Cerebral Microbleeds in CADASIL

Abstract

Background and Purpose-An increased frequency of clinically silent microbleeds (MB) has recently been observed in patients with sporadic small-vessel disease related to vascular amyloid deposition or hypertension. In this study, we searched for cerebral MBs in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a unique type of small-vessel disease caused by mutations in the Notch3 gene. Our purposes were (1) to determine the frequency, extent, and pattern of MBs in CADASIL; (2) to analyze the relationship between MBs and T2-hyperintense lesions; and (3) to evaluate the histopathology of brain tissue affected by MBs. Methods-Gradient-echo, T2/PD-weighted dual-echo, and T1-weighted MRI scans of the brain were obtained from 16 consecutive CADASIL subjects and 16 age-matched control subjects. T2-lesion volume measurements were made with a semiautomated segmentation technique based on local thresholding. Postmortem examinations were performed on the brains of 7 additional CADASIL subjects. Results-Focal areas of signal loss on gradient-echo images suggesting past MBs were found in 11 CADASIL individuals (69%) and no control subjects (PϽ0.001). The average number of MBs was 5.9Ϯ7.3 (range, 0 to 22) in individual CADASIL patients. MBs were associated with age (rϭ0.71, Pϭ0.002) and total lesion volume (rϭ0.75, Pϭ0.001). However, after correction for age, the correlation with lesion volume was no longer significant. MBs were located simultaneously in various parts of the brain with a preference for cortical-subcortical regions (38%), white matter (20%), thalamus (13%), and brainstem (14%). Eighty-two percent of the MBs were located outside areas appearing hyperintense on T2-weighted images. Postmortem examination revealed focal accumulations of hemosiderin-containing macrophages in 6 of the 7 brains (86%). They were always found outside ischemic lesions. Key Words: angiopathy Ⅲ CADASIL Ⅲ echo-planar imaging Ⅲ intracerebral hemorrhage C erebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease of small blood vessels caused by mutations in the Notch3 gene. 1,2 Clinical manifestations include recurrent ischemic episodes, cognitive deficits, and migraine mostly with aura, as well as psychiatric disorders. 3,4 There have been single reports of intracerebral hemorrhages (ICHs), 5,6 but the meaning of these observations remains unclear given the absence of ICH in large patient series. 3,4 MRIs show lacunar infarcts and less well demarcated subcortical T2 hyperintensities that may show different degrees of hypointensity on T1-weighted scans. 7-9 These alterations are caused by a unique type of nonarteriosclerotic, amyloid-negative angiopathy involving small arteries and capillaries primarily in the brain but also in other organs. 10 Ultrastructural examination reveals characteristic granular osmiophilic material within the vascular basal lamina, which is often seen in close association with vascular smooth muscle ...

Significance of the T2*-weighted gradient echo brain imaging in patients with infective endocarditis

“…Brain T2*-weighted MR imaging has been reported to demonstrate various etiologies of hypointense spots, which result from the deposition of hemosiderin (old hemorrhage), ferritin, calcium, the presence of other metallic materials and air [15]. It could also detect remnants of previous cerebral microbleeds (MBs) [16][17][18], which are usually defined as small, round, foci distinct from vascular flow voids, leptomeningeal hemosiderosis, and nonhemorrhagic subcortical mineralization [19]. MBs are considered as a general marker of microvascular vulnerability with the incidence of 3.1-6.4% [19,20] in healthy individuals, and 56% [21] in hypertensive patients.…”

CADASIL: pathogenesis, clinical and radiological findings and treatment

“…This vision has been, however, challenged, with case series referring up to 25% of patients with CADASIL with symptomatic hemorrhage 67 . Asymptomatic microbleeds (predominantly in the thalamus, basal ganglia and brainstem) are even more common, and seem to increase in incidence with advancing age of the patients [67][68][69] (Fig 2). Predisposing factors for cerebral bleeding are poorly understood but may include, in addition to microhemorrhages, the extent of white matter changes and ischemic lesion burden, the use of antiplatelet agents, disturbances in glucose metabolism and hypertension 68,70 .…”

Differences in proliferation rate between CADASIL and control vascular smooth muscle cells are related to increased TGFβ expression

“…In CADASIL, the outer layer of the vessels consisting of VSMCs becomes thinner, while the endothelial layer that is surrounded by the VSMCs becomes swollen and loses its integrity due to gap junction loss 25, 26. This leads to microbleeds, occlusion and/or thrombosis 27, 28…”