Clinical Significance of Cerebral Microbleeds Locations in CADASIL with R544C NOTCH3 Mutation

Abstract

Background and PurposeAlthough cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common single-gene disorder of cerebral small blood vessels caused by NOTCH3 mutations, little has been described about the variation in the clinical findings between its underlying types of mutations. In particular, the presence of cerebral microbleeds (CMBs) has been an increasingly recognized magnetic resonance imaging finding in CADASIL, but their clinical significance is not clear. The purpose of this study is to assess whether CMBs are associated with symptomatic stroke in the CADASIL patients with R544C mutation and to compare the cerebral distribution of CMBs between CADASIL patients with and without symptomatic stroke.MethodsThis is a cohort study of patients who were diagnosed with genotype-confirmed R544C-mutation CADASIL. Primary neurologic symptoms were recorded. Symptomatic strokes were defined as transient ischemic attack, ischemic strokes and hemorrhagic strokes. CMBs were defined as focal areas of round signal loss on T2*-weighted gradient echo planar images with a diameter of less than 10 mm. The locations of CMBs were divided into lobar, basal ganglia, thalamus, brain stem and cerebellum. Multiple logistic regressions were performed to identify the epidemiologic or vascular risk factors associated with symptomatic stroke in patients with CADASIL.ResultsAmong total of 51 subjects in this cohort, CMBs were present in 20 of 32 patients (64.5%) in the symptomatic stroke-group and in 8 of 19 patients (42.1%) in the non-stroke group (p = 0.16). CMBs were observed more frequently in the basal ganglia (p<0.001) and the cerebellum (p<0.018) in the symptomatic stoke group compared to the non-stroke group. The mean number of CMBs was significantly higher in the symptomatic stroke group (15.4±18.0 lesions per patients with CMBs) versus those without symptomatic stroke (3.3±3.0 lesions per patients with CMBs) (p = 0.003). Hypertension was an independent risk factor for symptomatic stroke in CADASIL (p = 0.014). It was independently associated with CMBs locations as basal ganglia (p = 0.016), thalamus (p = 0.010), brainstem (p = 0.044), and cerebellum (p = 0.049). However, It was not independently associated with CMBs on lobar lesion (p = 0.152).ConclusionsIn this study hypertension was an independent predictor of CMBs presence in specific brain locations, as well as symptomatic stroke in the CADASIL patients. The distribution and burden of CMBs might be a clinically useful marker for the risk of symptomatic stroke. However, further prospective studies on the relationship between CMBs distribution and symptomatic stroke are required in order to support these preliminary findings.

Notch Signaling in Development, Tissue Homeostasis, and Disease

“…Not only VSMC but also pericytes may be affected in CADASIL, as recent data show that pericytes accumulate GOM in CADASIL patients (229), and in keeping with a perturbed pericyte function, small hemorrhages are observed in CADASIL patients (399). Furthermore, some of the effects observed in the Notch3 Ϫ/Ϫ ; Notch1 ϩ/Ϫ mice may be linked to dysregulated pericytes (355).…”

Age-Related Spatial Distribution of Cerebral Microbleeds in Patients with CADASIL

“…Unlike in an earlier study 4 in which we found a significant difference in the number of lobar CMB between patients aged ≥60 years and those aged <60 years but not in the number of deep or infra-tentorial CMB, our more recent results demonstrated no association between age and presence of lobar CMB. 3 This discrepancy may in part reflect the different assessment methods used in the two mentioned studies. First, we have now used more sensitive MRI techniques to detect CMBs than those used previously: the effects of MRI sequences (traditional T2*-weighted gradient echo vs. SWI); section thickness (5 mm vs. 2 mm); and field strength (1.5 tesla vs. 3 tesla).…”

“…Second, in the present study, we used the MARS 10 system to calculate CMB. However, in our previous study, 3 we divided CMBs into five groups according to brain location (cortical-subcortical, basal ganglia, thalamus, brain stem, and cer-ebellum) and then calculated the number of CMBs. In addition, SWI, smaller section thickness, and a higher magnetic field are known to increase the number of CMBs detected.…”

“…2 Moreover, CADASIL predisposes to the development of cerebral microbleeds (CMB). 3,4 CMB are well defined brain lesions that are demonstrable on magnetic resonance imaging (MRI) and consist of tiny hemosiderin deposits surrounding macrophages adjacent to the abnormal small vessel. They are detectable using T2*-weighted gradient echo or susceptibility-weighted imaging (SWI).…”

Microvascular Lesions at the Bottom of the Brain: New Neuropathological Insights

“…Some clinically relevant data can also be extrapolated from other more 'pure' clinical cohorts. For example, in CADASIL, a 'pure' form of small vessel disease and vascular dementia (with affected individuals progressing to dementia at 40-60 years of age), the presence of coexistent Alzheimer's disease pathology and CAA in unlikely: microbleeds frequently occur in the cerebellum and are associated with symptomatic stroke presentation [10,11] .…”