{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T03:42:32Z","timestamp":1788838952800,"version":"build-2803163510"},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000890","name":"National Multiple Sclerosis Society","doi-asserted-by":"crossref","award":["RG-1601-07456"],"award-info":[{"award-number":["RG-1601-07456"]}],"id":[{"id":"10.13039\/100000890","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003000","name":"Stichting MS Research","doi-asserted-by":"publisher","award":["MS18-358"],"award-info":[{"award-number":["MS18-358"]}],"id":[{"id":"10.13039\/501100003000","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neuropathol"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Meningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, thereby contributing significantly to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. By extensive analysis of cortical microglia in post-mortem progressive MS tissue, we identified cortical areas with two MS-specific microglial populations, termed MS1 and MS2 cortex. The microglial population in MS1 cortex was characterized by a higher density and increased expression of the activation markers HLA class II and CD68, whereas microglia in MS2 cortex showed increased morphological complexity and loss of P2Y12 and TMEM119 expression. Interestingly, both populations associated with inflammation of the overlying meninges and were time-dependently replicated in an in vivo rat model for progressive MS-like chronic meningeal inflammation. In this recently developed animal model, cortical microglia at 1-month post-induction of experimental meningeal inflammation resembled microglia in MS1 cortex, and microglia at 2\u00a0months post-induction acquired a MS2-like phenotype. Furthermore, we observed that MS1 microglia in both MS cortex and the animal model were found closely apposing neuronal cell bodies and to mediate pre-synaptic displacement and phagocytosis, which coincided with a relative sparing of neurons. In contrast, microglia in MS2 cortex were not involved in these synaptic alterations, but instead associated with substantial neuronal loss. Taken together, our results show that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Furthermore, our in vivo data suggests that microglia initially protect neurons from meningeal inflammation-induced cell death by removing pre-synapses from the neuronal soma, but eventually lose these protective properties contributing to neuronal loss.<\/jats:p>","DOI":"10.1007\/s00401-021-02293-4","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:02:30Z","timestamp":1616976150000},"page":"881-899","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":85,"title":["Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration"],"prefix":"10.1007","volume":"141","author":[{"given":"Lynn","family":"van Olst","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Rodriguez-Mogeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Picon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"Kiljan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel E.","family":"James","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alwin","family":"Kamermans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne M. A.","family":"van der Pol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydian","family":"Knoop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iliana","family":"Michailidou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelien","family":"Drost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Franssen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert J.","family":"Schenk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen J. G.","family":"Geurts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Amor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas D.","family":"Mazarakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"van Horssen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helga E.","family":"de Vries","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Reynolds","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1407-6220","authenticated-orcid":false,"given":"Maarten E.","family":"Witte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,29]]},"reference":[{"key":"2293_CR1","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1002\/jemt.20829","volume":"73","author":"I Arganda-Carreras","year":"2010","unstructured":"Arganda-Carreras I, Fern\u00e1ndez-Gonz\u00e1lez R, Mu\u00f1oz-Barrutia A, Ortiz-De-Solorzano C (2010) 3D reconstruction of histological sections: Application to mammary gland tissue. Microsc Res Tech 73:1019\u20131029. https:\/\/doi.org\/10.1002\/jemt.20829","journal-title":"Microsc Res Tech"},{"key":"2293_CR2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17204-5","author":"P Bankhead","year":"2017","unstructured":"Bankhead P, Loughrey MB, Fern\u00e1ndez JA, Dombrowski Y, McArt DG, Dunne PD et al (2017) QuPath: Open source software for digital pathology image analysis. Sci Rep. https:\/\/doi.org\/10.1038\/s41598-017-17204-5","journal-title":"Sci Rep"},{"key":"2293_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2019.03090","volume":"10","author":"L Bell","year":"2020","unstructured":"Bell L, Lenhart A, Rosenwald A, Monoranu CM, Berberich-Siebelt F (2020) Lymphoid aggregates in the CNS of progressive multiple sclerosis patients lack regulatory T cells. Front Immunol 10:1\u201318. https:\/\/doi.org\/10.3389\/fimmu.2019.03090","journal-title":"Front Immunol"},{"key":"2293_CR4","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-018-0057-5","author":"O Butovsky","year":"2018","unstructured":"Butovsky O, Weiner HL (2018) Microglial signatures and their role in health and disease. Nat Rev Neurosci. https:\/\/doi.org\/10.1038\/s41583-018-0057-5","journal-title":"Nat Rev Neurosci"},{"key":"2293_CR5","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1038\/nrn3900","volume":"16","author":"M Calabrese","year":"2015","unstructured":"Calabrese M, Magliozzi R, Ciccarelli O, Geurts JJG, Reynolds R, Martin R (2015) Exploring the origins of grey matter damage in multiple sclerosis. Nat Rev Neurosci 16:147\u2013158. https:\/\/doi.org\/10.1038\/nrn3900","journal-title":"Nat Rev Neurosci"},{"key":"2293_CR6","doi-asserted-by":"publisher","first-page":"2952","DOI":"10.1093\/brain\/aws246","volume":"135","author":"M Calabrese","year":"2012","unstructured":"Calabrese M, Poretto V, Favaretto A, Alessio S, Bernardi V, Romualdi C et al (2012) Cortical lesion load associates with progression of disability in multiple sclerosis. Brain 135:2952\u20132961. https:\/\/doi.org\/10.1093\/brain\/aws246","journal-title":"Brain"},{"key":"2293_CR7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/ncomms5486","volume":"5","author":"Z Chen","year":"2014","unstructured":"Chen Z, Jalabi W, Hu W, Park H-J, Gale JT, Kidd GJ et al (2014) Microglial displacement of inhibitory synapses provides neuroprotection in the adult brain. Nat Commun 5:1\u201312. https:\/\/doi.org\/10.1038\/ncomms5486","journal-title":"Nat Commun"},{"key":"2293_CR8","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.1016\/S0140-6736(08)61620-7","volume":"372","author":"A Compston","year":"2008","unstructured":"Compston A, Coles A (2008) Multiple sclerosis. Lancet 372:1502\u20131517","journal-title":"Lancet"},{"key":"2293_CR9","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1126\/science.aax6752","volume":"367","author":"C Cser\u00e9p","year":"2020","unstructured":"Cser\u00e9p C, P\u00f3sfai B, L\u00e9n\u00e1rt N, Fekete R, L\u00e1szl\u00f3 ZI, Lele Z et al (2020) Microglia monitor and protect neuronal function through specialized somatic purinergic junctions. Science (80-) 367:528\u2013537. https:\/\/doi.org\/10.1126\/science.aax6752","journal-title":"Science (80-)"},{"key":"2293_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/sciadv.aba3239","volume":"6","author":"EC Damisah","year":"2020","unstructured":"Damisah EC, Hill RA, Rai A, Chen F, Rothlin CV, Ghosh S et al (2020) Astrocytes and microglia play orchestrated roles and respect phagocytic territories during neuronal corpse removal in vivo. Sci Adv 6:1\u201312. https:\/\/doi.org\/10.1126\/sciadv.aba3239","journal-title":"Sci Adv"},{"key":"2293_CR11","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1016\/j.cell.2018.05.003","volume":"173","author":"A Deczkowska","year":"2018","unstructured":"Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I (2018) Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell 173:1073\u20131081. https:\/\/doi.org\/10.1016\/j.cell.2018.05.003","journal-title":"Cell"},{"key":"2293_CR12","doi-asserted-by":"publisher","first-page":"10511","DOI":"10.1523\/JNEUROSCI.0405-14.2014","volume":"34","author":"L Dissing-Olesen","year":"2014","unstructured":"Dissing-Olesen L, LeDue JM, Rungta RL, Hefendehl JK, Choi HB, MacVicar BA (2014) Activation of neuronal NMDA receptors triggers transient ATP-mediated microglial process outgrowth. J Neurosci 34:10511\u201310527. https:\/\/doi.org\/10.1523\/JNEUROSCI.0405-14.2014","journal-title":"J Neurosci"},{"key":"2293_CR13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.07.049","author":"G Di Liberto","year":"2018","unstructured":"Di Liberto G, Pantelyushin S, Kreutzfeldt M, Page N, Musardo S, Coras R et al (2018) Neurons under T cell attack coordinate phagocyte-mediated synaptic stripping. Cell. https:\/\/doi.org\/10.1016\/j.cell.2018.07.049","journal-title":"Cell"},{"key":"2293_CR14","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1002\/ana.22337","volume":"69","author":"R Dutta","year":"2011","unstructured":"Dutta R, Chang A, Doud MK, Kidd GJ, Ribaudo MV, Young EA et al (2011) Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients. Ann Neurol 69:445\u2013454. https:\/\/doi.org\/10.1002\/ana.22337","journal-title":"Ann Neurol"},{"key":"2293_CR15","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.1093\/brain\/awy202","volume":"141","author":"AJC Eijlers","year":"2018","unstructured":"Eijlers AJC, Van Geest Q, Dekker I, Steenwijk MD, Meijer KA, Hulst HE et al (2018) Predicting cognitive decline in multiple sclerosis: A 5-year follow-up study. Brain 141:2605\u20132618. https:\/\/doi.org\/10.1093\/brain\/awy202","journal-title":"Brain"},{"key":"2293_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0035-2","author":"S Faissner","year":"2019","unstructured":"Faissner S, Plemel JR, Gold R, Yong VW (2019) Progressive multiple sclerosis: from pathophysiology to therapeutic strategies. Nat Rev Drug Discov. https:\/\/doi.org\/10.1038\/s41573-019-0035-2","journal-title":"Nat Rev Drug Discov"},{"key":"2293_CR17","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1242\/dev.099655","volume":"141","author":"T Ferreira","year":"2014","unstructured":"Ferreira T, Ou Y, Li S, Giniger E, van Meyel DJ (2014) Dendrite architecture organized by transcriptional control of the F-actin nucleator Spire. Dev 141:650\u2013660. https:\/\/doi.org\/10.1242\/dev.099655","journal-title":"Dev"},{"key":"2293_CR18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015973","author":"AM Fontainhas","year":"2011","unstructured":"Fontainhas AM, Wang M, Liang KJ, Chen S, Mettu P, Damani M et al (2011) Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission. PLoS ONE. https:\/\/doi.org\/10.1371\/journal.pone.0015973","journal-title":"PLoS ONE"},{"key":"2293_CR19","doi-asserted-by":"publisher","first-page":"3596","DOI":"10.1093\/brain\/awt279","volume":"136","author":"C Gardner","year":"2013","unstructured":"Gardner C, Magliozzi R, Durrenberger PF, Howell OW, Rundle J, Reynolds R (2013) Cortical grey matter demyelination can be induced by elevated pro-inflammatory cytokines in the subarachnoid space of MOG-immunized rats. Brain 136:3596\u20133608. https:\/\/doi.org\/10.1093\/brain\/awt279","journal-title":"Brain"},{"key":"2293_CR20","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.neuron.2006.09.011","volume":"52","author":"SL Hauser","year":"2006","unstructured":"Hauser SL, Oksenberg JR (2006) The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron 52:61\u201376","journal-title":"Neuron"},{"key":"2293_CR21","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.bbi.2015.11.008","volume":"55","author":"S Hellwig","year":"2016","unstructured":"Hellwig S, Brioschi S, Dieni S, Frings L, Masuch A, Blank T et al (2016) Altered microglia morphology and higher resilience to stress-induced depression-like behavior in CX3CR1-deficient mice. Brain Behav Immun 55:126\u2013137. https:\/\/doi.org\/10.1016\/j.bbi.2015.11.008","journal-title":"Brain Behav Immun"},{"key":"2293_CR22","doi-asserted-by":"publisher","first-page":"1784","DOI":"10.1093\/cercor\/bhs151","volume":"23","author":"M Hinwood","year":"2013","unstructured":"Hinwood M, Tynan RJ, Charnley JL, Beynon SB, Day TA, Walker FR (2013) Chronic stress induced remodeling of the prefrontal cortex: Structural re-organization of microglia and the inhibitory effect of minocycline. Cereb Cortex 23:1784\u20131797. https:\/\/doi.org\/10.1093\/cercor\/bhs151","journal-title":"Cereb Cortex"},{"key":"2293_CR23","doi-asserted-by":"publisher","first-page":"2755","DOI":"10.1093\/brain\/awr182","volume":"134","author":"OW Howell","year":"2011","unstructured":"Howell OW, Reeves CA, Nicholas R, Carassiti D, Radotra B, Gentleman SM et al (2011) Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 134:2755\u20132771. https:\/\/doi.org\/10.1093\/brain\/awr182","journal-title":"Brain"},{"key":"2293_CR24","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s40478-020-00938-1","volume":"8","author":"RE James","year":"2020","unstructured":"James RE, Schalks R, Browne E, Eleftheriadou I, Munoz CP, Mazarakis ND et al (2020) Persistent elevation of intrathecal pro-inflammatory cytokines leads to multiple sclerosis-like cortical demyelination and neurodegeneration. Acta Neuropathol Commun 8:66. https:\/\/doi.org\/10.1186\/s40478-020-00938-1","journal-title":"Acta Neuropathol Commun"},{"key":"2293_CR25","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1093\/brain\/awv353","volume":"139","author":"T J\u00fcrgens","year":"2016","unstructured":"J\u00fcrgens T, Jafari M, Kreutzfeldt M, Bahn E, Br\u00fcck W, Kerschensteiner M et al (2016) Reconstruction of single cortical projection neurons reveals primary spine loss in multiple sclerosis. Brain 139:39\u201346. https:\/\/doi.org\/10.1093\/brain\/awv353","journal-title":"Brain"},{"key":"2293_CR26","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1016\/j.cell.2017.05.018","volume":"169","author":"H Keren-Shaul","year":"2017","unstructured":"Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK et al (2017) A unique microglia type associated with restricting development of Alzheimer\u2019s disease. Cell 169:1276-1290.e17. https:\/\/doi.org\/10.1016\/j.cell.2017.05.018","journal-title":"Cell"},{"key":"2293_CR27","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.immuni.2017.08.008","volume":"47","author":"S Krasemann","year":"2017","unstructured":"Krasemann S, Madore C, Cialic R, Ochando J, Haass C, Krasemann S et al (2017) The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases article the TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47:566-581.e9. https:\/\/doi.org\/10.1016\/j.immuni.2017.08.008","journal-title":"Immunity"},{"key":"2293_CR28","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1212\/WNL.0000000000000560","volume":"83","author":"FD Lublin","year":"2014","unstructured":"Lublin FD, Reingold SC, Cohen JA, Cutter GR, S\u00f8rensen PS, Thompson AJ et al (2014) Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 83:278\u2013286","journal-title":"Neurology"},{"key":"2293_CR29","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1007\/s00401-018-1818-y","volume":"135","author":"S Luchetti","year":"2018","unstructured":"Luchetti S, Fransen NL, van Eden CG, Ramaglia V, Mason M, Huitinga I (2018) Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis. Acta Neuropathol 135:511\u2013528. https:\/\/doi.org\/10.1007\/s00401-018-1818-y","journal-title":"Acta Neuropathol"},{"key":"2293_CR30","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1093\/brain\/awm038","volume":"130","author":"R Magliozzi","year":"2007","unstructured":"Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M et al (2007) Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130:1089\u20131104. https:\/\/doi.org\/10.1093\/brain\/awm038","journal-title":"Brain"},{"key":"2293_CR31","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1002\/ana.22230","volume":"68","author":"R Magliozzi","year":"2010","unstructured":"Magliozzi R, Howell OW, Reeves C, Roncaroli F, Nicholas R, Serafini B et al (2010) A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol 68:477\u2013493. https:\/\/doi.org\/10.1002\/ana.22230","journal-title":"Ann Neurol"},{"key":"2293_CR32","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1002\/ana.25786","volume":"88","author":"R Magliozzi","year":"2020","unstructured":"Magliozzi R, Scalfari A, Pisani AI, Ziccardi S, Marastoni D, Pizzini FB et al (2020) The CSF profile linked to cortical damage predicts multiple sclerosis activity. Ann Neurol 88:562\u2013573. https:\/\/doi.org\/10.1002\/ana.25786","journal-title":"Ann Neurol"},{"key":"2293_CR33","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/S1474-4422(14)70256-X","volume":"14","author":"DH Mahad","year":"2015","unstructured":"Mahad DH, Trapp BD, Lassmann H (2015) Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 14:183\u2013193. https:\/\/doi.org\/10.1016\/S1474-4422(14)70256-X","journal-title":"Lancet Neurol"},{"key":"2293_CR34","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/0304-3940(87)90696-3","volume":"79","author":"PL McGeer","year":"1987","unstructured":"McGeer PL, Itagaki S, Tago H, McGeer EG (1987) Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 79:195\u2013200. https:\/\/doi.org\/10.1016\/0304-3940(87)90696-3","journal-title":"Neurosci Lett"},{"key":"2293_CR35","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24398","author":"I Michailidou","year":"2015","unstructured":"Michailidou I, Willems JGP, Kooi E-J, van Eden C, Gold SM, Geurts JJG et al (2015) Complement C1q\u2013C3 associated synaptic changes in multiple sclerosis hippocampus. Ann Neurol. https:\/\/doi.org\/10.1002\/ana.24398","journal-title":"Ann Neurol"},{"key":"2293_CR36","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1136\/jnnp.55.5.341","volume":"55","author":"DH Miller","year":"1992","unstructured":"Miller DH, Hornabrook RW, Purdie G (1992) The natural history of multiple sclerosis: a regional study with some longitudinal data. J Neurol Neurosurg Psychiatry 55:341\u2013346. https:\/\/doi.org\/10.1136\/jnnp.55.5.341","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2293_CR37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-017-13581-z","volume":"7","author":"H Morrison","year":"2017","unstructured":"Morrison H, Young K, Qureshi M, Rowe RK, Lifshitz J (2017) Quantitative microglia analyses reveal diverse morphologic responses in the rat cortex after diffuse brain injury. Sci Rep 7:1\u201312. https:\/\/doi.org\/10.1038\/s41598-017-13581-z","journal-title":"Sci Rep"},{"key":"2293_CR38","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.1126\/science.1110647","volume":"308","author":"A Nimmerjahn","year":"2005","unstructured":"Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314\u20131318. https:\/\/doi.org\/10.1126\/science.1110647","journal-title":"Science"},{"key":"2293_CR39","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1111\/j.1471-4159.2012.07693.x","volume":"121","author":"K Ohsawa","year":"2012","unstructured":"Ohsawa K, Sanagi T, Nakamura Y, Suzuki E, Inoue K, Kohsaka S (2012) Adenosine A3 receptor is involved in ADP-induced microglial process extension and migration. J Neurochem 121:217\u2013227. https:\/\/doi.org\/10.1111\/j.1471-4159.2012.07693.x","journal-title":"J Neurochem"},{"key":"2293_CR40","doi-asserted-by":"publisher","DOI":"10.3390\/metabo10050186","author":"Z Pang","year":"2020","unstructured":"Pang Z, Chong J, Li S, Xia J (2020) Metaboanalystr 3.0: toward an optimized workflow for global metabolomics. Metabolites. https:\/\/doi.org\/10.3390\/metabo10050186","journal-title":"Metabolites"},{"key":"2293_CR41","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1002\/ana.1123","volume":"50","author":"JW Peterson","year":"2001","unstructured":"Peterson JW, B\u00f6 L, M\u00f6rk S, Chang A, Trapp BD (2001) Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50:389\u2013400. https:\/\/doi.org\/10.1002\/ana.1123","journal-title":"Ann Neurol"},{"key":"2293_CR42","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25835","author":"N Petrova","year":"2020","unstructured":"Petrova N, Nutma E, Carassiti D, Newman J, Amor S, Altmann DR et al (2020) Synaptic loss in multiple sclerosis spinal cord. Ann Neurol. https:\/\/doi.org\/10.1002\/ana.25835","journal-title":"Ann Neurol"},{"key":"2293_CR43","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-021-02274-7","author":"C Picon","year":"2021","unstructured":"Picon C, Jayaraman A, James R, Beck C, Gallego P, Witte ME et al (2021) Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter. Acta Neuropathol. https:\/\/doi.org\/10.1007\/s00401-021-02274-7","journal-title":"Acta Neuropathol"},{"key":"2293_CR44","doi-asserted-by":"publisher","DOI":"10.1177\/1352458514562440","author":"V Popescu","year":"2015","unstructured":"Popescu V, Klaver R, Voorn P, Galis-de Graaf Y, Knol D, Twisk J et al (2015) What drives MRI-measured cortical atrophy in multiple sclerosis? Mult Scler. https:\/\/doi.org\/10.1177\/1352458514562440","journal-title":"Mult Scler"},{"key":"2293_CR45","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12841","author":"C Reali","year":"2020","unstructured":"Reali C, Magliozzi R, Roncaroli F, Nicholas R, Howell OW, Reynolds R (2020) B cell rich meningeal inflammation associates with increased spinal cord pathology in multiple sclerosis. Brain Pathol. https:\/\/doi.org\/10.1111\/bpa.12841","journal-title":"Brain Pathol"},{"key":"2293_CR46","doi-asserted-by":"publisher","first-page":"1900","DOI":"10.1002\/glia.23202","volume":"65","author":"BJ R\u00fcther","year":"2017","unstructured":"R\u00fcther BJ, Scheld M, Dreymueller D, Clarner T, Kress E, Brandenburg LO et al (2017) Combination of cuprizone and experimental autoimmune encephalomyelitis to study inflammatory brain lesion formation and progression. Glia 65:1900\u20131913. https:\/\/doi.org\/10.1002\/glia.23202","journal-title":"Glia"},{"key":"2293_CR47","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/s41586-019-1404-z","volume":"573","author":"L Schirmer","year":"2019","unstructured":"Schirmer L, Velmeshev D, Holmqvist S, Kaufmann M, Werneburg S, Jung D et al (2019) Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature 573:75\u201382. https:\/\/doi.org\/10.1038\/s41586-019-1404-z","journal-title":"Nature"},{"key":"2293_CR48","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1111\/j.1750-3639.2004.tb00049.x","volume":"14","author":"B Serafini","year":"2004","unstructured":"Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F (2004) Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 14:164\u2013174. https:\/\/doi.org\/10.1111\/j.1750-3639.2004.tb00049.x","journal-title":"Brain Pathol"},{"key":"2293_CR49","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.tins.2020.01.008","volume":"43","author":"K Sharma","year":"2020","unstructured":"Sharma K, Wu LJ, Eyo UB (2020) Calming neurons with a microglial touch. Trends Neurosci 43:197\u2013199. https:\/\/doi.org\/10.1016\/j.tins.2020.01.008","journal-title":"Trends Neurosci"},{"key":"2293_CR50","doi-asserted-by":"publisher","first-page":"6","DOI":"10.3389\/fncel.2013.00006","volume":"7","author":"A Sierra","year":"2013","unstructured":"Sierra A, Abiega O, Shahraz A, Neumann H (2013) Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis. Front Cell Neurosci 7:6","journal-title":"Front Cell Neurosci"},{"key":"2293_CR51","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1016\/j.bbi.2019.05.042","volume":"80","author":"KL Smith","year":"2019","unstructured":"Smith KL, Kassem MS, Clarke DJ, Kuligowski MP, Bedoya-P\u00e9rez MA, Todd SM et al (2019) Microglial cell hyper-ramification and neuronal dendritic spine loss in the hippocampus and medial prefrontal cortex in a mouse model of PTSD. Brain Behav Immun 80:889\u2013899. https:\/\/doi.org\/10.1016\/j.bbi.2019.05.042","journal-title":"Brain Behav Immun"},{"key":"2293_CR52","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-10-35","author":"DYS Vogel","year":"2013","unstructured":"Vogel DYS, Vereyken EJF, Glim JE, Heijnen PDAM, Moeton M, van der Valk P et al (2013) Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status. J Neuroinflamm. https:\/\/doi.org\/10.1186\/1742-2094-10-35","journal-title":"J Neuroinflamm"},{"key":"2293_CR53","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1212\/01.wnl.0000237551.26858.39","volume":"67","author":"C Wegner","year":"2006","unstructured":"Wegner C, Esiri MM, Chance SA, Palace J, Matthews PM (2006) Neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology 67:960\u2013967. https:\/\/doi.org\/10.1212\/01.wnl.0000237551.26858.39","journal-title":"Neurology"},{"key":"2293_CR54","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.12.004","author":"S Werneburg","year":"2019","unstructured":"Werneburg S, Jung J, Kunjamma RB, Ha S-K, Luciano NJ, Willis CM et al (2019) Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease. Immunity. https:\/\/doi.org\/10.1016\/j.immuni.2019.12.004","journal-title":"Immunity"},{"key":"2293_CR55","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1016\/j.it.2015.08.008","volume":"36","author":"Y Wu","year":"2015","unstructured":"Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B (2015) Microglia: dynamic mediators of synapse development and plasticity. Trends Immunol 36:605\u2013613","journal-title":"Trends Immunol"}],"container-title":["Acta Neuropathologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-021-02293-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00401-021-02293-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-021-02293-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T13:17:58Z","timestamp":1620739078000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00401-021-02293-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,29]]},"references-count":55,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,6]]}},"alternative-id":["2293"],"URL":"https:\/\/doi.org\/10.1007\/s00401-021-02293-4","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.09.03.281543","asserted-by":"object"}]},"ISSN":["0001-6322","1432-0533"],"issn-type":[{"value":"0001-6322","type":"print"},{"value":"1432-0533","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,29]]},"assertion":[{"value":"29 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 February 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 March 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 March 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}]}}