Progression Of Moyamoya Disease Research Articles

Isolated anterior cerebral artery occlusion: an atypical form of moyamoya disease

BackgroundThe relationship between anterior cerebral artery (ACA) occlusion and moyamoya disease (MMD) has rarely been studied. In this study, we focused on a special type of MMD: isolated ACA-occlusive MMD....

High Level of Serum Complement C3 Expression is Associated with Postoperative Vasculopathy Progression in Moyamoya Disease.

The immune system plays an important role in the onset and development of moyamoya disease (MMD), but the specific mechanisms remain unclear. This study aimed to explore the relationship between the expression of complements and immunoglobulin in serum and progression of MMD. A total of 84 patients with MMD and 70 healthy individuals were enrolled. Serum immunoglobulin and complement C3 and C4 expression were compared between healthy individuals and MMD patients. Follow-up was performed at least 6 months post-operation. Univariate and multivariate analysis after adjusting different covariates were performed to explore predictive factors associated with vasculopathy progression. A nomogram basing on the results of multivariate analysis was established to predict vasculopathy progression. Compared to healthy individuals, MMD patients had significantly lower expression of serum complements C3 (P = 0.003*). Among MMD patients, C3 was significantly lower in those with late-stage disease (P = 0.001*). Of 84 patients, 27/84 (32.1%) patients presented with vasculopathy progression within a median follow-up time of 13.0 months. Age (P=0.006*), diastolic blood pressure (P=0.004*) and serum complement C3 expression (P=0.015*) were associated with vasculopathy progression after adjusting different covariables. Complement C3 is downregulated in moyamoya disease and decreases even further in late-Suzuki stage disease. Age, diastolic blood pressure and serum complement C3 expression are associated with vasculopathy progression, suggesting that the complement might be involved in the development of moyamoya disease.

Acceleration of moyamoya disease after anti-vascular endothelial growth factor intravitreal injections

Abstract: Moyamoya disease (MMD) is a rare, progressive, irreversible vaso-occlusive disease affecting the cerebral vasculature. The progressive occlusion of blood vessels leads to the development of collateral vessels to compensate for the insufficient blood supply. Some growth factors such as vascular endothelial growth factor (VEGF) may cause excessive and aberrant angiogenesis in MMD. We report a case of a 55-year-old male, following up in retina clinics for diabetic retinopathy and macular edema who received anti-VEGF agents then he presented to the emergency room with left-sided face and body weakness, dysphagia, and dysarthria. Based on his clinical presentation and neuroimaging, he was diagnosed with moyamoya progression. We hypothesize that receiving anti-VEGF agents could have contributed to MMD progression in our patient and interfered with the collateral vessel development in a similar manner to their intended use in regressing neovascularization in diabetic retinopathy.

Mass cytometry revealed the circulating immune cell landscape across different Suzuki stages of Moyamoya disease.

Moyamoya disease (MMD) is a cerebrovascular disorder marked by progressive arterial narrowing, categorized into six stages known as Suzuki stages based on angiographic features. Growing evidence indicates a pivotal role of systemic immune and inflammatory responses in the initiation and advancement of MMD. This study employs high-dimensional mass cytometry to reveal the immunophenotypic characteristics of peripheral blood immune cells (PBMCs) at various Suzuki stages, offering insights into the progression of MMD. PBMC samples from eight patients with early-stage MMD (Suzuki stages II and III) and eight patients with later-stage MMD (Suzuki stages IV, V, and VI) were analyzed using high-dimensional mass cytometry to evaluate the frequency and phenotype of immune cell subtypes. We identified 15 cell clusters and found that the immunological features of early-stage MMD and later-stage MMD are composed of cluster variations. In this study, we confirmed that, compared to later-stage MMD, the early-stage MMD group exhibits an increase in non-classical monocytes. As the Suzuki stage level increases, the proportions of plasmacytoid DCs and monocyte-derived DCs decrease. Furthermore, T cells, monocytes, DCs, and PMN-MDSCs in the early-stage MMD group show activation of the canonical NF-κB signaling pathway. We summarized and compared the similarities and differences between early-stage MMD patients and later-stage MMD patients. There is a potential role of circulating immune dysfunction and inflammatory responses in the onset and development of MMD.

Neuregulin 1 as a potential biomarker for disease progression in moyamoya disease: A case-control study in Chinese population

ObjectiveMoyamoya disease (MMD) is a rare and progressive stenosis of cerebral arteries characterized by abnormally proliferative vasculopathy. Current studies have demonstrated that Neuregulin 1 (NRG1) plays a key role in angiogenesis-related disorders. Thus, the aim of our study is to investigate the serum NRG1 levels and their clinical correlations in MMD patients. MethodsIn this study, thirty adult patients with MMD and age-gender matched healthy controls were enrolled from our hospital between July 2020 and April 2022. Peripheral blood samples were collected at baseline, and clinical data were obtained from the electronic medical record system. Serum NRG1 concentrations were measured by enzyme-linked immunosorbent assay. Sanger sequencing was applied to detect the RNF213 p.R4810K mutation. ResultsThe serum NRG1 levels were significantly higher in MMD patients compared to controls (14.48 ± 10.81 vs.7.54 ± 6.35mmol/L, p < 0.001). No statistical difference in baseline clinical characteristics was found between both groups. Correlation analyses showed that NRG1 levels were positively associated with Suzuki staging (r = 0.4137, p = 0.023) while not related to other clinical features (reduced cerebral blood flow, posterior cerebral artery involvement, bilateral or unilateral steno-occlusive changes). Furthermore, subgroup analysis revealed that MMD patients with the RNF213 p.R4810K mutation presented with significantly higher NRG1 levels than those without the mutation (9.60 ± 0.929 vs. 25.89 ± 4.338 mmol/L, p = 0.001). ConclusionsOur study suggests that increased serum NRG1 levels may constitute a characteristic feature of MMD, indicating a potential positive correlation with disease progression and the presence of the RNF213 mutation. This positions NRG1 as a potentially crucial target for further studies aimed at comprehending the pathogenesis of MMD.

Proteomic and metabolomic characterizations of moyamoya disease patient sera.

The pathogenesis of moyamoya disease (MMD) is unclear. Inflammation and immune imbalance have been identified as potential factors contributing to the occurrence and progression of MMD. However, the specific proteins and metabolites responsible for triggering this process are yet to be established. The purpose of this study is to identify differentially expressed proteins and metabolites in patients with MMD and perform Kyoto Encyclopedia of Genes and Genomes pathway integration analysis to pinpoint crucial proteins and metabolites involved in the disease. We performed untargeted metabolomic and data-independent acquisition proteomic analyses on the serum samples of individuals with MMD and healthy controls (HC). In patients with MMD versus HC, 24 proteins and 60 metabolites, including 21 anionic metabolites and 39 cationic metabolites, which were significantly different, were identified. In patients with MMD, several proteins involved in inflammation and immune metabolism, such as tubulin beta-6 and complement C4, were found to have significantly altered levels. Similarly, many metabolites involved in inflammation and immune metabolisms, such as dimethyl 4-hydroxyisophthalate, beta-nicotinamide mononucleotide, 2-(3-(4-pyridyl)-1H-1,2,4-triazol-5-yl)pyridine, and PC (17:1/18:2), were significantly altered. Intriguingly, these proteins and metabolites are involved in the progression of atherosclerosis through immune and inflammatory pathways, although some have never been reported in MMD. Moreover, integrated proteomics and metabolomics studies were conducted to determine shared pathways involving cholesterol metabolism, vitamin digestion, fat digestion, and absorption pathways of proteins and metabolites, which warrant further investigation. Significant increases in pro-inflammatory and immunosuppressive abilities have been observed in patients with MMD, accompanied by significant reductions in anti-inflammatory and immune regulation. Various metabolites and proteins implicated in these processes have been identified for the first time. These findings hold immense significance for comprehending the pathogenesis of MMD and for the development of future drug therapies.

Bioinformatics analysis reveals the landscape of immune cell infiltration and novel immune-related biomarkers in moyamoya disease.

Objective: This study aimed to identify immune infiltration characteristics and new immunological diagnostic biomarkers in the cerebrovascular tissue of moyamoya disease (MMD) using bioinformatics analysis. Methods: GSE189993 and GSE141022 were downloaded from the GEO database. Differentially expressed gene and PPI analysis were performed. After performing WGCNA, the most significant module associated with MMD was obtained. Next, functional pathways according to GSEA, GO, and KEGG were enriched for the aforementioned core genes obtained from PPI and WGCNA. Additionally, immune infiltration, using the CIBERSORT deconvolution algorithm, immune-related biomarkers, and the relationship between these genes, was further explored. Finally, diagnostic accuracy was verified with ROC curves in the validation dataset GSE157628. Results: A total of 348 DEGs were screened, including 89 downregulated and 259 upregulated genes. The thistlel module was detected as the most significant module associated with MMD. Functional analysis of the core genes was chiefly involved in the immune response, immune system process, protein tyrosine kinase activity, secretory granule, and so on. Among 13 immune-related overlapping genes, 4 genes (BTK, FGR, PTPN11, and SYK) were identified as potential diagnostic biomarkers, where PTPN11 showed the highest specificity and sensitivity. Meanwhile, a higher proportion of eosinophils, not T cells or B cells, was demonstrated in the specific immune infiltration landscape of MMD. Conclusion: Immune activities and immune cells were actively involved in the progression of MMD. BTK, FGR, PTPN11, and SYK were identified as potential immune diagnostic biomarkers. These immune-related genes and cells may provide novel insights for immunotherapy in the future.

Application of Pseudo-Three-Dimensional Residual Network to Classify the Stages of Moyamoya Disease.

It is essential to assess the condition of moyamoya disease (MMD) patients accurately and promptly to prevent MMD from endangering their lives. A Pseudo-Three-Dimensional Residual Network (P3D ResNet) was proposed to process spatial and temporal information, which was implemented in the identification of MMD stages. Digital Subtraction Angiography (DSA) sequences were split into mild, moderate and severe stages in accordance with the progression of MMD, and divided into a training set, a verification set, and a test set with a ratio of 6:2:2 after data enhancement. The features of the DSA images were processed using decoupled three-dimensional (3D) convolution. To increase the receptive field and preserve the features of the vessels, decoupled 3D dilated convolutions that are equivalent to two-dimensional dilated convolutions, plus one-dimensional dilated convolution, were utilized in the spatial and temporal domains, respectively. Then, they were coupled in serial, parallel, and serial-parallel modes to form P3D modules based on the structure of the residual unit. The three kinds of module were placed in a proper sequence to create the complete P3D ResNet. The experimental results demonstrate that the accuracy of P3D ResNet can reach 95.78% with appropriate parameter quantities, making it easy to implement in a clinical setting.

Wavelet Analysis of Cerebral Oxygenation Signal Measured by Near-Infrared Spectroscopy in Moyamoya Disease.

Spontaneous low-frequency oscillations (LFOs) have been widely studied in cerebrovascular disease, but little is known about their role in moyamoya disease (MMD). The objective of this study was to assess the value of spontaneous LFOs in MMD based on wavelet analysis of near-infrared spectroscopy signals. Sixty-four consecutive idiopathic adult patients were prospectively enrolled. The regional tissue oxygenation index (TOI) obtained from continuous near-infrared spectroscopy signals. Five frequency intervals of spontaneous LFOs (I, 0.0095-0.02Hz; II, 0.02-0.06Hz; III, 0.06-0.15Hz; IV, 0.15-0.40Hz; and V, 0.40-2.00Hz) were extracted based on wavelet analysis. The data were compared between the patients and healthy control groups. Clinical features, cognitive function, and disease progression of MMD were analyzed using TOI and frequency interval data. Compared with the healthy control group, patients with MMD had a higher cerebral TOI in both hemispheres. Based on wavelet analysis, the spontaneous LFO of TOI was found to be significantly lower for patients with MMD in frequency intervals II to IV than that for the controls. The spontaneous LFO of TOI is also related to the Suzuki stages in intervals II to IV, stroke in interval III, and cognitive impairment in intervals III to Ⅳ. There were significant differences in spontaneous LFO between patients with MMD and healthy controls. The change in spontaneous LFO in MMD is related to Suzuki stage, cerebral infarction, and cognitive impairment. This might be an effective method for evaluating the severity and monitoring the progression of MMD.

Chinese expert consensus on the treatment of MMD

Moyamoya disease (MMD), also known as spontaneous occlusion of the circle of Willis, is defined by progressive stenosis or occlusion of the internal carotid arteries, and it can progress to the anterior, middle, and posterior cerebral arteries. As these arteries are gradually stenosed, a collateral network of capillaries develops at the base of the brain, producing the characteristic reticulate appearance (“puff of smoke”) on angiography. Therefore, it was named by Suzuki and Takaku in 1969 after the Japanese term “moyamoya” (Suzuki and Takaku, Arch Neurol 20:288–299, 1969). MMD is most common in East Asian countries such as Japan and Korea, and it shows a slight female predominance. MMD is mainly characterized by ischemia and hemorrhage. Hemorrhagic MMD is very rare in children, and most cases occur in adults due to the rupture of the compensatory blood vessels, which often leads to hemorrhagic symptoms (Scott and Smith, N Engl J Med 360:1226–1237, 2009). In recent years, the diagnosis rate has increased with the popularization of imaging techniques. However, the pathogenesis of MMD is still not completely understood, and there is currently no evidence to suggest that drug treatment can delay or even reverse the progression of MMD. The current drug treatment for in MMD only targets its clinical symptoms, including ischemia and hemorrhage. The main choice of treatment for MMD is surgical revascularization. As an increasing number of hospitals have developed surgical treatment for MMD, our compiling group has jointly discussed the formulation of a consensus among Chinese experts on the treatment of MMD.

CircZXDC Promotes Vascular Smooth Muscle Cell Transdifferentiation via Regulating miRNA-125a-3p/ABCC6 in Moyamoya Disease

Moyamoya disease (MMD) is an occlusive, chronic cerebrovascular disease affected by genetic mutation and the immune response. Furthermore, vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) participate in the neointima of MMD, but the etiology and pathophysiological changes in MMD vessels remain largely unknown. Therefore, we established the circZXDC (ZXD family zinc finger C)-miR-125a-3p-ABCC6 (ATP-binding cassette subfamily C member 6) axis from public datasets and online tools based on "sponge-like" interaction mechanisms to investigate its possible role in VSMCs. The results from a series of in vitro experiments, such as dual luciferase reporter assays, cell transfection, CCK-8 assays, Transwell assays, and Western blotting, indicate a higher level of circZXDC in the MMD plasma, especially in those MMD patients with the RNF213 mutation. Moreover, circZXDC overexpression results in a VSMC phenotype switching toward a synthetic status, with increased proliferation and migration activity. CircZXDC sponges miR-125a-3p to increase ABCC6 expression, which induces ERS (endoplasmic reticulum stress), and subsequently regulates VSMC transdifferentiation from the contractive phenotype to the synthetic phenotype, contributing to the intima thickness of MMD vessels. Our findings provide insight into the pathophysiological mechanisms of MMD and indicate that the circZXDC-miR-125a-3p-ABCC6 axis plays a pivotal role in the progression of MMD. Furthermore, circZXDC might be a diagnostic biomarker and an ABCC6-specific inhibitor and has the potential to become a promising therapeutic option for MMD.

Haley's beaded journey

Haley's beaded journey

Negative Remodeling of Carotid Canal during Spontaneous Disease Progression in Moyamoya Disease

This study was designed to observe the changes in the carotid canal over time by measuring the carotid canal diameter longitudinally in adult patients with moyamoya disease in whom disease stage progressed spontaneously. Of 70 adult patients with moyamoya disease, 10 adult patients on 15 sides with spontaneous progression of the disease stage during conservative follow-up were included in this study. Another 10 moyamoya cases on 15 sides were selected as the controls without disease progression. All patients were followed up for at least 60 months after the progression of disease stage was confirmed. In addition, 5 patients who underwent microvascular decompression were included as healthy controls. The carotid canal diameter was measured with bone window computed tomography (CT) and source images of time-of-flight magnetic resonance angiography at initial presentation, and then were serially monitored with the latter. There was a significant correlation between the values obtained from CT and magnetic resonance imaging (R2= 0.992, P < 0.001). The carotid canal diameter in moyamoya disease at initial presentation was 4.29 ± 0.61 mm, being smaller than 5.20 ± 0.51 mm in healthy controls (P < 0.01). In response to disease progression, the carotid canal diameter started to decrease at 6 months after disease progression was confirmed, and reduced to about 85% of the original level during 60 months (P < 0.01). The phenomenon was not observed in patients without disease progression. The carotid canal diameter can decrease in response to disease progression even in adult moyamoya disease. "Negative" bone remodeling may play a key role in this unique phenomenon.

Progression in Moyamoya Disease: Clinical Features, Neuroimaging Evaluation, and Treatment.

Moyamoya disease (MMD) is a chronic cerebrovascular disease characterized by progressive stenosis of the arteries of the circle of Willis, with the formation of collateral vascular network at the base of the brain. Its clinical manifestations are complicated. Numerous studies have attempted to clarify the clinical features of MMD, including its epidemiology, genetic characteristics, and pathophysiology. With the development of neuroimaging techniques, various neuroimaging modalities with different advantages have deepened the understanding of MMD in terms of structural, functional, spatial, and temporal dimensions. At present, the main treatment for MMD focuses on neurological protection, cerebral blood flow reconstruction, and neurological rehabilitation, such as pharmacological treatment, surgical revascularization, and cognitive rehabilitation. In this review, we discuss recent progress in understanding the clinical features, in the neuroimaging evaluation and treatment of MMD.

Quantification of vessel wall contrast enhancement to monitor disease progression in Moyamoya disease

Quantification of vessel wall contrast enhancement to monitor disease progression in Moyamoya disease

PHACTR1 is associated with disease progression in Chinese Moyamoya disease.

Moyamoya disease (MMD) is a progressive stenosis at the terminal portion of internal carotid artery and frequently occurs in East Asian countries. The etiology of MMD is still largely unknown. We performed a case-control design with whole-exome sequencing analysis on 31 sporadic MMD patients and 10 normal controls with matched age and gender. Patients clinically diagnosed with MMD was determined by digital subtraction angiography (DSA). Twelve predisposing mutations on seven genes associated with the sporadic MMD patients of Chinese ancestry (CCER2, HLA-DRB1, NSD-1, PDGFRB, PHACTR1, POGLUT1, and RNF213) were identified, of which eight single nucleotide variants (SNVs) were deleterious with CADD PHRED scaled score > 15. Sanger sequencing of nine cases with disease progression and 22 stable MMD cases validated that SNV (c.13185159G>T, p.V265L) on PHACTR1 was highly associated with the disease progression of MMD. Finally, we knocked down the expression of PHACTR1 by transfection with siRNA and measured the cell survival of human coronary artery endothelial cell (HCAEC) cells. PHACTR1 silence reduced the cell survival of HCAEC cells under serum starvation cultural condition. Together, these data identify novel predisposing mutations associated with MMD and reveal a requirement for PHACTR1 in mediating cell survival of endothelial cells.

Digital subtraction angiographic characteristics of progression of moyamoya disease 6 months prior to surgical revascularisation

BackgroundEvidence on the natural angiographic course of moyamoya disease (MMD) is lacking. It takes about 6 months for waiting for revascularisation surgery. The issue of when to perform subtraction angiography...

The Impact of Moyamoya Disease and RNF213 Mutations on the Spectrum of Plasma Protein and MicroRNA.

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by occlusion of bilateral internal carotid and intracerebral arteries with the compensatory growth of fragile small vessels. MMD patients develop recurrent infarctions in the basal ganglia and subcortical regions. Symptoms include transient ischemic attack or stroke, seizures, and headaches, which may occur suddenly or in a stepwise progression. Mutations in Ring Finger Protein 213 (RNF213), a Zinc ring finger protein, have been identified in some MMD patients but the etiology of MMD is still largely unknown. To gain insight into the pathophysiology of MMD, we characterized the impact of the RNF213 mutations on plasma protein and RNA profiles. Isobaric tags for relative and absolute quantitation and proximity extension assay were used to characterize the plasma proteome. Next generation sequencing-based small RNAseq was used to analyze the cell-free small RNAs in whole plasma and RNA encapsulated in extracellular vesicles. The changes of miRNAs and proteins identified are associated with signaling processes including angiogenesis and immune activities which may reflect the pathology and progression of MMD.

Progressive Shrinkage of Involved Arteries in Parallel with Disease Progression in Moyamoya Disease

Recent three-dimensional constructive interference in steady state (3D-CISS) studies have shown that the involved arteries decrease not only their own luminal caliber but also outer diameter in moyamoya disease (MMD). This study was aimed to clarify how the outer diameter of the involved arteries serially change during disease progression in MMD using qunatitaive 3D-CISS imaging. This study included 8 hemispheres of 7 patients with MMD whose Suzuki angiographic stage spontaneously progressed during follow-up. Using 3D-CISS, the outer diameter was quantified serially in supraclinoid portion of internal carotid artery (C1), the horizontal portion of middle and anterior cerebral arteries (M1 and A1, respectively) before and after the spontaneous disease progression, and also 3-12 months later. In 7 hemispheres with early disease stage (stage 1-3) at initial presentation, the involved arteries decreased in their outer dimater in parallel with luminal stenosis during spontaneous disease progression in the C1 (P= 0.005), M1 (P < 0.0001), and A1 portions (P= 0.0048). In the remaining 1 hemisphere with stage 4 at initial presentation, 3D-CISS imaging showed no significant change in the outer diameter of C1, M1, and A1 segments during disease progression. Using quantitative 3D-CISS imaging, this study clearly shows that the involved arteries serially decrease in their own outer diameter in parallel with luminal stenosis during spontaneous disease progression in early stages of MMD (stage 1-3). This phenomenon has not been reported previously and may result from the pathognomic mechanisms underlying the development of MMD.

Downregulation of Apolipoprotein-E and Apolipoprotein-J in Moyamoya Disease—A Proteome Analysis of Cerebrospinal Fluid

Genetic factors are closely involved in the etiology of moyamoya disease (MMD). However, its postgenomic mechanisms are still unknown. This study was aimed to identify specific biomarkers in the cerebrospinal fluid (CSF) of patients with MMD, using quantitative proteome technique. This study included 10 patients with MMD and 4 controls. The CSF was collected without blood contamination during surgery. A comparative 2-dimensional gel electrophoresis study (2D-PAGE) was performed. Protein spots that showed significant differences between moyamoya patients and controls were selected for further analysis by mass spectrometry. On 2D-PAGE, 2 proteins were significantly upregulated, and 2 other proteins were downregulated in the CSF of MMD. Further mass spectrometry analysis revealed that haptoglobin and α-1-B-glycoprotein (A1BG) were upregulated. On the other hand, apolipoprotein-E (apoE), apoE precursor, and apolipoprotein-J (apoJ) were significantly downregulated in the CSF of MMD. The observed probability-based MOWSE score was 72 for haptoglobin (P <.05), 521 for A1BG (P <.05), 62 for apoE (P <.05), 72 for apoE precursor (P <.05), and 112 for apoJ (P <.05). Although the role of A1BG in the central nervous system is still unknown, the overexpressed haptoglobin may indicate the inflammation and/or angiogenesis in MMD. The downregulation of apoE and apoJ strongly suggests a critical role of lipid metabolism in the development and progression of MMD. These proteins may be novel biomarkers in shedding light on the pathogenesis of MMD, although further studies would be warranted.