Development and Validation of a Functional MRI Biomarker of Cerebral Small Vessel Dysfunction in CADASIL

NCT06859658 | Not Yet Recruiting

• 1 other identifier: APHP240772
• Study Type: observational
• Target: 70
• Locations: 0 countries
• Sites: N/A

Brief Summary

Cerebral small vessel diseases (cSVD) are diseases of brain tissue involving vessels (arterioles or capillaries) with a diameter of less than 400 microns. Within this group, CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is the most common familial form. CADASIL is due to mutations in the NOTCH3 gene located on chromosome 19. It is considered a unique model for the study of cSVD. CADASIL begins between the ages of 20 and 40, with the appearance of cerebral white matter hyper-signals visible on MRI. Before the age of 30, patients are usually asymptomatic. To date, there are no available treatments. To test new therapeutic approaches, we need biomarkers that are robust and sensitive enough to assess the effects of these treatments at an early stage of cSVD and over a relatively short period of time. An ideal monitoring biomarker should be repeatedly and safely usable, easily accessible, accurate, reproducible and sensitive to disease progression or pharmacological intervention. Alterations in neurovascular coupling (NVC) have been recognized as one of the earliest functional alterations occurring during cSVD. Cerebral functional magnetic resonance imaging (fMRI) is a brain imaging technique that measures the activity of brain areas in vivo by detecting local changes in blood flow. An important advantage of blood oxygen level-dependent functional MRI is that it enables the NVC to be probed in vivo, safely and repeatedly in humans. Our central hypothesis is that functional MRI can provide such a biomarker for monitoring CNV disease progression in vivo using a dedicated fMRI protocol that can be used on a clinical MRI scanner, is reproducible and varies according to the severity of brain MRI lesions and/or clinical manifestations in CADASIL. A functional imaging study coupled with electroencephalogram has already revealed changes in the hemodynamic response to visual or motor stimuli in patients at the early stage of the disease. This study is exploring new imaging protocols to focus on the purest vascular response.

Conditions

CADASIL

Keywords

fMRI; Cerebral Small Vessel Diseases; Neurovascular coupling; CADASIL; Biomarkers

Outcome Measures

Primary Outcomes (2)

• Variation in BOLD response

  Variation in BOLD response on functional MRI during short-duration visual stimuli (area under the curve) and parameters derived from this response curve at the calcarine scissure For all patients and controls

  At inclusion

• Variation in BOLD response

  Variation in BOLD response on functional MRI during short-duration visual stimuli (area under the curve) and parameters derived from this response curve at the calcarine scissure For CADASIL patients

  At 2 years

Secondary Outcomes (11)

• Correlations between parameters derived from the response curve and age

  Up to 2 years

• Correlations between parameters derived from the response curve and gender

  Up to 2 years

• Correlations between parameters derived from the response curve and cardiovascular risk factors

  Up to 2 years

• Correlations between parameters derived from the response curve and modified Rankin score

  Up to 2 years

• Correlations between parameters derived from the response curve and stroke frequency

  Up to 2 years

Study Arms (3)

Control group

Radiation: Functional MRI at 3T

CADASIL patients with no disability or significant cognitive deficit

Radiation: Functional MRI at 3T

CADASIL Patients with mild to moderate disability or with a moderate cognitive deficit

Radiation: Functional MRI at 3T

Interventions

Functional MRI at 3T RADIATION

At inclusion

Control group

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with a known mutation in the NOTCH3 gene

You may qualify if:

• For CADASIL patients
• Diagnosis confirmed by detection of a pathogenic mutation in the NOTCH3 gene characteristic of CADASIL.
• Beneficiaries of a health insurance.
• Written consent.
• For controls:
• Beneficiary of a health insurance.
• Written consent

You may not qualify if:

• For patients
• Contraindication to MRI examination
• Disability: Rankin score ≥ 4
• Moderate to severe dementia according to DSM 5 criteria or MMSE score ≤ 19
• Person covered by articles L. 1121-5 to L. 1121-8 and L. 1122-12 of the French Public Health Code, defined by :
• Pregnant, parturient or breast-feeding woman
• Person deprived of liberty by judicial or administrative decision.
• Persons hospitalized without consent and not under legal protection, and persons admitted to a health or social establishment for purposes other than research.
• Minor
• Person of full age subject to a legal protection measure (guardianship, curatorship or safeguard of justice), person of full age unable to give consent and not subject to a protection measure.
• For controls :
• Contraindication to MRI examination
• Known cognitive complaint or deficit
• Presence of significant disability (mRS \>1)
• Focal neurological motor, sensory or visual deficit on clinical examination that may impair visual or motor stimulation tests

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

MeSH Terms

Conditions

CADASIL; Cerebral Small Vessel Diseases

Condition Hierarchy (Ancestors)

Cerebral Infarction; Brain Infarction; Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia, Vascular; Cerebral Arterial Diseases; Intracranial Arterial Diseases; Stroke; Dementia; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis

Central Study Contacts

Hugues Chabriat, MD PhD

CONTACT

+33 1 49 95 25 93; hugues.chabriat@aphp.fr

Jérôme Lambert, MD PhD

CONTACT

+33 1 42 49 97 42; jerome.lambert@u-paris.fr

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 28, 2025
• First Posted: March 5, 2025
• Study Start: April 1, 2025
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): April 1, 2029
• Last Updated: March 5, 2025

Record last verified: 2025-02