Neuropsychiatric Symptom Associations with NOTCH3 Genotype in the United States CADASIL Consortium
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Background and objectives 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 NOTCH3 variants and non-carrier biological family controls in the United States CADASIL Consortium (USCC). Methods 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 NOTCH3 variants and compared with controls. Results 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. Discussion 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. Trial Registration Information: The study is registered at ClinicalTrials.gov ( NCT05677880 , 12/12/2022).
Source: medRxiv
Authors: Megan R. Caruso, Barbara L. Fischer, William H. Adams, Deven K. Burks, Bianca Le, Arash Salardini, Jennifer J. Majersik, Stephen P. Salloway, Jamie L. Elliott, H. Jeremy Bockholt, Suman Jayadev, Michael D. Geschwind, José Biller, Helmi L. Lutsep, Sara J. Doyle, Jason D. Hinman, David S. Liebeskind, Imama A. Naqvi, Kelsey Eklund, Sudha Seshadri, Lisa C. Krishnamurthy, Myriam Fornage, Jane S. Paulsen, Edward D. Huey
Institutions: Butler Hospital, University of Wisconsin–Madison, Loyola University Chicago, University of Washington, The University of Texas at San Antonio Health Science Center, University of Utah, Georgia Institute of Technology, Emory University, Georgia State University, Center for Translational Research in Neuroimaging and Data Science, University of California, San Francisco, Oregon Health & Science University, University of California, Los Angeles, University of Southern California, Columbia University, University of Colorado Anschutz, The University of Texas Health Science Center at Houston
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Institute on Aging
OpenAlex ID: W7214979341