NOTCH3-associated small vessel disease
Conditions
Interventions
None listed
Sponsors
Klinische Genetica
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: For all participants in DiViNAS-II, the following inclusion criteria apply: o Is 20 years of age or older. o Is able to travel to the LUMC. o Is able to give informed consent. o Has participated in DiViNAS-I and/or has visited the CADASIL/CHA-clinic at the LUMC and/or has been recruited via a family member who has visited the LUMC. For the study sub-populations, there are additional inclusion criteria, as listed below: 1) DiViNAS-II CADASIL cohort o Has a confirmed NOTCH3 cysteine altering variant. 2) CADASIL-CSF cohort o Has a cysteine altering variant in exon 4 (EGFr 1-6) of the NOTCH3 gene 3) CADASIL-like hereditary-SVD cohort: o Has, or is a family member of a patient with, a pathogenic or likely pathogenic variant in one of the following hereditary SVD genes: CTSA or HTRA1 OR o Has, or is a family member of a patient with, a cerebral small vessel disease with unknown genetic aetiology with clear Mendelian inheritance in the pedigree, defined as follows: has clinical and neuroimaging features highly indicative of cerebral SVD, and has at least two affected family members, of whom the index patient and at least one first- or second degree family member have already had extensive clinical and genetic work-up at the CHA- clinic of the LUMC.
Exclusion criteria
Exclusion criteria: - Contra-indications for MRI-scan • Claustrophobia • Pacemakers and defibrillators • Nerve stimulators • Intracranial clips • Intraorbital or intraocular metallic fragments • Cochlear implants • Ferromagnetic implants • Hydrocephalus pump • Intra-uterine device (not all types) • Permanent make-up • Tattoos above the shoulders (only those older than 20 years) In CADASIL-CSF subgroup: 1. Contra-indications for lumbar puncture: • Known or possible raised intracranial pressure (ICP) with risk for cerebral herniation or intracranial tissue displacement (either clinically or as observed on MRI scan) • Occlusion of spinal canal • Thrombocytopenia or other bleeding diathesis including ongoing anticoagulant therapy • Local infection of the skin or suspected spinal epidural abscess • Lumbar neural tube defects 2. Presence of central nervous system disease other than CADASIL
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The occurrence and frequency of CADASIL-associated symptoms in the DiViNAS-II cohort will be assessed over the preceding 2 years (the duration of follow-up) and compared to data gathered in the DiViNAS-I study. In the case of new patients (either with rare CADASIL-like hereditary SVD or new CADASIL patients), all associated symptoms will be assessed over the entirety of the participant*s lifespan. Clinical end-points/parameters: - Number of strokes (and age at first stroke) during the 2 year follow-up period (or in the case of rare CADASIL-like hereditary SVD the other associated symptoms will be assessed over the entire lifespan) - Score on disability scale (mRS) - Scores on psychometric testing (TMT-A/B, Stroop) - Death Neuroimaging: - White matter hyperintensity volume (WMHv) - Lacune count and lacune volume - Cerebral atrophy | — |
Secondary
| Measure | Time frame |
|---|---|
| Clinical end-points/parameters TIA*s, migraines with- or without aura and other symptoms associated with CADASIL during the 2 year follow-up period (or in the case of rare CADASIL-like hereditary SVD the other associated symptoms will be assessed over the entire lifespan) Neuroimaging: - ASL - DTI - Microbleed count - Enlarged perivascular space count Vessel wall pathology markers (in skin biopsy): - NOTCH3 score [12] - GOM classification [7] Fluid biomarkers in serum and/or CSF (validation and discovery): - Neurofilament light chain - NOTCH3 - Vascular panels using commercial platforms e.g. O-link (https://www.olink.com) Retinal OCT(-A) measures: - Thickness of the Retinal Nerve Fiber Layer (RNFL) - Subfoveal Choroidal Thickness (SFCT) - Vessel density of the Deep Retinal Plexus (DRP) - Retinal vessel wall thickness - Arteriolar-to-venular diameter ratio (AVR) - Retinal perfusion measures Other study parameters include age, gender, level of education, current medical conditions and relevant medical history, medication, and cardiovascular risk factors (hypertension, hypercholesterolemia, diabetes mellitus type 2, daily intake alcohol/drugs, smoking, physical exercise, BMI). | — |
Countries
Netherlands
Outcome results
None listed