development and validation of a functional mri biomarker of cerebral small vessel dysfunction in cadasil

Conditions: CADASIL

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.


Eligibility criteria:
inclusion criteria : for cadasil patients * age between 18 and 80 at the time of inclusion * diagnosis confirmed by detection of a pathogenic mutation in the notch3 gene characteristic of cadasil. * beneficiaries of a health insurance. * written consent. for controls: * age between 18 and 80 at the time of inclusion * beneficiary of a health insurance. * written consent exclusion criteria : 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. * person subject to a period of exclusion for another research project 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 * history of neurological or psychiatric disease * history of migraine attacks with aura * vascular history (known disease of peripheral arteries, heart or brain) * known or treated diabetes * known or treated hypercholesterolemia * known or treated hypertension * active smoking or smoking cessation within the last year * regular alcohol consumption corresponding to \> 2 glasses/day for men and 1 glass/day for women in wine equivalent * treatment likely to interfere with neurovascular coupling (in particular any treatment with non-steroidal anti-inflammatory drugs, psychotropic drug(s), antihypertensive drug(s) or statins) * 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 institution 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. * person subject to a period of exclusion for another research project

Keywords: fmri cerebral small vessel diseases neurovascular coupling cadasil biomarkers