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High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study

Richard Nicholas Orcid Logo, Roberta Magliozzi Orcid Logo, Damiano Marastoni, Owain Howell Orcid Logo, Federico Roncaroli, Paolo Muraro, Richard Reynolds, Tim Friede Orcid Logo

Annals of Neurology, Volume: 95, Issue: 4, Pages: 706 - 719

Swansea University Author: Owain Howell Orcid Logo

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DOI (Published version): 10.1002/ana.26870

Abstract

Objective:Analysis of postmortem multiple sclerosis (MS) tissues combined with in vivo disease milestones suggeststhat whereas perivascular white matter infiltrates are associated with demyelinating activity in the initial stages,leptomeningeal immune cell infiltration, enriched in B cells, and asso...

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Published in: Annals of Neurology
ISSN: 0364-5134 1531-8249
Published: Wiley 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa65421
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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 perivenularinflammation (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 in35% of cases with high levels of PVI. Shorter time from onset of progression to death was associated with increasedprevalence and higher levels of PVI (bothp&lt; 0.0001). Shorter time from onset of progression to wheelchair use wasassociated with higher prevalence of ALs (odds ratio [OR]=0.921, 95% confidence interval [CI]=0.858&#x2013;0.989,p=0.0230) and higher level of PVI (OR=0.932, 95% CI=0.886&#x2013;0.981,p=0.0071). High levels of PVI were associ-ated with meningeal inflammation and increased cortical demyelination and significantly higher levels of B lymphocyteswithin the PVI.Interpretation:ALs, a feature of early disease stage, persist up to death in a subgroup with high levels of PVI. Thesefeatures link to a rapid progressive phase and higher levels of meningeal inflammation and B-cell infiltrates, supportingthe hypothesis that chronic inflammation drives progression in MS.</abstract><type>Journal Article</type><journal>Annals of Neurology</journal><volume>95</volume><journalNumber>4</journalNumber><paginationStart>706</paginationStart><paginationEnd>719</paginationEnd><publisher>Wiley</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0364-5134</issnPrint><issnElectronic>1531-8249</issnElectronic><keywords/><publishedDay>16</publishedDay><publishedMonth>4</publishedMonth><publishedYear>2024</publishedYear><publishedDate>2024-04-16</publishedDate><doi>10.1002/ana.26870</doi><url/><notes>Data Availability:Data used for this article are available upon reasonablerequest.</notes><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm/><funders>This study was supported by the Laboratory of Neuropa-thology at University Laboratory of Medical Research andthe Excellence Project 2023&#x2013;2027 (funded by ItalianMinistry of University and Research) of the Departmentof Neuroscience, Biomedicine, and Movement Sciences,University of Verona; and the National MS Society (grantRFA-2305-41332). Work undertaken at Imperial CollegeHealthcare NHS Trust and Imperial College receivedfunding from the Department of Health&#x2019;s NIHR Biomed-ical Research Centres funding scheme.We thank the UK MS Society Tissue Bank at Impe-rial College and Dr D. 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spelling 2024-10-02T14:13:04.0539454 v2 65421 2024-01-08 High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study 58c995486fc93a242b987640b692db8c 0000-0003-2157-9157 Owain Howell Owain Howell true false 2024-01-08 MEDS Objective:Analysis of postmortem multiple sclerosis (MS) tissues combined with in vivo disease milestones suggeststhat whereas perivascular white matter infiltrates are associated with demyelinating activity in the initial stages,leptomeningeal immune cell infiltration, enriched in B cells, and associated cortical lesions contribute to disease pro-gression. 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 perivenularinflammation (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 in35% of cases with high levels of PVI. Shorter time from onset of progression to death was associated with increasedprevalence and higher levels of PVI (bothp< 0.0001). Shorter time from onset of progression to wheelchair use wasassociated with higher prevalence of ALs (odds ratio [OR]=0.921, 95% confidence interval [CI]=0.858–0.989,p=0.0230) and higher level of PVI (OR=0.932, 95% CI=0.886–0.981,p=0.0071). High levels of PVI were associ-ated with meningeal inflammation and increased cortical demyelination and significantly higher levels of B lymphocyteswithin the PVI.Interpretation:ALs, a feature of early disease stage, persist up to death in a subgroup with high levels of PVI. Thesefeatures link to a rapid progressive phase and higher levels of meningeal inflammation and B-cell infiltrates, supportingthe hypothesis that chronic inflammation drives progression in MS. Journal Article Annals of Neurology 95 4 706 719 Wiley 0364-5134 1531-8249 16 4 2024 2024-04-16 10.1002/ana.26870 Data Availability:Data used for this article are available upon reasonablerequest. COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University This study was supported by the Laboratory of Neuropa-thology at University Laboratory of Medical Research andthe Excellence Project 2023–2027 (funded by ItalianMinistry of University and Research) of the Departmentof Neuroscience, Biomedicine, and Movement Sciences,University of Verona; and the National MS Society (grantRFA-2305-41332). Work undertaken at Imperial CollegeHealthcare NHS Trust and Imperial College receivedfunding from the Department of Health’s NIHR Biomed-ical Research Centres funding scheme.We thank the UK MS Society Tissue Bank at Impe-rial College and Dr D. Gveric (funding from the MS Soci-ety of Great Britain, grant 007/14 to R.R. and R.N.) forthe supply of postmortem MS samples. 2024-10-02T14:13:04.0539454 2024-01-08T09:35:31.3989248 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Richard Nicholas 0000-0003-0414-1225 1 Roberta Magliozzi 0000-0001-8284-7763 2 Damiano Marastoni 3 Owain Howell 0000-0003-2157-9157 4 Federico Roncaroli 5 Paolo Muraro 6 Richard Reynolds 7 Tim Friede 0000-0001-5347-7441 8 65421__29784__18e1387580bb489d935b5d763dcbb08f.pdf 65421_VoR.pdf 2024-03-21T14:00:39.8790165 Output 2128396 application/pdf Version of Record true © 2023 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License true eng http://creativecommons.org/licenses/by-nc/4.0/
title High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study
spellingShingle High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study
Owain Howell
title_short High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study
title_full High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study
title_fullStr High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study
title_full_unstemmed High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study
title_sort High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study
author_id_str_mv 58c995486fc93a242b987640b692db8c
author_id_fullname_str_mv 58c995486fc93a242b987640b692db8c_***_Owain Howell
author Owain Howell
author2 Richard Nicholas
Roberta Magliozzi
Damiano Marastoni
Owain Howell
Federico Roncaroli
Paolo Muraro
Richard Reynolds
Tim Friede
format Journal article
container_title Annals of Neurology
container_volume 95
container_issue 4
container_start_page 706
publishDate 2024
institution Swansea University
issn 0364-5134
1531-8249
doi_str_mv 10.1002/ana.26870
publisher Wiley
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
active_str 0
description Objective:Analysis of postmortem multiple sclerosis (MS) tissues combined with in vivo disease milestones suggeststhat whereas perivascular white matter infiltrates are associated with demyelinating activity in the initial stages,leptomeningeal immune cell infiltration, enriched in B cells, and associated cortical lesions contribute to disease pro-gression. 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 perivenularinflammation (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 in35% of cases with high levels of PVI. Shorter time from onset of progression to death was associated with increasedprevalence and higher levels of PVI (bothp< 0.0001). Shorter time from onset of progression to wheelchair use wasassociated with higher prevalence of ALs (odds ratio [OR]=0.921, 95% confidence interval [CI]=0.858–0.989,p=0.0230) and higher level of PVI (OR=0.932, 95% CI=0.886–0.981,p=0.0071). High levels of PVI were associ-ated with meningeal inflammation and increased cortical demyelination and significantly higher levels of B lymphocyteswithin the PVI.Interpretation:ALs, a feature of early disease stage, persist up to death in a subgroup with high levels of PVI. Thesefeatures link to a rapid progressive phase and higher levels of meningeal inflammation and B-cell infiltrates, supportingthe hypothesis that chronic inflammation drives progression in MS.
published_date 2024-04-16T08:27:28Z
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score 11.04748

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