Arterial Changes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) in Relation to Pathogenesis of Diffuse Myelin Loss of Cerebral White Matter

Abstract

Background and Purpose-There is little information regarding the pathogenesis underlying diffuse myelin loss in the cerebral white matter and sparing of the U fibers in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), in which the medial smooth muscle cells of systemic arteries are characteristically involved. We sought to examine the precise extent and severity of changes in the cerebral arteries in an autopsy case of CADASIL in relation to pathogenesis of the diffuse myelin loss. Methods-We reconstructed 1000 serial sections of the frontal cerebral medullary arteries of an autopsy subject, which was the first identified Japanese case of CADASIL, as confirmed by the presence of ultrastructural deposits of granular osmiophilic material in the media of some visceral arteries and by genetic analysis. Results-We reconstructed 11 medullary arteries of the frontal lobe showing diffuse myelin loss and atrophy of the white matter with sparing of the U fibers. All of these showed complete loss of medial smooth muscle cells over their entire length and severe adventitial fibrosis. Although intimal fibrosis or hyalinosis was present, luminal occlusion was scarce. These changes were also observed in the small and large arachnoidal arteries but were relatively mild in the latter and in the cortical and subcortical medullary arteries. Conclusions-These arterial changes resulted in transformation of the cerebral arteries, in particular almost all the medullary arteries, to a so-called earthen pipe state. This supports the reported findings of a reduction in vascular reactivity to fluctuations in CO 2 levels and systemic blood pressure in CADASIL.

Scanning Laser Doppler Flowmetry Shows Reduced Retinal Capillary Blood Flow in CADASIL

“…The measurement in this study was done relatively proximally, ie, where the average diameters were Ϸ100 m. On clinical examination, assessing also smaller retinal arterioles, the vessels appeared somewhat narrowed in all but 1 patient, similarly as reported by others. 9 This agrees with postmortem findings that in the brain the short cortical arteries may even be dilated 11 or are only slightly narrowed, 12 whereas the long white matter penetrating arteries are markedly stenosed: in arteries with external diameters Ͼ100 m, the profuse fibrosis may have reduced the internal diameters to smaller than 30 m. 12 This indicates that when examining the retina of CADASIL patients, emphasis should be placed on small caliber vessels. The retinal arterial caliber and arteriovenous ratio of the controls decreased with age and eventually resembled those of the patients.…”

CADASIL accelerated by acute hypotension

“…1,2 and pathologic studies 3 in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have demonstrated impaired vascular reactivity in subcortical vessels, in part due to arterial changes of thickened hyalinized walls, smooth muscle degeneration, and accumulation of granular osmiophilic material (GOM). This "earthen pipe" state of vessels impairs autoregulation with dependence on systemic blood pressure for perfusion of subcortical regions.…”

CADASIL: pathogenesis, clinical and radiological findings and treatment

“…This dynamic process is also associated with deposition of granular osmeophylic material (GOM) and degeneration of the middle layer of cerebral arteries (and other organs and territories), and results in reduced CBF in brain white matter. Cerebral and leptomeningeal arteries and arterioles become thickened, with stenosis of penetrating arteries in the white matter and cortex [21][22][23] . Gradually, diffuse myelin pallor and rarefaction of hemispheric white matter (sparing the U fibers), deep focal lesions, particularly in periventricular areas and centrum semiovale, and lacunar infarctions in the white matter, basal ganglia and pons add up 21,24 .…”