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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and a phenotypically similar recessive condition (CARASIL) have emerged as important genetic model diseases for studying the molecular pathomechanisms of cerebral small vessel disease (SVD). CADASIL, the most frequent and intensely explored monogenic SVD, is characterized by a severe pathology in the cerebral vasculature including the mutation-induced aggregation of the Notch3 extracellular domain (Notch3 ECD ) and the formation of protein deposits of insufficiently determined composition in vessel walls. To identify key molecules and pathways involved in this process, we quantitatively determined the brain vessel proteome from CADASIL patient and control autopsy samples ( n  = 6 for each group), obtaining 95 proteins with significantly increased abundance. Intriguingly, high-temperature requirement protein A1 (HTRA1), the extracellular protease mutated in CARASIL, was found to be strongly enriched (4.9-fold, p  = 1.6 × 10 −3 ) and to colocalize with Notch3 ECD deposits in patient vessels suggesting a sequestration process. Furthermore, the presence of increased levels of several HTRA1 substrates in the CADASIL proteome was compatible with their reduced degradation as consequence of a loss of HTRA1 activity. Indeed, a comparison with the brain vessel proteome of HTRA1 knockout mice ( n  = 5) revealed a highly significant overlap of 18 enriched proteins ( p  = 2.2 × 10 −16 ), primarily representing secreted and extracellular matrix factors. Several of them were shown to be processed by HTRA1 in an in   vitro proteolysis assay identifying them as novel substrates. Our study provides evidence for a loss of HTRA1 function as a critical step in the development of CADASIL pathology linking the molecular mechanisms of two distinct SVD forms.

The evolutionary conserved Notch signaling pathway functions as a mediator of direct cell–cell communication between neighboring cells during development. Notch plays a crucial role in various fundamental biological processes in a wide range of tissues. Accordingly, the aberrant signaling of this pathway underlies multiple genetic pathologies such as developmental syndromes, congenital disorders, neurodegenerative diseases, and cancer. Over the last two decades, significant data have shown that the Notch signaling pathway displays a significant function in the mature brains of vertebrates and invertebrates beyond neuronal development and specification during embryonic development. Neuronal connection, synaptic plasticity, learning, and memory appear to be regulated by this pathway. Specific mutations in human Notch family proteins have been linked to several neurodegenerative diseases including Alzheimer’s disease, CADASIL, and ischemic injury. Neurodegenerative diseases are incurable disorders of the central nervous system that cause the progressive degeneration and/or death of brain nerve cells, affecting both mental function and movement (ataxia). There is currently a lot of study being conducted to better understand the molecular mechanisms by which Notch plays an essential role in the mature brain. In this study, an in silico analysis of polymorphisms and mutations in human Notch family members that lead to neurodegenerative diseases was performed in order to investigate the correlations among Notch family proteins and neurodegenerative diseases. Particular emphasis was placed on the study of mutations in the Notch3 protein and the structure analysis of the mutant Notch3 protein that leads to the manifestation of the CADASIL syndrome in order to spot possible conserved mutations and interpret the effect of these mutations in the Notch3 protein structure. Conserved mutations of cysteine residues may be candidate pharmacological targets for the potential therapy of CADASIL syndrome.

Loss of arterial smooth muscle cells (SMCs) and abnormal accumulation of the extracellular domain of the NOTCH3 receptor (Notch3 ECD ) are the 2 core features of CADASIL, a common cerebral small vessel disease caused by highly stereotyped dominant mutations in NOTCH3 . Yet the relationship between NOTCH3 receptor activity, Notch3 ECD accumulation, and arterial SMC loss has remained elusive, hampering the development of disease-modifying therapies. Using dedicated histopathological and multiscale imaging modalities, we could detect and quantify previously undetectable CADASIL-driven arterial SMC loss in the CNS of mice expressing the archetypal Arg169Cys mutation. We found that arterial pathology was more severe and Notch3 ECD accumulation greater in transgenic mice overexpressing the mutation on a wild-type Notch3 background (Tg Notch3 R169C ) than in knockin Notch3 R170C/R170C mice expressing this mutation without a wild-type Notch3 copy. Notably, expression of Notch3 -regulated genes was essentially unchanged in Tg Notch3 R169C arteries. We further showed that wild-type Notch3 ECD coaggregated with mutant Notch3 ECD and that elimination of 1 copy of wild-type Notch3 in Tg Notch3 R169C was sufficient to attenuate Notch3 ECD accumulation and arterial pathology. These findings suggest that Notch3 ECD accumulation, involving mutant and wild-type NOTCH3, is a major driver of arterial SMC loss in CADASIL, paving the way for NOTCH3-lowering therapeutic strategies.

Purpose CADASIL is a small-vessel disease caused by a cysteine-altering pathogenic variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of the NOTCH3 protein. We recently found that pathogenic variant in EGFr domains 7–34 have an unexpectedly high frequency in the general population (1:300). We hypothesized that EGFr 7–34 pathogenic variant more frequently cause a much milder phenotype, thereby explaining an important part of CADASIL disease variability. Methods Age at first stroke, survival and white matter hyperintensity volume were compared between 664 CADASIL patients with either a NOTCH3 EGFr 1–6 pathogenic variant or an EGFr 7–34 pathogenic variant. The frequencies of NOTCH3 EGFr 1–6 and EGFr 7–34 pathogenic variant were compared between individuals in the genome  Aggregation Database and CADASIL patients. Results CADASIL patients with an EGFr 1–6 pathogenic variant have a 12-year earlier onset of stroke than those with an EGFr 7–34 pathogenic variant, lower survival, and higher white matter hyperintensity volumes. Among diagnosed CADASIL patients, 70% have an EGFr 1–6 pathogenic variant, whereas EGFr 7–34 pathogenic variant strongly predominate in the population. Conclusion NOTCH3 pathogenic variant position is the most important determinant of CADASIL disease severity, with EGFr 7–34 pathogenic variant predisposing to a later onset of stroke and longer survival.

Background Mutations in the Notch3 gene are the cause of CADASIL, a hereditary small vessel disease leading to stroke and vascular dementia. The disease is characterized by ultrastructural granular deposits within small arterial vessels and degeneration of vascular smooth muscle cells. Yet, little is known about endothelial function in CADASIL. Vasoreactivity induced by L-arginine, which is the substrate for endothelial nitric oxide synthase, is a parameter of endothelial function and has been shown to be altered in patients with cerebrovascular disease. Methods To assess endothelial function in CADASIL, L-arginine-induced vasoreactivity was studied in 25 CADASIL subjects and 24 non-CADASIL control subjects without previous history of cerebrovascular disease by transcranial Doppler sonography of the middle cerebral artery. Results Resting mean flow velocity was significantly reduced in patients (43.7 ± 14.5 cm/s) compared to controls (57.0 ± 10.4 cm/s) [p < 0.001]. Patients exhibited a significantly higher pulsatility index (PI = 0.94 ± 0.19) than control subjects (PI = 0.79 ± 0.11) [p < 0.01]. L-arginine-induced vasoreactivity was significantly increased in patients (36.1 ± 15.5 % ) versus controls (27.9 ± 8.5 %) [p < 0.05]. In patients, there was a significant reduction of the PI following L-arginine application (PI = 0.86 ± 0.13) compared to resting PI [p < 0.01]. Conclusions Our results may indicate a pathogenic role of impaired cerebral hemodynamics and endothelial dysfunction in CADASIL. Our finding of enhanced L-arginine vasoreactivity might have therapeutic implications for CADASIL and sporadic small vessel disease.

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke and is associated with early-onset stroke and dementia. Whether its clinical phenotype is becoming milder with better risk factor treatments and other care improvements is unknown. In a large longitudinal CADASIL cohort, we determined whether the prognosis has changed over 23 years.MethodsPatients were identified from the Cambridge CADASIL register and the UK Familial stroke study. Change in age at stroke over the time of recruitment was determined using linear mixed-effects model, and the impact of genetic and vascular risk factors on stroke and dementia risk was further evaluated using Cox proportional hazard regression.ResultsA total of 555 patients with CADASIL were recruited between 2001 and 2023. The age of stroke onset significantly increased over time (p<0.001), with the mean age of stroke onset for patients recruited before 2016 (n=265) at 46.7±9.2 years and 51.6±9.5 years for those recruited since 2016 (n=290). Patients recruited since 2016 had lower risks of both stroke (HR 0.36, 95% CI 0.26 to 0.50, p<0.001) and dementia (HR 0.43, 95% CI 0.19 to 0.99, p=0.046) after adjusting for sex, hypertension history, smoking status, epidermal growth factor-like repeat position and calendar effect.ConclusionsThe clinical phenotype of CADASIL is improving. While this may be partly explained by reduced vascular risk factors such as smoking and the identification of milder cases, differences persisted after controlling for risk factors and mutation sites. These updated risk estimates should be used when counselling patients with CADASIL on prognosis.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by mutations in the NOTCH3 gene, affecting the number of cysteines in the extracellular domain of the receptor, causing protein misfolding and receptor aggregation. The pathogenic role of cysteine-sparing NOTCH3 missense mutations in patients with typical clinical CADASIL syndrome is unknown. The aim of this article is to describe these mutations to clarify if any could be potentially pathogenic. Articles on cysteine-sparing NOTCH3 missense mutations in patients with clinical suspicion of CADASIL were reviewed. Mutations were considered potentially pathogenic if patients had: (a) typical clinical CADASIL syndrome; (b) diffuse white matter hyperintensities; (c) the 33 NOTCH3 exons analyzed; (d) mutations that were not polymorphisms; and (e) Granular osmiophilic material (GOM) deposits in the skin biopsy. Twenty-five different mutations were listed. Four fulfill the above criteria: p.R61W; p.R75P; p.D80G; and p.R213K. Patients carrying these mutations had typical clinical CADASIL syndrome and diffuse white matter hyperintensities, mostly without anterior temporal pole involvement. Cysteine-sparing NOTCH3 missense mutations are associated with typical clinical CADASIL syndrome and typical magnetic resonance imaging (MRI) findings, although with less involvement of the anterior temporal lobe. Hence, these mutations should be further studied to confirm their pathological role in CADASIL.

Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular readouts, remains vastly incomplete. Here, we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences of Notch3 loss in the brain vasculature, we used single-cell transcriptomics and found that Notch3 inactivation alters regulation of calcium and contractile function and promotes a notable increase in extracellular matrix. These alterations adversely impact vascular reactivity, manifesting as dilation, tortuosity, microaneurysms, and decreased cerebral blood flow, as observed by MRI. Combined, these vascular impairments hinder glymphatic flow and result in buildup of glycosaminoglycans within the brain parenchyma. Remarkably, this phenomenon mirrors a key pathological feature found in brains of patients with CADASIL, a hereditary vascular dementia associated with NOTCH3 missense mutations. Additionally, single-cell RNA sequencing of the neuronal compartment in aging Notch3-null mice unveiled patterns reminiscent of those observed in neurodegenerative diseases. These findings offer direct evidence that age-related NOTCH3 deficiencies trigger a progressive decline in vascular function, subsequently affecting glymphatic flow and culminating in neurodegeneration.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by NOTCH3, and characterized by recurrent cerebral ischemic events without vascular risk factors, mood disturbance, and dementia. MRI testing shows cerebral white matter hyperintensities, especially in the external capsule and temporal pole. Typical mutations are cysteine-related missense ones located in one of 34 EGF-like repeats (EGFr) in the NOTCH3 receptor. To identify genotype–phenotype correlations, 179 Japanese CADASIL probands were recruited. Of the 68 mutations identified, p.Cys388Arg, p.Cys435Phe, p.Gly481Cys, p.Cys743Tyr, and p.Cys1009Phe were novel ones. The genotype–phenotype correlation was analyzed based on the three most common mutations: p.Arg75Pro, p.Arg141Cys, and p.Arg182Cys. p.Arg141Cys showed typical CADASIL phenotypes, whereas p.Arg75Pro showed mild and atypical phenotypes, a low frequency of stroke/TIA, high frequency of hypertension, and low frequency of temporal pole lesions. p.Arg182Cys showed various initial symptoms other than stroke/TIA. Subsequently, we analyzed the effect of the mutation location on the age at onset of stroke/TIA. We found that mutations in EGFr 1–6 excluding the cysteine-sparing mutation p.Arg75Pro were significantly correlated with a younger age at onset of stroke/TIA compared with those in EGFr 7–34. This was in agreement with a recent European report, suggesting that the effect of the mutation location is a consensus finding in CADASIL worldwide.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common hereditary small vessel disease, leads to early-onset stroke and vascular cognitive impairment (VCI). Despite its importance, data from Latin America remain scarce. The CADASIL Argentine registry (CADASILAr) was created to harmonize clinical data, promote international collaboration, and provide a reproducible, longitudinal framework to study disease progression and expand to neighboring countries. This study aims to present the cohort design and preliminary results from the cross-sectional phase. CADASILAr was developed to document demographic, clinical, imaging, and genetic features of CADASIL patients and to explore factors associated with disease progression and cognitive decline in an Argentinian multisite cohort. The study includes two phases: (1) a cross-sectional phase (CADASILAR-C) and (2) a longitudinal phase (CADASILAR-Long), following adults aged ≥18 years with genetically confirmed or suspected CADASIL. Variables collected include demographics, symptom onset, clinical features, neuroimaging, genetic data, and vascular risk factors. The study also examines socio-economic disparities, integrates biobanks, and harmonizes data collection with international CADASIL and dementia registries. Longitudinal follow-ups are planned annually over 5 years (Figure 1), with cognitive batteries aligned with international cohorts and a brain donation program to establish a CADASIL brain bank in Argentina. Preliminary data from 90 patients (50% female) show a mean age of 43.8 ± 11.9 years, with family history in 91.6% (Figure 2). The most common clinical presentations were cerebrovascular events (72.9%), cognitive impairment (56.7%), and migraine (69%). The most frequent comorbidities included hypertension (64%) and dyslipidemia (55%). Among 86 confirmed cases, 63 were diagnosed through genetic testing and 20 through skin biopsy. Genetic analysis identified cysteine-altering NOTCH3 mutations in all confirmed cases, predominantly affecting epidermal growth factor-like repeats (Figure 3). Of the 33 patients assessed with the MMSE, the median score was 28 (IQR: 22-29). CADASILAr is the first systematic effort to study this disease in Latin America and the twelfth global CADASIL registry. By integrating baseline and longitudinal data, it offers a robust platform to investigate genetic, neuroimaging, and cognitive outcomes while fostering international collaborations to advance research and understanding of CADASIL.