{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:37:34Z","timestamp":1792132654205,"version":"4.4.0"},"reference-count":55,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,7,30]],"date-time":"2022-07-30T00:00:00Z","timestamp":1659139200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007366","name":"Fondazione Italiana Sclerosi Multipla","doi-asserted-by":"publisher","award":["FISM 16\/17\/F14"],"award-info":[{"award-number":["FISM 16\/17\/F14"]}],"id":[{"id":"10.13039\/100007366","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      Leptomeningeal and perivenular infiltrates are important contributors to cortical grey matter damage and disease progression in multiple sclerosis (MS). Whereas perivenular inflammation induces vasculocentric lesions, leptomeningeal involvement follows a subpial \u201csurface\u2010in\u201d gradient. To determine whether similar gradient of damage occurs in deep grey matter nuclei, we examined the dorsomedial thalamic nuclei and cerebrospinal fluid (CSF) samples from 41 postmortem secondary progressive MS cases compared with 5 non\u2010neurological controls and 12 controls with other neurological diseases. CSF\/ependyma\u2010oriented gradient of reduction in NeuN\n                      <jats:sup>+<\/jats:sup>\n                      neuron density was present in MS thalamic lesions compared to controls, greatest (26%) in subventricular locations at the ependyma\/CSF boundary and least with increasing distance (12% at 10\u2009mm). Concomitant graded reduction in SMI31\n                      <jats:sup>+<\/jats:sup>\n                      axon density was observed, greatest (38%) at 2\u2009mm from the ependyma\/CSF boundary and least at 10\u2009mm (13%). Conversely, gradient of major histocompatibility complex (MHC)\u2010II\n                      <jats:sup>+<\/jats:sup>\n                      microglia density increased by over 50% at 2\u2009mm at the ependyma\/CSF boundary and only by 15% at 10\u2009mm and this gradient inversely correlated with the neuronal (\n                      <jats:italic>R<\/jats:italic>\n                      \u00a0=\u00a0\u22120.91,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) and axonal (\n                      <jats:italic>R<\/jats:italic>\n                      \u00a0=\u00a0\u22120.79,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) thalamic changes. Observed gradients were also detected in normal\u2010appearing thalamus and were associated with rapid\/severe disease progression; presence of leptomeningeal tertiary lymphoid\u2010like structures; large subependymal infiltrates, enriched in CD20\n                      <jats:sup>+<\/jats:sup>\n                      B cells and occasionally containing CXCL13\n                      <jats:sup>+<\/jats:sup>\n                      CD35\n                      <jats:sup>+<\/jats:sup>\n                      follicular dendritic cells; and high CSF protein expression of a complex pattern of soluble inflammatory\/neurodegeneration factors, including chitinase\u20103\u2010like\u20101, TNFR1, parvalbumin, neurofilament\u2010light\u2010chains and TNF. Substantial \u201cependymal\u2010in\u201d gradient of pathological cell alterations, accompanied by presence of intrathecal inflammation, compartmentalized either in subependymal lymphoid perivascular infiltrates or in CSF, may play a key role in MS progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Summary for Social Media<\/jats:title>\n                    <jats:p>Imaging and neuropathological evidences demonstrated the unique feature of \u201csurface\u2010in\u201d gradient of damage in multiple sclerosis (MS) since early pediatric stages, often associated with more severe brain atrophy and disease progression. In particular, increased inflammation in the cerebral meninges has been shown to be strictly associated with an MS\u2010specific gradient of neuronal, astrocyte, and oligodendrocyte loss accompanied by microglial activation in subpial cortical layers, which is not directly related to demyelination.<\/jats:p>\n                    <jats:p>To determine whether a similar gradient of damage occurs in deep grey matter nuclei, we examined the potential neuronal and microglia alterations in the dorsomedial thalamic nuclei from postmortem secondary progressive MS cases in combination with detailed neuropathological characterization of the inflammatory features and protein profiling of paired CSF samples.<\/jats:p>\n                    <jats:p>We observed a substantial \u201csubependymal\u2010in\u201d gradient of neuro\u2010axonal loss and microglia activation in active thalamic lesions of progressive MS cases, in particular in the presence of increased leptomeningeal and cerebrospinal fluid (CSF) inflammation. This altered graded pathology was found associated with more severe and rapid progressive MS and increased inflammatory degree either in large perivascular subependymal infiltrates, enriched in B cells, or within the paired CSF, in particular with elevated levels of a complex pattern of soluble inflammatory and neurodegeneration factors, including chitinase 3\u2010like\u20101, TNFR1, parvalbumin, neurofilament light\u2010chains and TNF.<\/jats:p>\n                    <jats:p>These data support a key role for chronic, intrathecally compartmentalized inflammation in specific disease endophenotypes. CSF biomarkers, together with advance imaging tools, may therefore help to improve not only the disease diagnosis but also the early identification of specific MS subgroups that would benefit of more personalized treatments. ANN NEUROL 2022;92:670\u2013685<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.26448","type":"journal-article","created":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T08:49:11Z","timestamp":1656060551000},"page":"670-685","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["\u201cEpendymal\u2010in\u201d Gradient of Thalamic Damage in Progressive Multiple Sclerosis"],"prefix":"10.1002","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8284-7763","authenticated-orcid":false,"given":"Roberta","family":"Magliozzi","sequence":"first","affiliation":[{"name":"Neurology Section of Department of Neurological and Movement Sciences University of Verona  Verona Italy"},{"name":"Department of Brain Sciences, Faculty of Medicine Imperial College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9658-815X","authenticated-orcid":false,"given":"Giulia","family":"Fadda","sequence":"additional","affiliation":[{"name":"Center for Neuroinflammation and Experimental Therapeutics and the Department of Neurology, Perelman School of Medicine University of Pennsylvania  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Brown","sequence":"additional","affiliation":[{"name":"ShadowLab Research Inc.  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Bar\u2010Or","sequence":"additional","affiliation":[{"name":"Center for Neuroinflammation and Experimental Therapeutics and the Department of Neurology, Perelman School of Medicine University of Pennsylvania  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2157-9157","authenticated-orcid":false,"given":"Owain W.","family":"Howell","sequence":"additional","affiliation":[{"name":"Department of Brain Sciences, Faculty of Medicine Imperial College London  London UK"},{"name":"Institute of Life Sciences Swansea University  Swansea UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Hametner","sequence":"additional","affiliation":[{"name":"Brain Research Center Medical University of Vienna  Vienna 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