Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by a cerebral non-atherosclerotic, nonamyloid angiopathy mainly affecting the small arteries penetrating the white matter. In the brain vessels of two patients with CADASIL, abnormal patches of granular osmiophilic material have recently been described. Here we report the observation of similar granular osmiophilic material within the vessel walls of muscle and skin biopsies from a 54-year-old woman belonging to a CADASIL family, who suffered from subcortical dementia with leukoencephalopathy demonstrated on neuroimaging. Postmortem examination disclosed changes of the vessel walls in all the organs chiefly leading to cerebral lesions. Ultrastructural study showed destruction of the vascular smooth muscle cells (VSMC) and the granular osmiophilic material already found in muscle and skin biopsies in this patient. Both changes were found all along the arterial tree. The findings of this study indicate that CADASIL is a systemic vascular disease involving arterial VSMC and that the lesions are different in each organ and vessel wall, depending on their fine structure. Moreover, it emphasizes that skin and muscle biopsies might be useful for diagnosis of and research into CADASIL.

CADASIL: Ultrastructural insights into the morphology of granular osmiophilic material

“…The GOM deposits identified in the 13 CADASIL patients all had the ultrastructural features described in the literature (Baudrimont et al., 1993; Kalimo et al., 2002; Lewandowska et al., 2011; Morroni & Lorenzi, 2013; Ragno et al., 2012, 2013, 2013; Ruchoux et al., 1995; Schröder et al., 2005). They were variable in size (from 0.2 to 0.8 μm), shape, and number; they were made up of granules 10–15 nm in diameter; and were found at extracellular sites, most often near VSMC indentations or close to VSMCs of small and medium‐size arteries.…”

“…An electron‐lucent space had previously been described between the GOM and the cell membrane in skeletal muscle (Ruchoux et al., 1995) and skin (Ishiko et al., 2005) from CADASIL patients. However, in this study, the halo was also detected on the outer side in all biopsy types examined; moreover, some deposits were completely surrounded, a finding that may be related to the plane of section.…”

“…The disease induces progressive degeneration and eventual disappearance of VSMCs and accumulation of the extracellular domain of NOTCH3 protein (N3ECD) in the walls of affected arteries (Brulin, Godfraind, Leteurtre, & Ruchoux, 2002; Joutel, 2011; Joutel et al., 2000). A distinctive early feature of CADASIL is the buildup of deposits of granular osmiophilic material (GOM) on or close to degenerating VSMCs (Ruchoux et al., 1995). N3ECD is a component of GOM (Ishiko et al., 2006; Yamamoto et al., 2013).…”

“…GOM has already been investigated by EM (Baudrimont, Dubas, Joutel, Tournier‐Lasserve, & Bousser, 1993; Kalimo, Ruchoux, Viitanen, & Kalaria, 2002; Lewandowska, Dziewulska, Parys, & Pasennik, 2011; Morroni & Lorenzi, 2013; Ragno, Nardi, Manca, Morroni, & Trojano, 2013; Ragno et al., 2012, 2013; Ruchoux et al., 1995; Schröder, Züchner, Dichgans, & Nagy, 2005). The aim of this study was to gain further insights into CADASIL pathobiology by in‐depth analysis of the ultrastructure of GOM deposits.…”

“…The aim of this study was to gain further insights into CADASIL pathobiology by in‐depth analysis of the ultrastructure of GOM deposits. The examination of biopsy samples from 13 patients with the clinical, genetic, and ultrastructural features of CADASIL confirmed earlier reports of an electron‐lucent halo around several GOM deposits and their nonuniform osmiophilia (Ishiko, Shimizu, Nagata, Ohta, & Tanaka, 2005; Lewandowska et al., 2011; Ruchoux et al., 1995). …”