Etiology Of Moyamoya Disease Research Articles

SAT474 A Case Report Of Moyamoya Disease Associated With Uncontrolled Graves' Disease

Abstract Disclosure: Z. Tan: None. E. Briggie: None. M. Correia: None. Background: Moyamoya disease is an uncommon cerebrovascular disease that is featured by narrowing of large intracranial arteries and the development of prominent small-vessel collaterals. The etiology of Moyamoya disease is unknown, but it can be associated with multiple conditions including atherosclerosis, sickle cell disease, and Protein S deficiency. It is rarely associated with uncontrolled Graves’ disease. Clinical Case: A 37-year-old female with a history of Graves’ disease and type 1 diabetes presented with sudden onset of slurred speech and right-sided weakness. A CTA of the head and neck showed a small hypodensity in the left basal ganglia without corresponding perfusion deficit and narrowed left internal carotid arteries without focal stenosis. In addition, a brain MRI showed patchy infarcts in the left middle cerebral artery territory. A cervical and cerebral angiogram showed multiple areas of stenosis which was concerning for Moyamoya disease. She ultimately underwent balloon angioplasty of the left internal carotid artery with improvement in perfusion. During the workup for secondary causes of Moyamoya disease, her TSH was < 0.01 µIU/mL (0.270-4.20 µIU/mL), with elevated T4 at 3.84 ng/dl (0.80-1.80 ng/dl) and elevated TSI at 15.5 IU/L (< 0.54 IU/L). Importantly, she was diagnosed with Graves’ disease 2 years before admission, and this condition has never been well controlled due to poor compliance with methimazole. A TSH measured 5 months before admission was also undetectable with elevated T4 at 2.8 ng/dl. Her other workups for Moyamoya disease were negative including HIV antigen/antibody, syphilis IgG antibody, Lyme disease IgG & IgM antibodies, hepatitis panel antibodies, ANA, ANCA, free protein S, dsDNA antibody, factor 5 Leiden mutation, vascular endothelial growth factor-D and urine drug screening test. She started methimazole 20 mg daily and was discharged to acute rehabilitation. After rehabilitation, her Graves’ disease is slowly improving with most recent TSH < 0.008 µIU/mL and free T4 at 2.39 ng/dl. She is almost back to her baseline with significant improvement in speech and strength. Conclusion: Uncontrolled Graves’ disease should be considered in the differential diagnosis of Moyamoya disease in young subjects who present with stroke-like symptoms. Reference: Ischemic Stroke and Intraventricular Hemorrhage in Moyamoya Syndrome Associated With Graves' Disease: A Case Report. Neurologist 2022 Presentation Date: Saturday, June 17, 2023

Application of Induced Pluripotent Stem Cells in Moyamoya Disease: Progress and Promises.

Moyamoya disease (MMD) is a chronic steno-occlusion cerebrovascular disease accompanied by the formation of the abnormal vascular network at the base of the brain. The etiology of MMD is not fully clarified. Lack of pathological specimens hinders the research progress. Induced pluripotent stem cells (iPSC) derived from patients with outstanding differentiation potential and infinite proliferation ability could conquer the problem of insufficient samples. The technology of iPSC holds the promise of clarifying the underlying molecular mechanism in the development of MMD. In this review, we summarized the latest progress and difficulties in the research of mechanism and detailed the application of iPSC in MMD, aiming to provide an outlook of iPSC in molecular mechanism and novel therapies of MMD.

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

BackgroundAt 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.MethodsTwo 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.ResultsFor 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.ConclusionsOur study can provide information for the diagnosis and treatment of moyamoya disease.

Rare variants in ANO1, encoding a calcium-activated chloride channel, predispose to moyamoya disease.

Moyamoya disease, a cerebrovascular disease leading to strokes in children and young adults, is characterized by progressive occlusion of the distal internal carotid arteries and the formation of collateral vessels. Altered genes play a prominent role in the aetiology of moyamoya disease, but a causative gene is not identified in the majority of cases. Exome sequencing data from 151 individuals from 84 unsolved families were analysed to identify further genes for moyamoya disease, then candidate genes assessed in additional cases (150 probands). Two families had the same rare variant in ANO1, which encodes a calcium-activated chloride channel, anoctamin-1. Haplotype analyses found the families were related, and ANO1 p.Met658Val segregated with moyamoya disease in the family with an LOD score of 3.3. Six additional ANO1 rare variants were identified in moyamoya disease families. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harbouring these gain-of-function ANO1 variants had classic features of moyamoya disease, but also had aneurysm, stenosis and/or occlusion in the posterior circulation. Our studies support that ANO1 gain-of-function pathogenic variants predispose to moyamoya disease and are associated with unique involvement of the posterior circulation.

Familial Risk for Moyamoya Disease Among First-Degree Relatives, Based on a Population-Based Aggregation Study in Korea

Genetic factors have been known to play a role in the etiology of moyamoya disease (MMD); however, population-level studies quantifying familial risk estimates are unavailable. We aimed to quantify familial incidence and risk for MMD in first-degree relatives (FDR) in the general population of Korea. By using the Korean National Health Insurance database which has complete population coverage and confirmed FDR information, we constructed a cohort of 21 940 795 study subjects constituting 12 million families with blood-related FDR and followed them for a familial occurrence of MMD from 2002 to 2017. Incidence risk ratios were calculated as MMD incidence in individuals with affected FDR compared with those without affected FDR, according to age, sex, and family relationships. Among total study subjects, there were 22 459 individuals with affected FDR, of whom 712 familial cases developed MMD with an incidence of 21.8/104 person-years. Overall, the familial risk for MMD was 132-fold higher in individuals with versus without affected FDR. Familial risk (incidence risk ratio; incidence/104 person-years) increased with the degree of genetic relatedness, being highest in individuals with an affected twin (1254.1; 230.0), followed by a sibling (212.4; 35.6), then mother (87.7; 14.4) and father (62.5; 10.4). Remarkably, there was no disease concordance between spouses. The risks were age-dependent and were particularly high in younger age groups. Familial risks were similar in males and females, and the risk of disease transmission was higher in same-sex parent-offspring and sibling pairs. Our study indicates that genetic predisposition is the predominant driver in MMD pathogenesis, with minimal contribution of environmental factors. These results could be utilized to direct future genetic studies and clinical risk counseling.

Decreased cortical perfusion in areas with blood-brain barrier dysfunction in Moyamoya disease.

Recently, several studies have focused on the relationship between blood-brain barrier (BBB) impairment and the etiology of Moyamoya disease (MMD). However, in vivo studies investigating about BBB impairment and cortical perfusion in MMD patients were really rare. This study included 16 patients diagnosed with MMD and 9 patients with atherosclerotic cerebrovascular disease (ACVD); all of who were treated with superficial temporal artery-middle cerebral artery (STA-MCA) bypass. Cortical perfusion was assessed using intraoperative indocyanine green (ICG) videoangiography by calculating the blood flow index (BFI). In addition, we used sodium fluorescein (NaFl) to evaluate the permeability of BBB in vivo during operation. The results showed that BBB impairment in MMD patients was more significant than that in ACVD patients, whereas, the cortical perfusion was comparable between two groups. BFI was significantly improved after STA-MCA bypass both in the MMD group (post-operation vs pre-operation: 109.2 ± 67.7 vs 64.3 ± 35.0, p = 0.004) and the ACVD group (post-operation vs pre-operation: 137.6 ± 89.6 vs 90.8 ± 58.3, p = 0.015). Moreover, BFI was significantly decreased in the cortex with BBB impairment as compared with that in the cortex with intact BBB (impaired BBB vs intact BBB: 55.7 ± 26.5 vs 87.6 ± 55.1, p = 0.025). Following bypass, the cortical perfusion significantly improved in the area of BBB impairment (post-operation vs pre-operation: 93.8 ± 75.2 vs 55.7 ± 26.5, p = 0.004), which was not observed in the BBB intact area (post-operation vs pre-operation: 92.4 ± 50.4 vs 87.6 ± 55.1, p = 0.58). In summary, we observed that BBB impairment in MMD patients was more significant than that in ACVD patients. This study also demonstrated for the first time that cortical perfusion was significantly decreased in the cortex with BBB impairment as compared with that in the cortex with intact BBB in MMD patients. We also observed that After STA-MCA bypass, the cortical perfusion was significantly improved in the cortex with BBB impairment. These results may provide a new insight for BBB impairment and cortical perfusion in the etiology of MMD.

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.

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.

Arterial wall contrast enhancement in progressive moyamoya disease.

The purpose of this study was to evaluate chronological patterns of arterial wall contrast enhancement in contrast-enhanced high-resolution MRI (CE-HR-MRI) in patients with moyamoya disease (MMD). The authors performed a blinded analysis of clinical and imaging data from MMD patients. Data were analyzed chronologically for each patient and the intensity of arterial wall enhancement was correlated with the clinical and imaging-based progression status of the disease. A total of 31 MMD patients and 61 imaging time points were included. CE-HR-MRI results were available for 56 time points, representing 112 hemispheric analyses. No arterial wall contrast enhancement (grade 1) was seen in 54 (48%) of the analyses, mild enhancement (grade 2) in 24 (21%), moderate enhancement (grade 3) in 15 (13%), and strong (grade 4) mainly concentric arterial wall contrast enhancement in 19 (17%). Grade 4 contrast enhancement was significantly (p < 0.001) associated with clinical disease progression within 6 months (before or after the MRI) compared to grades 1-3, with positive and negative predictive values of 0.8 and 0.88, respectively. Grades 1 and 2 (no contrast enhancement and only mild contrast enhancement) were highly predictive for stable disease (negative predictive value: 0.95). A specific chronological increasing and decreasing pattern of arterial wall contrast enhancement associated with "beginning" as well as progression of angiopathy occurs in MMD patients. In clinical practice, CE-HR-MRI of the arterial wall may help to identify patients at risk of new strokes caused by disease progression and hence impel early treatment for future stroke prevention. Understanding of this temporary enhancement of the arterial wall might also bring new insights into the etiology of MMD.

Association of CD40 SNPs with Moyamoya in a Chinese children population

Background: The etiology of Moyamoya disease (MMD) remains unknown to a large extent. Immune and inflammation dysfunction may play a role in the pathogenesis of this rare disease. Coexisting Kawasaki disease (KD) with MMD were reported and both diseases have a feature of vasculopathy, raising the hypothesis that there may be some common pathologic factors. We investigated single nucleotide polymorphisms (SNPs) previously identified in KD and performed a genetic analysis among Chinese pediatric patients with MMD.Results: We analyzed patients’ DNA for the SNPs in B lymphoid tyrosine kinase, CD40, and coatomer protein complex beta-2 subunit, which had been associated with KD by literatures. Genotyping was performed by sequencing the genetic regions containing the SNPs with customized primers. A total of 5 genotype polymorphisms were examined among 48 pediatric MMD cases and 50 healthy controls. The mean age of MMD children was 6.72 ± 3.63 years old, while 7.31 ± 3.79 in controls. We found two SNPs of CD40 were associated with MMD. Polymorphisms rs4813003 major allele CC and rs1535045 minor allele TT were significantly higher in MMD cases. The other SNPs showed no statistical difference between MMD cases and controls.Conclusions: Our findings provide evidence that there may be a relationship between MMD and auto-immune dysfunction. We hypothesize that these genetic features may lead to the pathogenesis within the vascular wall. Further study regarding whether CD40 can function as the personalized target of MMD should be investigated in future.

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.

Abstract TP211: Plasma Cytokine Levels Differ Between Primary and Syndromic Moyamoya and Pediatric and Adult Moyamoya Disease

Background: Moyamoya disease (MMD) is a progressive intracranial arteriopathy of unknown etiology affecting adults and children. We aimed to explore plasma cytokines in pediatric and adult cases of MMD. We hypothesized that quantitative and qualitative differences exist between adults and children, and primary idiopathic versus secondary syndromic cases of MMD. Methods: We performed plasma cytokine analysis using 63-plex Luminex immunoassay on 227 adults, 90% with primary MMD, and 30 children aged &lt;21 years, 80% with primary MMD, from a single center. Patients with a history of stroke within 1-month of plasma collection were excluded. We fitted a linear regression model using pooled data, with adjustment for age and sex, to assess for differences between primary and secondary patients with respect to each of 60 cytokines. We then conducted a stratified analysis by fitting a set of linear regression models for adults and children separately to examine potential interactions between etiology and age. Statistical significance was adjusted using Bonferroni method to account for multiple testing. Results: Three cytokines differed significantly between primary and secondary cases of MMD after Bonferroni correction (p&lt;0.00083), with secondary cases exhibiting higher levels of MCP3 (p=3.8x10 -8 ), IP10 (p=5.1x10 -4 ), and IL12P40 (p=6.4x10 -4 ). Stratified analysis by age identified two cytokines, VEGF (p=7.2x10 -4 ) and IL12P70 (p=7.8x10 -4 ), that differed significantly among children, with higher levels among secondary versus primary MMD, while the difference was not significant among adults (interaction p&lt;2x10 -4 ) (figure 1). Conclusions: Syndromic cases of MMD demonstrate higher levels of plasma cytokines compared to primary cases of MMD, and the difference between primary versus secondary MMD is modified by age for some cytokines. This study suggests the importance of including age and etiology of MMD in investigating biomarkers and disease pathogenesis.

Role of Ring Finger Protein 213 in Moyamoya Disease.

Objective:The aim of this study was to help people comprehensively understand the research advances related to ring finger protein 213 (RNF213) in moyamoya disease (MMD) and to understand the disease at the molecular level to provide a new perspective of the diagnosis of the disease.Data Sources:This review was based on data in articles published between 2005 and 2015 that were retrieved from the PubMed database. The search terms included RNF213, MMD, intracranial major artery stenosis/occlusion (ICASO), genotype, phenotype, mutant and variants, and the combinations of these terms.Study Selection:Articles related to MMD and RNF213 were selected for review, and we also reviewed publications related to ICASO.Results:RNF213 is not only associated with MMD but also associated with intracranial major artery stenosis. In addition, RNF213 variants exhibit apparent ethnic diversity; specifically, the c.14576G>A variant is mainly detected in Korean, Chinese, and Japanese populations, particularly the latter population. The genotypes of RNF213 correlate with the phenotypes of MMD; for example, the homozygous c.14576G>A variant is associated with early-onset, severe symptoms, and an unfavorable prognosis. Furthermore, the RNF213 c.14576G>A variant should be considered during the diagnosis of MMD because no patients with quasi-MMD have been reported to carry the RNF213 c.14576G>A variant whereas 66 of 78 patients with definite MMD have been found to carry this variant.Conclusions:The growing literature demonstrates that MMD is primarily caused by the synergy of genetic and environmental factors, and unknown genetic modifiers might play roles in the etiology of MMD. Further research should be conducted to clarify the pathogenic mechanism of MMD.

Exome Sequencing Identified CCER2 as a Novel Candidate Gene for Moyamoya Disease

The etiology of Moyamoya disease (MMD) is still largely unclear, despite identification of RNF213 as the most significant susceptibility gene in East Asian patients. Following up our previous study confirming genetic heterogeneity in Japanese patients with MMD, we extensively surveyed novel candidate genes for a new perspective on the etiology of this disease. Two characteristic pedigrees without susceptibility variants in RNF213 were selected for whole-exome sequencing; 1 harbored 3 affected members, and the other included discordant monozygotic twins. In the former pedigree, 12 rare mutations in 12 genes were co-segregated with MMD. One of the most deleterious amino acid changes among these was p.T76_G80delinsPS in CCER2, which was also mutated in the latter pedigree (p.E242K), although the unaffected twin sister shared the same mutation reflecting reduced penetrance. These CCER2 mutations were predicted to promote aggregation or oligomerization of their protein product, using in silico functional analysis. Subsequent CCER2 re-sequencing in an additional 135 MMD probands identified 1 recurrent and an additional 2 in-frame insertion-deletion mutations, recurrent p.T76_G80delinsPS, p.H218_H220del, and p.E299del. Although CCER2 molecular function is not well characterized, it is a secretory protein expressed in the brain; therefore, it constitutes a potential biomarker of MMD.

The Pathophysiology of Moyamoya Disease: An Update.

Moyamoya disease (MMD) is a unique cerebrovascular disease characterized by the progressive stenosis of large intracranial arteries and a hazy network of basal collaterals called moyamoya vessels. Because the etiology of MMD is unknown, its diagnosis is based on characteristic angiographic findings. Re-vascularization techniques (e.g., bypass surgery) are used to restore perfusion, and are the primary treatment for MMD. There is no specific treatment to prevent MMD progression. This review summarizes the recent advances in MMD pathophysiology, including the genetic and circulating factors related to disease development. Genetic and environmental factors may play important roles in the development of the vascular stenosis and aberrant angiogenesis in complex ways. These factors include the related changes in circulating endothelial/smooth muscle progenitor cells, cytokines related to vascular remodeling and angiogenesis, and endothelium, such as caveolin which is a plasma membrane protein. With a better understanding of MMD pathophysiology, nonsurgical approaches targeting MMD pathogenesis may be available to stop or slow the progression of this disease. The possible strategies include targeting growth factors, retinoic acid, caveolin-1, and stem cells.

Biochemical and Functional Characterization of RNF213 (Mysterin) R4810K, a Susceptibility Mutation of Moyamoya Disease, in Angiogenesis In Vitro and In Vivo.

BackgroundP.R4810K of RNF213 (mysterin: rs112735431), which is an AAA+ ATPase, is the susceptibility polymorphism for moyamoya disease (MMD) in East Asians. However, the role of RNF213 R4810K in the etiology of MMD is unknown.Methods and ResultsTo clarify the role of RNF213 in known angiogenic pathways, RNF213 expression was analyzed in endothelial cells (ECs) treated with several angiogenic and antiangiogenic factors, including interferons (IFNs). RNF213 was upregulated by IFN-β through signal transducer and activator of transcription x in the promoter and mediated antiangiogenic activity of IFN-β. RNF213 wild-type (WT) overexpression could not lower angiogenesis without IFN-β, but RNF213 R4810K overexpression could. To correlate biochemical function as ATPase and the role of RNF213 oligomer formation with antiangiogenic activity, we investigated the effects of mutations in the AAA+ module. A mutation of the Walker B motif (WEQ), which stabilizes oligomerization, inhibited angiogenesis, but AAA+ module deletion, which cannot initiate oligomerization, did not. Intriguingly, R4810K, similar to WEQ, decreased ATPase activity, suggesting its antiangiogenic activity through stabilizing oligomers. To confirm the antiangiogenic effect of RNF213 upregulation in vivo, vascular EC- or smooth muscle cell-specific Rnf213 R4757K (R4810K ortholog) or WT transgenic (Tg) mice were exposed to hypoxia. Cerebral angiogenesis by hypoxia was suppressed in EC-specific Rnf213 R4757K Tg mice, whereas it was not suppressed in other mice.ConclusionsThis study suggests the importance of inflammatory signals as environmental factors and R4810K carriers for susceptibility to cerebral hypoxia. A specific inhibitor of ATP binding to the first AAA+ could be a promising therapeutic candidate for MMD.

Abstract W P119: Identification of Novel Candidate Biomarkers to Define Moyamoya Disease by CSF Proteome Analysis

Purpose: Moyamoya disease (MMD) is a cerebrovascular disease characterized by progressive stenosis or occlusion of the terminal portion of internal carotid arteries. Genetic factors are closely involved in the etiology of moyamoya disease. However, the post-genomic mechanisms are still unknown. This study was aimed to identify specific biomarkers in the cerebrospinal fluid (CSF) of patients with moyamoya disease. Methods: This study included 6 patients with moyamoya disease and three patients with unruptured cerebral aneurysm. Their CSF was obtained from the Sylvian fissure during surgery. A comparative two-dimensional (2D) gel electrophoresis study was performed. Protein spots that showed significant differences between moyamoya patients and controls were selected for further analysis by mass spectrometry. Results: On 2D gel electrophoresis, two proteins were upregulated and other two proteins were downregulated in the CSF of moyamoya disease. Further mass spectrometry analysis revealed that haptoglobin and alpha-1-B-glycoprotein were upregulated and apolipoprotein (Apo)-E and Apo-J were downregulated in the CSF of moyamoya disease. Discussion and Conclusion: Upregulation of haptoglobin and alpha-1-B-glycoprotein may result from inflammatory reactions and/or angiogenesis. Downregulation of Apo-E and Apo-J may promote the cascade of endothelial apoptosis in carotid terminations. Furthermore, Apo-E is produced in the astrocytes and microglia and contributes to lipid transport to the neurons. Therefore, the downregulation of Apo-E may also be involved in the neuronal damage in moyamoya disease. The findings strongly suggest that these novel four proteins could be the candidate biomarkers to define moyamoya disease, and may shed the light on the pathogenesis of moyamoya disease, although further studies would be warranted.

Temporal profile of the vascular anatomy evaluated by 9.4-T magnetic resonance angiography and histopathological analysis in mice lacking RNF213: A susceptibility gene for moyamoya disease

Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease with unknown etiology. Recent genome-wide and locus-specific association studies identified RNF213 as an important MMD susceptibility gene. However, the exact mechanism by which an abnormality in RNF213 leads to MMD is unknown. To evaluate the role of RNF213 in the etiology of MMD, we generated RNF213-deficient mice (RNF213−/−) by deleting exon 32 of RNF213 by the Cre-lox system, and investigated whether they developed MMD. The temporal profile of cervical/intracranial arteries was evaluated by 9.4-T magnetic resonance angiography (MRA). The anatomy of the circle of Willis was analyzed by a trans-cardiac injection of carbon black dye. The common carotid arteries (CCA) were sectioned and the arterial wall thickness/thinness was evaluated by Elastica-Masson staining before and after CCA ligation, which selectively induced vascular hyperplasia. As a result, RNF213−/− grew normally, and no significant difference was observed in MRA findings, the anatomy of the circle of Willis, or vascular wall thickness/thinness between RNF−/− and wild-type littermates (Wt.) under normal conditions until 64 weeks of age. However, Elastica-Masson staining demonstrated that both the intima and medial layer were significantly thinner after CCA ligation in RNF213−/− than in Wt. after 14 days (P<0.01). In conclusion, mice lacking the RNF213 gene did not spontaneously develop MMD, indicating that a functional loss of RNF213 did not sufficiently induce MMD. Suppression of vascular remodeling in RNF213−/− requires further examination to clarify the role of RNF213.

Review of Past Research and Current Concepts on the Etiology of Moyamoya Disease

Research on moyamoya disease has progressed remarkably in the past several decades. Indeed, many new facts concerning the epidemiology of the disease have been revealed and surgical treatments have been drastically improved. However, despite extensive research, the mechanism of moyamoya disease is still unknown. Consequently, the cardinal treatment of this disease has not yet been developed. For further clarification of its etiology, innovative studies are therefore indispensable. The aim of this paper is to review research on the pathogenesis of moyamoya disease to identify milestones in the direction of its true solution. Many hypotheses of the pathogenesis of moyamoya disease have been proposed in the past half century, including infection (viral and bacterial), autoimmune disorders, proteins abnormality, and gene abnormality. Some of these are now considered to be historical achievements. Others, however, can be still subjected to contemporary research. Currently, several genetic abnormalities are considered to offer the most probable hypothesis. In addition, interesting papers have been presented on the role of the endothelial progenitor cell on the pathogenesis of moyamoya disease. Intuitively, however, it appears that a single theory cannot always explain the pathogenesis of this disease adequately. In other words, the complex mechanism of several factors may comprehensively explain the formation of moyamoya disease. The "double hit hypothesis" is probably the best explanation for the complicated pathology and epidemiology of this disease.

Moyamoya Disease Presenting as Thalamic Hemorrhage in A Patient With Neuromyelitis Optica and Sjögren's Syndrome

A 52-year-old woman was admitted to the hospital with right thalamic hemorrhage. A carotid angiogram revealed occlusion of the terminal portions of the bilateral internal carotid arteries with basal moyamoya vessels, which was diagnosed as moyamoya disease (MMD). At 31 years of age, she was diagnosed with multiple sclerosis because of optic neuritis and myelitis. Paraplegia appeared 14 days after admission. T2-weighted thoracic magnetic resonance imaging revealed a high intensity lesion extending from T4 to T6. Her left upper limb was partially paralytic and her lower limbs exhibited paraplegia and dysesthesia. Anti-aquaporin 4 and anti-Sjögren's syndrome-A and -B antibodies were positive. The pathogenesis of neuromyelitis optica may be associated with such immunologic factors, but there are no reports of simultaneous presentations of neuromyelitis optica and MMD. Autoimmunity may be associated with the etiology of MMD.