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Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most common inherited cerebral small vessel diseases caused by the NOTCH3 gene mutation. This mutation leads to the accumulation of NOTCH3 extracellular domain protein (NOTCH3ECD) into the cerebral arterioles, causing recurrent stroke, white matter lesions, and cognitive impairment. With the development of gene sequencing technology, cysteine-sparing mutations can also cause CADASIL disease, however, the pathogenicity and pathogenic mechanisms of cysteine-sparing mutations remain controversial. Objective: To analyze the pathogenicity and pathological features of cysteine-sparing mutations in both in vitro and in vivo mouse models. Methods: A cysteine-sparing mutant of NOTCH3ECD R75Q was constructed by lentiviral transfection in vitro , and the NOTCH3 R75Q knock-in mouse model was constructed by CRISPR/Cas-mediated genome engineering in vivo. A cycloheximide pulse-chase experiment was used to analyze the degradation of NOTCH3 extracellular domain proteins, and the deposition characteristics of NOTCH3ECD were quantitatively analyzed by immunohistochemical staining. The characteristics of the smooth muscle cells and granular osmiophilic materials were observed using electron microscopy. Results: We elucidated that the NOTCH3 R75Q mutation is pathogenic. NOTCH3ECD R75Q was found to be resistant to protein degradation and more likely to cause abnormal aggregation of NOTCH3ECD, resulting in reduced cell activity in vitro. The NOTCH3 R75Q mouse model showed pathological characteristics of CADASIL, with age-dependent NOTCH3ECD, granular osmiophilic material, and degenerated smooth muscle cells detected in the brain. Conclusion: To our knowledge, this is the first study to analyze the pathogenicity of NOTCH3 R75Q cysteine-sparing mutations in both in vitro and in vivo models. We demonstrate that NOTCH3ECD induced by NOTCH3 R75Q mutation has toxic effects on cells and reveal the deposition characteristics of NOTCH3ECD in the brain. This provides a feasible model and lays the foundation for further studies on the pathogenesis and therapeutic strategies of NOTCH3 cysteine-sparing mutations. [ABSTRACT FROM AUTHOR]

Enlarged perivascular spaces have been previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, but their significance and pathophysiology remains unclear. We investigated associations of white matter enlarged perivascular spaces with classical imaging measures, cognitive measures and plasma proteins to better understand what enlarged perivascular spaces represent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and whether radiographic measures of enlarged perivascular spaces would be of value in future therapeutic discovery studies for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Twenty-four individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and 24 age- and sex-matched controls were included. Disease status was determined based on the presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity, brain parenchymal fraction, white matter enlarged perivascular space volumes, clinical and cognitive measures as well as plasma proteomics were used in models. White matter enlarged perivascular space volumes were calculated via a novel, semiautomated pipeline, and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of enlarged perivascular spaces with global burden of white matter hyperintensity, brain atrophy, functional status, neurocognitive measures and plasma proteins was modelled with linear regression models. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and control groups did not exhibit differences in mean enlarged perivascular space volumes. However, increased enlarged perivascular space volumes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy were associated with increased white matter hyperintensity volume (β = 0.57, P = 0.05), Clinical Dementia Rating Sum-of-Boxes score (β = 0.49, P = 0.04) and marginally with decreased brain parenchymal fraction (β = -0.03, P = 0.10). In interaction term models, the interaction term between cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease status and enlarged perivascular space volume was associated with increased white matter hyperintensity volume (β = 0.57, P = 0.02), Clinical Dementia Rating Sum-of-Boxes score (β = 0.52, P = 0.02), Mini-Mental State Examination score (β = -1.49, P = 0.03) and marginally with decreased brain parenchymal fraction (β = -0.03, P = 0.07). Proteins positively associated with enlarged perivascular space volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with enlarged perivascular space volumes: CXC motif chemokine ligand 8/interleukin-8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. The levels of CXC motif chemokine ligand 8/interleukin-8 were also associated with increased white matter hyperintensity volume (β = 42.86, P = 0.03), and levels of C-C motif chemokine ligand 2/monocyte chemoattractant protein 1 were further associated with decreased brain parenchymal fraction (β = -0.0007, P < 0.01) and Mini-Mental State Examination score (β = -0.02, P < 0.01) and increased Trail Making Test B completion time (β = 0.76, P < 0.01). No proteins were associated with all three studied imaging measures of pathology (brain parenchymal fraction, enlarged perivascular spaces, white matter hyperintensity). Based on associations uncovered between enlarged perivascular space volumes and cognitive functions, imaging and plasma proteins, we conclude that white matter enlarged perivascular space volumes may capture pathologies contributing to chronic brain dysfunction and degeneration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease (CSVD), pathologically characterized by a non-atherosclerotic and non-amyloid diffuse angiopathy primarily involving small to medium-sized penetrating arteries and leptomeningeal arteries. In 1996, mutation in the notch receptor 3 gene (NOTCH3) was identified as the cause of CADASIL. However, since that time other genetic CSVDs have been described, including the HtrA serine peptidase 1 gene-associated CSVD and the cathepsin A gene-associated CSVD, that clinically mimic the original phenotype. Though NOTCH3-associated CSVD is now a well-recognized hereditary disorder and the number of studies investigating this disease is increasing, the role of NOTCH3 in the pathogenesis of CADASIL remains elusive. Aim of review: This review aims to provide insights into the pathogenesis and the diagnosis of hereditary CSVDs, as well as personalized therapy, predictive approach, and targeted prevention. In this review, we summarize the current progress in CADASIL, including the clinical, neuroimaging, pathological, genetic, diagnostic, and therapeutic aspects, as well as differential diagnosis, in which the role of NOTCH3 mutations is highlighted. Key scientific concepts of review: In this review, CADASIL is revisited as a NOTCH3-associated CSVD along with other hereditary CSVDs.

Abstract Background We developed a framework for segmenting and modeling lenticulostriate arteries (LSAs) on 7-T time-of-flight magnetic resonance angiography and tested its performance on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients and controls. Methods We prospectively included 29 CADASIL patients and 21 controls. The framework includes a small-patch convolutional neural network (SP-CNN) for fine segmentation, a random forest for modeling LSAs, and a screening model for removing wrong branches. The segmentation performance of our SP-CNN was compared to competitive networks. External validation with different resolution was performed on ten patients with aneurysms. Dice similarity coefficient (DSC) and Hausdorff distance (HD) between each network and manual segmentation were calculated. The modeling results of the centerlines, diameters, and lengths of LSAs were compared against manual labeling by four neurologists. Results The SP-CNN achieved higher DSC (92.741 ± 2.789, mean ± standard deviation) and lower HD (0.610 ± 0.141 mm) in the segmentation of LSAs. It also outperformed competitive networks in the external validation (DSC 82.6 ± 5.5, HD 0.829 ± 0.143 mm). The framework versus manual difference was lower than the manual inter-observer difference for the vessel length of primary branches (median -0.040 mm, interquartile range -0.209 to 0.059 mm) and secondary branches (0.202 mm, 0.016–0.537 mm), as well as for the offset of centerlines of primary branches (0.071 mm, 0.065–0.078 mm) and secondary branches (0.072, 0.064–0.080 mm), with p

Background and Purpose: The role of asymptomatic diffusion‐weighted imaging‐positive (aDWI+) lesions in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients remains unclear, and their radiographic features may differ from those of symptomatic diffusion‐weighted imaging‐positive (sDWI+) lesions. We aimed to investigate the clinicoradiographic characteristics of aDWI+ lesions in CADASIL patients. Methods: We conducted a retrospective analysis using data from the Taiwan CADASIL Registry. aDWI+ lesions were defined as incidentally detected DWI+ lesions without corresponding acute neurological deficits. We compared the baseline clinical characteristics of patients with and without aDWI+ lesions and analyzed their radiological features and evolution in relation to sDWI+ lesions. Results: Among 154 enrolled patients (mean age 62 ± 10 years), 17 (11%) had aDWI+ lesions. Baseline clinical characteristics were similar in the two groups, but those with aDWI+ lesions had more lacunes (median 8 vs. 2), multiple cerebral microbleeds (CMBs; 85% vs. 40%), and anterior temporal white matter hyperintensity (WMH; 47% vs. 14%). Multivariable analysis showed that aDWI+ lesions were associated with anterior temporal WMH (odds ratio 5.7, 95% confidence interval 1.5–21.0) after adjusting for multiple lacunes, multiple CMBs, and total WMH score. Compared to sDWI+ lesions, aDWI+ lesions were more often small infarcts (<1 cm; 89% vs. 23%) and less likely to involve the corticospinal tract (11% vs. 96%). Among the 11 aDWI+ lesions with follow‐up magnetic resonance imaging, seven became microinfarcts, three became lacunes, and one disappeared. Conclusions: aDWI+ lesions in CADASIL are not uncommon and are associated with higher burdens of small vessel disease and anterior temporal WMH. Further research is needed to assess their long‐term impact on CADASIL. [ABSTRACT FROM AUTHOR]

[Display omitted] • Progress of CADASIL like clinical, pathological, genetic, and therapeutic aspects is presented. • The role of NOTCH3 mutations in CADASIL is highlighted in this review. • Genetic testing is very important for diagnosis of CADASIL and CADASIL-like phenotypes. • The viewpoint CADASIL should be revisited as a NOTCH3 -associated CSVD was proposed. • Hereditary CSVD caused by NOTCH3 mutations may be better understood with advanced research. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease (CSVD), pathologically characterized by a non-atherosclerotic and non-amyloid diffuse angiopathy primarily involving small to medium-sized penetrating arteries and leptomeningeal arteries. In 1996, mutation in the notch receptor 3 gene (NOTCH3) was identified as the cause of CADASIL. However, since that time other genetic CSVDs have been described, including the HtrA serine peptidase 1 gene-associated CSVD and the cathepsin A gene-associated CSVD, that clinically mimic the original phenotype. Though NOTCH3 -associated CSVD is now a well-recognized hereditary disorder and the number of studies investigating this disease is increasing, the role of NOTCH3 in the pathogenesis of CADASIL remains elusive. This review aims to provide insights into the pathogenesis and the diagnosis of hereditary CSVDs, as well as personalized therapy, predictive approach, and targeted prevention. In this review, we summarize the current progress in CADASIL, including the clinical, neuroimaging, pathological, genetic, diagnostic, and therapeutic aspects, as well as differential diagnosis, in which the role of NOTCH3 mutations is highlighted. In this review, CADASIL is revisited as a NOTCH3 -associated CSVD along with other hereditary CSVDs. [ABSTRACT FROM AUTHOR]

Background: We developed a framework for segmenting and modeling lenticulostriate arteries (LSAs) on 7-T time-of-flight magnetic resonance angiography and tested its performance on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients and controls. Methods: We prospectively included 29 CADASIL patients and 21 controls. The framework includes a small-patch convolutional neural network (SP-CNN) for fine segmentation, a random forest for modeling LSAs, and a screening model for removing wrong branches. The segmentation performance of our SP-CNN was compared to competitive networks. External validation with different resolution was performed on ten patients with aneurysms. Dice similarity coefficient (DSC) and Hausdorff distance (HD) between each network and manual segmentation were calculated. The modeling results of the centerlines, diameters, and lengths of LSAs were compared against manual labeling by four neurologists. Results: The SP-CNN achieved higher DSC (92.741 ± 2.789, mean ± standard deviation) and lower HD (0.610 ± 0.141 mm) in the segmentation of LSAs. It also outperformed competitive networks in the external validation (DSC 82.6 ± 5.5, HD 0.829 ± 0.143 mm). The framework versus manual difference was lower than the manual inter-observer difference for the vessel length of primary branches (median -0.040 mm, interquartile range -0.209 to 0.059 mm) and secondary branches (0.202 mm, 0.016–0.537 mm), as well as for the offset of centerlines of primary branches (0.071 mm, 0.065–0.078 mm) and secondary branches (0.072, 0.064–0.080 mm), with p < 0.001 for all comparisons. Conclusion: Our framework for LSAs modeling/quantification demonstrated high reliability and accuracy when compared to manual labeling. Trial registration: NCT05902039 (https://clinicaltrials.gov/study/NCT05902039?cond=NCT05902039). Relevance statement: The proposed automatic segmentation and modeling framework offers precise quantification of the morphological parameters of lenticulostriate arteries. This innovative technology streamlines diagnosis and research of cerebral small vessel disease, eliminating the burden of manual labeling, facilitating cohort studies and clinical diagnosis. Key Points: The morphology of LSAs is important in the diagnosis of CSVD but difficult to quantify. The proposed algorithm achieved the performance equivalent to manual labeling by neurologists. Our method can provide standardized quantitative results, reducing radiologists' workload in cohort studies. [ABSTRACT FROM AUTHOR]

Human blood vessel organoids (hBVOs) offer a promising platform for investigating vascular diseases and identifying therapeutic targets. In this study, we focused on in vitro modeling and therapeutic target finding of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary stroke disorder caused by mutations in the NOTCH3 gene. Despite the identification of these mutations, the underlying pathological mechanism is elusive, and effective therapeutic approaches are lacking. CADASIL primarily affects the blood vessels in the brain, leading to ischemic strokes, migraines, and dementia. By employing CRISPR/Cas9 base-editing technology, we generated human induced pluripotent stem cells (hiPSCs) carrying Notch3 mutations. These mutant hiPSCs were differentiated into hBVOs. The NOTCH3 mutated hBVOs exhibited CADASIL-like pathology, characterized by a reduced vessel diameter and degeneration of mural cells. Furthermore, we observed an accumulation of Notch3 extracellular domain (Notch3ECD), increased apoptosis, and cytoskeletal alterations in the NOTCH3 mutant hBVOs. Notably, treatment with ROCK inhibitors partially restored the disconnection between endothelial cells and mural cells in the mutant hBVOs. These findings shed light on the pathogenesis of CADASIL and highlight the potential of hBVOs for studying and developing therapeutic interventions for this debilitating human vascular disorder. [ABSTRACT FROM AUTHOR]

CADASIL is the most frequent hereditary cerebral small vessel disease worldwide. The disease is responsible for a slow and progressive accumulation of cerebral ischemic insults that lead to disabling cognitive and motor symptoms at late age. Although there is currently no cure for this condition, future therapies may concern subjects only at early stage of the disease. This will raise the question of the participation of asymptomatic carriers of pathogenic NOTCH3 gene mutation in future clinical trials, which will presuppose acceptance of presymptomatic genetic diagnosis. In this study, we questioned the population at risk of CADASIL who had not undergone a diagnostic procedure yet. Based on a questionnaire survey carried out by an independent team of sociologists, we analyzed what underlies the choice of people at risk to undergo or not to undergo a genetic test, and what could constitute the tipping point that could lead people who were initially not interested in their diagnosis to have recourse to it. Our results suggest that, far from being a simple, unequivocal path, the decision-making process leading to the choice of diagnosis is initially slowed down by the need to distance oneself from the disease so that it doesn't take over one's life, and then evolves under the influence of a complex tangle between advancing age, the presence of early symptoms, and the personal relationship with uncertainty. It cannot be ruled out that the real and imminent prospect of therapy may also modify responses to this type of survey. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Genetics of cerebral amyloid angiopathy (CAA) remains understudied. METHODS: We assessed variants in Alzheimer's disease (AD) risk factor genes and differential diagnosis genes by performing exome sequencing among 78 patients with early‐onset definite or probable CAA, after negative screening for APP mutation or duplication. RESULTS: Among 14 genes involved in non‐Aβ CAA, or vascular leukoencephalopathies, we detected pathogenic NOTCH3 variants in two patients, who exhibited lobar hematomas at the ages of 58 and 65, leading to a diagnosis redirection toward CADASIL. Of the remaining 76 patients, 23.1% carried at least one apolipoprotein E (APOE) ε2 allele and 43.6% carried at least one APOE ε4 allele, known as CAA risk factors. A total of 15 out of 76 (19.7%) carried either a loss‐of‐function or a rare predicted damaging missense or known AD risk variant in SORL1, TREM2, ABCA7, ABCA1, and ATP8B4. DISCUSSION: Exome sequencing allowed the redirection toward CADASIL in two patients and suggested shared genetic factors between AD and CAA, beyond the APOE gene. Highlights: The genetic component of cerebral amyloid angiopathy (CAA) remains understudied.Rare differential diagnoses such as CADASIL should be considered, even in cases of cerebral hemorrhage.Our study suggests shared genetic factors between AD and CAA, beyond the APOE gene.Rare variants in SORL1, TREM2, ABCA7, ABCA1 and ATP8B4 might be susceptibility factors in early‐onset CAA., [ABSTRACT FROM AUTHOR]

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene, characterized by recurrent strokes, cognitive decline, and psychiatric symptoms. This report presents a novel NOTCH3 c.1564 T > A (p.Cys522Ser) mutation associated with early-onset parkinsonism and significant white matter lesions. We describe a patient who presented with early-onset parkinsonism, characterized by bradykinesia and rigidity, alongside extensive white matter lesions observed through neuroimaging. Genetic testing revealed a novel c.1564 T > A (p.Cys522Ser) mutation in the NOTCH3 gene, contributing to the clinical diagnosis of CADASIL. This case underscores the phenotypic variability of CADASIL and the potential for atypical presentations, including parkinsonism. Early identification of genetic mutations can facilitate appropriate management and counseling for affected individuals and their families. Further research is warranted to explore the mechanisms underlying the association between NOTCH3 mutations and parkinsonism. Our findings contribute to the understanding of CADASIL, suggesting that clinicians should consider CADASIL in differential diagnoses of early-onset parkinsonism, especially in patients with concurrent white matter lesions.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare neuro vascular disease that is caused by mutations in Notch3. Here, we developed an iPSC line harboring the R133C mutation in Notch3, which is among the most common mutations leading to CADASIL. This mutation alters the disulfide bonding pattern leading to Notch3 protein aggregation, granular osmiophilic material (GOM) formation and vascular changes. The iPSC line was generated using CRISPR/Cas9 and edits were confirmed by PCR and Sanger sequencing. This resource is a valuable tool for studying molecular mechanisms of CADASIL and enabling the development and screening of targeted therapies for Notch3-related pathologies.

Background: Cerebral autosomal-dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL) is an inherited small-vessel disease that affects the white matter of the brain. Recent studies have confirmed that the deposition of NOTCH3ECD is the main pathological basis of CADASIL; however, whether different mutations present the same pathological characteristics remains to be further studied. Some studies have found that mitochondrial dysfunction is related to CADASIL; however, the specific effects of NOTCH3ECD on mitochondrial remain to be determined. Objective: We aimed to explore the role of mitochondrial dysfunction in CADASIL. Methods: We established transgenic human embryonic kidney-293T cell models (involving alterations in cysteine and non-cysteine residues) via lentiviral transfection. Mitochondrial function and structure were assessed using flow cytometry and transmission electron microscopy, respectively. Mitophagy was assessed using western blotting and immunofluorescence. Results: We demonstrated that NOTCH3ECD deposition affects mitochondrial morphology and function, and that its protein levels are significantly correlated with mitochondrial quality and can directly bind to mitochondria. Moreover, NOTCH3ECD deposition promoted the induction of autophagy and mitophagy. However, these processes were impaired, leading to abnormal mitochondrial accumulation. Conclusions: This study revealed a common pathological feature of NOTCH3ECD deposition caused by different NOTCH3 mutations and provided new insights into the role of NOTCH3ECD in mitochondrial dysfunction and mitophagy. [ABSTRACT FROM AUTHOR]

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by NOTCH3 mutations affecting the number of cysteines. The pathogenic role of cysteine-sparing NOTCH3 mutations with typical clinical CADASIL syndrome is still debated. This review aimed to characterize NOTCH3 cysteine-sparing mutations in patients with clinical suspicion of CADASIL. Articles on NOTCH3 cysteine-sparing mutations with clinical suspicion of CADASIL were reviewed. Clinical and radiological cerebral phenotypes data were extracted and characterized across regions and compared with phenotypes of typical CADASIL patients. We screened 298 NOTCH3 cysteine-sparing mutation individuals from 20 publications, and mutations in exon 3 were the most frequently reported (21.46%). Gait impairment (76.47%), cognitive impairment (67.47%), and stroke (62.37%) were the three most common clinical phenotypes; the most frequent radiological cerebral phenotypes were lacunes (74.29%) and cerebral microbleeds (72.73%). Compared with CADASIL patients, cognitive impairment and cerebral microbleed frequencies were significantly higher in patients with NOTCH3 cysteine-sparing mutations, while the white matter hyperintensities in anterior temporal polar and external capsule were rarely observed. Compared with Western patients, radiological phenotypes were more common than clinical phenotypes in cysteine-sparing Asian patients. More than half of cysteine-sparing patients had positive granular osmiophilic material deposits. NOTCH3 cysteine-sparing mutations in patients with clinical suspicion of CADASIL mainly manifested with gait and cognitive impairment but rare white matter hyperintensities in anterior temporal pole and external capsule. Further studies are warranted to pay attention to atypical NOTCH3 variants, which could guide specific diagnosis and help unravel underlying mechanisms. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) shares clinical/radiological features with several monogenic diseases that can mimic MS. Objective: We aimed to determine if exome sequencing can identify monogenic diseases in patients diagnosed with MS according to the McDonald criteria thus uncovering them as being misdiagnosed. Methods: We performed whole exome sequencing in a cohort of 278 patients with MS, clinically or radiologically isolated syndrome without cerebrospinal fluid-specific oligoclonal bands (CSF-OCBs) (n = 228), a positive family history of MS (n = 44), or both (n = 6), thereby focusing on individuals potentially more likely to have underlying monogenic conditions mimicking MS. We prioritized 495 genes associated with monogenic diseases sharing features with MS. Results: A disease-causing variant in NOTCH3 was identified in one patient without CSF-OCBs, no spinal lesions, with non-response to immunotherapy, and a family history of dementia, thereby converting the diagnosis to cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Moreover, 18 patients (6.5% of total) carried variants of unclear significance. Conclusion: Monogenic diseases being misdiagnosed as MS seem rare in patients diagnosed with MS according to the McDonald criteria, even in CSF-OCB negative cases. The detected pathogenic NOTCH3 variant emphasizes CADASIL as a rare differential diagnosis and highlights the relevance of genetic testing in selected MS cases with atypical presentations. [ABSTRACT FROM AUTHOR]

A major hurdle to therapeutic development in cerebral small vessel diseases is the lack of in-vivo method that can be used repeatedly for evaluating directly cerebral microvessels. We hypothesised that Adaptive Optics (AO), which allows resolution images up to 1–2 μm/pixel at retinal level, could provide a biomarker for monitoring vascular changes in CADASIL, a genetic form of such condition. In 98 patients and 35 healthy individuals, the wall to lumen ratio (WLR), outer and inner diameter, wall thickness and wall cross-sectional area were measured in a parapapillary and/or paramacular retinal artery. The ratio of vessel diameters before and after light flicker stimulations was also calculated to measure vasoreactivity (VR). Multivariate mixed-model analysis showed that WLR was increased and associated with a larger wall thickness and smaller internal diameter of retinal arteries in patients. The difference was maximal at the youngest age and gradually reduced with aging. Average VR in patients was less than half of that of controls since the youngest age. Any robust association was found with clinical or imaging manifestations of the disease. Thus, AO enables the detection of early functional or structural vascular alterations in CADASIL but with no obvious link to the clinical or imaging severity. [ABSTRACT FROM AUTHOR]

Anderson–Fabry disease (AFD) is a genetic sphingolipidosis involving virtually the entire body. Among its manifestation, the involvement of the central and peripheral nervous system is frequent. In recent decades, it has become evident that, besides cerebrovascular damage, a pure neuronal phenotype of AFD exists in the central nervous system, which is supported by clinical, pathological, and neuroimaging data. This neurodegenerative phenotype is often clinically characterized by an extrapyramidal component similar to the one seen in prodromal Parkinson's disease (PD). We analyzed the biological, clinical pathological, and neuroimaging data supporting this phenotype recently proposed in the literature. Moreover, we compared the neurodegenerative PD phenotype of AFD with a classical monogenic vascular disease responsible for vascular parkinsonism and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). A substantial difference in the clinical and neuroimaging features of neurodegenerative and vascular parkinsonism phenotypes emerged, with AFD being potentially responsible for both forms of the extrapyramidal involvement, and CADASIL mainly associated with the vascular subtype. The available studies share some limitations regarding both patients' information and neurological and genetic investigations. Further studies are needed to clarify the potential association between AFD and extrapyramidal manifestations. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We explored how blood‐brain barrier (BBB) leakage rate of gadolinium chelates (Ktrans) and BBB water exchange rate (kw) varied in cerebral small vessel disease (cSVD) subtypes. METHODS: Thirty sporadic cSVD, 40 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 13 high‐temperature requirement factor A serine peptidase 1 (HTRA) ‐related cSVD subjects were investigated parallel to 40 healthy individuals. Subjects underwent clinical, cognitive, and MRI assessment. RESULTS: In CADASIL, no difference in Ktrans, but lower kw was observed in multiple brain regions. In sporadic cSVD, no difference in kw, but higher Ktrans was found in the whole brain and normal‐appearing white matter. In HTRA1‐related cSVD, both higher Ktrans in the whole brain and lower kw in multiple brain regions were observed. In each patient group, the altered BBB measures were correlated with lesion burden or clinical severity. DISCUSSION: In cSVD subtypes, distinct alterations of kw and Ktrans were observed. The combination of Ktrans and kw can depict the heterogeneous BBB dysfunction. Highlights: We measured BBB leakage to gadolinium‐based contrast agent (Ktrans) and water exchange rate (kw) across BBB in three subtypes of cSVD.CADASIL is characterized by lower kw, HTRA1‐related cSVD exhibits both higher Ktrans and lower kw, while sporadic cSVD is distinguished by higher Ktrans.There are distinct alterations in kw and Ktrans among subtypes of cSVD, indicating the heterogeneous nature of BBB dysfunction. [ABSTRACT FROM AUTHOR]

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant inherited arterial disease, with lacunar infarction resulting from intracranial small vessel lesions being the most prevalent clinical manifestation of CADASIL. However, large-scale cerebral infarction caused by intracranial non-small vessels occlusion is relatively uncommon, and reports of vascular intervention and long-term antiplatelet drug treatment for patients with CADASIL and largescale cerebral infarction are rarer. Methods: We reported a 52 year-old male who experienced a significant cerebral infarction due to an occlusion in the second segment of the left middle cerebral artery, 4 months subsequent to being diagnosed with CADASIL. Following the benefit and risk assessment, the patient underwent intracranial vascular thrombectomy and balloon dilation angioplasty. Subsequently, he was administered dual antiplatelet therapy for 3 months, followed by mono antiplatelet therapy. Results: After undergoing intracranial vascular intervention and receiving antiplatelet therapy, significant improvement in the symptoms were observed. The National Institutes of Health Stroke Scale score decreased from 6 to 2 points, and no bleeding lesions were detected on the head computed tomography during regular follow-up visits after discharge. Conclusion: Our case highlights the possibility that patients with CADASIL may also encounter extensive cerebral infarction resulting from stenosis or occlusion of intracranial non-small vessels. Considering the specific circumstances of the patient, intravascular intervention and antiplatelet therapy can be regarded as viable treatment options for individuals with CADASIL. [ABSTRACT FROM AUTHOR]

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most common inherited cerebral small vessel diseases caused by the NOTCH3 gene mutation. This mutation leads to the accumulation of NOTCH3 extracellular domain protein (NOTCH3ECD) into the cerebral arterioles, causing recurrent stroke, white matter lesions, and cognitive impairment. With the development of gene sequencing technology, cysteine-sparing mutations can also cause CADASIL disease, however, the pathogenicity and pathogenic mechanisms of cysteine-sparing mutations remain controversial.ObjectiveTo analyze the pathogenicity and pathological features of cysteine-sparing mutations in both in vitro and in vivo mouse models.MethodsA cysteine-sparing mutant of NOTCH3ECD R75Q was constructed by lentiviral transfection in vitro, and the NOTCH3 R75Q knock-in mouse model was constructed by CRISPR/Cas-mediated genome engineering in vivo. A cycloheximide pulse-chase experiment was used to analyze the degradation of NOTCH3 extracellular domain proteins, and the deposition characteristics of NOTCH3ECD were quantitatively analyzed by immunohistochemical staining. The characteristics of the smooth muscle cells and granular osmiophilic materials were observed using electron microscopy.ResultsWe elucidated that the NOTCH3 R75Q mutation is pathogenic. NOTCH3ECD R75Q was found to be resistant to protein degradation and more likely to cause abnormal aggregation of NOTCH3ECD, resulting in reduced cell activity in vitro. The NOTCH3 R75Q mouse model showed pathological characteristics of CADASIL, with age-dependent NOTCH3ECD, granular osmiophilic material, and degenerated smooth muscle cells detected in the brain.ConclusionTo our knowledge, this is the first study to analyze the pathogenicity of NOTCH3 R75Q cysteine-sparing mutations in both in vitro and in vivo models. We demonstrate that NOTCH3ECD induced by NOTCH3 R75Q mutation has toxic effects on cells and reveal the deposition characteristics of NOTCH3ECD in the brain. This provides a feasible model and lays the foundation for further studies on the pathogenesis and therapeutic strategies of NOTCH3 cysteine-sparing mutations.

Abstract INTRODUCTION Genetics of cerebral amyloid angiopathy (CAA) remains understudied. METHODS We assessed variants in Alzheimer's disease (AD) risk factor genes and differential diagnosis genes by performing exome sequencing among 78 patients with early‐onset definite or probable CAA, after negative screening for APP mutation or duplication. RESULTS Among 14 genes involved in non‐Aβ CAA, or vascular leukoencephalopathies, we detected pathogenic NOTCH3 variants in two patients, who exhibited lobar hematomas at the ages of 58 and 65, leading to a diagnosis redirection toward CADASIL. Of the remaining 76 patients, 23.1% carried at least one apolipoprotein E (APOE) ε2 allele and 43.6% carried at least one APOE ε4 allele, known as CAA risk factors. A total of 15 out of 76 (19.7%) carried either a loss‐of‐function or a rare predicted damaging missense or known AD risk variant in SORL1, TREM2, ABCA7, ABCA1, and ATP8B4. DISCUSSION Exome sequencing allowed the redirection toward CADASIL in two patients and suggested shared genetic factors between AD and CAA, beyond the APOE gene. Highlights The genetic component of cerebral amyloid angiopathy (CAA) remains understudied. Rare differential diagnoses such as CADASIL should be considered, even in cases of cerebral hemorrhage. Our study suggests shared genetic factors between AD and CAA, beyond the APOE gene. Rare variants in SORL1, TREM2, ABCA7, ABCA1 and ATP8B4 might be susceptibility factors in early‐onset CAA.,

Cerebral microbleeds (CMBs) detected on magnetic resonance imaging are common in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The neuropathologic correlates of CMBs are unclear. In this study, we characterized findings relevant to CMBs in autopsy brain tissue of 8 patients with genetically confirmed CADASIL and 10 controls within the age range of the CADASIL patients by assessing the distribution and extent of hemosiderin/iron deposits including perivascular hemosiderin leakage (PVH), capillary hemosiderin deposits, and parenchymal iron deposits (PID) in the frontal cortex and white matter, basal ganglia and cerebellum. We also characterized infarcts, vessel wall thickening, and severity of vascular smooth muscle cell degeneration. CADASIL subjects had a significant increase in hemosiderin/iron deposits compared with controls. This increase was principally seen with PID. Hemosiderin/iron deposits were seen in the majority of CADASIL subjects in all brain areas. PVH was most pronounced in the frontal white matter and basal ganglia around small to medium sized arterioles, with no predilection for the vicinity of vessels with severe vascular changes or infarcts. CADASIL subjects have increased brain hemosiderin/iron deposits but these do not occur in a periarteriolar distribution. Pathogenesis of these lesions remains uncertain.

Cerebral microvascular disease (MVD) is an important cause of vascular cognitive impairment. MVD is heterogeneous in aetiology, ranging from universal ageing to the sporadic (hypertension, sporadic cerebral amyloid angiopathy [CAA] and chronic kidney disease) and the genetic (e.g., familial CAA, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL] and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy [CARASIL]). The brain parenchymal consequences of MVD predominantly consist of lacunar infarcts (lacunes), microinfarcts, white matter disease of ageing and microhaemorrhages. MVD is characterised by substantial arteriolar neuropathology involving ubiquitous vascular smooth muscle cell (SMC) abnormalities. Cerebral MVD is characterised by a wide variety of arteriolar injuries but only a limited number of parenchymal manifestations. We reason that the cerebral arteriole plays a dominant role in the pathogenesis of each type of MVD. Perturbations in signalling and function (i.e., changes in proliferation, apoptosis, phenotypic switch and migration of SMC) are prominent in the pathogenesis of cerebral MVD, making cerebral angiomyopathy an appropriate term to describe the spectrum of pathologic abnormalities. The evidence suggests that the cerebral arteriole acts as both source and mediator of parenchymal injury in MVD.

Background/Objectives: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary small vessel disease leading to significant morbidity and mortality. Despite advances in genetic diagnosis, the underlying pathophysiology remains incompletely understood. Proteomic studies offer insights into disease mechanisms by identifying altered protein expression patterns. Here, we conducted a proteomic analysis to elucidate molecular pathways associated with CADASIL. Methods: We enrolled genetically diagnosed CADASIL patients and healthy, genetically related controls. Plasma samples were subjected to proteomic analysis using the Olink platform, measuring 552 proteins across six panels. The data were analyzed from several approaches by using three different statistical methods: Exploratory Principal Component Analysis (PCA) and Partial Least Squares–Discriminant Analysis (PLS-DA), differential expression with moderated t-test, and gene set enrichment analysis (GSEA). In addition, bioinformatics analysis, including volcano plot, heatmap, and Variable Importance on Projection (VIP) scores from the PLS-DA model were drawn. Results: Significant differences in protein expression were observed between CADASIL patients and controls. RSPO1 and FGF-19 exhibited elevated levels (p < 0.05), while PPY showed downregulation (p < 0.05) in CADASIL patients, suggesting their involvement in disease pathogenesis. Furthermore, MIC-A/B expression varied significantly between patients with mutations in exon 4 versus exon 11 of the NOTCH3 gene (p < 0.05), highlighting potential immunological mechanisms underlying CADASIL. We identified altered pathways using GSEA, applied after ranking the study data. Conclusions: Our study provides novel insights into the proteomic profile of CADASIL, identifying dysregulated proteins associated with vascular pathology, metabolic dysregulation, and immune activation. These findings contribute to a deeper understanding of CADASIL pathophysiology and may inform the development of targeted therapeutic strategies. Further research is warranted to validate these biomarkers and elucidate their functional roles in disease progression. [ABSTRACT FROM AUTHOR]

Background: NOTCH3 variants are known to be linked to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, some null NOTCH3 variants with homozygous inheritance cause neurological symptoms distinct from CADASIL. The aim of this study was to expand the clinical spectrum of this distinct condition and provide further evidence of its autosomal recessive inheritance. Methods and results: Whole exome sequencing (WES) was performed on a proband who exhibited livedo racemosa, ataxia, cognitive decline, seizures, and MRI white matter abnormalities without anterior temporal pole lesions. Segregation analysis was conducted with Sanger sequencing. WES of the proband identified a novel homozygous NOTCH3 null variant (c.2984delC). The consanguineous parents were confirmed as heterozygous variant carriers. In addition, three heterozygous NOTCH3 null variants were reported as incidental findings in three unrelated cases analyzed in our center. Conclusion: The findings of this study suggest an autosomal recessive inheritance pattern in this early-onset leukoencephalopathy, in contrast to CADASIL's dominant gain-of-function mechanism; which is a clear example of genotype-phenotype correlation. Comprehensive genetic analysis provides valuable insights into disease mechanisms and facilitates diagnosis and family planning for NOTCH3-associated neurological disorders. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]