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Extensive subpial cortical demyelination is specific to multiple sclerosis.

ABSTRACT: Cortical demyelinated lesions are frequent and widespread in chronic multiple sclerosis (MS) patients, and may contribute to disease progression. Inflammation and related oxidative stress have been proposed as central mediators of cortical damage, yet meningeal and cortical inflammation is not specific to MS, but also occurs in other diseases. The first aim of this study was to test whether cortical demyelination was specific for demyelinating CNS diseases compared to other CNS disorders with prominent meningeal and cortical inflammation. The second aim was to assess whether oxidative tissue damage was associated with the extent of neuroaxonal damage. We studied a large cohort of patients diagnosed with demyelinating CNS diseases and non-demyelinating diseases of autoimmune, infectious, neoplastic or metabolic origin affecting the meninges and the cortex. Included were patients with MS, acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO), viral and bacterial meningoencephalitis, progressive multifocal leukoencephalopathy (PML), subacute sclerosing panencephalitis (SSPE), carcinomatous and lymphomatous meningitis and metabolic disorders such as extrapontine myelinolysis, thus encompassing a wide range of adaptive and innate cytokine signatures. Using myelin protein immunohistochemistry, we found cortical demyelination in MS, ADEM, PML and extrapontine myelinolysis, whereby each condition showed a disease-specific histopathological pattern. Remarkably, extensive ribbon-like subpial demyelination was only observed in MS, thus providing an important pathogenetic and diagnostic cue. Cortical oxidative injury was detected in both demyelinating and non-demyelinating CNS disorders. Our data demonstrate that meningeal and cortical inflammation alone accompanied by oxidative stress are not sufficient to generate the extensive subpial cortical demyelination found in MS, but require other MS-specific factors.

SUBMITTER: Junker A

PROVIDER: S-EPMC8018087 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cortical disease has emerged as a critical aspect of the pathogenesis of multiple sclerosis, being associated with disease progression and cognitive impairment. Most studies of cortical lesions have focused on autopsy findings in patients with long-standing, chronic, progressive multiple sclerosis, and the noninflammatory nature of these lesions has been emphasized. Magnetic resonance imaging studies indicate that cortical damage occurs early in the disease.We evaluated the prevalence and character of demyelinating cortical lesions in patients with multiple sclerosis. Cortical tissues were obtained in passing during biopsy sampling of white-matter lesions. In most cases, biopsy was done with the use of stereotactic procedures to diagnose suspected tumors. Patients with sufficient cortex (138 of 563 patients screened) were evaluated for cortical demyelination. Using immunohistochemistry, we characterized cortical lesions with respect to demyelinating activity, inflammatory infiltrates, the presence of meningeal inflammation, and a topographic association between cortical demyelination and meningeal inflammation. Diagnoses were ascertained in a subgroup of 77 patients (56%) at the last follow-up visit (at a median of 3.5 years).Cortical demyelination was present in 53 patients (38%) (104 lesions and 222 tissue blocks) and was absent in 85 patients (121 tissue blocks). Twenty-five patients with cortical demyelination had definite multiple sclerosis (81% of 31 patients who underwent long-term follow-up), as did 33 patients without cortical demyelination (72% of 46 patients who underwent long-term follow-up). In representative tissues, 58 of 71 lesions (82%) showed CD3+ T-cell infiltrates, and 32 of 78 lesions (41%) showed macrophage-associated demyelination. Meningeal inflammation was topographically associated with cortical demyelination in patients who had sufficient meningeal tissue for study.In this cohort of patients with early-stage multiple sclerosis, cortical demyelinating lesions were frequent, inflammatory, and strongly associated with meningeal inflammation. (Funded by the National Multiple Sclerosis Society and the National Institutes of Health.).

Project description:ObjectivesCortical demyelination is common in multiple sclerosis (MS) and can be extensive. Cortical lesions contribute to disability independently from white matter lesions and may form via a distinct mechanism. However, current magnetic resonance imaging methods at 3 T are insensitive to cortical, and especially subpial cortical, lesions. Subpial lesions are well seen on T2*-weighted imaging at 7 T, but T2*-weighted methods on 3 T scanners are limited by poor lesion-to-cortex and cerebrospinal fluid-to-lesion contrast. We aimed to develop and evaluate a cerebrospinal fluid-suppressed, T2*-weighted sequence optimized for subpial cortical lesion visualization.Materials and methodsWe developed a new magnetic resonance imaging sequence, inversion recovery susceptibility weighted imaging with enhanced T2 weighting (IR-SWIET; 0.8 mm × 0.8 mm in plane, 0.64 mm slice thickness with whole brain coverage, acquisition time ~5 minutes). We compared cortical lesion visualization independently on IR-SWIET (median signal from 4 acquisitions), magnetization-prepared 2 rapid acquisition gradient echoes (MP2RAGE), double inversion recovery (DIR), T2*-weighted segmented echo-planar imaging, and phase-sensitive inversion recovery images for 10 adults with MS. We also identified cortical lesions with a multicontrast reading of IR-SWIET (median of 2 acquisitions), MP2RAGE, and fluid-attenuated inversion recovery (FLAIR) images for each case. Lesions identified on 3 T images were verified on "gold standard" 7 T T2* and MP2RAGE images.ResultsCortical, and particularly subpial, lesions appeared much more conspicuous on IR-SWIET compared with other 3 T methods. A total of 101 true-positive subpial lesions were identified on IR-SWIET (average per-participant sensitivity vs 7 T, 29% ± 8%) versus 36 on MP2RAGE (5% ± 2%; comparison to IR-SWIET sensitivity, P = 0.07), 17 on FLAIR (2% ± 1%; P < 0.05), 28 on DIR (6% ± 2%; P < 0.05), 42 on T2*-weighted segmented echo-planar imaging (11% ± 5%; P < 0.05), and 13 on phase-sensitive inversion recovery (4% ± 2%; P < 0.05). When a combination of IR-SWIET, MP2RAGE, and FLAIR images was used, a total of 147 subpial lesions (30% ± 5%) were identified versus 83 (16% ± 3%, P < 0.01) on a combination of DIR, MP2RAGE, and FLAIR. More cases had at least 1 subpial lesion on IR-SWIET, and IR-SWIET improved cortical lesion subtyping accuracy and correlation with 7 T subpial lesion number.ConclusionsSubpial lesions are better visualized on IR-SWIET compared with other 3 T methods. A 3 T protocol combining IR-SWIET with MP2RAGE, in which leukocortical lesions are well seen, improves cortical lesion visualization over existing approaches. Therefore, IR-SWIET may enable improved MS diagnostic specificity and a better understanding of the clinical implications of cortical demyelination.

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Extensive subpial cortical demyelination is specific to multiple sclerosis.

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