title: Magnetic resonance imaging in CADASIL and small vessel disease
Creators: name: Neilson, Samuel James
Publisher: name: University of Glasgow
Year: 2024

description: Introduction:

CADASIL is the most common monogenic cause of small vessel disease affecting the brain. CADASIL results in subcortical infarcts, dementia, and disability. Magnetic resonance imaging reveals often extensive white matter hyperintensities, multiple lacunes, cerebral microbleeds and enlarged perivascular spaces. These generally occur at a younger age and in the absence of conventional vascular risk factors when compared to sporadic small vessel disease. The location of the cysteine altering NOTCH3 variant on the EGFr domain is recognised as significant in determining disease progression and extent of imaging abnormalities. Other factors, that are not completely delineated, influence the rate of disease progression, and must account for the significant variation and unpredictable nature of this within CADASIL.

Methods:

We used conventional MRI and ultra-high field intensity MRI to further investigate the relationships between clinical and imaging features in CADASIL and make comparisons with sporadic cerebral small vessel disease. We updated the population data for CADASIL in Scotland to estimate the current disease prevalence. We used 7-Tesla MRI in people who have recently had a lacunar infarct to detect the susceptibility vessel sign on susceptibility-weighted imaging and correlated this with time-of-flight magnetic resonance imaging to confirm small vessel thrombotic occlusion. We quantified differences between 1.5, 3 and 7-Tesla MRI in this setting for detection of lacunes, cerebral microbleeds and enlarged perivascular spaces. We used 7-Tesla MRI in a human volunteer study to establish measurement of flow velocity in the lenticulostriate branches of the middle cerebral arteries as a surrogate measure of blood flow to the basal ganglia region.

Main results:

We estimated a disease prevalence of 2.76 per 100,000 based on clinical attendance at a national specialist clinic. The majority of people had a proximal genetic mutation with 59.7% mutations found at exon 4. The distribution of white matter hyperintensities, lacunes and cerebral microbleeds differed between CADASIL and sporadic small vessel disease. For white matter hyperintensities the anterior temporal pole and parietal lobe were significantly more commonly affected in CADASIL. Lacunes were more likely to be present in the temporal and frontal lobes, and cerebral microbleeds were more likely to be found in the thalamus and brainstem in CADASIL and there was a suggestion of more microbleeds in the internal capsule. MRI in CADASIL displays significantly larger volumes of white matter hyperintensities, and larger numbers of lacunes and cerebral microbleeds than in sporadic small vessel disease even when compared to an older cohort with more extensive co-morbidities. Our cohort continues the previous genetic pattern of proximal genetic mutations (EGFR 1 to 6) displaying more extensive white matter hyperintensities, lacunes and cerebral microbleeds and suffering from earlier onset of stroke, as compared to those with distal mutations (EGFR 7 to 34) who are more likely hypertensive. 7-Tesla MRI provides detailed images of cerebral microbleeds and may identify susceptibility vessel sign on relevant sequences. We have not been able to corroborate this by visualising an associated occluded vessel on time-of flight magnetic resonance angiography in any of the cases. We used these images to discover that 7-Tesla allows visualisation of higher numbers of enlarged perivascular spaces compared to 1.5 and 3-Tesla. We were able to use phase-contrast imaging at 7-Tesla to assess the flow velocity of lenticulostriate vessels which may serve as a correlate to cerebral blood flow measured using alternative methods.

Conclusions:

CADASIL is a rare small vessel disease with distinct imaging features. The extensive imaging abnormalities do not consistently correlate with extent of disability and symptom burden. Although there is increasing recognition of the genetic and clinical factors that influence outcome in CADASIL, there is a need to better understand the reasons behind and potential protective factors that cause such variable outcome. Further investigation of small vessel dysfunction and blood flow using ultra-high field strength will hopefully allow us to better understand these mechanisms, appreciate differences between genetic and sporadic small vessel disease and provide utility in investigating therapeutic interventions.