{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T08:39:51Z","timestamp":1792485591227,"version":"4.5.0"},"reference-count":31,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100020950","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["110-2314-B-002-155-MY3"],"award-info":[{"award-number":["110-2314-B-002-155-MY3"]}],"id":[{"id":"10.13039\/501100020950","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020950","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["110-2314-B-075-014-MY3"],"award-info":[{"award-number":["110-2314-B-075-014-MY3"]}],"id":[{"id":"10.13039\/501100020950","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020950","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["112-2314- B-075-034-MY3"],"award-info":[{"award-number":["112-2314- B-075-034-MY3"]}],"id":[{"id":"10.13039\/501100020950","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020950","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["113-2314-B-002-102-MY3"],"award-info":[{"award-number":["113-2314-B-002-102-MY3"]}],"id":[{"id":"10.13039\/501100020950","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020950","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["113-2314-B-075-051-MY3"],"award-info":[{"award-number":["113-2314-B-075-051-MY3"]}],"id":[{"id":"10.13039\/501100020950","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011912","name":"Taipei Veterans General Hospital","doi-asserted-by":"publisher","award":["V112C-001"],"award-info":[{"award-number":["V112C-001"]}],"id":[{"id":"10.13039\/501100011912","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011912","name":"Taipei Veterans General Hospital","doi-asserted-by":"publisher","award":["V113C-124"],"award-info":[{"award-number":["V113C-124"]}],"id":[{"id":"10.13039\/501100011912","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["International Journal of Stroke"],"published-print":{"date-parts":[[2026,1]]},"abstract":"\n Background:<\/jats:title>\n \n Heterozygous\n HTRA1<\/jats:italic>\n mutations are the second most common cause of monogenic dominant cerebral small vessel disease (\n HTRA1<\/jats:italic>\n -AD-cSVD or CADASIL2), after cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) due to\n NOTCH3<\/jats:italic>\n cysteine-altering mutations. However, there have been few studies of cohorts of\n HTRA1<\/jats:italic>\n -AD-cSVD and whether it can be differentiated clinically and on neuroimaging from CADASIL is unclear.\n <\/jats:p>\n <\/jats:sec>\n \n Aims:<\/jats:title>\n \n This retrospective study aims to characterize and compare the clinical and neuroimaging features of\n HTRA1<\/jats:italic>\n -AD-cSVD with those of CADASIL.\n <\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n \n We identified 21 unrelated Taiwanese subjects carrying 15 heterozygous\n HTRA1<\/jats:italic>\n variants, all functionally validated as pathogenic through in vitro protease activity assays.\n HTRA1<\/jats:italic>\n -AD-cSVD patients were compared with 406 CADASIL patients, including 44 cases carrying\n NOTCH3<\/jats:italic>\n mutations within the high-risk epidermal growth factor-like repeat domains (EGFr), 358 with moderate-risk EGFr mutations, and 4 with low-risk EGFr mutations. Multivariate regression analyses were conducted with adjustments for age at MRI examination and hypertension.\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n Stroke occurred in 81.0% of\n HTRA1<\/jats:italic>\n -AD-cSVD patients, and 47.6% exhibited cognitive dysfunction. MRI revealed moderate-to-severe white matter hyperintensity (WMH) in the deep white matter and external capsule (modified Scheltens\u2019 scale: 5.3\u2009\u00b1\u20091.0 and 4.1\u2009\u00b1\u20091.7), mild WMH in the temporal pole (1.0\u2009\u00b1\u20091.7), lacunes in 90.5%, \u2a7e10 cerebral microbleeds (CMBs) in 66.7%, and intracranial hemorrhage (ICH) lesions in 46.7%, indicating susceptibility to both ischemic and hemorrhagic strokes. Patients with\n HTRA1<\/jats:italic>\n loss-of-function mutations or protease domain missense mutations exhibited a higher prevalence of \u2a7e10 CMBs on SWI\/T2* imaging (100% and 83.3%) compared to those with missense mutations outside this domain (20%). Symptom onset occurred earliest in patients with\n NOTCH3<\/jats:italic>\n high-risk EGFr mutations (49.2\u2009\u00b1\u200910.5\u2009years), followed by those with heterozygous\n HTRA1<\/jats:italic>\n mutations (54.3\u2009\u00b1\u200910.7\u2009years), and latest in\n NOTCH3<\/jats:italic>\n moderate-risk EGFr mutations carriers (59.7\u2009\u00b1\u20099.5\u2009years). Temporal pole involvement was most prevalent in\n NOTCH3<\/jats:italic>\n high-risk EGFr mutations (88.6%), followed by\n NOTCH3<\/jats:italic>\n moderate-risk EGFr mutations (32.4%), and least common in heterozygous\n HTRA1<\/jats:italic>\n mutations (28.6%). Even after adjusting for age and hypertension,\n HTRA1<\/jats:italic>\n -AD-cSVD patients exhibited significantly milder temporal pole WMH severity compared to\n NOTCH3<\/jats:italic>\n high-risk EGFr mutation carriers (adjusted\n p<\/jats:italic>\n \u2009<\u20090.001). In addition, ICH lesions were more frequently observed in\n HTRA1<\/jats:italic>\n -AD-cSVD patients (46.7%) than in patients with\n NOTCH3<\/jats:italic>\n high-risk or moderate-risk EGFr mutations (18.2% and 21.2%), although the difference was not statistically significant.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion:<\/jats:title>\n \n HTRA1<\/jats:italic>\n -AD-cSVD shares overlapping clinical and neuroimaging features with CADASIL. Temporal pole WMH involvement can occur in\n HTRA1<\/jats:italic>\n -AD-cSVD but is more common in CADASIL. The high prevalence of ICH in\n HTRA1<\/jats:italic>\n -AD-cSVD has been under-recognized.\n <\/jats:p>\n <\/jats:sec>\n \n Data access statement:<\/jats:title>\n Data are available upon reasonable request from third parties.<\/jats:p>\n <\/jats:sec>","DOI":"10.1177\/17474930251359110","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T07:08:30Z","timestamp":1751526510000},"page":"79-88","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["Comparison of clinical and imaging features of cerebral small vessel disease associated with heterozygous\n HTRA1<\/i>\n and\n NOTCH3<\/i>\n mutations"],"prefix":"10.1177","volume":"21","author":[{"given":"Yi-Chung","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Neurology, Taipei Veterans General Hospital, Taipei City, Taiwan"},{"name":"School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan"},{"name":"Brain Research Center, National Yang Ming Chiao Tung University, Taipei City, Taiwan"},{"name":"Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1258-8775","authenticated-orcid":false,"given":"Chih-Hao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Taiwan University Hospital, Taipei City, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Tsen","family":"Chou","sequence":"additional","affiliation":[{"name":"Department of Neurology, Taipei Veterans General Hospital, Taipei City, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3054-6333","authenticated-orcid":false,"given":"Yu-Wen","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Taiwan University Hospital, Taipei City, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9419-9070","authenticated-orcid":false,"given":"Chih-Ping","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Neurology, Taipei Veterans General Hospital, Taipei City, Taiwan"},{"name":"School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan"},{"name":"Brain Research Center, National Yang Ming Chiao Tung University, Taipei City, 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