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The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome

Benjamin Cooze, Matthew Dickerson, Rukshikah Loganathan, Lewis Watkins, Ethan Grounds, Benjamin Rothschild-Pearson, Ryan Jack Bevan, B. Paul Morgan, Roberta Magliozzi, Richard Reynolds, James Neal, Owain Howell Orcid Logo

Brain Pathology, Volume: 32, Issue: 5, Start page: e13054

Swansea University Authors: Benjamin Cooze, Matthew Dickerson, Rukshikah Loganathan, Lewis Watkins, Benjamin Rothschild-Pearson, James Neal, Owain Howell Orcid Logo

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DOI (Published version): 10.1111/bpa.13054

Abstract

The extent of grey matter demyelination and neurodegeneration in the progressive multiple sclerosis (PMS) brains at post‐mortem associates with more severe disease. Regional tissue atrophy, especially affecting the cortical and deep grey matter, including the thalamus, is prognostic for poor outcome...

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Published in: Brain Pathology
ISSN: 1015-6305 1750-3639
Published: Wiley 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa59390
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Regional tissue atrophy, especially affecting the cortical and deep grey matter, including the thalamus, is prognostic for poor outcomes. Microglial and complement activation are important in the pathogenesis and contribute to damaging processes that underlie tissue atrophy in PMS. We investigated the extent of pathology and innate immune activation in the thalamus in comparison to cortical grey and white matter in blocks from 21 cases of PMS and 10 matched controls. Using a digital pathology workflow, we show that the thalamus is invariably affected by demyelination and had a far higher proportion of active inflammatory lesions than forebrain cortical tissue blocks from the same cases. Lesions were larger and more frequent in the medial nuclei near the ventricular margin, whilst neuronal loss was greatest in the lateral thalamic nuclei. The extent of thalamic neuron loss was not associated with thalamic demyelination but correlated with the burden of white matter pathology in other forebrain areas (Spearman r = 0.79, p &lt; 0.0001). Only thalamic neuronal loss, and not that seen in other forebrain cortical areas, correlated with disease duration (Spearman r = &#x2212;0.58, p = 0.009) and age of death (Spearman r = &#x2212;0.47, p = 0.045). Immunoreactivity for the complement pattern recognition molecule C1q, and products of complement activation (C4d, Bb and C3b) were elevated in thalamic lesions with an active inflammatory pathology. Complement regulatory protein, C1 inhibitor, was unchanged in expression. We conclude that active inflammatory demyelination, neuronal loss and local complement synthesis and activation in the thalamus, are important to the pathological and clinical disease outcomes of PMS.</abstract><type>Journal Article</type><journal>Brain Pathology</journal><volume>32</volume><journalNumber>5</journalNumber><paginationStart>e13054</paginationStart><paginationEnd/><publisher>Wiley</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>1015-6305</issnPrint><issnElectronic>1750-3639</issnElectronic><keywords>atrophy, complement activation, CSF, meningeal inflammation, microglial activation, neuron loss</keywords><publishedDay>7</publishedDay><publishedMonth>2</publishedMonth><publishedYear>2022</publishedYear><publishedDate>2022-02-07</publishedDate><doi>10.1111/bpa.13054</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm/><funders>Multiple Sclerosis Society. Grant Number: 993; Life Science Research Network Wales</funders><projectreference/><lastEdited>2023-01-04T14:25:05.7785686</lastEdited><Created>2022-02-14T10:02:51.6415971</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Benjamin</firstname><surname>Cooze</surname><order>1</order></author><author><firstname>Matthew</firstname><surname>Dickerson</surname><order>2</order></author><author><firstname>Rukshikah</firstname><surname>Loganathan</surname><order>3</order></author><author><firstname>Lewis</firstname><surname>Watkins</surname><orcid/><order>4</order></author><author><firstname>Ethan</firstname><surname>Grounds</surname><order>5</order></author><author><firstname>Benjamin</firstname><surname>Rothschild-Pearson</surname><order>6</order></author><author><firstname>Ryan Jack</firstname><surname>Bevan</surname><order>7</order></author><author><firstname>B. 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spelling 2023-01-04T14:25:05.7785686 v2 59390 2022-02-14 The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome 785346ffc3dae14c560e63727f4017d3 Benjamin Cooze Benjamin Cooze true false 931ede560f6d56bd89d7cd8cce8e396c Matthew Dickerson Matthew Dickerson true false 1ebaeb8e45c371be5f639c07fbfd8af5 Rukshikah Loganathan Rukshikah Loganathan true false 255b8c16eb0ed44b6a3f85f584916bc3 Lewis Watkins Lewis Watkins true false 8ebbc60ba1ef47da6813448b5226b2e8 Benjamin Rothschild-Pearson Benjamin Rothschild-Pearson true false 3d905ecd4df7a2ee050a8804c1140de1 James Neal James Neal true false 58c995486fc93a242b987640b692db8c 0000-0003-2157-9157 Owain Howell Owain Howell true false 2022-02-14 BMS The extent of grey matter demyelination and neurodegeneration in the progressive multiple sclerosis (PMS) brains at post‐mortem associates with more severe disease. Regional tissue atrophy, especially affecting the cortical and deep grey matter, including the thalamus, is prognostic for poor outcomes. Microglial and complement activation are important in the pathogenesis and contribute to damaging processes that underlie tissue atrophy in PMS. We investigated the extent of pathology and innate immune activation in the thalamus in comparison to cortical grey and white matter in blocks from 21 cases of PMS and 10 matched controls. Using a digital pathology workflow, we show that the thalamus is invariably affected by demyelination and had a far higher proportion of active inflammatory lesions than forebrain cortical tissue blocks from the same cases. Lesions were larger and more frequent in the medial nuclei near the ventricular margin, whilst neuronal loss was greatest in the lateral thalamic nuclei. The extent of thalamic neuron loss was not associated with thalamic demyelination but correlated with the burden of white matter pathology in other forebrain areas (Spearman r = 0.79, p < 0.0001). Only thalamic neuronal loss, and not that seen in other forebrain cortical areas, correlated with disease duration (Spearman r = −0.58, p = 0.009) and age of death (Spearman r = −0.47, p = 0.045). Immunoreactivity for the complement pattern recognition molecule C1q, and products of complement activation (C4d, Bb and C3b) were elevated in thalamic lesions with an active inflammatory pathology. Complement regulatory protein, C1 inhibitor, was unchanged in expression. We conclude that active inflammatory demyelination, neuronal loss and local complement synthesis and activation in the thalamus, are important to the pathological and clinical disease outcomes of PMS. Journal Article Brain Pathology 32 5 e13054 Wiley 1015-6305 1750-3639 atrophy, complement activation, CSF, meningeal inflammation, microglial activation, neuron loss 7 2 2022 2022-02-07 10.1111/bpa.13054 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Multiple Sclerosis Society. Grant Number: 993; Life Science Research Network Wales 2023-01-04T14:25:05.7785686 2022-02-14T10:02:51.6415971 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Benjamin Cooze 1 Matthew Dickerson 2 Rukshikah Loganathan 3 Lewis Watkins 4 Ethan Grounds 5 Benjamin Rothschild-Pearson 6 Ryan Jack Bevan 7 B. Paul Morgan 8 Roberta Magliozzi 9 Richard Reynolds 10 James Neal 11 Owain Howell 0000-0003-2157-9157 12 59390__22369__be33cd88b4014f24a50d9b49fb46625d.pdf bpa.13054.pdf 2022-02-14T10:02:51.6274631 Output 1214797 application/pdf Version of Record true © 2022 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License true eng http://creativecommons.org/licenses/by-nc-nd/4.0/
title The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome
spellingShingle The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome
Benjamin Cooze
Matthew Dickerson
Rukshikah Loganathan
Lewis Watkins
Benjamin Rothschild-Pearson
James Neal
Owain Howell
title_short The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome
title_full The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome
title_fullStr The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome
title_full_unstemmed The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome
title_sort The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome
author_id_str_mv 785346ffc3dae14c560e63727f4017d3
931ede560f6d56bd89d7cd8cce8e396c
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58c995486fc93a242b987640b692db8c
author_id_fullname_str_mv 785346ffc3dae14c560e63727f4017d3_***_Benjamin Cooze
931ede560f6d56bd89d7cd8cce8e396c_***_Matthew Dickerson
1ebaeb8e45c371be5f639c07fbfd8af5_***_Rukshikah Loganathan
255b8c16eb0ed44b6a3f85f584916bc3_***_Lewis Watkins
8ebbc60ba1ef47da6813448b5226b2e8_***_Benjamin Rothschild-Pearson
3d905ecd4df7a2ee050a8804c1140de1_***_James Neal
58c995486fc93a242b987640b692db8c_***_Owain Howell
author Benjamin Cooze
Matthew Dickerson
Rukshikah Loganathan
Lewis Watkins
Benjamin Rothschild-Pearson
James Neal
Owain Howell
author2 Benjamin Cooze
Matthew Dickerson
Rukshikah Loganathan
Lewis Watkins
Ethan Grounds
Benjamin Rothschild-Pearson
Ryan Jack Bevan
B. Paul Morgan
Roberta Magliozzi
Richard Reynolds
James Neal
Owain Howell
format Journal article
container_title Brain Pathology
container_volume 32
container_issue 5
container_start_page e13054
publishDate 2022
institution Swansea University
issn 1015-6305
1750-3639
doi_str_mv 10.1111/bpa.13054
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 - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description The extent of grey matter demyelination and neurodegeneration in the progressive multiple sclerosis (PMS) brains at post‐mortem associates with more severe disease. Regional tissue atrophy, especially affecting the cortical and deep grey matter, including the thalamus, is prognostic for poor outcomes. Microglial and complement activation are important in the pathogenesis and contribute to damaging processes that underlie tissue atrophy in PMS. We investigated the extent of pathology and innate immune activation in the thalamus in comparison to cortical grey and white matter in blocks from 21 cases of PMS and 10 matched controls. Using a digital pathology workflow, we show that the thalamus is invariably affected by demyelination and had a far higher proportion of active inflammatory lesions than forebrain cortical tissue blocks from the same cases. Lesions were larger and more frequent in the medial nuclei near the ventricular margin, whilst neuronal loss was greatest in the lateral thalamic nuclei. The extent of thalamic neuron loss was not associated with thalamic demyelination but correlated with the burden of white matter pathology in other forebrain areas (Spearman r = 0.79, p < 0.0001). Only thalamic neuronal loss, and not that seen in other forebrain cortical areas, correlated with disease duration (Spearman r = −0.58, p = 0.009) and age of death (Spearman r = −0.47, p = 0.045). Immunoreactivity for the complement pattern recognition molecule C1q, and products of complement activation (C4d, Bb and C3b) were elevated in thalamic lesions with an active inflammatory pathology. Complement regulatory protein, C1 inhibitor, was unchanged in expression. We conclude that active inflammatory demyelination, neuronal loss and local complement synthesis and activation in the thalamus, are important to the pathological and clinical disease outcomes of PMS.
published_date 2022-02-07T04:16:39Z
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