Objective: Analysis of post-mortem multiple sclerosis (MS) tissues combined with in-vivo disease milestones suggest that while perivascular white matter infiltrates associate with demyelinating activity in the initial stages; leptomeningeal immune cell infiltration, enriched in B cells and associated with cortical lesions, contribute to disease progression. We systematically examine the association of inflammatory features and white matter demyelination at post-mortem with clinical milestones. Methods: In 269 MS brains; 20 sites were examined using immunohistochemistry for active lesions (ALs) and perivenular inflammation (PVI). In a subset of 22 a detailed count of CD20+ B cells and CD3+ T cells in PVIs was performed. Results: ALs were detected in 22%, whereas high levels of PVI were detected in 52% of cases. ALs were present in 35% of cases with high levels of PVI. Shorter time from onset of progression to death associated with increased prevalence and higher levels of PVI (both p<0.0001). Shorter time from onset of progression to wheelchair use associated with higher prevalence of ALs (OR 0.921, 95% CI (0.858, 0.989), p=0.0230) and higher level of PVI (0.932, (0.886, 0.981), p=0.0071). High levels of PVI were associated with meningeal inflammation and increased cortical demyelination and significantly higher levels of B lymphocytes within the PVI. Interpretation: ALs, a feature of early disease stage, persist up to death in a subgroup with high levels of PVI. These features link to a rapid progressive phase and higher levels of meningeal inflammation and B-cell infiltrates, supporting the hypothesis that chronic inflammation drives progression in MS. This article is protected by copyright. All rights reserved.

High levels of perivascular inflammation and active demyelinating lesions at time of death associated with rapidly progressive multiple sclerosis disease course: a retrospective post-mortem cohort study

Magliozzi, Roberta
;
Marastoni, Damiano;
2023-01-01

Abstract

Objective: Analysis of post-mortem multiple sclerosis (MS) tissues combined with in-vivo disease milestones suggest that while perivascular white matter infiltrates associate with demyelinating activity in the initial stages; leptomeningeal immune cell infiltration, enriched in B cells and associated with cortical lesions, contribute to disease progression. We systematically examine the association of inflammatory features and white matter demyelination at post-mortem with clinical milestones. Methods: In 269 MS brains; 20 sites were examined using immunohistochemistry for active lesions (ALs) and perivenular inflammation (PVI). In a subset of 22 a detailed count of CD20+ B cells and CD3+ T cells in PVIs was performed. Results: ALs were detected in 22%, whereas high levels of PVI were detected in 52% of cases. ALs were present in 35% of cases with high levels of PVI. Shorter time from onset of progression to death associated with increased prevalence and higher levels of PVI (both p<0.0001). Shorter time from onset of progression to wheelchair use associated with higher prevalence of ALs (OR 0.921, 95% CI (0.858, 0.989), p=0.0230) and higher level of PVI (0.932, (0.886, 0.981), p=0.0071). High levels of PVI were associated with meningeal inflammation and increased cortical demyelination and significantly higher levels of B lymphocytes within the PVI. Interpretation: ALs, a feature of early disease stage, persist up to death in a subgroup with high levels of PVI. These features link to a rapid progressive phase and higher levels of meningeal inflammation and B-cell infiltrates, supporting the hypothesis that chronic inflammation drives progression in MS. This article is protected by copyright. All rights reserved.
2023
multiple sclerosis
disease progression
early active lesions
perivenular inflammation
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/1116328
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