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Intrathecal Inflammatory Profile and Gray Matter Damage Predict Progression Independent of Relapse Activity in Early Multiple Sclerosis

Damiano Marastoni Orcid Logo, Elisa Colato Orcid Logo, Matteo Foschi Orcid Logo, Agnese Tamanti Orcid Logo, Stefano Ziccardi Orcid Logo, Chiara Eccher, Francesco Crescenzo Orcid Logo, Albulena Bajrami, Gian Marco Schiavi, Valentina Camera Orcid Logo, Daniela Anni Orcid Logo, Federica Virla Orcid Logo, Maddalena Guandalini Orcid Logo, Ermanna Turano Orcid Logo, Francesca Benedetta Pizzini, Stefania Montemezzi Orcid Logo, Bruno Bonetti Orcid Logo, Owain Howell Orcid Logo, Roberta Magliozzi Orcid Logo, Richard S. Nicholas, Antonio Scalfari Orcid Logo, Cristina Granziera Orcid Logo, Ludwig Kappos Orcid Logo, Massimiliano Calabrese Orcid Logo

Neurology Neuroimmunology & Neuroinflammation, Volume: 12, Issue: 4

Swansea University Author: Owain Howell Orcid Logo

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DOI (Published version): 10.1212/nxi.0000000000200399

Abstract

Background and ObjectivesThe objective of this study was to determine, at the time of diagnosis, a CSF and MRI profile of intrathecal compartmentalized inflammation predictive of progression independent of relapse activity (PIRA) in early relapsing-remitting multiple sclerosis (RRMS).MethodsThis fiv...

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Published in: Neurology Neuroimmunology & Neuroinflammation
ISSN: 2332-7812
Published: Ovid Technologies (Wolters Kluwer Health) 2025
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2025-08-11T15:06:49.2036626</datestamp><bib-version>v2</bib-version><id>69891</id><entry>2025-07-04</entry><title>Intrathecal Inflammatory Profile and Gray Matter Damage Predict Progression Independent of Relapse Activity in Early Multiple Sclerosis</title><swanseaauthors><author><sid>58c995486fc93a242b987640b692db8c</sid><ORCID>0000-0003-2157-9157</ORCID><firstname>Owain</firstname><surname>Howell</surname><name>Owain Howell</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2025-07-04</date><deptcode>MEDS</deptcode><abstract>Background and ObjectivesThe objective of this study was to determine, at the time of diagnosis, a CSF and MRI profile of intrathecal compartmentalized inflammation predictive of progression independent of relapse activity (PIRA) in early relapsing-remitting multiple sclerosis (RRMS).MethodsThis five-year prospective study included 80 treatment-na&#xEF;ve patients with RRMS enrolled at time of diagnosis. All patients underwent a lumbar puncture, regular neurologic evaluations including an Expanded Disability Status Scale (EDSS) assessment every 6 months, and an annual 3T brain MRI. PIRA was defined as having a confirmed disability progression independent of relapse activity. CSF levels of 68 inflammatory molecules were evaluated in combination with white matter and cortical lesion number (CLn) and volume, and regional gray matter thickness and volume.ResultsDuring the follow-up, 23 patients with RRMS (28.8%) experienced PIRA. At diagnosis, participants with PIRA were older (44.0 &#xB1; 10.7 vs 37.4 &#xB1; 12.4, p = 0.017) and with more disability (median EDSS score [interquartile range] of 3 [range 2&#x2013;4] for PIRA vs 1.5 [range 1&#x2013;2] for no PIRA group, p &lt; 0.001). Random forest selected LIGHT, CXCL13, sTNFR1, sTNFR2, CCL7, MIF, sIL6Rbeta, IL35, CCL2, and IFN&#x3B2; as the CSF markers best associated with PIRA. sTNFR1 (hazard ratio [HR] 10.11 [2.61&#x2013;39.10], p = 0.001), sTNFR2 (HR 5.05 [1.63&#x2013;15.64], p = 0.005), and LIGHT (HR 1.79 [1.11&#x2013;2.88], p = 0.018) were predictors of PIRA at regression analysis. Baseline thalamus volume (HR 0.98 [0.97&#x2013;0.99], p = 0.005), middle frontal gyrus thickness (HR 0.05 [0.01&#x2013;0.72], p = 0.028), and CLn (HR 1.15 [1.05&#x2013;1.25], p = 0.003) were MRI predictors of PIRA.DiscussionA specific intrathecal inflammatory profile associated with TNF superfamily markers, CLn, and atrophy of several cortical and deep gray matter regions, assessed at time of diagnosis, is predictive of PIRA in early MS.</abstract><type>Journal Article</type><journal>Neurology Neuroimmunology &amp;amp; Neuroinflammation</journal><volume>12</volume><journalNumber>4</journalNumber><paginationStart/><paginationEnd/><publisher>Ovid Technologies (Wolters Kluwer Health)</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2332-7812</issnElectronic><keywords/><publishedDay>1</publishedDay><publishedMonth>7</publishedMonth><publishedYear>2025</publishedYear><publishedDate>2025-07-01</publishedDate><doi>10.1212/nxi.0000000000200399</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>D. Marastoni was supported by the GR-2021-12373041 grant from Italian Ministry of Health. M. Calabrese was supported by the RF-2021-12373319 grant from Italian Ministry of Health. R. Magliozzi was supported by grant from the Italian MS Foundation (FISM 2023/R-Single/038), #NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006)- A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022).</funders><projectreference/><lastEdited>2025-08-11T15:06:49.2036626</lastEdited><Created>2025-07-04T09:20:57.1643625</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Damiano</firstname><surname>Marastoni</surname><orcid>0000-0003-0358-9431</orcid><order>1</order></author><author><firstname>Elisa</firstname><surname>Colato</surname><orcid>0000-0002-4101-7058</orcid><order>2</order></author><author><firstname>Matteo</firstname><surname>Foschi</surname><orcid>0000-0002-0321-7155</orcid><order>3</order></author><author><firstname>Agnese</firstname><surname>Tamanti</surname><orcid>0000-0001-9972-4348</orcid><order>4</order></author><author><firstname>Stefano</firstname><surname>Ziccardi</surname><orcid>0000-0003-0426-7223</orcid><order>5</order></author><author><firstname>Chiara</firstname><surname>Eccher</surname><order>6</order></author><author><firstname>Francesco</firstname><surname>Crescenzo</surname><orcid>0000-0003-1396-7774</orcid><order>7</order></author><author><firstname>Albulena</firstname><surname>Bajrami</surname><order>8</order></author><author><firstname>Gian Marco</firstname><surname>Schiavi</surname><order>9</order></author><author><firstname>Valentina</firstname><surname>Camera</surname><orcid>0000-0002-4925-9000</orcid><order>10</order></author><author><firstname>Daniela</firstname><surname>Anni</surname><orcid>0000-0002-5825-6303</orcid><order>11</order></author><author><firstname>Federica</firstname><surname>Virla</surname><orcid>0009-0001-7346-9139</orcid><order>12</order></author><author><firstname>Maddalena</firstname><surname>Guandalini</surname><orcid>0000-0003-2341-9253</orcid><order>13</order></author><author><firstname>Ermanna</firstname><surname>Turano</surname><orcid>0000-0002-0760-1787</orcid><order>14</order></author><author><firstname>Francesca Benedetta</firstname><surname>Pizzini</surname><order>15</order></author><author><firstname>Stefania</firstname><surname>Montemezzi</surname><orcid>0000-0003-0216-2954</orcid><order>16</order></author><author><firstname>Bruno</firstname><surname>Bonetti</surname><orcid>0000-0002-3944-4165</orcid><order>17</order></author><author><firstname>Owain</firstname><surname>Howell</surname><orcid>0000-0003-2157-9157</orcid><order>18</order></author><author><firstname>Roberta</firstname><surname>Magliozzi</surname><orcid>0000-0001-8284-7763</orcid><order>19</order></author><author><firstname>Richard S.</firstname><surname>Nicholas</surname><order>20</order></author><author><firstname>Antonio</firstname><surname>Scalfari</surname><orcid>0000-0002-7757-0293</orcid><order>21</order></author><author><firstname>Cristina</firstname><surname>Granziera</surname><orcid>0000-0002-4917-8761</orcid><order>22</order></author><author><firstname>Ludwig</firstname><surname>Kappos</surname><orcid>0000-0003-4175-5509</orcid><order>23</order></author><author><firstname>Massimiliano</firstname><surname>Calabrese</surname><orcid>0000-0002-3362-7403</orcid><order>24</order></author></authors><documents><document><filename>69891__34938__f4b8e6466fea49fbb6a32836dcbf8b21.pdf</filename><originalFilename>69891.VoR.pdf</originalFilename><uploaded>2025-08-11T15:03:43.0789513</uploaded><type>Output</type><contentLength>634448</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>Copyright &#xA9; 2025 The Author(s). 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spelling 2025-08-11T15:06:49.2036626 v2 69891 2025-07-04 Intrathecal Inflammatory Profile and Gray Matter Damage Predict Progression Independent of Relapse Activity in Early Multiple Sclerosis 58c995486fc93a242b987640b692db8c 0000-0003-2157-9157 Owain Howell Owain Howell true false 2025-07-04 MEDS Background and ObjectivesThe objective of this study was to determine, at the time of diagnosis, a CSF and MRI profile of intrathecal compartmentalized inflammation predictive of progression independent of relapse activity (PIRA) in early relapsing-remitting multiple sclerosis (RRMS).MethodsThis five-year prospective study included 80 treatment-naïve patients with RRMS enrolled at time of diagnosis. All patients underwent a lumbar puncture, regular neurologic evaluations including an Expanded Disability Status Scale (EDSS) assessment every 6 months, and an annual 3T brain MRI. PIRA was defined as having a confirmed disability progression independent of relapse activity. CSF levels of 68 inflammatory molecules were evaluated in combination with white matter and cortical lesion number (CLn) and volume, and regional gray matter thickness and volume.ResultsDuring the follow-up, 23 patients with RRMS (28.8%) experienced PIRA. At diagnosis, participants with PIRA were older (44.0 ± 10.7 vs 37.4 ± 12.4, p = 0.017) and with more disability (median EDSS score [interquartile range] of 3 [range 2–4] for PIRA vs 1.5 [range 1–2] for no PIRA group, p < 0.001). Random forest selected LIGHT, CXCL13, sTNFR1, sTNFR2, CCL7, MIF, sIL6Rbeta, IL35, CCL2, and IFNβ as the CSF markers best associated with PIRA. sTNFR1 (hazard ratio [HR] 10.11 [2.61–39.10], p = 0.001), sTNFR2 (HR 5.05 [1.63–15.64], p = 0.005), and LIGHT (HR 1.79 [1.11–2.88], p = 0.018) were predictors of PIRA at regression analysis. Baseline thalamus volume (HR 0.98 [0.97–0.99], p = 0.005), middle frontal gyrus thickness (HR 0.05 [0.01–0.72], p = 0.028), and CLn (HR 1.15 [1.05–1.25], p = 0.003) were MRI predictors of PIRA.DiscussionA specific intrathecal inflammatory profile associated with TNF superfamily markers, CLn, and atrophy of several cortical and deep gray matter regions, assessed at time of diagnosis, is predictive of PIRA in early MS. Journal Article Neurology Neuroimmunology &amp; Neuroinflammation 12 4 Ovid Technologies (Wolters Kluwer Health) 2332-7812 1 7 2025 2025-07-01 10.1212/nxi.0000000000200399 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee D. Marastoni was supported by the GR-2021-12373041 grant from Italian Ministry of Health. M. Calabrese was supported by the RF-2021-12373319 grant from Italian Ministry of Health. R. Magliozzi was supported by grant from the Italian MS Foundation (FISM 2023/R-Single/038), #NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006)- A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022). 2025-08-11T15:06:49.2036626 2025-07-04T09:20:57.1643625 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Damiano Marastoni 0000-0003-0358-9431 1 Elisa Colato 0000-0002-4101-7058 2 Matteo Foschi 0000-0002-0321-7155 3 Agnese Tamanti 0000-0001-9972-4348 4 Stefano Ziccardi 0000-0003-0426-7223 5 Chiara Eccher 6 Francesco Crescenzo 0000-0003-1396-7774 7 Albulena Bajrami 8 Gian Marco Schiavi 9 Valentina Camera 0000-0002-4925-9000 10 Daniela Anni 0000-0002-5825-6303 11 Federica Virla 0009-0001-7346-9139 12 Maddalena Guandalini 0000-0003-2341-9253 13 Ermanna Turano 0000-0002-0760-1787 14 Francesca Benedetta Pizzini 15 Stefania Montemezzi 0000-0003-0216-2954 16 Bruno Bonetti 0000-0002-3944-4165 17 Owain Howell 0000-0003-2157-9157 18 Roberta Magliozzi 0000-0001-8284-7763 19 Richard S. Nicholas 20 Antonio Scalfari 0000-0002-7757-0293 21 Cristina Granziera 0000-0002-4917-8761 22 Ludwig Kappos 0000-0003-4175-5509 23 Massimiliano Calabrese 0000-0002-3362-7403 24 69891__34938__f4b8e6466fea49fbb6a32836dcbf8b21.pdf 69891.VoR.pdf 2025-08-11T15:03:43.0789513 Output 634448 application/pdf Version of Record true Copyright © 2025 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CC-BY-NC-ND). true eng http://creativecommons.org/licenses/by-nc-nd/4.0/
title Intrathecal Inflammatory Profile and Gray Matter Damage Predict Progression Independent of Relapse Activity in Early Multiple Sclerosis
spellingShingle Intrathecal Inflammatory Profile and Gray Matter Damage Predict Progression Independent of Relapse Activity in Early Multiple Sclerosis
Owain Howell
title_short Intrathecal Inflammatory Profile and Gray Matter Damage Predict Progression Independent of Relapse Activity in Early Multiple Sclerosis
title_full Intrathecal Inflammatory Profile and Gray Matter Damage Predict Progression Independent of Relapse Activity in Early Multiple Sclerosis
title_fullStr Intrathecal Inflammatory Profile and Gray Matter Damage Predict Progression Independent of Relapse Activity in Early Multiple Sclerosis
title_full_unstemmed Intrathecal Inflammatory Profile and Gray Matter Damage Predict Progression Independent of Relapse Activity in Early Multiple Sclerosis
title_sort Intrathecal Inflammatory Profile and Gray Matter Damage Predict Progression Independent of Relapse Activity in Early Multiple Sclerosis
author_id_str_mv 58c995486fc93a242b987640b692db8c
author_id_fullname_str_mv 58c995486fc93a242b987640b692db8c_***_Owain Howell
author Owain Howell
author2 Damiano Marastoni
Elisa Colato
Matteo Foschi
Agnese Tamanti
Stefano Ziccardi
Chiara Eccher
Francesco Crescenzo
Albulena Bajrami
Gian Marco Schiavi
Valentina Camera
Daniela Anni
Federica Virla
Maddalena Guandalini
Ermanna Turano
Francesca Benedetta Pizzini
Stefania Montemezzi
Bruno Bonetti
Owain Howell
Roberta Magliozzi
Richard S. Nicholas
Antonio Scalfari
Cristina Granziera
Ludwig Kappos
Massimiliano Calabrese
format Journal article
container_title Neurology Neuroimmunology &amp; Neuroinflammation
container_volume 12
container_issue 4
publishDate 2025
institution Swansea University
issn 2332-7812
doi_str_mv 10.1212/nxi.0000000000200399
publisher Ovid Technologies (Wolters Kluwer Health)
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 Background and ObjectivesThe objective of this study was to determine, at the time of diagnosis, a CSF and MRI profile of intrathecal compartmentalized inflammation predictive of progression independent of relapse activity (PIRA) in early relapsing-remitting multiple sclerosis (RRMS).MethodsThis five-year prospective study included 80 treatment-naïve patients with RRMS enrolled at time of diagnosis. All patients underwent a lumbar puncture, regular neurologic evaluations including an Expanded Disability Status Scale (EDSS) assessment every 6 months, and an annual 3T brain MRI. PIRA was defined as having a confirmed disability progression independent of relapse activity. CSF levels of 68 inflammatory molecules were evaluated in combination with white matter and cortical lesion number (CLn) and volume, and regional gray matter thickness and volume.ResultsDuring the follow-up, 23 patients with RRMS (28.8%) experienced PIRA. At diagnosis, participants with PIRA were older (44.0 ± 10.7 vs 37.4 ± 12.4, p = 0.017) and with more disability (median EDSS score [interquartile range] of 3 [range 2–4] for PIRA vs 1.5 [range 1–2] for no PIRA group, p < 0.001). Random forest selected LIGHT, CXCL13, sTNFR1, sTNFR2, CCL7, MIF, sIL6Rbeta, IL35, CCL2, and IFNβ as the CSF markers best associated with PIRA. sTNFR1 (hazard ratio [HR] 10.11 [2.61–39.10], p = 0.001), sTNFR2 (HR 5.05 [1.63–15.64], p = 0.005), and LIGHT (HR 1.79 [1.11–2.88], p = 0.018) were predictors of PIRA at regression analysis. Baseline thalamus volume (HR 0.98 [0.97–0.99], p = 0.005), middle frontal gyrus thickness (HR 0.05 [0.01–0.72], p = 0.028), and CLn (HR 1.15 [1.05–1.25], p = 0.003) were MRI predictors of PIRA.DiscussionA specific intrathecal inflammatory profile associated with TNF superfamily markers, CLn, and atrophy of several cortical and deep gray matter regions, assessed at time of diagnosis, is predictive of PIRA in early MS.
published_date 2025-07-01T05:29:52Z
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