Moyamoya disease (MMD) is a type of cerebrovascular disease characterized by occlusion of the distal end of the internal carotid artery and the formation of collateral blood vessels. Over the past 20 years, the landscape of research on MMD has significantly transformed. In this review, we provide insights into the pathogenesis, diagnosis, and therapeutic interventions in MMD. The development of high‐throughput sequencing technology has expanded our understanding of genetic susceptibility, identifying MMD‐related genes beyond RNF213, such as ACTA2, DIAPH1, HLA, and others. The genetic susceptibility of MMD to its pathological mechanism was summarized and discussed. Based on the second‐hit theory, the influences of inflammation, immunity, and environmental factors on MMD were also appropriately summarized. Despite these advancements, revascularization surgery remains the primary treatment for MMD largely because of the lack of effective in vivo and in vitro models. In this study, 16 imaging diagnostic methods for MMD were summarized. Regarding therapeutic intervention, the influences of drugs, endovascular procedures, and revascularization surgeries on patients with MMD were discussed. Future research on the central MMD vascular abnormalities and peripheral circulating factors will provide a more comprehensive understanding of the pathogenic mechanisms of MMD.

Background: Ischemic Moyamoya disease is one of the important causes of stroke, which leads to severe impairment in cognitive functions. This cognitive impairment occurs prior to stroke. However, the cognitive functions that are impaired and the mechanisms of these impairments have not been determined.Methods: We analyzed 12 patients with Moyamoya disease and 12 controls. All participants underwent cognitive tests and magnetic resonance imaging (MRI) scans. The diffusion tensor imaging (DTI) data was processed using Tract-Based Spatial Statistics (TBSS). Significantly different white matter areas were correlated with different cognitive functions.Results: There were significant differences in intelligence and subtraction between the patients and controls (p < 0.05). The parameters of DTI such as fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) have different changes in anterior thalamic radiation, inferior fronto-occipital fasciculus (IFO), superior longitudinal fasciculus (SLF), uncinate fasciculus (UF), inferior longitudinal fasciculus, forceps minor, and other regions between the two groups.Conclusion: Left UF and IFO may be the key brain regions affecting arithmetic function, while bilateral IFO has an effect on intelligence. RD and AD may be better indicators for early prediction of chronic white matter damage than FA, while MD tends to have a comprehensive indirect change. There is cognitive impairment in ischemic MMD, which is closely related to white matter impairment.Trial registration: Clinical Trial Registration, Unique identifier:ChiCTR1900023610. Registered 4 June 2019 – Prospective study registered.

Background. The association of DNA methylation with the pathogenesis of adult ischemic moyamoya disease (MMD) is unknown. Here, we investigated the genome‐wide DNA methylation profiles in patients with MMD and identified the genes related to the pathogenesis of MMD. Methods. Whole blood samples were collected from 20 individuals, including 10 patients with ischemic moyamoya disease without any underlying disease and 10 healthy individuals. Genome‐wide DNA methylation analysis was performed using Illumina 850K microarrays. Transcriptional correlation was verified using quantitative reverse transcription‐polymerase chain reaction. In vitro experiments were used to analyze the association of functional defects with candidate epigenetic markers. Results. The genome‐wide methylation level in the whole blood of adults with ischemic MMD was higher than that in the healthy individuals. In total, 759 methylation probes differed significantly between the case and control. The hypermethylated regions were mostly concentrated in the gene spacer regions. Among genes with the highest degree of the differential expression, KCNMA1 and GALNT2 were upregulated, whereas SOX6 and RBM33 were downregulated. Conclusions. This is the first study showing that the low expression of genes associated with epigenetic regulation, such as SOX6 and RBM33, may be related to vascular occlusion in MMD, whereas the overexpression of KCNMA1 and GALNT2 may be related to the vascular hyperplasia. The results suggest that DNA methylation was involved in the pathogenesis of MMD, and new pathogenic genes were proposed as biological markers.

Introduction: Moyamoya disease (MMD) is a chronic cerebrovascular disease that can lead to ischemia and hemorrhagic stroke. The relationship between oxidative phosphorylation (OXPHOS) and MMD pathogenesis remains unknown.Methods: The gene expression data of 60 participants were acquired from three Gene Expression Omnibus (GEO) datasets, including 36 and 24 in the MMD and control groups. Differentially expressed genes (DEGs) between MMD patients MMD and control groups were identified. Machine learning was used to select the key OXPHOS-related genes associated with MMD from the intersection of DEGs and OXPHOS-related gene sets. Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), gene set enrichment analysis (GSEA), Immune infiltration and microenvironments analysis were used to analyze the function of key genes. Machine learning selected four key OXPHOS-related genes associated with MMD: CSK, NARS2, PTPN6 and SMAD2 (PTPN6 was upregulated and the other three were downregulated).Results: Functional enrichment analysis showed that these genes were mainly enriched in the Notch signaling pathway, GAP junction, and RNA degradation, which are related to several biological processes, including angiogenesis, proliferation of vascular smooth muscle and endothelial cells, and cytoskeleton regulation. Immune analysis revealed immune infiltration and microenvironment in these MMD samples and their relationships with four key OXPHOS-related genes. APC co-inhibition (p = 0.032), HLA (p = 0.001), MHC I (p = 0.013), T cellco- inhibition (p = 0.032) and Type I IFN responses (p < 0.001) were significantly higher in the MMD groups than those in the control groups. The CSK positively correlated with APC co-inhibition and T cell-co-inhibition. The NARS2 negatively correlated with Type I IFN response. The SMAD2 negatively correlated with APC co-inhibition and Type I IFN response. The PTPN6 positively correlated with HLA, MHC I and Type I IFN responses.Discussion: This study provides a comprehensive understanding of the role of OXPHOS in MMD and will contribute to the development of new treatment methods and exploration of MMD pathogenesis.

Background: The cellular composition and molecular mechanisms of the pathological arteries in Moyamoya disease (MMD) remain poorly understood. To improve our understanding of pathogenesis in MMD, we aimed to comprehensively map the cellular composition and molecular alterations within the pathological arteries of patients with MMD. Methods: Superficial temporal artery samples were collected from patients with MMD (n=2) and healthy controls (n=3), yielding a total of 26 371 cells that were used for single‐cell RNA sequencing. Differentially expressed genes, pathway enrichment, and cell–cell communication analyses were performed to examine disease‐related changes. In vitro experiments were performed to validate the changes in endothelial cells (ECs) and smooth‐muscle cells (SMCs), as well as the interactions between immune cells and ECs and SMCs. Results: We identified 8 major cell types in the human superficial temporal artery. We observed an increased proportion of SMCs in the superficial temporal artery of MMD. Two distinct SMC clusters, SMC1 and SMC2, were identified and exhibited different gene expression. Immune profiling revealed significant upregulation of genes in natural killer T cells, suggesting increased immune activity in MMD. Cell–cell communication analysis highlighted the role of the macrophage migration inhibitory factor pathway in promoting interactions between immune cells, SMCs, and ECs. In vitro experiments confirmed that the colocalization of CD74 with CD44 or CXCR4 in ECs promotes EC proliferation and angiogenesis. Natural killer T cells can promote cytoskeletal enlargement in ECs and SMCs, enhancing their migratory and proliferative capacities, as well as promoting angiogenesis in ECs. Conclusions: This study provides a single‐cell transcriptomic map of the superficial temporal artery in MMD, revealing key immune and vascular cell populations. Immune cells, particularly natural killer T cells, play a critical role in promoting SMC and EC proliferation and migration, contributing to vascular occlusion. These findings make contributions to understanding the pathogenesis of MMD and suggest potential therapeutic targets.

Moyamoya disease (MMD) is a cerebrovascular narrowing and occlusive condition characterized by progressive stenosis of the terminal portion of the internal carotid artery and the formation of an abnormal network of dilated, fragile perforators at the base of the brain. However, the role of PANoptosis, an apoptotic mechanism associated with vascular disease, has not been elucidated in MMD. In our study, a total of 40 patients’ genetic data were included, and a total of 815 MMD-related differential genes were screened, including 215 upregulated genes and 600 downregulated genes. Among them, DNAJA3, ESR1, H19, KRT18 and STK3 were five key genes. These five key genes were associated with a variety of immune cells and immune factors. Moreover, GSEA (gene set enrichment analysis) and GSVA (gene set variation analysis) showed that the different expression levels of the five key genes affected multiple signaling pathways associated with MMD. In addition, they were associated with the expression of MMD-related genes. Then, based on the five key genes, a transcription factor regulatory network was constructed. In addition, targeted therapeutic drugs against MMD-related genes were obtained by the Cmap drug prediction method: MST-312, bisacodyl, indirubin, and tropanyl-3,5-dimethylbenzoate. These results suggest that the PANoptosis-related genes may contribute to the pathogenesis of MMD through multiple mechanisms.