Oligodendroglia in cortical multiple sclerosis lesions decrease with disease progression, but regenerate after repeated experimental demyelination.

Cerebral cortex shows a high endogenous propensity for remyelination. Yet, widespread subpial cortical demyelination (SCD) is a common feature in progressive multiple sclerosis (MS) and can already be found in early MS. In the present study, we compared oligodendroglial loss in SCD in early and chronic MS. Furthermore, we addressed in an experimental model whether repeated episodes of inflammatory SCD could alter oligodendroglial repopulation and subsequently lead to persistently demyelinated cortical lesions. NogoA(+) mature oligodendrocytes and Olig2(+) oligodendrocyte precursor cells were examined in SCD in patients with early and chronic MS, normal-appearing MS cortex, and control cortex as well as in the rat model of repeated targeted cortical experimental autoimmune encephalomyelitis (EAE). NogoA(+) and Olig2(+) cells were significantly reduced in SCD in patients with chronic, but not early MS. Repeated induction of SCD in rats resulted only in a transient loss of NogoA(+), but not Olig2(+) cells during the demyelination phase. This phase was followed by complete oligodendroglial repopulation and remyelination, even after four episodes of demyelination. Our data indicate efficient oligodendroglial repopulation in subpial cortical lesions in rats after repeated SCD that was similar to early, but not chronic MS cases. Accordingly, four cycles of experimental de- and remyelination were not sufficient to induce sustained remyelination failure as found in chronic cortical MS lesions. This suggests that alternative mechanisms contribute to oligodendrocyte depletion in chronic cortical demyelination in MS.

Increased Meningeal T and Plasma Cell Infiltration is Associated with Early Subpial Cortical Demyelination in Common Marmosets with Experimental Autoimmune Encephalomyelitis.

Subpial cortical demyelination (SCD) accounts for the greatest proportion of demyelinated cortex in multiple sclerosis (MS). SCD is already found in biopsy cases with early MS and in marmosets with experimental autoimmune encephalomyelitis (EAE), but the pathogenesis of SCD is not well understood. The objective of this study was to investigate whether and, if so, which meningeal inflammatory cells were associated with early SCD in marmosets with EAE. Immunohistochemistry was performed to analyze brain samples from eight control animals and eight marmosets immunized with myelin oligodendrocyte glycoprotein. Meningeal T, B and plasma cells were quantified adjacent to SCD, normal-appearing EAE cortex (NAC) and control marmoset cortex. SCD areas appeared mostly hypocellular with low-grade microglial activation. In marmosets with EAE, meninges adjacent to SCD showed significantly increased T cells paralleled by elevated plasma cells, but unaltered B cell numbers compared with NAC. The elevation of meningeal T and plasma cells was a specific finding topographically associated with SCD, as the meninges overlying NAC displayed similarly low T, B and plasma cell numbers as control cortex. These findings suggest that local meningeal T and plasma cell infiltration contributes to the pathogenesis of SCD in marmosets with EAE.