Subpial Demyelination Research Articles

A new mouse model of inflammatory cortical demyelination

Cortical damage is prominent in multiple sclerosis (MS) and associated with disease progression and cognitive impairment. Although subpial cortical demyelination is more specific for MS than demyelination of the white matter, little is known about the pathogenic requirements for inflammatory cortical demyelination. This study combines transgenic mice on a C57BL/6 background with a stereotactic targeting approach to characterize the immunological mechanisms of inflammatory cortical demyelination. Cortical demyelination as assessed by immunohistochemistry against myelin basic protein (MBP), was most pronounced at day 5 after lesion induction and paralleled by a significant reduction of p25+ adult and Olig2+ precursor oligodendrocytes. Time course experiments demonstrated the rapid resolution of cortical demyelination and a significant decrease of perivascular intracortical demyelination was already observable at day 20 after lesion induction. The number of APP+ axons was significantly higher around perivascularly demyelinated vessels, while the density of cortical neurons was not reduced. The inflammatory cortical infiltrate was composed of inflammatory monocytes, T cells, polymorphonuclear cells (PMNs) and natural killer (NK) cells. We depleted each cell population genetically or by antibody mediated cell depletion to assess their relevance for inflammatory cortical demyelination. A pathogenic antibody response and inflammatory monocytes were required for subpial cortical demyelination. Perivascular cortical demyelination was required in addition to encephalitogenic T cells and was augmented by NK cells. Adoptive transfer studies in RAG mice demonstrated that the antigen presenting functions of B cells were dispensable. In summary, we developed and characterized a novel inflammatory cortical demyelination model.

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.

Meningeal inflammation and demyelination in a patient clinically diagnosed with acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) are both CNS inflammatory demyelinating diseases with overlapping clinical features. A case is reported of a 51-year-old female who presented with headache, progressive aphasia and hemiparesis without preceding infection or vaccination. Brain MRI revealed multiple, often confluent, subcortical white matter lesions without enhancement, affecting predominantly the left cerebral hemisphere. CSF examination failed to reveal oligoclonal bands. Brain biopsy revealed both pathological features of ADEM and findings are consistent with the early stage of MS, including meningeal B and T lymphocytic infiltration, perivenular demyelination, subpial demyelination and discrete confluent plaque-like foci of demyelination. Steroid treatment resulted in remarkable clinical and radiological improvement and there has been no recurrence in six years of follow-up. This case highlights the difficulties in differentiating between ADEM and the first attack of MS and further suggests that ADEM and the early stage of MS, and its tumefactive variant, may have a common underlying pathologic mechanism, which may have a therapeutic implication in treating these diseases.

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1260-8) contains supplementary material, which is available to authorized users.

Surface-based analysis reveals regions of reduced cortical magnetization transfer ratio in patients with multiple sclerosis: a proposed method for imaging subpial demyelination.

The in vivo detection of subpial cortical gray matter lesions in multiple sclerosis is challenging. We quantified the spatial extent of subpial decreases in the magnetization transfer ratio (MTR) of cortical gray matter in subjects with multiple sclerosis, as such reductions may indicate regions of cortical demyelination. We exploited the unique geometry of cortical lesions by using two-dimensional parametric surface models of the cortex instead of traditional three-dimensional voxel-wise analyses. MTR images were mapped onto intermediate surfaces between the pial and white matter surfaces and were used to compute differences between secondary-progressive MS (n = 12), relapsing-remitting MS (n = 12), and normal control (n = 12) groups as well as between each individual patient and the normal controls. We identified large regions of significantly reduced cortical MTR in secondary-progressive patients when compared with normal controls. We also identified large regions of reduced cortical MTR in 11 individual patients (8 secondary-progressive, 3 relapsing-remitting). The secondary-progressive patients showed larger areas of abnormally low MTR compared with relapsing-remitting patients both at the group level and on an individual basis. The spatial distributions of abnormal MTR preferentially involved cingulate cortex, insula, and the depths of sulci, in agreement with pathological descriptions of subpial gray matter lesion distribution. These findings suggest that our method is a plausible in vivo imaging technique for quantifying subpial cortical demyelinating lesions in patients with multiple sclerosis and, furthermore, can be applied at the typical clinical field strength of 1.5 T.

Cortical grey matter demyelination can be induced by elevated pro-inflammatory cytokines in the subarachnoid space of MOG-immunized rats

A substantial proportion of cases with secondary progressive multiple sclerosis have extensive inflammation in the leptomeninges that is associated with increased subpial demyelination, neuronal loss and an exacerbated disease course. However, the mechanisms underlying this extensive subpial pathology are poorly understood. We hypothesize that pro-inflammatory cytokine production within the meninges may be a key to this process. Post-mortem cerebrospinal fluid and dissected cerebral leptomeningeal tissue from patients with multiple sclerosis were used to study the presence of tumour necrosis factor and interferon gamma protein and messenger RNA levels. A novel model of subpial cortical grey matter demyelination was set up in Dark Agouti rats and analysed using quantitative immunohistochemistry. Increased expression of the pro-inflammatory cytokines tumour necrosis factor and interferon gamma was found in the meninges of cases with secondary progressive multiple sclerosis exhibiting tertiary lymphoid-like structures. Injection of tumour necrosis factor and interferon gamma into the subarachnoid space of female Dark Agouti rats pre-immunized with a subclinical dose of myelin oligodendrocyte glycoprotein mimicked the pathology seen in multiple sclerosis, including infiltration of lymphocytes (CD4+ and CD8+ T cells and CD79+ B cells) into the meninges and extensive subpial demyelination. Extensive microglial/macrophage activation was present in a gradient from the pial surface to deeper cortical layers. Demyelination did not occur in control animals immunized with incomplete Freund's adjuvant and injected with cytokines. These results support the hypothesis that pro-inflammatory molecules produced in the meninges play a major role in cortical demyelination in multiple sclerosis, but also emphasize the involvement of an anti-myelin immune response.

Blood-Brain Barrier Alterations in the Cerebral Cortex in Experimental Autoimmune Encephalomyelitis

The pathophysiology of cerebral cortical lesions in multiple sclerosis (MS) is not understood. We investigated cerebral cortex microvessels during immune-mediated demyelination in the MS model chronic murine experimental autoimmune encephalomyelitis (EAE) by immunolocalization of the endothelial cell tight junction (TJ) integral proteins claudin-5 and occludin, a structural protein of caveolae, caveolin-1, and the blood-brain barrier-specific endothelial transporter, Glut 1. In EAE-affected mice, there were areas of extensive subpial demyelination and well-demarcated lesions that extended to deeper cortical layers. Activation of microglia and absence of perivascular inflammatory infiltrates were common in these areas. Microvascular endothelial cells showed increased expression of caveolin-1 and a coincident loss of both claudin-5 and occludin normal junctional staining patterns. At a very early disease stage, claudin-5 molecules tended to cluster and form vacuoles that were also Glut 1 positive; the initially preserved occludin pattern became diffusely cytoplasmic at more advanced stages. Possible internalization of claudin-5 on TJ dismantling was suggested by its coexpression with the autophagosomal marker MAP1LC3A. Loss of TJ integrity was confirmed by fluorescein isothiocyanate-dextran experiments that showed leakage of the tracer into the perivascular neuropil. These observations indicate that, in the cerebral cortex of EAE-affected mice, there is a microvascular disease that differentially targets claudin-5 and occludin during ongoing demyelination despite only minimal inflammation.

Heterogeneity of cortical lesions in multiple sclerosis

Autopsy cases show that cortical lesions (CLs) in multiple sclerosis (MS) lack lymphocyte/macrophage influx, blood-brain barrier breakdown, and complement activation. However, some CLs were demonstrated to harbor activated microglia. Here, we assessed the clinical significance of microglia activation in CLs in a large autopsy sample, and we investigated possible interrelationships with other pathologic characteristics. We cross-sectionally investigated the clinicopathologic characteristics of 22 patients with MS with extensive subpial demyelination (CL group) and 19 patients with MS with only little demyelination of the cerebral cortex (non-CL group). A subset of the patients in the CL group (12 patients) showed rims of activated microglia (RAM) at the border of the CLs (RAM-CL group), whereas the other 10 patients in this group did not show microglia activation (non-RAM-CL group). A subsequent comparison between groups showed that patients with MS harboring RAM-CLs were significantly younger at the time of their death (53.5 years) than patients harboring mainly non-RAM-CLs (68.7 years; p < 0.05) or patients without extensive numbers of CLs (66.9 years; p < 0.01). In addition, a significantly shorter disease duration was found for the RAM-CL group (mean 20.9 years) than for the non-CL group (mean 34.5 years; p < 0.05). We also found that the presence of RAM-CLs is associated with a higher number of chronic active white matter (WM) lesions (Spearman ρ = 0.74; p < 0.0001). RAM-CLs were found in a subset of patients with MS who also have more active WM inflammation and a less favorable disease course.

A case of multiple sclerosis with pure, massive superficial demyelination

Although multiple sclerosis (MS) has been classically regarded as a primarily white matter disorder, recent histopathologic studies have shown that the gray matter may be also heavily affected. Subpial demyelination appears as large bands of myelin loss extending from the surface of the cortex into its deeper layers.1 In vivo this change can only be visualized by ultra-high-fields MRI.2 We describe a patient presenting a neurologic disease that rapidly led to spastic paraplegia and death. Plaques of demyelination were absent in the white matter of the brain, but the neuropathologic diagnosis was MS, based on severe and widespread loss of myelin in the spinal cord. Extensive subpial demyelination involved the …

BBB-endothelial cell response to cerebral cortex demyelination in a mouse model of chronic EAE

Changes in blood-brain barrier (BBB) function have been implicated in demyelinating diseases. This study aimed to investigate the response of cerebral cortex microvessels to nerve fibre demyelination in a chronic model of murine experimental autoimmune encephalomyelitis (EAE) characterized by areas of extensive subpial demyelination along with well-demarcated lesions extended to deeper cortex layers. These cortices showed activation of microglia and astrogliosis with absence of typical perivascular inflammatory infiltrates. On the basis of these data, we have analyzed the expression of two integral proteins of endothelial tight junctions, claudin-5 and occludin, a structural protein of caveolae, caveolin-1, as well as the BBB-specific endothelial transporter, Glut1 in the cerebral cortex of EAE-affected mice by immunofluorescence confocal microscopy. Microvascular endothelial cells showed an increased expression of caveolin-1 and a coincident decrease of both claudin-5 and occludin junctional staining pattern. At a very early disease stage, claudin-5 molecules formed aggregates and vacuoles that also stained for Glut 1, whereas occludin pattern became diffusely cytoplasmic at advanced stages of the disease. Internalization/dismantling and loss of tight junction proteins and impairment of BBB function were confirmed by coexpression of claudin-5 whit the autophagosomal marker MAP1LC3A and by FITC-dextran experiments that showed leakage of the tracer into the perivascular neuropil. Overall, these observations indicate that in the cerebral cortex of EAE mice, during demyelination and independently from the inflammatory involvement of the cortex, a ‘microvascular disease’ characterized by a differential involvement of claudin-5 and occludin occurs, thereby possibly contributing to demyelinating disease progression.

Cerebral cortex demyelination and oligodendrocyte precursor response to experimental autoimmune encephalomyelitis

Experimentally induced autoimmune encephalomyelitis (EAE) in mice provides an animal model that shares many features with human demyelinating diseases such as multiple sclerosis (MS). To what extent the cerebral cortex is affected by the process of demyelination and how the corollary response of the oligodendrocyte lineage is explicated are still not completely known aspects of EAE. By performing a detailed in situ analysis of expression of myelin and oligodendrocyte markers we have identified areas of subpial demyelination in the cerebral cortex of animals with conventionally induced EAE conditions. On EAE-affected cerebral cortices, the distribution and relative abundance of cells of the oligodendrocyte lineage were assessed and compared with control mouse brains. The analysis demonstrated that A2B5+ glial restricted progenitors (GRPs) and NG2+/PDGFR-α+ oligodendrocyte precursor cells (OPCs) were increased in number during “early” disease, 20days post MOG immunization, whereas in the “late” disease, 39days post-immunization, they were strongly diminished, and there was an accompanying reduction in NG2+/O4+ pre-oligodendrocytes and GST-π mature oligodendrocytes. These results, together with the observed steady-state amount of NG2−/O4+ pre-myelinating oligodendrocytes, suggested that oligodendroglial precursors attempted to compensate for the progressive loss of myelin, although these cells appeared to fail to complete the last step of their differentiation program. Our findings confirm that this chronic model of EAE reproduces the features of neocortex pathology in progressive MS and suggest that, despite the proliferative response of the oligodendroglial precursors, the failure to accomplish final differentiation may be a key contributing factor to the impaired remyelination that characterizes these demyelinating conditions.

In vivo evidence of disseminated subpial T2* signal changes in multiple sclerosis at 7 T: A surface-based analysis

Cortical subpial demyelination is frequent in multiple sclerosis (MS) and is closely associated with disease progression and poor neurological outcome. Although cortical lesions have been difficult to detect using conventional MRI, preliminary data using T2*-weighted imaging at ultra-high field 7T MRI showed improved sensitivity for detecting and categorizing different histological types of cortical MS lesions. In this study we combined high-resolution 7T MRI with a surface-based analysis technique to quantify and map subpial T2*-weighted signal changes in seventeen patients with MS. We applied a robust method to register 7T data with the reconstructed cortical surface of each individual and used a general linear model to assess in vivo an increase in subpial T2*-weighted signal in patients versus age-matched controls, and to investigate the spatial distribution of cortical subpial changes across the cortical ribbon. We also assessed the relationship between subpial T2* signal changes at 7T, Expanded Disability Status Scale (EDSS) score and white matter lesion load (WMLL). Patients with MS showed significant T2*-weighted signal increase in the frontal lobes (parsopercularis, precentral gyrus, middle and superior frontal gyrus, orbitofrontal cortex), anterior cingulate, temporal (superior, middle and inferior temporal gyri), and parietal cortices (superior and inferior parietal cortex, precuneus), but also in occipital regions of the left hemisphere. We found significant correlations between subpial T2*-weighted signal and EDSS score in the precentral gyrus (ρ=0.56, P=0.02) and between T2*-weighted signal and WMLL in the lateral orbitofrontal, superior parietal, cuneus, precentral and superior frontal regions. Our data support the presence of disseminated subpial increases in T2* signal in subjects with MS, which may reflect the diffuse subpial pathology described in neuropathology.

MS cortical lesion or not?

Histopathologic analyses of postmortem brains from patients with multiple sclerosis (MS) have revealed that demyelinated cortical lesions are a common occurrence1 and may account for a larger proportion of brain demyelination than white matter (WM) lesions.2,–,4 Unlike WM lesions, cortical lesions are typically not revealed in vivo by conventional MRI (only 16% detected using fluid-attenuated inversion recovery [FLAIR] MRI3). As a result, our overall understanding of the incidence and role of cortical lesions in MS remains relatively poor. Double inversion recovery (DIR) is an advanced MRI technique that improves visualization of the cortex by selectively suppressing both the CSF signal (as in FLAIR) and the normal WM signal, resulting in an image with hyperintense gray matter (GM) that is relatively noisy. In MS, DIR has revealed cortical foci that are hyperintense relative to surrounding normal-appearing GM, which are believed to be associated with demyelinated cortical lesions. Unfortunately, DIR is not reliably sensitive to subpial demyelination,5,6 which represents the most common type of cortical demyelination in MS.2,5 Despite this weakness, significant associations have been reported between DIR hyperintense cortical foci and disability in MS.7,–,9 In practice, DIR is not standardized across imaging …

A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis

Prominent inflammation with formation of ectopic B-cell follicle-like structures in the meninges in secondary progressive multiple sclerosis (MS) (SPMS) is associated with extensive cortical pathology and an exacerbated disease course. Our objective was to evaluate the cellular substrates of the cortical damage to understand the role of meningeal inflammation in MS pathology. Using >600 tissue blocks from 37 cases of SPMS and 14 non-neurological controls, we carried out a detailed quantitative analysis of cortical atrophy and layer-specific changes in cell populations in SPMS cases with (F(+) SPMS) and without (F⁻ SPMS) B-cell follicle-like structures. B-cell follicle-like structures were detected in the inflamed meninges of 20 of 37 SPMS cases (54%) and were associated with increased subpial cortical demyelination and cortical atrophy. A clear gradient of neuronal loss was observed in grey matter lesions and normal-appearing grey matter in the motor cortex of F(+) SPMS cases. The density of pyramidal neurons was significantly reduced in layers III and V of the motor cortex. Neuronal loss was accompanied by glia limitans damage with astrocyte loss and an opposite gradient of increased density of activated microglia. No gradient of neuronal loss was seen in F⁻ SPMS cases. We demonstrate substantial cortical neurodegeneration and generalized cell loss in progressive MS in association with meningeal inflammation and lymphoid tissue formation, supporting the hypothesis that cytotoxic factors diffusing from the meningeal compartment contribute to grey matter pathology and the consequent increase in clinical disability.

Meningeal Inflammation is not Associated With Cortical Demyelination in Chronic Multiple Sclerosis

Cortical demyelination can be extensive in chronic multiple sclerosis (MS) patients. Cortical lesions are not associated with lymphocyte infiltration, blood-brain barrier disruption, or complement deposition; therefore, their pathogenesis is unclear. We analyzed the extent and cellular composition of leptomeningeal inflammatory infiltrates and their relationship with cortical demyelinated lesions in brain autopsy samples from 28 chronic MS patients; samples from 6 nonneurological disease control patients were also studied. Immunohistochemistry was used to detect meningeal T cells, B cells, macrophages, mature and immature dendritic cells, T-helper cells, (activated) cytotoxic T cells, and plasma cells. Quantitative analysis revealed significant meningeal inflammation in chronic MS patients; T cells were the predominant inflammatory cells. Morphometric analysis was performed on coronal hemisphere sections of the MS cases to assess subpial demyelination; no correlation between the extent of subpial demyelination and extent of meningeal inflammation was identified. Moreover, no differences were observed in the degree or cellular composition of meningeal infiltrates in areas directly adjacent to subpial lesions compared with areas adjacent to normal-appearing gray matter in the MS cases. In addition, no follicle-like structures were found in the MS samples. Our data suggest that the occurrence of cortical lesions is not related to the presence of meningeal inflammation in a large number of chronic MS patients.

Disseminated Subpial Demyelination Presenting as Respiratory Stridor

A 61‐year‐old female with long‐standing bipolar disorder presented with recurrent episodes of laryngeal stridor occurring over 2 years. Her stridor was worse while lying supine, and examination of her vocal cords show paradoxical movement. MRI showed scattered diffuse white matter lesions in the cerebral hemispheres without brainstem involvement. Her final episode of stridor was fatal, and an autopsy was performed revealing no abnormalities of laryngeal structures. Examination of her brain showed diffuse anoxic encephalopathy with acute and remote infarctions in or adjacent to bilateral caudate nuclei. There were numerous chronic demyelinating lesions, demonstrated by LFB/PAS and Bielschowsky stains, located in the optic chiasm, cerebellum, midbrain, pons and medulla. Many of these lesions were localized to the subpial parenchyma, a finding which was most evident in the pons and medulla. Involvement of the dorsal motor nucleus and other fibers contributing to the formation cranial nerve X as it exits the medulla was also noted and may have contributed to her stridor. The pattern of demyelination demonstrated in this case has been referred to as disseminated subpial demyelination, which has only been reported twice in the literature in the absence of classic patterns of demyelination, and it may represent an unusual phenotype of multiple sclerosis.

Lack of Correlation Between Cortical Demyelination and White Matter Pathologic Changes in Multiple Sclerosis

Histopathologic studies have shown that subpial cortical demyelination is extensive in chronic multiple sclerosis (MS). To study whether subpial cortical demyelination in MS is associated with focal or diffuse white matter (WM) pathologic features on magnetic resonance imaging (MR imaging). Comparison of postmortem MR imaging findings with histopathologic findings. Brain donations from a general community. Three patients with MS with extensive cortical demyelination and 3 patients with minor cortical demyelination were selected from an MS autopsy data set. The postmortem MR imaging and histopathologic data of the patients were compared. Two observers blinded to the results of each other assessed the presence, extent, and distribution of focal and diffuse pathologic changes in WM by MR imaging and by histopathology. Extensive subpial demyelination was not associated with a significant increase in the area of focal and diffuse WM pathologic changes as assessed by Luxol fast blue histochemistry or by MR imaging or with the presence or extent of juxtacortical abnormalities on MR imaging. The lack of association of MS gray matter demyelination with diffuse or focal WM changes indicates that gray matter demyelination in MS occurs largely independent of WM pathologic changes. The extent or distribution of WM abnormalities cannot be used to identify extensive cortical demyelination in the clinical setting.

A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination

Recent studies have revealed widespread demyelination in the cortex of patients with chronic multiple sclerosis. In contrast to white matter lesions, cortical multiple sclerosis lesions are accompanied by only minor inflammation. Research into the pathogenesis of cortical lesion formation has been hampered by the fact that the conventional rodent model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), does not regularly affect the cortex. To overcome this limitation we developed a new rat model of cortical multiple sclerosis. Lesions were stereotactically targeted to the cerebral cortex by injection of pro-inflammatory mediators in animals that were immunized subclinically with myelin oligodendrocyte glycoprotein (MOG). We thus generated highly reproducible demyelinated lesions in the neocortex with remarkable histological similarities to cortical multiple sclerosis lesions. The focal cortical EAE model led to the typical pattern of intracortical and subpial demyelination, infiltration with inflammatory cells, complement deposition, acute axonal damage and neuronal cell death. Surprisingly, extensive cortical inflammation largely resolved within 2 weeks. Furthermore, cortical demyelination was readily compensated by rapid remyelination. Our data thus suggest that cortical inflammation is a transient phenomenon, and that remyelination of cortical inflammatory-demyelinating lesions may occur rapidly.

Differential Macrophage/Microglia Activation in Neocortical EAE Lesions in the Marmoset Monkey

Recent studies revealed an important involvement of the cerebral cortex in multiple sclerosis (MS) patients. Cortical lesions in MS were reported to be less inflammatory and to show less structural damage than white matter lesions. Animal models reflecting the histopathological hallmarks of cortical demyelinated lesions in MS are sparse. Induction of experimental autoimmune encephalomyelitis (EAE) in the common marmoset has turned out to be an attractive non-human-primate model for MS. In the present study we investigated the presence and detailed cellular composition of cortical inflammatory demyelinating pathology in the common marmoset upon immunization with myelin oligodendrocyte glycoprotein (MOG). Extensive cortical demyelination reflecting the topographically distinct cortical lesion types in MS patients was revealed by immunohistochemistry for myelin basic protein (MBP). We explored the density of T- and B-lymphocytes, MHC-II expressing macrophages/microglia cells and early activated macrophages (MRP14) at perivascular and parenchymal lesions sites in neocortex and subcortical white matter. Despite a similar density of perivascular inflammatory infiltrates in the demyelinated neocortex, a considerable lower fraction of macrophages was found to express MRP14 in the neocortex indicating a different activation pattern in cortical compared with white matter lesions. Furthermore, cortical EAE lesions in marmoset monkeys revealed immunoglobulin leakage and complement component C9 deposition in intracortical but not subpial demyelination. Our findings indicate that the inflammatory response, especially macrophage and microglia activation, may be regulated differently in gray matter areas in primate brain.

Grey matter pathology in multiple sclerosis

Although multiple sclerosis (MS) has been considered a white matter disease, MS lesions are known to occur in grey matter. Recent immunohistochemical studies have demonstrated extensive grey matter demyelination in chronic MS. The most common lesion type consists of purely cortical lesions extending inward from the surface of the brain, this lesion subgroup is grossly underestimated by standard histochemical myelin staining methods. Some MS patients have subpial demyelination in all cortical areas of the brain; this pattern has been termed ''general cortical subpial demyelination''. Extensive cortical demyelination is associated with the progressive phases of disease, as less cortical demyelination has been detected in relapsing-remitting MS. The pathology of grey matter lesions differs from that of white matter lesions; grey matter lesions are less inflammatory, with less macrophage and lymphocyte infiltration. In purely cortical lesions there is no significant increase in lymphocytes compared with non-demyelinated adjacent cortical areas in MS patients or cerebral cortex in control patients. Significant axonal transection and neuronal loss have been demonstrated in grey matter MS lesions. Current magnetic resonance imaging (MRI) methods are not sensitive for purely cortical MS lesions. The clinical significance of cortical MS lesions may not be characterised until more sensitive MRI methods are developed.