{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T04:48:49Z","timestamp":1791607729098,"version":"4.3.4"},"reference-count":29,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Identification of cerebral amyloid angiopathy (CAA) before its hemorrhagic manifestations remains limited. We aimed to determine whether severe enlarged perivascular spaces in the centrum semiovale (EPVS\u2010CSO) identify a prehemorrhagic stage of sporadic CAA by predicting the first appearance of CAA\u2010related hemorrhagic lesions or incident cognitive decline in amyloid\u2010positive, cognitively unimpaired, hemorrhage\u2010free older adults.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a secondary analysis of the Anti\u2010Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial, a phase 3 randomized study in cognitively unimpaired, amyloid\u2010positive older adults. Participants with baseline hemorrhagic lesions were excluded. Baseline EPVS\u2010CSO severity was dichotomized as severe versus nonsevere. Severe basal ganglia EPVS, more closely associated with hypertensive small vessel disease, was evaluated as a topographical negative\u2010control exposure. The primary outcome was incident strictly lobar cerebral microbleeds or cortical superficial siderosis. The secondary outcome was longitudinal cognitive trajectories measured by the Preclinical Alzheimer Cognitive Composite.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 932 participants (mean age 71.7\u2009\u00b1\u20094.8\u2009years; 61.3% female), 101 (10.8%) had severe EPVS\u2010CSO at baseline. Over a median follow up of 5.1\u2009years (IQR 3.3\u20135.5\u2009years), 33.7% of those with severe EPVS\u2010CSO developed incident CAA\u2010related hemorrhagic lesions compared with 13.6% of those with nonsevere EPVS\u2010CSO (adjusted HR 2.85, 95% CI 1.91\u20134.25;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001). Severe basal ganglia EPVS was not associated with incident hemorrhagic lesions (adjusted HR 0.87, 95% CI 0.35\u20132.18;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.77). Severe EPVS\u2010CSO was not associated with early cognitive differences, and participants who developed incident hemorrhagic lesions showed more pronounced cognitive decline.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>These findings identify severe EPVS\u2010CSO as a strong predictor of first appearance of CAA\u2010related hemorrhagic lesions in amyloid\u2010positive individuals, supporting integration of amyloid biomarkers into magnetic resonance imaging\u2010based Boston criteria. Identifying markers of the transition of CAA from a nonhemorrhagic to a hemorrhagic stage provides a potential foundation for approaching primary prevention of CAA\u2010related hemorrhage. ANN NEUROL 2026<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78388","type":"journal-article","created":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T03:52:16Z","timestamp":1791604336000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Centrum Semiovale Perivascular Spaces Predict First Hemorrhagic Lesion in Asymptomatic Amyloid\u2010Positive Individuals"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1842-7099","authenticated-orcid":false,"given":"Baris","family":"Alten","sequence":"first","affiliation":[{"name":"Division of Vascular Neurology, Department of Neurology Hospital of the University of Pennsylvania  Philadelphia PA USA"},{"name":"Division of Vascular Neurology, Department of Neurology Massachusetts General Hospital, Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3309-4368","authenticated-orcid":false,"given":"Elif","family":"Gokcal","sequence":"additional","affiliation":[{"name":"Division of Vascular Neurology, Department of Neurology Massachusetts General Hospital, Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reisa A.","family":"Sperling","sequence":"additional","affiliation":[{"name":"Center for Alzheimer Research and Treatment, Brigham and Women's Hospital and Massachusetts General Hospital, Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6854-9356","authenticated-orcid":false,"given":"Zahra","family":"Shirzadi","sequence":"additional","affiliation":[{"name":"Center for Alzheimer Research and Treatment, Brigham and Women's Hospital and Massachusetts General Hospital, Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7792-1698","authenticated-orcid":false,"given":"Jasmeer P.","family":"Chhatwal","sequence":"additional","affiliation":[{"name":"Center for Alzheimer Research and Treatment, Brigham and Women's Hospital and Massachusetts General Hospital, Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Edip","family":"Gurol","sequence":"additional","affiliation":[{"name":"Division of Vascular Neurology, Department of Neurology Massachusetts General Hospital, Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott E.","family":"Kasner","sequence":"additional","affiliation":[{"name":"Division of Vascular Neurology, Department of Neurology Hospital of the University of Pennsylvania  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1792-8887","authenticated-orcid":false,"given":"Steven M.","family":"Greenberg","sequence":"additional","affiliation":[{"name":"Division of Vascular Neurology, Department of Neurology Massachusetts General Hospital, Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5218-9015","authenticated-orcid":false,"given":"Brett L.","family":"Cucchiara","sequence":"additional","affiliation":[{"name":"Division of Vascular Neurology, Department of Neurology Hospital of the University of Pennsylvania  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41582-019-0281-2","article-title":"Cerebral amyloid angiopathy and Alzheimer disease\u2013one peptide, two pathways","volume":"16","author":"Greenberg SM","year":"2020","journal-title":"Nat Rev Neurol"},{"key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1002\/alz.12366","article-title":"Prevalence of cerebral amyloid angiopathy: a systematic review and meta\u2010analysis","volume":"18","author":"Jakel L","year":"2022","journal-title":"Alzheimers Dement"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/S1474-4422(23)00114-X","article-title":"Progression of cerebral amyloid angiopathy: a pathophysiological framework","volume":"22","author":"Koemans EA","year":"2023","journal-title":"Lancet Neurol"},{"key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/S1474-4422(22)00208-3","article-title":"The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI\u2010neuropathology diagnostic accuracy study","volume":"21","author":"Charidimou A","year":"2022","journal-title":"Lancet Neurol"},{"key":"e_1_2_9_6_1","doi-asserted-by":"crossref","DOI":"10.1212\/WNL.0000000000213460","article-title":"Validation of the Boston criteria version 2.0 for cerebral amyloid angiopathy in patients presenting with intracerebral hemorrhage","volume":"104","author":"Downes MH","year":"2025","journal-title":"Neurology"},{"key":"e_1_2_9_7_1","doi-asserted-by":"crossref","DOI":"10.1212\/WNL.0000000000207940","article-title":"Sensitivity and specificity of the Boston criteria version 2.0 for the diagnosis of cerebral amyloid angiopathy in a community\u2010based sample","volume":"102","author":"Zanon Zotin MC","year":"2024","journal-title":"Neurology"},{"key":"e_1_2_9_8_1","doi-asserted-by":"crossref","DOI":"10.1212\/WNL.0000000000209386","article-title":"Boston criteria v2.0 for cerebral amyloid angiopathy without hemorrhage: an MRI\u2010neuropathologic validation study","volume":"102","author":"Switzer AR","year":"2024","journal-title":"Neurology"},{"key":"e_1_2_9_9_1","doi-asserted-by":"crossref","DOI":"10.1007\/s00018-024-05277-1","article-title":"Is CAA a perivascular brain clearance disease? 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