An observational study in CADASIL, sponsored by University of Wisconsin, Madison. Recruiting at 12 sites in United States. Open to participants aged 18 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-01-15.
Sponsored by University of Wisconsin, Madison · Observational
This is an observational study to better understand the risk factors and progression of CADASIL, a leading cause of vascular cognitive impairment and dementia (VCID). 575 participants will be enrolled and can expect to be on study for up to 5 years.
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common monogenic vascular dementia. Individuals with CADASIL are destined to develop vascular cognitive impairment and dementia (VCID), which can be studied in pre-symptomatic and prodromal disease stages to detect the earliest changes in biological fluids, neuroimaging, and the emerging phenotype of symptomatic VCID.
The objective of the proposed research is to exploit an autosomal dominant vascular dementia as a model to investigate specific features of VCID and to examine interactions with risk factors impacting the aging life course.
The study will enroll a total of 575 participants with a CADASIL family history who have had a genetic test for a NOTCH3 variant. Participants will complete: a clinical interview, a neurological exam, neurocognitive and behavior assessments, MRI, and a blood draw at each study visit. Participants will complete 3 in-person visits in total as part of this study: baseline, visit 2 (18 months after baseline), visit 3 (36 months after baseline). Additional contact will occur by phone, mail, email or the internet as needed and will be referred to as "remote visits".
33 studies on the registry are indexed under CADASIL; 18 are open to participants now.
This study's planned enrollment of 660 is above the median of 168 across 22 observational studies indexed under CADASIL.
Browse CADASIL studies →University of Wisconsin, Madison is the lead sponsor of 1,188 studies on the registry; 181 are open to participants now.
Of its 157 completed or terminated interventional studies of FDA-regulated products, 118 (75%) have results posted.
Counted across the registry records on this site, refreshed daily.
The study will enroll a total of 500 participants with a CADASIL family history who have had a genetic test for a NOTCH3 variant.
All ethnicities, sexes and ages throughout the adult lifespan will be recruited. CADASIL research participants will be recruited across the earlier part of the disease spectrum from pre-symptomatic (no symptoms or signs) through the prodromal phase (having symptoms and signs without significant functional decline) to varying levels of early dementia or mild to moderate functional impairment.
Inclusion Criteria for CADASIL Participants:
Willing to provide documentation of all current medications to study team
a. All medications will be allowed throughout the course of study. Documentation of medications will be used for analyses to assess potential impact of medications on study outcomes.
Must have a designated "study companion"
a. A "study companion" is someone who knows the participant well (has greater than or equal to 3 hours/month of contact with the CADASIL participant) and can provide additional information to the study team (either remotely or in-person).
Inclusion Criteria for Healthy Controls (HC):
1. Must meet same criteria as CADASIL participants, EXCEPT have negative NOTCH3 genetic testing
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
About 100 participants who are at-risk, healthy family members with No NOTCH3 Mutation and no symptoms or signs of cognitive decline.
Other: Study Procedures
About 133 participants who are pre-symptomatic, at-risk, and healthy (with verified NOTCH3 mutation) family members with no symptoms.
Other: Study Procedures
About 134 participants who are symptomatic (with verified NOTCH3 mutation) family members and no functional decline (e.g., mild cognitive impairment (MCI) with premorbid functional levels maintained).
Other: Study Procedures
About 133 participants who are symptomatic family members with a verified NOTCH3 CADASIL mutation and evidence of functional decline consistent with early dementia.
Other: Study Procedures
Participants will experience * Neurocognitive Tests and Self-Report Measures * Clinical Interviews * Neurological Exam * MRI screening at baseline, 18 months, 36 months * Fasted Blood draw
Performance Measured by Change in Cognitive Executive Function Composite Z-Score
A composite Cognitive Executive Function Score will be reported based on data from two electronic assessments (Favorites and Match). Favorites tests both episodic and associative memory and consists of 2 learning trials followed by an immediate recall trial, 10 minute delayed recall, and delayed recognition trials. The Match assessment tests the processing speed and executive functions. The primary performance metric is the total correct score in 2 minutes. Scores are reported on a continuous scale with greater values indicating better performance. Demographically adjusted regression based z score for Favorites Total Recall and Match Total Correct are calculated to produce the composite score.
Time frame: baseline and 36 months
Change in total brain volume between baseline and 36 months
MRI structural integrity is measured using available analytic packages as well as newly validated outcome measures from the investigator's imaging core. MRI outcomes will reflect changes in the total brain volume from two time points. Less volumes will reflect greater brain loss and greater change over time will suggest a more rapid rate of progression.
Time frame: baseline and 36 months
Change in total cerebral spinal volume between baseline and 36 months
MRI structural integrity is measured using available analytic packages as well as newly validated outcome measures from the investigator's imaging core. MRI outcomes will reflect changes in the total cerebral spinal fluid volume from two time points. Less volumes will reflect greater brain loss and greater change over time will suggest a more rapid rate of progression.
Time frame: baseline and 36 months
Percent change in brain connectivity from baseline to 36 months
MRI functional integrity is measured using available analytic packages as well as newly validated outcome measures from the investigator's imaging core. MRI outcomes will reflect the strength of connectivity among different areas of the brain. Levels of connectivity will be associated with cognitive performances. Greater connectivity is associated with better cognition.
Time frame: baseline and 36 months
Change in Neurofilament Light (Nfl)
Blood will be analyzed using validated assays to measure the amount of NfL. Greater levels of NfL reflect worsened brain atrophy and change over time will demonstrate worsening over time.
Time frame: baseline and 36 months
Change in World Health Organization Disability Assessment Schedule (WHODAS) Score
Functional capacity is assessed using the WHODAS instrument. The measure consists of 12 items and allows responses on a 5-point scale for each item, the total possible range of scores is converted to 0-100 where 0 is no disability and 100 is full disability. The change in total WHODAS score from baseline to 36 months will show the rate of progression in loss of capacity.
Time frame: baseline and 36 months
Change in CADASIL Severity Score
CADASIL severity is determined using established disease-specific scales involving the frequency, severity, and duration of clinical signs and symptoms of CADASIL. The CADASIL scale is a 12-item scale of CADASIL symptoms and signs. Each item is given a weighted score according to a large sample of patients in Europe. A summary of all items is the total CADASIL score which can range from 0-25. Higher scores represent greater CADASIL severity. Change in total score from baseline to 36 months is used to measure the rate of symptomatic worsening or improvements over time.
Time frame: baseline and 36 months
Age of Disease Onset
Date of disease onset is determined by family and medical history and self-, proxy- and clinician-reported symptoms and signs. Earlier disease onset will suggest worsened burden for the participant.
Time frame: baseline
NOTCH3 variant characteristics
There are various methods used to define the NOTCH3 variations: Specific mutations are documented in available databases and hypothesis testing will include those with and without a cysteine residue and the location of variant as determined by the 34 epidermal growth factor-like repeat domains (EGFrs). Participants will gene mutations in exons 1-6 are expected to demonstrate worsened cognition, MRI abnormality, biofluid NfL marker, functional capacity and symptomatic severity than participants having gene mutation in exons 7-34.
Time frame: baseline
Frequency of NOTCH2 CADASIL Genetic Variations associated with VCID
All mutations in the NOTCH3 CADASIL gene will be characterized and the frequency of each mutation will be tallied. Gene mutations that are present for the most participants will be determined.
Time frame: baseline
Polygenic Risk Score (PRS)
Polygenic risk scores (PRS) for cerebral small vessel disease and dementia will be derived for each participant. We will derive PRSs for phenotypes in the data, such as worsened white matter hyperintensities or disabling headache. The best-fit PRS for each phenotype will be used to address how the PRS may impact the association of NOTCH3 canonical mutations with clinical, neuroimaging, and fluid markers of CADASIL and whether PRSs will add information to a predictive risk model to inform management of CADASIL.
Time frame: baseline
Statistical Analysis of Risk Factors that Modify Clinical Meaningful Outcomes
Lifestyle risk factors for VCID (e.g., inactivity, obesity, heavy alcohol use, smoking, SES) and comorbid health conditions (e.g., hypertension, hyperlipidemia, hypercholesterolemia, atrial fibrillation, diabetes) may contribute to disease outcomes.
Time frame: baseline
Plan to share: Yes — All clinical research data collected as part of this study will be stored in a designated NIH database such as the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) NIA Genetic and for sharing with approved researchers worldwide. Summaries of studies and the contents of measured variables as well as original study document text are generally available to the public, while access to individual-level data including phenotypic data tables and genotypes require varying levels of authorization. Data to be de-identified such that the identities of data subjects cannot be readily ascertained or otherwise associated with the data by the repository staff or secondary data users.
Supporting information: Study protocol, Statistical analysis plan, Informed consent form, Clinical study report
Time frame: De-identified data will be shared with the research community one year following the end of the research study.
Access criteria: Data sharing will be granted to persons with appropriate scientific and professional expertise to advance knowledge of CADASIL.
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