A1 Refereed original research article in a scientific journal
Broad rim lesions are a new pathological and imaging biomarker for rapid disease progression in multiple sclerosis
Authors: Klotz, Luisa; Smolders, Joost; Lehto, Jussi; Matilainen, Markus; Lütje, Lukas; Buchholz, Luzia; Albrecht, Stefanie; Walter, Carolin; Varghese, Julian; Wiendl, Heinz; Nylund, Marjo; Thomas, Christian; Gardberg, Maria; van den Bosch, Aletta M. R.; Airas, Laura; Huitinga, Inge; Kuhlmann, Tanja
Publisher: Springer Nature
Publishing place: BERLIN
Publication year: 2025
Journal: Nature Medicine
Journal name in source: NATURE MEDICINE
Journal acronym: NAT MED
Volume: 31
First page : 2016
Last page: 2026
Number of pages: 31
ISSN: 1078-8956
eISSN: 1546-170X
DOI: https://doi.org/10.1038/s41591-025-03625-7
Web address : https://www.nature.com/articles/s41591-025-03625-7
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/498727317
Current multiple sclerosis (MS) treatments reduce relapse activity but have limited impact on disease progression. Clinical trials targeting progression often fail because of insufficient understanding of its underlying mechanisms. This study analyzed a clinically well-characterized MS autopsy cohort from the Netherland Brain Bank (186 individuals) from which we selected donors exhibiting opposite disease trajectories of slow versus rapid progression. We performed extensive unbiased histology and spatial transcriptomics, which unveiled a distinct MS lesion type marked by an extensive myeloid cell rim with cellular and transcriptional signatures of innate immune activation, inflammatory cytokine production, unfolded protein response and apoptosis. Presence of this particular lesion type was linked to rapid disease progression. An independent translocator protein 18-kDa positron emission tomography study (114 individuals) validates the association between lesions with a broad myeloid cell rim and disease progression in individuals with MS. Our findings offer crucial insights into the mechanisms behind MS progression, identifying broad rim lesions as a biomarker for rapid disease progression and potentially guiding patient selection for future therapeutic trials targeting central nervous system intrinsic inflammation.
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Funding information in the publication:
We are grateful to the brain donors and their families for their commitment to the NBB donor program and the study participants for their support making this work possible. This work was supported by the DFG (German Research Foundation), Collaborative Research Center (CRC) TR128 project A08 to L.K. and B07 to T.K., TRR332 project B2 to L.K. and Ku1477/13-1 to T.K., the National MS Society (RFA180-2202-39141 to L.K., J.S., I.H. and T.K.), the Interdisciplinary Center for Clinical Research (KuT3/010/24 to T.K. and L.K.), CRC TR128 projects A09, A10 and Z02 to H.W., the InFLAMES Flagship Program of the Research Council of Finland (Decision nos. 337530, 357910 and 358823), the Research Council of Finland Clinical Investigator Grant Program (decision no. 330902), the US National MS Society (no. RFA-2203-39281), the Jane and Aatos Erkko Foundation to L.A. and by a MOVES Inspiration grant and MS research grant (no. MS23-506i) to I.H.
Open access funding provided by Universität Münster.
