Extensive loss of arterial medial smooth muscle cells and mural extracellular matrix in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)

Abstract

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a distinctive clinicopathologic entity characterized by young adult-onset non-hypertensive vasculopathic encephalopathy accompanied by alopecia and disco-vertebral degeneration. CARASIL arteriopathy is histopathologically characterized by intense arteriosclerosis without the deposition of granular osmiophilic materials. Until now, the obliterative arteriosclerosis is the presumptive cause of subcortical ischemia in CARASIL; however, a detailed vascular pathology leading to diffuse leukoencephalopathy remains unclear. In this study, we examined two autopsied CARASIL brains in comparison with an autopsy case of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Intensity of arterial sclerotic changes of CARASIL was evaluated by sclerotic index analysis. Immunohistochemical investigations were performed using a battery of primary antibodies, which recognized vascular cellular and extracellular components. As a result, sclerotic changes were disclosed to be mild and infrequent in CARASIL, in contrast to CADASIL that showed severe obliterative arterial changes. In CARASIL, conversely, most of the arteries were centrifugally enlarged and some were collapsed. We further revealed that arterial medial smooth muscle cells (SMCs) in patients with CARASIL were extensively lost, even in arteries without sclerotic changes. Arterial adventitia in CARASIL was conspicuously thin and immunoreactivities for type I, III, and VI collagens and fibronectin were appreciably weak in this region, indicating a reduction in the mural extracellular matrix (ECM). Because of the medial and adventitial degeneration, CARASIL brains likely receive marked fluctuations in blood flow because of deviations in the structural and functional basis of autoregulation mechanisms. We thus consider that diffuse leukoencephalopathy in CARASIL may be caused by arterial medial SMC loss with mural ECM reduction. We speculate that the abnormalities in the ECM are causatively related to the SMC degeneration, since the ECM is a crucial signal determining the biophysiological properties of arterial SMCs.

Features of Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

“…Arterial adventitia was thin and decreased immunoreactivity for type I, type III, and type VI collagens. 23 These changes were relatively limited in cerebral small arteries and were not detected in intracranial large arteries and extracranial arteries. Lysosome-like bodies were found in the cytoplasm of smooth muscle cells in small arteries.…”

“…8,12,22,23 In the cerebral small arteries, smooth muscle cells were extensively lost, even in arteries without sclerotic changes. Sclerotic changes were mild and infrequent; most of the arteries were enlarged rather than exhibiting luminal stenosis.…”

A CARASIL Patient from Americas with Novel Mutation and Atypical Features: Case Presentation and Literature Review

“…There is dilatation of arterial lumen rather than luminal stenosis [7]; the ischemic brain insults are thought to be due to the disturbance of autoregulatory mechanisms for cerebral blood flow [8]. The findings are limited to the cerebral small arteries; skin biopsy is not helpful in diagnosis [1,9]. …”

Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

“…27,28 Typical features include the recessive mode of inheritance, an early age of onset (20 to 30 years) and the frequent occurrence of spondylosis and alopecia as associated non-neurologic manifestations. 29,30 The genetic cause of CARASIL, identified only recently by linkage analysis in five consanguineous families, 31 was mapped to the HTRA1 gene encoding high temperature requirement protein A1, a highly conserved serine protease.…”