Absinta M, Maric D, Gharagozloo M, Garton T, Smith MD, Jin J et al (2021) A lymphocyte–microglia–astrocyte axis in chronic active multiple sclerosis. Nature 597:709–714. https://doi.org/10.1038/s41586-021-03892-7

Article  CAS  PubMed  PubMed Central  Google Scholar 

Airas L, Yong VW (2022) Microglia in multiple sclerosis—pathogenesis and imaging. Curr Opin Neurol 35:299–306. https://doi.org/10.1097/WCO.0000000000001045

Article  CAS  PubMed  Google Scholar 

Borenstein M, Higgins JP, Hedges LV, Rothstein HR (2017) Basics of meta-analysis: I(2) is not an absolute measure of heterogeneity. Res Synth Methods 8:5–18. https://doi.org/10.1002/jrsm.1230

Article  PubMed  Google Scholar 

Boziki M, Theotokis P, Kesidou E, Karafoulidou E, Konstantinou C, Michailidou I et al (2022) Sex, aging and immunity in multiple sclerosis and experimental autoimmune encephalomyelitis: an intriguing interaction. Front Neurol 13:1104552. https://doi.org/10.3389/fneur.2022.1104552

Article  PubMed  Google Scholar 

Ching AS, Kuhnast B, Damont A, Roeda D, Tavitian B, Dolle F (2012) Current paradigm of the 18-kDa translocator protein (TSPO) as a molecular target for PET imaging in neuroinflammation and neurodegenerative diseases. Insights Imaging 3:111–119. https://doi.org/10.1007/s13244-011-0128-x

Article  PubMed  Google Scholar 

Chong SY, Rosenberg SS, Fancy SP, Zhao C, Shen YA, Hahn AT et al (2012) Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination. Proc Natl Acad Sci USA 109:1299–1304. https://doi.org/10.1073/pnas.1113540109

Article  PubMed  Google Scholar 

Confavreux C, Vukusic S (2006) Age at disability milestones in multiple sclerosis. Brain 129:595–605

Article  PubMed  Google Scholar 

Confavreux C, Vukusic S (2006) Natural history of multiple sclerosis: a unifying concept. Brain 129:606–616

Article  PubMed  Google Scholar 

Cornejo F, von Bernhardi R (2016) Age-dependent changes in the activation and regulation of microglia. Adv Exp Med Biol 949:205–226. https://doi.org/10.1007/978-3-319-40764-7_10

Article  CAS  PubMed  Google Scholar 

Cosenza-Nashat M, Zhao ML, Suh HS, Morgan J, Natividad R, Morgello S et al (2009) Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol 35:306–328. https://doi.org/10.1111/j.1365-2990.2008.01006.x

Article  CAS  PubMed  Google Scholar 

Elkjaer ML, Frisch T, Reynolds R, Kacprowski T, Burton M, Kruse TA et al (2019) Molecular signature of different lesion types in the brain white matter of patients with progressive multiple sclerosis. Acta Neuropathol Commun 7:205. https://doi.org/10.1186/s40478-019-0855-7

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fernandez-Castaneda A, Lu P, Geraghty AC, Song E, Lee MH, Wood J et al (2022) Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell 185:2452-2468 e2416. https://doi.org/10.1016/j.cell.2022.06.008

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gallego-Delgado P, James R, Browne E, Meng J, Umashankar S, Tan L et al (2020) Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier. PLoS Biol 18:e3001008. https://doi.org/10.1371/journal.pbio.3001008

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gartner J, Chitnis T, Ghezzi A, Pohl D, Bruck W, Haring DA et al (2018) Relapse rate and MRI activity in young adult patients with multiple sclerosis: a post hoc analysis of phase 3 fingolimod trials. Mult Scler J Exp Transl Clin 4:2055217318778610. https://doi.org/10.1177/2055217318778610

Article  PubMed  PubMed Central  Google Scholar 

Goldschmidt T, Antel J, Konig FB, Brück W, Kuhlmann T (2009) Remyelination capacity of the MS brain decreases with disease chronicity. Neurology 72:1914–1921

Article  CAS  PubMed  Google Scholar 

Gorman MP, Healy BC, Polgar-Turcsanyi M, Chitnis T (2009) Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol 66:54–59. https://doi.org/10.1001/archneurol.2008.505

Article  PubMed  Google Scholar 

Graves JS, Krysko KM, Hua LH, Absinta M, Franklin RJM, Segal BM (2023) Ageing and multiple sclerosis. Lancet Neurol 22:66–77. https://doi.org/10.1016/S1474-4422(22)00184-3

Article  PubMed  Google Scholar 

Guneykaya D, Ivanov A, Hernandez DP, Haage V, Wojtas B, Meyer N et al (2018) Transcriptional and translational differences of microglia from male and female brains. Cell Rep 24:2773-2783 e2776. https://doi.org/10.1016/j.celrep.2018.08.001

Article  CAS  PubMed  Google Scholar 

Harrington EP, Bergles DE, Calabresi PA (2020) Immune cell modulation of oligodendrocyte lineage cells. Neurosci Lett 715:134601. https://doi.org/10.1016/j.neulet.2019.134601

Article  CAS  PubMed  Google Scholar 

Hendrickx DAE, van Scheppingen J, van der Poel M, Bossers K, Schuurman KG, van Eden CG et al (2017) Gene expression profiling of multiple sclerosis pathology identifies early patterns of demyelination surrounding chronic active lesions. Front Immunol 8:1810. https://doi.org/10.3389/fimmu.2017.01810

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hess K, Starost L, Kieran NW, Thomas C, Vincenten MCJ, Antel J et al (2020) Lesion stage-dependent causes for impaired remyelination in MS. Acta Neuropathol 140:359–375. https://doi.org/10.1007/s00401-020-02189-9

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hoftberger R, Fink S, Aboul-Enein F, Botond G, Olah J, Berki T et al (2010) Tubulin polymerization promoting protein (TPPP/p25) as a marker for oligodendroglial changes in multiple sclerosis. Glia 58:1847–1857. https://doi.org/10.1002/glia.21054

Article  PubMed  Google Scholar 

Kappos L, Wolinsky JS, Giovannoni G, Arnold DL, Wang Q, Bernasconi C et al (2020) Contribution of relapse-independent progression vs. relapse-associated worsening to overall confirmed disability accumulation in typical relapsing multiple sclerosis in a pooled analysis of 2 randomized clinical trials. JAMA Neurol 77:1132–1140. https://doi.org/10.1001/jamaneurol.2020.1568

Article  PubMed  Google Scholar 

Kirby L, Jin J, Cardona JG, Smith MD, Martin KA, Wang J et al (2019) Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination. Nat Commun 10:3887. https://doi.org/10.1038/s41467-019-11638-3

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kuhlmann T, Ludwin S, Prat A, Antel J, Bruck W, Lassmann H (2017) An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol 133:13–24. https://doi.org/10.1007/s00401-016-1653-y

Article  CAS  PubMed  Google Scholar 

Kuhlmann T, Moccia M, Coetzee T, Cohen JA, Correale J, Graves J et al (2022) Multiple sclerosis progression: time for a new mechanism-driven framework. Lancet Neurol. https://doi.org/10.1016/S1474-4422(22)00289-7

Article  PubMed  Google Scholar 

Kutzelnigg A, Lucchinetti CF, Stadelmann C, Brück W, Rauschka H, Bergmann M et al (2005) Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128:2705–2712

Article  PubMed  Google Scholar 

Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen PS, Thompson AJ et al (2014) Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 83:278–286. https://doi.org/10.1212/WNL.0000000000000560

Article  PubMed  PubMed Central  Google Scholar 

Luchicchi A, Hart B, Frigerio I, van Dam AM, Perna L, Offerhaus HL et al (2021) Axon-myelin unit blistering as early event in MS normal appearing white matter. Ann Neurol 89:711–725. https://doi.org/10.1002/ana.26014

Article  CAS  PubMed  PubMed Central  Google Scholar 

Macnair W, Calini D, Agirre E, Bryois J, Jäkel S, Kukanja P et al (2022) Single nuclei RNAseq stratifies multiple sclerosis patients into three distinct white matter glia responses. bioRxiv. https://doi.org/10.1101/2022.04.06.487263

Article  Google Scholar 

Maeda J, Higuchi M, Inaji M, Ji B, Haneda E, Okauchi T et al (2007) Phase-dependent roles of reactive microglia and astrocytes in nervous system injury as delineated by imaging of peripheral benzodiazepine receptor. Brain Res 1157:100–111. https://doi.org/10.1016/j.brainres.2007.04.054

Article  CAS  PubMed  Google Scholar 

Magliozzi R, Fadda G, Brown RA, Bar-Or A, Howell OW, Hametner S et al (2022) “Ependymal-in” gradient of thalamic damage in progressive multiple sclerosis. Ann Neurol 92:670–685. https://doi.org/10.1002/ana.26448

Article  CAS  PubMed  PubMed Central  Google Scholar 

Magliozzi R, Howell OW, Reeves C, Roncaroli F, Nicholas R, Serafini B et al (2010) A g