Pathophysiological Mechanisms and Potential Therapeutic Targets in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a hereditary small-vessels angiopathy caused by mutations in the NOTCH 3 gene, located on chromosome 19, usually affecting middleages adults, whose clinical manifestations include migraine with aura, recurrent strokes, mood disorders, and cognitive impairment leading to dementia and disability. In this review, we provide an overview of the current knowledge on the pathogenic mechanisms underlying the disease, focus on the corresponding therapeutic targets, and discuss the most promising treatment strategies currently under investigations. The hypothesis that CADASIL is an appropriate model to explore the pathogenesis of sporadic cerebral small vessel disease is also reviewed.

Multiple internal border zone infarcts in a patient with COVID-19 and CADASIL

“…CADASIL is an inherited angiopathy caused by pathogenic mutations in the NOTCH3 gene on chromosome 19, characterised by aberrant protein formation, the presence of granular osmiophilic deposits and fibrosis of the walls of small arteries. Clinical presentation includes solitary ischaemic strokes, cognitive deficits, migraine, psychiatric symptoms, and encephalopathy with characteristic radiological features including T2/FLAIR hyperintensities specifically affecting the anterior temporal lobes [1].…”

“…There is evidence of chronic cerebral hypoperfusion in CADASIL, with a proposed mechanism being impairment in the myogenic component of autoregulation where vascular smooth muscle constricts or dilates to transmural pressure changes [1]. Internal border zone infarcts have been reported in nine patients with CADASIL; whereby six had documented systemic hypotension, one occurring with intercurrent Influenza A infection [7].…”

“…Additional mechanisms may involve endothelial dysfunction in CADASIL as a predisposing factor with limited reserve when challenged with such an insult as COVID-19 [1]; or a superimposed secondary parainfectious autoimmune disorder for which there is growing radiological and histological evidence [10].…”

Ischemic Stroke in a Patient with Stable CADASIL during COVID-19: A Case Report

“…CADASIL is an autosomal dominant inherited disease caused by pathogenic mutations involving the NOTCH3 gene [ 2 ], which encodes a large transmembrane receptor, mainly expressed on vascular smooth muscle cells of the blood vessels and pericytes. The presence of this mutated receptor would lead to a dysregulation of the endothelial cells, which become more sensitive to oxidative stress, hypoxia and mechanical injuries, eventually leading to vessel occlusion and stroke [ 3 ]. The clinical manifestations of the disease are heterogeneous but most commonly include migraine with aura, mood disturbances, cognitive impairment evolving into early-onset dementia, and recurrent strokes [ 2 , 4 ].…”

COVID-19 Infection and Circulating Microparticles—Reviewing Evidence as Microthrombogenic Risk Factor for Cerebral Small Vessel Disease

“…The endothelial dysfunction can be further aggravated by COVID-19-mediated RAS disruption that may result in a secondary CBF dys-autoregulation [ 75 ], leading to cerebral hypoperfusion. This has been shown in CADASIL patients with COVID-19 where CSVD lesion manifested at the cerebral internal border zone, a region that is prone to hypoperfusion [ 184 ]. Locatelli and colleagues posited that CADASIL patients may suffer from a chronic cerebral hypoperfusion mainly from the disruption in the myogenic component of CBF autoregulation where SMCs become constricted or dilated in response to changes of transmural pressure [ 184 ].…”