Molecular Biomarkers Affecting Moyamoya Disease.

Although the pathogenetic pathway of moyamoya disease (MMD) remains unknown, studies have indicated that variations in the RING finger protein RNF 213 is the strongest susceptible gene of MMD. In addition to the polymorphism of this gene, many circulating angiogenetic factors such as growth factors, vascular progenitor cells, inflammatory and immune mediators, angiogenesis related cytokines, as well as circulating proteins promoting intimal hyperplasia, excessive collateral formation, smooth muscle migration and atypical migration may also play critical roles in producing this disease. Identification of these circulating molecules biomarkers may be used for the early detection of this disease. In this chapter, how the hypothesized pathophysiology of these factors affect MMD and the interactive modulation between them are summarized.

Identification of diagnostic markers for moyamoya disease by combining bulk RNA-sequencing analysis and machine learning.

Moyamoya disease (MMD) remains a chronic progressive cerebrovascular disease with unknown etiology. A growing number of reports describe the development of MMD relevant to infection or autoimmune diseases. Identifying biomarkers of MMD is to understand the pathogenesis and development of novel targeted therapy and may be the key to improving the patient's outcome. Here, we analyzed gene expression from two GEO databases. To identify the MMD biomarkers, the weighted gene co-expression network analysis (WGCNA) and the differential expression analyses were conducted to identify 266 key genes. The KEGG and GO analyses were then performed to construct the protein interaction (PPI) network. The three machine-learning algorithms of support vector machine-recursive feature elimination (SVM-RFE), random forest and least absolute shrinkage and selection operator (LASSO) were used to analyze the key genes and take intersection to construct MMD diagnosis based on the four core genes found (ACAN, FREM1, TOP2A and UCHL1), with highly accurate AUCs of 0.805, 0.903, 0.815, 0.826. Gene enrichment analysis illustrated that the MMD samples revealed quite a few differences in pathways like one carbon pool by folate, aminoacyl-tRNA biosynthesis, fat digestion and absorption and fructose and mannose metabolism. In addition, the immune infiltration profile demonstrated that ACAN expression was associated with mast cells resting, FREM1 expression was associated with T cells CD4 naive, TOP2A expression was associated with B cells memory, UCHL1 expression was associated with mast cells activated. Ultimately, the four key genes were verified by qPCR. Taken together, our study analyzed the diagnostic biomarkers and immune infiltration characteristics of MMD, which may shed light on the potential intervention targets of moyamoya disease patients.

Comparison of Changes in Retinal Vascular Parameters and Density in Patients with Moyamoya Disease: A Retrospective Study.

INTRODUCTION: This study aimed to compare retinal vascular parameters and density in patients with moyamoya disease using the optical coherence tomography angiography. METHODS: This clinical trial totally enrolls 78 eyes from 39 participants, and all these patients with moyamoya disease (N = 13) are set as experimental group and participants with health who matched with age and gender are considered as the control group (N = 26). Then all these participants receive optical coherence tomography angiography detection. Participants' general data are collected and analyzed. Skeleton density (SD) value, vessel density (VD) value, fractal dimension (FD) value, vessel diameter index (VDI) value, foveal avascular zone (FAZ) value are analyzed. RESULTS: A total of 39 participants are included in this study. The SD value in the experimental group was significantly lower than that in control group (0.175 [0.166, 0.181] vs. 0.184 [0.175, 0.188], p = 0.017). Similarly, the VD value in the experimental group was significantly lower than that in the control group (0.333 [0.320, 0.350] vs. 0.354 [0.337, 0.364], p = 0.024). Additionally, the FD value in the experimental group was significantly lower than that in the control group (2.088 [2.083, 2.094] vs. 2.096 [2.090, 2.101], p = 0.022). As for the VDI and FAZ, VDI and FAZ values in the experimental group were lower than those in the control group, there was no significant difference in VDI and FAZ values between the two groups. CONCLUSIONS: Our study, using non-invasive and rapid OCTA imaging, confirmed decreased retinal vascular parameters and density in patients with moyamoya disease.

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

OBJECTIVE: Moyamoya 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. METHODS: In 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. RESULTS: The 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). CONCLUSIONS: Our 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.

Long-term stroke risk in Moyamoya disease.

BACKGROUND: Moyamoya disease (MMD) is considered a progressive disease with an ongoing risk of recurrent stroke. However, there is a lack of long-term observational data to quantify the extent of the stroke risk. METHODS: This study aimed to provide insight into the long-term stroke risk in MMD and explore possible risk factors for stroke. Records from all patients diagnosed with MMD in 13 clinical departments from 6 different Danish hospitals between 1994 and 2017 were retrospectively reviewed until 2021. RESULTS: The cohort comprised 50 patients (33 females and 17 males). Patients were followed up for a median of 9.4 years, with more than 10 years of follow-up for 24 patients. Ten patients had 11 new stroke events-6 ischemic strokes and 5 brain hemorrhages. Events occurred at a median of 7 years and up to 25 years after diagnosis. The overall Kaplan-Meier 5-year stroke risk was 10%. Patients with bypass performed had significantly fewer events than conservatively treated patients (HR 0.25, 95% confidence interval (CI) 0.07-0.91, p < 0.05). All but one event occurred in females, a difference that reached statistical significance. CONCLUSIONS: The study provides data on the extent of the risk of recurrent stroke in MMD. Bypass surgery patients had fewer stroke events than those treated conservatively. There was a trend toward a higher stroke risk in females. DATA ACCESS STATEMENT: The data supporting this study's findings are available from the corresponding author upon reasonable request.

Recurrent Cerebral Infarction Due to Moyamoya Disease Complicated With Systemic Lupus Erythematosus: A Case Report and Literature Review.

INTRODUCTION: We report a rare case of moyamoya disease caused by an RNF213 mutation, complicated with systemic lupus erythematosus. CASE REPORT: A 32-year-old woman experienced 4 cerebral ischemia stroke events within 6 months. The main symptom was left limb weakness with blurred vision in the right eye. Results of digital subtraction angiography conducted at another hospital were consistent with moyamoya disease. On genetic testing, we found that the patient carried 2 mutations in the moyamoya disease-related gene RNF213 (p.R4810K, p.T1727M). On the basis of the laboratory immunologic indicators, such as positive antibodies and abnormal immunoglobulin levels and imaging examinations, the patient was finally diagnosed as moyamoya disease complicated with systemic lupus erythematosus. She was treated with aspirin, butylphthalide, urinary kallidinogenase, and sodium methylprednisolone. CONCLUSIONS: This was a 32-year-old young patient diagnosed with moyamoya disease carrying RNF213 gene mutation and accompanied by lupus with cerebral ischemic event as the first occurrence. The patient's condition was complex; therefore, comprehensive analysis and in-depth consideration were needed to avoid a missed diagnosis and misdiagnosis. When the primary disease cannot be identified, genetic testing can help to clarify the diagnosis of moyamoya disease.

Yield of genetic evaluation in non-syndromic pediatric moyamoya patients.

PURPOSE: Few guidelines exist for genetic testing of patients with moyamoya arteriopathy. This study aims to characterize the yield of genetic testing of non-syndromic moyamoya patients given the current pre-test probability. METHODS: All pediatric moyamoya patients who received revascularization surgery at one institution between 2018 and 2022 were retrospectively reviewed. Patients with previously diagnosed moyamoya syndromes or therapeutic cranial radiation were excluded. RESULTS: Of 117 patients with moyamoya, 74 non-syndromic patients (44 females, 59%) were eligible. The median age at surgery was 8.1 years. Neurosurgeons referred 18 (24%) patients for neurogenetic evaluation. Eleven (61%) patients subsequently underwent genetic testing. Eight (73%) patients had available testing results. Five (62.5%) of these patients had developmental delay compared to 16 (22%) of the entire cohort. Six (75%) patients who underwent genetic testing were found to have at least one genetic variant. These results led to diagnosis of a new genetic disorder for 1 (12.5%) patient and screening recommendations for 2 (25%) patients. An RNF213 variant in one patient led to recommendations for family member screening and pulmonary hypertension screening. Another patient was diagnosed with CBL disorder and referred for cancer screening. The median age at surgery in patients with clinically actionable findings was 4.6 years compared to 9.2 years in those who were referred for genetic testing. All 3 patients who had an actionable finding had developmental delay. CONCLUSION: It may be beneficial to refer moyamoya patients under 5 for genetic screening given the high likelihood of discovering actionable mutations.

Moyamoya disease/cerebral vasculopathy in osteopathia striata with cranial sclerosis: a rare but important complication.

Osteopathia striata with cranial sclerosis (OSCS) is a rare X-linked dominant sclerosing osteodysplasia, due to AMER1 pathogenic variants. Characteristic features include craniofacial sclerosis and long-bone metaphyseal striations. Moyamoya disease (a type of progressive cerebral vasculopathy) and other types of cerebral vascular disease are not currently clearly associated with OSCS (except for two separate case reports), and can often first present with stroke. Through informal networks with UK-based bone experts and the UK skeletal dysplasia group, three cases from the UK and Ireland were identified. Medical literature was also reviewed to identify the known cases of OSCS with the described complications. We report four females, in whom OSCS and cerebral vasculopathy co-exist, with varying clinical outcomes. There appears to be an emerging association between OSCS and cerebral vasculopathy, which pre-disposes patients to stroke. Given this, screening OSCS patients for cerebral vasculopathy may be of value, especially pre-surgery. Further research regarding optimal screening and management is needed. The mechanism of cerebral vasculopathy and its progression remain unclear.

RNF213 vasculopathy manifested in various forms within a family: A case report.

RATIONALE: The ring finger protein 213 (RNF213) p.R4810K variant has been identified as being associated with Moyamoya disease (MMD), a condition that is more prevalent in East Asians. This association extends beyond cerebral vessels and has been implicated in coronary artery disease. PATIENT CONCERNS: A 36-year-old female was admitted to the emergency room with chest pain. Although the patient had no known underlying conditions or risk factors for atherosclerosis, she was diagnosed with unstable angina and underwent percutaneous coronary intervention. Given her older sister's ongoing treatment for MMD, it was suspected that the patient's coronary artery disease might be linked to the MMD-associated gene mutation. DIAGNOSES: Coronary angiography revealed 80% narrowing of the proximal left anterior descending artery. Based on clinical symptoms and coronary angiography, we diagnosed it as unstable angina. INTERVENTION: Due to the family history of MMD and detection of the RNF213 p.R4810K heterozygous variant in the patient's older sister, genetic counseling was recommended. Next-generation sequencing for vascular diseases was performed. OUTCOMES: Genetic testing confirmed the presence of an RNF213 p.R4810K heterozygous variant in the patient, mirroring that in her sister. An RNF213 p.C4397R heterozygous variant was identified concomitantly, although it was categorized as a variant of uncertain significance. Coronary artery disease has been attributed to the RNF213 p.R4810K variant. LESSONS: Although MMD is rare in Western populations, it is more common in East Asian populations. Traditionally, MMD diagnoses have focused solely on the cerebral vessels without guidelines for the assessment of other vascular involvements. This familial case underscores the fact that a single genetic mutation can manifest in diverse ways in different diseases. Hence, the need and regularity of systemic vessel screening should be thoughtfully considered in such a context.

Safe delivery planning of patients with moyamoya disease in pregnancy: Case series of a single center.

OBJECTIVE: Moyamoya disease (MMD) is a rare cerebral vascular disease and there is limited clinical experience for pregnant women. Cerebrovascular condition might deteriorated during pregnancy. Management and mode of delivery is challenging for obstetrics specialist. CASE REPORT: Three cases of parturients with moyamoya disease delivered in National Taiwan University Hospital are presented. All were previously diagnosed and one had stroke incidence before current pregnancy course. Two delivered with Cesarean section and one with vaginal delivery, and all delivered at term without maternal or neonatal complication. CONCLUSION: Although delivery method of parturients with MMD has been debating, vaginal delivery may be suitable for certain cases under adequate monitoring and case selection.

Clinical features, surgical treatment, and long-term outcomes of moyamoya disease in a single institution of Fujian, Southeast China: A retrospective study.

At present, detailed demographic and clinical data of moyamoya disease (MMD) in the population of Southeast China are lacking. Therefore, this study aimed to evaluate the epidemiological and clinical features of MMD in Southeast China. Our cohort included 170 patients diagnosed with MMD over the preceding 5 years. Clinical characteristics were obtained through a retrospective chart review, while follow-up information and outcomes were obtained through clinical visits and imaging. The median age at symptom onset was 49 years (range 4-73), with a peak in the age distribution observed at 41 to 60 years. The female-to-male ratio was 1.125 (90/80), and the ratio of the ischemic type to the hemorrhagic type was 2.33 (119/50). The most common initial symptom was an ischemic event. The 5-year Kaplan-Meier risk of stroke was 4.9% for all patients treated with surgical revascularization. Of all patients, 83.9% were able to live independently with no significant disability, and 89.8% showed improved cerebral hemodynamics. Our study provided detailed demographic and clinical data on Southeastern Chinese patients with MMD, which was consistent with findings in other parts of China. Raising clinical awareness of MMD in primary hospitals is important to facilitate early diagnosis and timely treatment of MMD patients.

How I do it: direct pressure measurement in moyamoya bypass.

BACKGROUND: The direct quantitative measurement of donor and recipient pressures in patients with moyamoya vasculopathy (MMV) during superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery has yet to be reported in academic literature. METHOD: Using a wireless pressure wire, we describe our approach to measuring seven pressure parameters in MMV patients step-by-step. CONCLUSION: Direct intraluminal pressure measurement of donor and recipient arteries provides a practical and accurate means to quantify cerebral hemodynamic parameters in MMV patients, enhancing understanding of individualized hemodynamic changes pre- and post-surgery.

Adult Moyamoya Disease and Syndrome: Current Perspectives and Future Directions: A Scientific Statement From the American Heart Association/American Stroke Association.

Adult moyamoya disease and syndrome are rare disorders with significant morbidity and mortality. A writing group of experts was selected to conduct a literature search, summarize the current knowledge on the topic, and provide a road map for future investigation. The document presents an update in the definitions of moyamoya disease and syndrome, modern methods for diagnosis, and updated information on pathophysiology, epidemiology, and both medical and surgical treatment. Despite recent advancements, there are still many unresolved questions about moyamoya disease and syndrome, including lack of unified diagnostic criteria, reliable biomarkers, better understanding of the underlying pathophysiology, and stronger evidence for treatment guidelines. To advance progress in this area, it is crucial to acknowledge the limitations and weaknesses of current studies and explore new approaches, which are outlined in this scientific statement for future research strategies.

Single-cell sequencing analysis of peripheral blood in patients with moyamoya disease.

BACKGROUND: At present, the etiology of moyamoya disease is not clear, and it is necessary to explore the mechanism of its occurrence and development. Although some bulk sequencing data have previously revealed transcriptomic changes in Moyamoya disease, single-cell sequencing data has been lacking. METHODS: Two DSA(Digital Subtraction Angiography)-diagnosed patients with moyamoya disease were recruited between January 2021 and December 2021. Their peripheral blood samples were single-cell sequenced. CellRanger(10 x Genomics, version 3.0.1) was used to process the raw data, demultiplex cellular barcodes, map reads to the transcriptome, and dowm-sample reads(as required to generate normalized aggregate data across samples). There were 4 normal control samples, including two normal samples GSM5160432 and GSM5160434 of GSE168732, and two normal samples of GSE155698, namely GSM4710726 and GSM4710727. Weighted co-expression network analysis was used to explore the gene sets associated with moyamoya disease. GO analysis and KEGG analysis were used to explore gene enrichment pathways. Pseudo-time series analysis and cell interaction analysis were used to explore cell differentiation and cell interaction. RESULTS: For the first time, we present a peripheral blood single cell sequencing landscape of Moyamoya disease, revealing cellular heterogeneity and gene expression heterogeneity. In addition, by combining with WGCNA analysis in public database and taking intersection, the key genes in moyamoya disease were obtained. namely PTP4A1, SPINT2, CSTB, PLA2G16, GPX1, HN1, LGALS3BP, IFI6, NDRG1, GOLGA2, LGALS3. Moreover, pseudo-time series analysis and cell interaction analysis revealed the differentiation of immune cells and the relationship between immune cells in Moyamoya disease. CONCLUSIONS: Our study can provide information for the diagnosis and treatment of moyamoya disease.

Plasma exosomal microRNAs are non-invasive biomarkers of moyamoya disease: A pilot study.

BACKGROUND: As a progressive cerebrovascular disease, Moyamoya Disease (MMD) is a common cause of stroke in children and adults. However, the early biomarkers and pathogenesis of MMD remain poorly understood. METHODS AND MATERIAL: This study was conducted using plasma exosome samples from MMD patients. Next-generation high-throughput sequencing, real-time quantitative PCR, gene ontology analysis, and Kyoto Encyclopaedia of Genes and Genomes pathway analysis of ideal exosomal miRNAs that could be used as potential biomarkers of MMD were performed. The area under the Receiver Operating Characteristic (ROC) curve was used to evaluate the sensitivity and specificity of biomarkers for predicting events. RESULTS: Exosomes were successfully isolated and miRNA-sequence analysis yielded 1,002 differentially expressed miRNAs. Functional analysis revealed that they were mainly enriched in axon guidance, regulation of the actin cytoskeleton and the MAPK signaling pathway. Furthermore, 10 miRNAs (miR-1306-5p, miR-196b-5p, miR-19a-3p, miR-22-3p, miR-320b, miR-34a-5p, miR-485-3p, miR-489-3p, miR-501-3p, and miR-487-3p) were found to be associated with the most sensitive and specific pathways for MMD prediction. CONCLUSIONS: Several plasma secretory miRNAs closely related to the development of MMD have been identified, which can be used as biomarkers of MMD and contribute to differentiating MMD from non-MMD patients before digital subtraction angiography.

A case of moyamoya disease diagnosed as cerebral infarction in the early postpregnancy period and surgically treated by bilateral revascularization after term delivery.

We treated a 37-year-old Japanese woman with moyamoya disease who developed cerebral infarction in the early period after pregnancy and had undergone infertility treatment. After being adequately informed, including regarding the risk of stroke in the perinatal period and the option to prioritize the treatment of moyamoya disease even if the pregnancy was interrupted, the patient decided to continue the pregnancy and underwent surgical treatment after a full-term delivery by caesarean section. No new stroke was observed throughout the perinatal period or postoperative course. Since serious stroke during the perinatal period has also been reported in moyamoya disease, it is important to plan "tailored" treatment by sufficiently informing patients considering individual backgrounds and for multiple medical departments, including obstetrics, neurology, and neurosurgery departments, to carry out close outpatient follow-up in the perinatal period and carefully careful medication usage and radiological examinations.

Assessment of plasma soluble Tie-2 level to distinguish moyamoya disease from atherosclerotic cerebrovascular disease and predict postoperative neovascularization.

OBJECTIVE: Moyamoya disease (MMD) is a chronic steno-occlusive cerebrovascular disease and features the formation of hazy collateral vessels at the base of the brain. Angiopoietin (Ang)-1 and -2, their receptor Tie-2, and vascular endothelial growth factor (VEGF) that regulate angiogenesis might be important in MMD pathophysiology and postoperative collateral formation. The goal of this study was to determine whether levels of these angiogenic factors could predict collateralization in patients with MMD. METHODS: A total of 196 patients with MMD and 57 with atherosclerotic cerebrovascular disease serving as controls were enrolled. Ang-1, Ang-2, Tie-2, and VEGF mRNA levels were analyzed in middle cerebral artery (MCA) arterial wall specimens by using real-time quantitative polymerase chain reaction. MCA and peripheral plasma concentrations of Ang-1, Ang-2, soluble Tie-2 (sTie-2), and VEGF were examined by enzyme-linked immunosorbent assay. Cerebral arteriography was performed 6 months after bypass surgery to assess the postoperative collateralization. RESULTS: In MCA specimens, patients with MMD exhibited higher expression levels of Ang-1 and Ang-2 but lowered VEGF expression. The patients with MMD had significantly higher concentrations of Ang-1 and Ang-2 but lower levels of VEGF in MCA plasma. Peripheral plasma concentrations of these growth factors were not changed. MCA and peripheral plasma sTie-2 levels were both reduced in patients with MMD. The 6-month follow-up showed that patients with good collateral formation had lower sTie-2 levels in both MCA and peripheral plasma. Furthermore, the Suzuki stage and peripheral plasma sTie-2 level were significantly correlated with good postoperative collateral formation on multivariate analysis. CONCLUSIONS: Ang-1, Ang-2, Tie-2, and VEGF are involved in MMD pathogenesis. The peripheral plasma level of sTie-2 can differentiate MMD from atherosclerotic cerebrovascular disease and serve as a novel biomarker to predict postoperative collateral formation.

Disappearance of hemichorea as the initial presentation of moyamoya disease after revascularization surgery regardless of residual hypoperfusion evaluated by quantitative N-isopropyl-p-123I-iodoamphetamine SPECT.

BACKGROUND AND IMPORTANCE: Although hypoperfusion of the basal ganglia or the frontal subcortical matter is suspected, the pathology of chorea in moyamoya disease remains unclarified. Herein, we report a case of moyamoya disease presenting with hemichorea and evaluate pre- and postoperative perfusion using single photon emission computed tomography with N-isopropyl-p-123I-iodoamphetamine (123I-IMP SPECT). CLINICAL PRESENTATION: An 18-year-old woman presented with choreic movement of her left limbs. Magnetic resonance imaging revealed an ivy sign, and 123I-IMP SPECT demonstrated decreased cerebral blood flow (CBF) and cerebral vascular reserve (CVR) values in the right hemisphere. The patient underwent direct and indirect revascularization surgery to improve cerebral hemodynamic impairment. The choreic movements entirely resolved immediately after surgery. Although CBF and CVR values in the ipsilateral hemisphere demonstrated by quantitative SPECT increased, these did not reach the normal values threshold. CONCLUSION: Choreic movement in moyamoya disease may be related to cerebral hemodynamic impairment. Further studies are required to elucidate its pathophysiological mechanisms.