{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:20:21Z","timestamp":1792794021720,"version":"4.5.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2020,9,16]],"date-time":"2020-09-16T00:00:00Z","timestamp":1600214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"National Institute of Aging","award":["K99 AG059893"],"award-info":[{"award-number":["K99 AG059893"]}]},{"name":"National Institute of Aging","award":["R01 AG026484"],"award-info":[{"award-number":["R01 AG026484"]}]},{"name":"Heitman Young Investigator Career Development Award","id":[{"id":"https:\/\/ror.org\/02xjhr934","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cortical superficial siderosis is an established haemorrhagic neuroimaging marker of cerebral amyloid angiopathy. In fact, cortical superficial siderosis is emerging as a strong independent risk factor for future lobar intracerebral haemorrhage. However, the underlying neuropathological correlates and pathophysiological mechanisms of cortical superficial siderosis remain elusive. Here we use an in vivo MRI, ex vivo MRI, histopathology approach to assess the neuropathological correlates and vascular pathology underlying cortical superficial siderosis. Fourteen autopsy cases with cerebral amyloid angiopathy (mean age at death 73 years, nine males) and three controls (mean age at death 91 years, one male) were included in the study. Intact formalin-fixed cerebral hemispheres were scanned on a 3 T MRI scanner. Cortical superficial siderosis was assessed on ex vivo gradient echo and turbo spin echo MRI sequences and compared to findings on available in vivo MRI. Subsequently, 11 representative areas in four cases with available in vivo MRI scans were sampled for histopathological verification of MRI-defined cortical superficial siderosis. In addition, samples were taken from predefined standard areas of the brain, blinded to MRI findings. Serial sections were stained for haematoxylin and eosin and Perls\u2019 Prussian blue, and immunohistochemistry was performed against amyloid-\u03b2 and GFAP. Cortical superficial siderosis was present on ex vivo MRI in 8\/14 cases (57%) and 0\/3 controls (P\u2009=\u20090.072). Histopathologically, cortical superficial siderosis corresponded to iron-positive haemosiderin deposits in the subarachnoid space and superficial cortical layers, indicative of chronic bleeding events originating from the leptomeningeal vessels. Increased severity of cortical superficial siderosis was associated with upregulation of reactive astrocytes. Next, cortical superficial siderosis was assessed on a total of 65 Perls\u2019-stained sections from MRI-targeted and untargeted sampling combined in cerebral amyloid angiopathy cases. Moderate-to-severe cortical superficial siderosis was associated with concentric splitting of the vessel wall (an advanced form of cerebral amyloid angiopathy-related vascular damage) in leptomeningeal vessels (P\u2009&amp;lt;\u20090.0001), but reduced cerebral amyloid angiopathy severity in cortical vessels (P\u2009=\u20090.048). In terms of secondary tissue injury, moderate-to-severe cortical superficial siderosis was associated with the presence of microinfarcts (P\u2009=\u20090.025), though not microbleeds (P\u2009=\u20090.973). Collectively, these data suggest that cortical superficial siderosis on MRI corresponds to iron-positive deposits in the superficial cortical layers, representing the chronic manifestation of bleeding episodes from leptomeningeal vessels. Cortical superficial siderosis appears to be the result of predominantly advanced cerebral amyloid angiopathy of the leptomeningeal vessels and may trigger secondary ischaemic injury in affected areas.<\/jats:p>","DOI":"10.1093\/brain\/awaa266","type":"journal-article","created":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T15:22:21Z","timestamp":1595431341000},"page":"3343-3351","source":"Crossref","is-referenced-by-count":78,"title":["Neuropathological correlates of cortical superficial siderosis in cerebral amyloid angiopathy"],"prefix":"10.1093","volume":"143","author":[{"given":"Andreas","family":"Charidimou","sequence":"first","affiliation":[{"name":"J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA"},{"name":"Boston Medical Center, Boston University, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Perosa","sequence":"additional","affiliation":[{"name":"J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew P","family":"Frosch","sequence":"additional","affiliation":[{"name":"Neuropathology Service, C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley A","family":"Scherlek","sequence":"additional","affiliation":[{"name":"MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M","family":"Greenberg","sequence":"additional","affiliation":[{"name":"J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne J","family":"van Veluw","sequence":"additional","affiliation":[{"name":"J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA"},{"name":"MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,9,16]]},"reference":[{"key":"2021092108020412300_awaa266-B1","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1161\/STROKEAHA.110.595082","article-title":"Microinfarct pathology, dementia, and cognitive systems","volume":"42","author":"Arvanitakis","year":"2011","journal-title":"Stroke"},{"key":"2021092108020412300_awaa266-B2","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1177\/0271678X17744736","article-title":"Acute diffusion-weighted imaging lesions in cerebral amyloid angiopathy-related convexal subarachnoid hemorrhage","volume":"38","author":"Beitzke","year":"2018","journal-title":"J Cereb Blood Flow Metab"},{"key":"2021092108020412300_awaa266-B3","doi-asserted-by":"crossref","first-page":"89ra57","DOI":"10.1126\/scitranslmed.3002156","article-title":"Human apoE isoforms differentially regulate brain amyloid-\u03b2 peptide clearance","volume":"3","author":"Castellano","year":"2011","journal-title":"Sci Transl Med"},{"key":"2021092108020412300_awaa266-B4","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1159\/000353989","article-title":"Cerebral amyloid angiopathy and transient focal neurological episodes","volume":"36","author":"Charidimou","year":"2013","journal-title":"Cerebrovasc Dis"},{"key":"2021092108020412300_awaa266-B5","doi-asserted-by":"crossref","first-page":"e2192","DOI":"10.1212\/WNL.0000000000008590","article-title":"Cortical superficial siderosis and bleeding risk in cerebral amyloid angiopathy: a meta-analysis","volume":"93","author":"Charidimou","year":"2019","journal-title":"Neurology"},{"key":"2021092108020412300_awaa266-B6","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1093\/brain\/awv162","article-title":"Cortical superficial siderosis: detection and clinical significance in cerebral amyloid angiopathy and related conditions","volume":"138","author":"Charidimou","year":"2015","journal-title":"Brain"},{"key":"2021092108020412300_awaa266-B7","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1161\/STROKEAHA.112.657759","article-title":"Spectrum of transient focal neurological episodes in cerebral amyloid angiopathy: multicentre magnetic resonance imaging cohort study and meta-analysis","volume":"43","author":"Charidimou","year":"2012","journal-title":"Stroke"},{"key":"2021092108020412300_awaa266-B8","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1212\/01.wnl.0000435298.80023.7a","article-title":"Cortical superficial siderosis and intracerebral hemorrhage risk in cerebral amyloid angiopathy","volume":"81","author":"Charidimou","year":"2013","journal-title":"Neurology"},{"key":"2021092108020412300_awaa266-B9","doi-asserted-by":"crossref","first-page":"e358","DOI":"10.1212\/WNL.0000000000007818","article-title":"APOE and cortical superficial siderosis in CAA: meta-analysis and potential mechanisms","volume":"93","author":"Charidimou","year":"2019","journal-title":"Neurology"},{"key":"2021092108020412300_awaa266-B10","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1159\/000355042","article-title":"Superficial siderosis of the central nervous system: a post-mortem 7.0-tesla magnetic resonance imaging study with neuropathological correlates","volume":"36","author":"De Reuck","year":"2013","journal-title":"Cerebrovasc Dis"},{"key":"2021092108020412300_awaa266-B11","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1161\/01.STR.14.6.915","article-title":"Cerebral amyloid angiopathy: incidence and complications in the aging brain. 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