{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:29:04Z","timestamp":1791239344217,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,22]]},"group-title":"Neurology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"funder":[{"award":["RF1AG074608"],"award-info":[{"award-number":["RF1AG074608"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AG082208"],"award-info":[{"award-number":["R01AG082208"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AG085602"],"award-info":[{"award-number":["R01AG085602"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01FD008399"],"award-info":[{"award-number":["U01FD008399"]}],"id":[{"id":"https:\/\/ror.org\/034xvzb47","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and Objectives<\/jats:title>\n                  <jats:p>Vascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of dementia and a common comorbidity for reduced functional capacity in many individuals, but clinical management and clinical trial readiness are severely hindered by extreme phenotypic and mechanistic heterogeneity. This study establishes the baseline clinical, functional, and multimodal biomarker characteristics of the first United States (US) cohort of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), serving as a single-cause, monogenic small vessel disease model for sporadic VCID.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Cross-sectional analysis of baseline data collected from October 2022 through January 2025 from a longitudinal cohort at 12 US enrollment sites. Adults from families with a documented\n                    <jats:italic>NOTCH3<\/jats:italic>\n                    variant were recruited through clinical referrals, medical record review, advocacy organizations, and community outreach. Exclusion criteria included other conditions that prevented interpretation of findings and modified Rankin Scale (mRS) scores greater than 3. Central genetic characterization assigned persons with a pathogenic or likely pathogenic\n                    <jats:italic>NOTCH3<\/jats:italic>\n                    variant to low-, medium-, or high-risk tiers based on epidermal growth factor-like repeat domains. Standardized assessments included clinical histories, exams, objective cognitive and physical assessments, self-reported, companion-reported, and clinician-rated measures, MRI, genetics, and proteomics acquired under harmonized protocols. Group comparisons used Fishers exact and Kruskal\u2013Wallis tests. Multivariable regression used adjustment for age, sex, race, and education.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Of 560 participants completing baseline visits, 46 had variants of unknown significance, and 55 had pending genetic analyses. The analytic cohort included 343 persons with a CADASIL-causing\n                    <jats:italic>NOTCH3<\/jats:italic>\n                    variant and 116 non-carrier family controls. Median age was 47.9 years (IQR 38.7\u201359.1), median education was 16 years (IQR 14\u2013 17), 62.5% were female, and 91.4% were White. Carriers were classified in CADASIL risk tiers: low (7.0%), medium (18.4%), or high (74.6%). Compared with controls, adjusted odds of classification into a more impaired CDR category were higher in all tiers (OR 2.55-5.08, 95% CI 1.22\u201311.34).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>The US CADASIL Consortium has established a large, genetics-confirmed cohort spanning presymptomatic to moderate disease stages, providing a robust, harmonized platform to define early biomarker signatures and endpoints for targeted VCID therapies.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.20.26363512","type":"posted-content","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:25:24Z","timestamp":1790097924000},"source":"Crossref","is-referenced-by-count":1,"title":["The United States CADASIL Consortium: Baseline Findings from a Natural History Study"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0983-228X","authenticated-orcid":false,"given":"Jane S.","family":"Paulsen","sequence":"first","affiliation":[{"name":"University of Wisconsin\u2013Madison, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8523-3361","authenticated-orcid":false,"given":"H. Jeremy","family":"Bockholt","sequence":"additional","affiliation":[{"name":"Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory University, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5608-3808","authenticated-orcid":false,"given":"William H.","family":"Adams","sequence":"additional","affiliation":[{"name":"Loyola University Chicago, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5200-9678","authenticated-orcid":false,"given":"Deven K.","family":"Burks","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2013Madison, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3191-262X","authenticated-orcid":false,"given":"Jennifer J.","family":"Majersik","sequence":"additional","affiliation":[{"name":"The University of Utah, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2631-0942","authenticated-orcid":false,"given":"Stephen P.","family":"Salloway","sequence":"additional","affiliation":[{"name":"Butler Hospital, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6003-2336","authenticated-orcid":false,"given":"Songmi","family":"Lee","sequence":"additional","affiliation":[{"name":"University of Texas Health Science Center at Houston, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0677-8158","authenticated-orcid":false,"given":"Myriam","family":"Fornage","sequence":"additional","affiliation":[{"name":"University of Texas Health Science Center at Houston, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0468-8271","authenticated-orcid":false,"given":"Cara","family":"Joyce","sequence":"additional","affiliation":[{"name":"Loyola University Chicago, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2356-4138","authenticated-orcid":false,"given":"Jamie L.","family":"Elliott","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2013Madison, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8295-5884","authenticated-orcid":false,"given":"Edward D.","family":"Huey","sequence":"additional","affiliation":[{"name":"Butler Hospital, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5129-3547","authenticated-orcid":false,"given":"Megan R.","family":"Caruso","sequence":"additional","affiliation":[{"name":"Butler Hospital, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3164-9665","authenticated-orcid":false,"given":"Suman","family":"Jayadev","sequence":"additional","affiliation":[{"name":"University of Washington, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7791-0462","authenticated-orcid":false,"given":"Jos\u00e9","family":"Biller","sequence":"additional","affiliation":[{"name":"Loyola University Chicago, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8519-7652","authenticated-orcid":false,"given":"Helmi L.","family":"Lutsep","sequence":"additional","affiliation":[{"name":"Oregon Health & Science University, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3413-5141","authenticated-orcid":false,"given":"Sara J.","family":"Doyle","sequence":"additional","affiliation":[{"name":"University of Texas Health Science Center at San Antonio, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5109-8736","authenticated-orcid":false,"given":"David S.","family":"Liebeskind","sequence":"additional","affiliation":[{"name":"University of Southern California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1120-2797","authenticated-orcid":false,"given":"Kelsey","family":"Eklund","sequence":"additional","affiliation":[{"name":"University of Colorado, Anschutz, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4228-7500","authenticated-orcid":false,"given":"Imama A.","family":"Naqvi","sequence":"additional","affiliation":[{"name":"Columbia University, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0193-6217","authenticated-orcid":false,"given":"Arash","family":"Salardini","sequence":"additional","affiliation":[{"name":"University of Texas Health Science Center at San Antonio, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6135-2622","authenticated-orcid":false,"given":"Sudha","family":"Seshadri","sequence":"additional","affiliation":[{"name":"University of Texas Health Science Center at San Antonio, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0872-5044","authenticated-orcid":false,"given":"Jason D.","family":"Hinman","sequence":"additional","affiliation":[{"name":"David Geffen School of Medicine, University of California, Los Angeles, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3899-9510","authenticated-orcid":false,"given":"Lisa C.","family":"Krishnamurthy","sequence":"additional","affiliation":[{"name":"Emory University, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara L.","family":"Fischer","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2013Madison, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2861-3776","authenticated-orcid":false,"given":"Michael D.","family":"Geschwind","sequence":"additional","affiliation":[{"name":"University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the United States CADASIL Consortiusm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092522250684000_2026.09.20.26363512v2.1","doi-asserted-by":"publisher","DOI":"10.1161\/STR.0000000000000494"},{"key":"2026092522250684000_2026.09.20.26363512v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2025.11.008"},{"key":"2026092522250684000_2026.09.20.26363512v2.3","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000214113"},{"key":"2026092522250684000_2026.09.20.26363512v2.4","doi-asserted-by":"publisher","DOI":"10.1002\/ana.78040"},{"key":"2026092522250684000_2026.09.20.26363512v2.5","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-017-0778-8"},{"key":"2026092522250684000_2026.09.20.26363512v2.6","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(09)70127-9"},{"key":"2026092522250684000_2026.09.20.26363512v2.7","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2025.1662012"},{"key":"2026092522250684000_2026.09.20.26363512v2.8","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac486"},{"key":"2026092522250684000_2026.09.20.26363512v2.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0088-3"},{"key":"2026092522250684000_2026.09.20.26363512v2.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cccb.2023.100195"},{"key":"2026092522250684000_2026.09.20.26363512v2.11","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2020-325838"},{"key":"2026092522250684000_2026.09.20.26363512v2.12","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.344"},{"key":"2026092522250684000_2026.09.20.26363512v2.13","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008700"},{"key":"2026092522250684000_2026.09.20.26363512v2.14","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.c3666"},{"key":"2026092522250684000_2026.09.20.26363512v2.15","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-147-8-200710160-00010"},{"key":"2026092522250684000_2026.09.20.26363512v2.16","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12216"},{"key":"2026092522250684000_2026.09.20.26363512v2.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2016.10.006"},{"key":"2026092522250684000_2026.09.20.26363512v2.18","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00131-X"},{"key":"2026092522250684000_2026.09.20.26363512v2.19","unstructured":"Dwass M. Some k-Sample Rank-Order Tests. In: Olkin I , Ghurye SG , Hoeffding W , Madow WG , Mann HB , eds. Contributions to probability and statistics: essays in honor of Harold Hotelling. Stanford University Press; 1960:198\u2013202."},{"key":"2026092522250684000_2026.09.20.26363512v2.20","doi-asserted-by":"publisher","DOI":"10.2307\/1266545"},{"key":"2026092522250684000_2026.09.20.26363512v2.21","doi-asserted-by":"publisher","DOI":"10.1080\/03610929108830487"},{"key":"2026092522250684000_2026.09.20.26363512v2.22","unstructured":"University of Wisconsin School of Medicine and Public Health. Data from: Area Deprivation Index v. 4.0. 2026."},{"key":"2026092522250684000_2026.09.20.26363512v2.23","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.7559"},{"key":"2026092522250684000_2026.09.20.26363512v2.24","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2025.12289"},{"key":"2026092522250684000_2026.09.20.26363512v2.25","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/1965394"},{"key":"2026092522250684000_2026.09.20.26363512v2.26","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.2005.53221.x"},{"key":"2026092522250684000_2026.09.20.26363512v2.27","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.43.11.2412"},{"key":"2026092522250684000_2026.09.20.26363512v2.28","doi-asserted-by":"publisher","DOI":"10.1176\/appi.neuropsych.12.2.233"},{"key":"2026092522250684000_2026.09.20.26363512v2.29","doi-asserted-by":"publisher","DOI":"10.1111\/j.1753-4887.1996.tb03793.x"},{"key":"2026092522250684000_2026.09.20.26363512v2.30","unstructured":"Vellas BJ , Campbell AJ , eds. The Mini Nutritional Assessment, MNA: Nutrition in the Elderly. 2 ed. Serdi; 1994."},{"key":"2026092522250684000_2026.09.20.26363512v2.31","unstructured":"Facts and Research in Gerontology; vol Supplement 2."},{"key":"2026092522250684000_2026.09.20.26363512v2.32","unstructured":"World Health Organization . Global Physical Activity Questionnaire (GPAQ) Analysis Guide. World Health Organization; 2010."},{"key":"2026092522250684000_2026.09.20.26363512v2.33","unstructured":"Agresti A. Categorical Data Analysis. 3rd ed. Wiley; 2013."},{"key":"2026092522250684000_2026.09.20.26363512v2.34","doi-asserted-by":"publisher","DOI":"10.1080\/09602011.2016.1231121"},{"key":"2026092522250684000_2026.09.20.26363512v2.35","doi-asserted-by":"publisher","DOI":"10.1016\/0895-4356(94)90129-5"},{"key":"2026092522250684000_2026.09.20.26363512v2.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cccb.2023.100170"},{"key":"2026092522250684000_2026.09.20.26363512v2.37","doi-asserted-by":"publisher","DOI":"10.1097\/NRL.0000000000000478"},{"key":"2026092522250684000_2026.09.20.26363512v2.38","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2023.1203985"},{"key":"2026092522250684000_2026.09.20.26363512v2.39","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000200744"},{"key":"2026092522250684000_2026.09.20.26363512v2.40","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000200353"},{"key":"2026092522250684000_2026.09.20.26363512v2.41","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0136501"},{"key":"2026092522250684000_2026.09.20.26363512v2.42","doi-asserted-by":"publisher","DOI":"10.1111\/cns.13917"},{"key":"2026092522250684000_2026.09.20.26363512v2.43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0157613"},{"key":"2026092522250684000_2026.09.20.26363512v2.44","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.120.030343"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.20.26363512","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:25:13Z","timestamp":1790400313000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.09.20.26363512"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":44,"URL":"https:\/\/doi.org\/10.64898\/2026.09.20.26363512","relation":{},"subject":[],"published":{"date-parts":[[2026,9,22]]},"subtype":"preprint"}}