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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.

Loss of arterial smooth muscle cells (SMCs) and abnormal accumulation of the extracellular domain of the NOTCH3 receptor (Notch3ECD) 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, Notch3ECD 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 Notch3ECD accumulation greater in transgenic mice overexpressing the mutation on a wild-type Notch3 background (TgNotch3R169C) than in knockin Notch3R170C/R170C mice expressing this mutation without a wild-type Notch3 copy. Notably, expression of Notch3-regulated genes was essentially unchanged in TgNotch3R169C arteries. We further showed that wild-type Notch3ECD coaggregated with mutant Notch3ECD and that elimination of 1 copy of wild-type Notch3 in TgNotch3R169C was sufficient to attenuate Notch3ECD accumulation and arterial pathology. These findings suggest that Notch3ECD 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.

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.

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 (Notch3ECD) 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 Notch3ECD 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.

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.

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraines, psychiatric disorders, recurrent strokes, and dementia. Omic technologies allow the massive study of different molecules for understanding diseases in a non-biased manner or even for discovering targets and their possible treatments. We analyzed the progress in understanding CADASIL that has been made possible by omics sciences. For this purpose, we included studies that focused on CADASIL and used omics techniques, searching bibliographic resources, such as PubMed. We excluded studies with other phenotypes, such as migraine or leukodystrophies. A total of 18 articles were reviewed. Due to the high prevalence of NOTCH3 mutations considered pathogenic to date in genomic repositories, one can ask whether all of them produce CADASIL, different degrees of the disease, or whether they are just a risk factor for small vessel disease. Besides, proteomics and transcriptomics studies found that the molecules that are significantly altered in CADASIL are mainly related to cell adhesion, the cytoskeleton or extracellular matrix components, misfolding control, autophagia, angiogenesis, or the transforming growth factor β (TGFβ) signaling pathway. The omics studies performed on CADASIL have been useful for understanding the biological mechanisms and could be key factors for finding potential drug targets.

Background Migraine with aura (MA) is a hallmark feature of CADASIL, a hereditary small-vessel disease caused by NOTCH3 mutations. While MA is prevalent in CADASIL, its underlying mechanisms remain unclear, and the links observed can be questioned or debated. This study examined the prevalence, clinical characteristics, and pathophysiology of MA in patients with CADASIL. Methods Clinical and experimental data were reviewed to assess MA prevalence, aura characteristics, sex differences, and pathophysiological insights from CADASIL models to confirm the indisputable pathophysiological links between migraine and aura and this unique genetic model of cerebral small vessel disease. Results MA was 10–20 times more prevalent in patients with CADASIL than in the general population, with frequent atypical and prolonged auras. The altered sex distribution and delayed onset suggest disease-specific mechanisms. Experimental data also revealed heightened susceptibility to cortical spreading depression (CSD) in preclinical CADASIL models, linked to greater fragility in maintaining cortical ionic homeostasis. Conclusion The high prevalence and distinct MA features, as well as the data obtained at the preclinical level, strongly support a causal relationship mediated by neurovascular dysfunction in CADASIL. Accumulating data in this condition sheds new light on the much-debated relationship between migraine and cerebrovascular diseases.

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 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke and is characterised by early onset stroke and dementia. Most strokes are lacunar ischaemic strokes, but intracerebral haemorrhage (ICH) has also been reported, although there are limited published data on its frequency and characteristics. Methods A retrospective review of a prospectively recruited CADASIL register from the British National Referral clinic was performed to identify acute ICH cases and their characteristics. In addition, a systematic review of ICH in CADASIL was performed. MEDLINE (Pubmed), Embase, and Web of Science were searched for articles published from inception until 31/05/2023. Results Ten cases of ICH were identified from the National clinic register of 516 symptomatic patients, giving an estimated point prevalence of 1.9%. An additional 119 cases were identified from the systematic review, comprising 129 cases and 142 ICH events in total. Including all identified cases, the mean age at onset of ICH was 56.6 ± 15.7 (SD) years, and 74 (57.4%) were male. ICH was the first manifestation of the disease in 32 patients (38.1%), and ICH recurrence occurred in 16 (12.4%). Most ICHs were subcortical, with the thalamus, 58 (40.8%), and basal ganglia, 34 (23.9%), being the commonest sites. Anticoagulation, but not antiplatelet agents, was associated with an increased risk of ICH (20.0% vs. 1.9%, p  = 0.006). Conclusions ICH is a relatively rare manifestation of CADASIL, occurring in about 2% of symptomatic cases. Most of the haemorrhages occurred in the subcortical regions.

The aim of our study is to explore the expression levels of inflammatory cytokines in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and to assess the correlation between inflammatory cytokines and clinical/magnetic resonance imaging (MRI) features of the patients. We recruited 54 patients with CADASIL and 28 healthy controls and detected the expression levels of the following inflammatory cytokines in peripheral blood: interferon (IFN)-γ, tumor necrosis factor (TNF)-α, TNF-β, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-17F, and IL-22. We also analyzed the relationship between the expression levels of the inflammatory cytokines and the clinical/MRI features. The expression of most inflammatory cytokines were significantly higher in CADASIL patients than in healthy controls, including IFN-γ (z = -5.335, < 0.001), TNF-α (z = -4.880, < 0.001), TNF-β (z = -2.401, = 0.019), IL-1β (z = -2.831, = 0.007), IL-4 (z = -4.039, < 0.001), IL-5 (z = -4.523, < 0.001), IL-6 (z = -3.545, < 0.001), IL-8 (z = -5.667, < 0.001), IL-17F (z = -3.986, < 0.001) and IL-22 (z = -5.325, < 0.001). The increased expression level of TNF-β was correlated with abnormal mRS scores in patients with CADASIL (odds ratio [OR] = 6.147, 95% CI: 1.324-28.535; = 0.020) after adjustment for age, sex, history of hypertension and history of diabetes. The expression level of TNF-β was also associated with MMSE (β = -0.281, 95% CI:-5.325-0.866, = 0.008) and apathy scores (β = 0.388, 95% CI:2.554-16.328, = 0.008) after adjusting for age, sex, educational years, history of hypertension and history of diabetes. There was also a positive correlation between the expression level of TNF-β and the number of CMBs in deep (β = 0.314, 95% CI:2.989-39.461, = 0.023) and lobar region (β = 0.433, 95% CI:15.363-59.857, = 0.001) after adjusting for age, sex, history of hypertension and history of diabetes. Our results indicate that diffuse inflammatory pathway activation occurs in CADASIL. The increased expression level of TNF-β was associated with higher CMBs burden and poor clinical scores. Our findings suggest that the inflammatory pathway, particularly the TNF-related inflammatory pathway, may be involved in the disease progression of CADASIL.