cognitive impairment. Subpial (Type III) lesions are the most common demyelinated cortical lesions. We investigated neurodegenerative features of subpial lesions in cerebral cortex samples from 11 patients with MS and 6 nondemented non-MS controls. There were no significant differences in neuron and axon density between normally myelinated normal-appearing gray matter (NAGM) and Type III MS lesions. Neurons were 11.2% smaller in Type III lesions than in NAGM in the cingulate cortex only; Type III lesions contained 25.4% fewer NeuN-positive neurons compared with control cortex. Neurons in MS NAGM were 13.6% smaller than those in control cortex. Finally, the same regions, immunostained with anti-SMI312 antibodies, showed reduced axon densities in Type III lesions (-31.4%) and NAGM (-33.0%) compared with controls. In conclusion, both NAGM and Type III lesions showed neurodegenerative changes, but they had no consistent differences in neuronal and axonal alterations. This suggests that neurodegeneration in the cerebral cortex of patients with MS may be independent of cortical demyelination.