{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:02:38Z","timestamp":1791201758704,"version":"4.2.0"},"posted":{"date-parts":[[2026,9,30]]},"group-title":"Neurology","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"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":[[2026,9,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and objectives<\/jats:title>\n                  <jats:p>\n                    Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common monogenic cerebral small vessel disease. Though neuropsychiatric symptoms (NPS) of CADASIL profoundly impact function and quality of life, these symptoms remain understudied. This analysis characterizes the prevalence, severity, and profile of NPS among individuals with CADASIL-causing\n                    <jats:italic>NOTCH3<\/jats:italic>\n                    variants and non-carrier biological family controls in the United States CADASIL Consortium (USCC).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    This cross-sectional analysis used multimodal baseline data from 12 enrollment sites across the country. Statistical analyses used nonparametric tests and regression models to compare clinical and neuropsychiatric outcomes across CADASIL risk tiers and controls, adjusting for age, sex, race, and education where appropriate. The primary outcome measure was the Neuropsychiatric Inventory Questionnaire (NPI-Q), an informant-reported measure which assesses 12 categories of NPS. NPI-Q item severity and distress were evaluated for individuals with confirmed cysteine-altering pathogenic\n                    <jats:italic>NOTCH3<\/jats:italic>\n                    variants and compared with controls.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Four hundred fifty-nine USCC participants were included in the analytic cohort: 343 cases [256 high-risk (HR); 63 medium-risk (MR); 24 low-risk (LR)]; and 116 controls. Among participants with available NPI-Q data, at least one neuropsychiatric symptom was reported by 72.6% (n = 228\/314) of cases compared with 53.2% (n = 58\/109) of controls. Reported symptoms were more common among CADASIL cases than controls, occurring in 75.0%, 71.2%, and 72.7% of participants in the LR, MR, and HR groups, respectively, compared with 53.2% of controls. Compared with controls, participants in the MR group and HR group had higher NPI-Q severity scores. HR participants also had higher NPI-Q distress scores than controls.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>Our findings support the notion that NPS are an important clinical manifestation of CADASIL. Beyond previously reported symptoms, additional neuropsychiatric manifestations were identified. Given the higher burden and variability in the neuropsychiatric presentation of CADASIL, the relationships among neuropsychiatric, neurological, and patient-reported outcomes merit further investigation. The NPS profile may enhance the evaluation of the safety and efficacy of different treatments to target these symptoms for CADASIL patients.<\/jats:p>\n                  <jats:p>\n                    Trial Registration Information: The study is registered at ClinicalTrials.gov (\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05677880\">NCT05677880<\/jats:ext-link>\n                    , 12\/12\/2022).\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.24.26363718","type":"posted-content","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:55:15Z","timestamp":1790794515000},"source":"Crossref","is-referenced-by-count":0,"title":["Neuropsychiatric Symptom Associations with\n                  <i>NOTCH3<\/i>\n                  Genotype in the United States CADASIL Consortium"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5129-3547","authenticated-orcid":false,"given":"Megan R.","family":"Caruso","sequence":"first","affiliation":[{"name":"Butler Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara L.","family":"Fischer","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2013Madison"}],"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"}],"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Le","sequence":"additional","affiliation":[{"name":"University of Washington"}],"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"}],"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"}],"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"}],"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8523-3361","authenticated-orcid":false,"given":"H. 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