The role of atorvastatin in collateral circulation formation induced by encephaloduroarteriosynangiosis: a prospective trial.

OBJECTIVE: This prospective study was designed to confirm the role of atorvastatin in collateral circulation formation induced by encephaloduroarteriosynangiosis (EDAS) in patients with moyamoya disease (MMD). METHODS: Patients who were diagnosed with MMD at the Department of Neurosurgery in the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China, between June 2017 and May 2018 were included. Blood samples were obtained from an antecubital vein and were analyzed using flow cytometry. Endothelial progenitor cells (EPCs) were defined as CD34brCD133+CD45dimKDR+. All patients included in the study underwent EDAS. Patients voluntarily chose whether to undergo atorvastatin treatment after EDAS. The correlation between atorvastatin and good postoperative collateral circulation was evaluated. RESULTS: A total of 106 patients with MMD were included in this study. Fifty-three patients (50%) received atorvastatin treatment. The baseline characteristics did not display statistically significant differences between the atorvastatin-treated and non-atorvastatin groups. Seventy-eight (42.9%) of the 182 hemispheres investigated postoperatively were classified as grade A collateral circulation, 47 (25.8%) as grade B, and 57 (31.3%) as grade C. Multivariate analysis revealed that only atorvastatin was significantly correlated with good collateral circulation after EDAS (p = 0.041). CONCLUSIONS: The results of this prospective clinical trial have indicated that atorvastatin administered at 20 mg daily is safe and effective for the formation of postoperative collateral induced by EDAS.

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

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Clinical and genetic factors associated with contralateral progression in unilateral moyamoya disease: Longitudinal and Cross-Sectional Study.

Objective: This study aimed to explore the long-term outcome of unilateral moyamoya disease and predict the clinical and genetic factors associated with contralateral progression in unilateral moyamoya disease. Methods: We retrospectively recruited unilateral moyamoya disease patients with available genetic data who underwent encephaloduroarteriosynangiosis (EDAS) surgery at our institution from January 2009 to November 2017. Long-term follow-up data, including clinical outcomes, angiographic features, and genetic information, were analyzed. Results: A total of 83 unilateral moyamoya disease patients with available genetic data were enrolled in our study. The mean duration of clinical follow-up was 7.9 ± 2.0 years. Among all patients, 19 patients demonstrated contralateral progression to bilateral disease. Heterozygous Ring Finger Protein 213 p.R4810K mutations occurred significantly more frequently in unilateral moyamoya disease patients with contralateral progression. Furthermore, patients with contralateral progression typically demonstrated an earlier age of onset than those with non-progressing unilateral moyamoya disease. In the contralateral progression group, posterior circulation involvement was observed in 11 (11/19, 57.9%) patients compared to 12 (12/64, 18.8%) in the non-contralateral progression group (P = 0.001). The time to peak of cerebral perfusion and neurological status showed significant postoperative improvement. Conclusion: Long-term follow-up revealed that the EDAS procedure might provide benefits for unilateral moyamoya disease patients. Ring Finger Protein 213 p.R4810K mutations, younger age, and posterior circulation involvement might predict the contralateral progression of unilateral moyamoya disease.

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

BACKGROUND: The 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. We investigated clinical attributes, genotypes and progression risk factors in patients with ACA-occlusive MMD, providing initial insights into the relationship between ACA occlusion and MMD. METHODS: We retrospectively analysed digital subtraction angiography (DSA) from 2486 patients and diagnosed 139 patients with ACA-occlusive MMD. RNF213 p.R4810K (rs112735431) mutation analysis was performed. Patients were categorised into progression and non-progression groups based on whether they progressed to typical MMD. Differences in clinical characteristics, neuropsychological assessment, radiological findings and genotypes were evaluated. Logistic regression analyses identified risk factors for ACA-occlusive MMD progression. RESULTS: The median age of patients with ACA-occlusive MMD was 36 years, and the primary symptom was transient ischaemic attack (TIA). 72.3% of ACA-occlusive MMD patients had cognitive decline. Of 116 patients who underwent RNF213 gene mutation analysis, 90 patients (77.6%) carried the RNF213 p.R4810K GG allele and 26 (22.4%) carried the GA allele. Of 102 patients with follow-up DSA data, 40 patients (39.2%) progressed. Kaplan-Meier curve estimates indicated a higher incidence of ischaemic stroke in the progression group during follow-up (p=0.035). Younger age (p=0.041), RNF213 p.R4810K GA genotype (p=0.037) and poor collateral compensation from the middle cerebral artery (MCA) to ACA (p<0.001) were risk factors of ACA-occlusive MMD progression to typical MMD. CONCLUSIONS: Cognitive decline and TIA might be the main manifestations of ACA-occlusive MMD. Isolated ACA occlusion may be an early signal of MMD. The initial lesion site of MMD is not strictly confined to the terminal portion of the internal carotid artery. Younger patients, patients with RNF213 p.R4810K GA genotype or those with inadequate MCA-to-ACA compensation are more likely to develop typical MMD.

A long-term study of posterior circulation changes after revascularization in patients with moyamoya disease.

OBJECTIVE: This study aimed to explore the long-term course of posterior circulation changes and predictors in patients with moyamoya disease (MMD). METHODS: The authors retrospectively enrolled patients who were diagnosed with MMD and underwent encephaloduroarteriosynangiosis (EDAS) surgery at the authors' department from December 2002 to September 2011. A comparative study between short-term (6-12 months) and long-term (≥ 9 years) follow-up angiography was conducted. The progression of lesions was defined from lower to higher stages of the posterior cerebral artery (PCA). RESULTS: Eighty-eight patients who received indirect EDAS were enrolled in the study. The mean age at first surgery was 28.1 ± 15.0 years. Among these 88 patients with MMD, 39 (44.3%) exhibited transient ischemic attack and 27 (30.7%) exhibited infarction, comprising 5 with occipital lobe infarction, 14 (15.9%) with hemorrhagic symptoms, and 8 (9.1%) with atypical symptoms as the initial symptoms. Heterozygous mutations occurred significantly more frequently in the cases that presented with PCA involvement. During follow-up, stage progression of PCA was observed in 21 patients (28 hemispheres). At short-term follow-up, 21/176 (11.9%) hemispheres had progression of steno-occlusive lesions in the PCA. At long-term follow-up, 7 (4.0%) hemispheres had progression of steno-occlusive lesions in the PCA. At short-term follow-up, the progression of steno-occlusive lesions in the PCA was associated with progression of the internal carotid artery. Stage progression of PCA occurred significantly more frequently in the cases with PCA involvement on preoperative angiography. Nine strokes (10.2%) occurred in 88 patients during long-term follow-up. Four patients (4.5%) presented with ischemic stroke, including 2 with occipital lobe infarctions. CONCLUSIONS: Progression of PCA stenosis is common in patients with MMD, even if the PCA is normal initially. Mutations of RNF213 p.R4810K may predict PCA involvement or progression. Follow-up of the PCA in MMD patients should be conducted, and timely surgical revascularization is needed.

Natural course and risk factors of moyamoya disease with unruptured intracranial aneurysm.

Background and objective: The natural course and risk factors of moyamoya disease (MMD) associated with unruptured intracranial aneurysms involving stenosed parental arteries are scarcely studied. This study aimed to elucidate the natural course of MMD and its associated risk factors in patients with MMD with unruptured aneurysms. Methods: Between September 2006 and October 2021, patients with MMD with intracranial aneurysms at our center were examined. The natural course, clinical features, radiological features, and follow-up outcomes after revascularization were analyzed. Results: This study included 42 patients with MMD with intracranial aneurysms (42 aneurysms). The age distribution of MMD cases ranged from 6 to 69 years, with four children (9.5%) and 38 adults (90.5%). A total of 17 male and 25 female subjects were included (male-to-female ratio: 1:1.47). The first symptom was cerebral ischemia in 28 cases, and cerebral hemorrhage occurred in 14 cases. There were 35 trunk aneurysms and seven peripheral aneurysms. There were 34 small aneurysms (<5 mm) and eight medium aneurysms (5-15 mm). During the average clinical follow-up period of 37.90 ± 32.53 months, there was no rupture or bleeding from aneurysms. Twenty-seven of these patients underwent a cerebral angiography review, in which it was found that one aneurysm had enlarged, 16 had remained unchanged, and 10 had shrunk or disappeared. A correlation exists between the reduction or disappearance of aneurysms and the progression of the Suzuki stages of MMD (P = 0.015). Nineteen patients underwent EDAS on the aneurysm side, and nine aneurysms disappeared, while eight patients did not undergo EDAS on the aneurysm side and one aneurysm disappeared. Conclusion: The risk of rupture and hemorrhage of unruptured intracranial aneurysms is low when the parent artery already has stenotic lesions, thus, direct intervention may not be necessary for such aneurysms. The progression of the Suzuki stage of moyamoya disease may play a role in the shrinkage or disappearance of the aneurysms, thereby decreasing the risk of rupture and hemorrhage. Encephaloduroarteriosynangiosis (EDAS) surgery may also help promote atrophy or even the disappearance of the aneurysm, thus reducing the risk of further rupture and bleeding.

Association of cognitive function and hypoperfusion in Moyamoya disease patients without stroke.

The influence of hypoperfusion on cognition in patients with Moyamoya disease (MMD) is unclear. This study investigated cognitive function changes in MMD patients without stroke and illustrated the relationship between cognitive impairment and hypoperfusion. We prospectively performed a structured battery of seven neurocognitive tests on 115 adult MMD patients without stroke and 82 healthy controls. Hemodynamic assessment was performed using dynamic susceptibility contrast-enhanced MRI. The best subset regression (BSR) strategy was used to identify risk factors. Global cognition (MoCA), speed of information processing (TMT-A), executive function (TMT-B), visuospatial function (CDT), and verbal memory (CAVLT) were significantly poorer in MMD patients without stroke than in healthy controls. The TMT-B score significantly correlated with cerebral blood flow (CBF) in the bilateral lateral frontal lobes, centrum semiovale, and temporal lobes. The TMT-A and CAVLT scores significantly correlated with CBF in the left centrum semiovale (L-CSO) and temporal lobes. According to the BSR results, age, education, white matter lesions, and hypoperfusion of the L-CSO were risk factors for cognitive impairment. Hypoperfusion leads to multiple cognitive impairments in MMD patients without stroke. The perfusion of particular areas may help evaluate the cognitive function of MMD patients and guide therapeutic strategies.

Proteomic and metabolomic characterizations of moyamoya disease patient sera.

BACKGROUND: 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. METHODS: We performed untargeted metabolomic and data-independent acquisition proteomic analyses on the serum samples of individuals with MMD and healthy controls (HC). RESULTS: 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. CONCLUSIONS: 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.

Recognition of the Effect of Indirect Revascularization for Moyamoya Disease: The Balance Between the Stage Progression and Neoangiogenesis.

Objective: To explore the long-term progression of neoangiogenesis after indirect revascularization for moyamoya disease (MMD). Methods: We enrolled patients who were diagnosed with MMD and treated by encephaloduroarteriosynangiosis (EDAS) surgery at our center from December 2002 through September 2009. A comparative study between short-term (6-12 months) and long-term (duration ≥ 8 years) follow-up angiographies was performed. The development of collateral circulation through EDAS was graded according to the system described by the Matsushima grade system. Results: A total of 78 patients who received indirect EDAS were enrolled in the study. The mean age at the first operation was 26.9 ± 15.0 years. The Matsushima grades of the same hemisphere were higher at the long-term follow-up compared with the short-term follow-up. Importantly, no attenuation was observed in any hemisphere during the long-term follow-up. In total, 51 hemispheres (32.7%) and 26 hemispheres (16.6%) had progression during the short-term and the long-term follow-up, respectively. The ipsilateral Suzuki stage showed a significant negative correlation with progression pace. Furthermore, higher Suzuki stages were significantly correlated with the postsurgical Matsushima grade at both time points. A total of nine strokes (11.5%) occurred in 78 patients was reported at the long-term follow-up. The annual incidence rate of recurrent strokes was higher for the stage progression group than for the stable group. Conclusion: For patients with MMD, postsurgical neoangiogenesis after indirect bypass continuously improved with time. The short-term progression of the internal carotid artery (ICA) might be attributed to cerebral revascularization, while the long-term progression should be attributed to the natural progression of the disease.

Dynamic Changes of Collateral Vessels After Encephaloduroarteriosynangiosis in Moyamoya Disease: Childhood to Adulthood.

BACKGROUND: Moyamoya disease (MMD) often presents as ischemic stroke in pediatric patients and hemorrhage in adults. This situation raises questions as to whether the phenotype of moyamoya disease changes with age. OBJECTIVE: We performed self-precontrol and postcontrol observation monitoring until adulthood on abnormal collateral vessels (ACVs) with the potential risk of bleeding to evaluate the chance of further hemorrhage. METHODS: Fifteen pediatric patients with >10 years angiography-based follow-up were analyzed. The Matsushima grades were divided into 2 groups (good group, representing Matsushima stage A; and mild group, representing Matsushima stages B and C) to investigate the relationship between Matsushima grades and ACVs derived from vessels likely to cause intracranial hemorrhage. RESULTS: Four patients (26.7%) had infarction type and 11 (73.3%) patients had transient ischemic attack type. No patient experienced late-onset cerebral hemorrhagic events. One patient experienced recurrent ischemic stroke 6 months after the second surgery and recovered completely after the third surgery. The angiography-based follow-up was conducted at least 10 years after the encephaloduroarteriosynangiosis (EDAS). The good Matsushima group showed a significant positive correlation with the reduction of the anterior choroidal artery (odds ratio, 56.00; P = 0.003), whereas the posterior communicating artery showed no significant decrease before and after the EDAS procedure (odds ratio, 2.00; P = 1.00). CONCLUSIONS: The EDAS procedure can effectively attenuate the dilation and ACVs of the anterior choroidal artery, which may reduce the incidence of further hemorrhage in adulthood.

The Potential Mechanism Behind Native and Therapeutic Collaterals in Moyamoya.

Background and Purpose: To explore the genetic basis and molecular mechanism of native arteriogenesis and therapeutic synangiosis in moyamoya disease (MMD). Methods: An angiography-based study using patients from a prospective trial of encephaloduroarteriosynangiosis (EDAS) surgery was performed. The spontaneous collaterals grades were evaluated according to the system described by a new grading system. Blood samples were collected from all the recruited patients before EDAS and during the second hospitalization 3 months post-EDAS. We performed Boolean analysis using a combination of specific cell surface markers of CD34briCD133+CD45dimKDR+. Genotyping of p.R4810K was also performed. The correlation of age, sex, initial symptoms at diagnosis, collateral grade, Suzuki stages, the RNF213 genotype, time to peak (TTP), and endothelial progenitor cell (EPC) count with good collateral circulation was evaluated. Results: Eighty-five patients with MMD were included in this study. The mutation rate of RNF213 p.R4810K in our study was 25.9% (22/85). The heterozygous mutations were occurred significantly more frequently in the cases that were presented with infarction, worse neurological status, severe posterior cerebral artery (PCA) stenosis, and longer TTP delay. Further, the heterozygous mutations occurred significantly more frequently in the poor collateral stage group. Lower grades were significantly correlated with severe ischemia symptoms, worse neurological status, and a longer TTP delay. The post-operative angiographic findings showed that a good Matsushima grade was correlated with heterozygous mutations, a lower collateral stage, and a longer TTP delay. The CD34briCD133+CD45dimKDR+ cell count in patients 3 months post-EDAS was significantly higher as compared to the count before EDAS in the good Matsushima grade group. However, this change was not observed in the poor Matsushima grade group. Conclusions: These data imply that mutations of RNF213 p.R4810K affect the establishment of spontaneous collateral circulation, and EPCs are involved in the process of formation of new EDAS collaterals.

Endothelial Progenitor Cells Induce Angiogenesis: a Potential Mechanism Underlying Neovascularization in Encephaloduroarteriosynangiosis.

Encephaloduroarteriosynangiosis (EDAS) is one of the most commonly used indirect vascular reconstruction methods. EDAS aids in the formation of collateral vessels from the extracranial to the intracranial circulation in patients with moyamoya disease (MMD). However, the underlying mechanism of collateral vessel formation is not well understood. Endothelial progenitor cells (EPCs) differentiate to form the vascular endothelial cells and play a very important role in angiogenesis. We designed this prospective clinical trial to investigate the presence of EPCs in patients with MMD and to explore the neovascularization mechanism mediated by the EPCs in EDAS. The patients who were diagnosed with MMD were recruited between February 5, 2017, and January 7, 2018. The blood samples were obtained from an antecubital vein and were analyzed using flow cytometry. EPCs were defined as CD34brCD133+CD45dimKDR+. All the patients enrolled in the study underwent EDAS. Cerebral arteriography was performed 6 months post-EDAS to assess the efficacy of synangiosis. The correlation between EPC count and good collateral circulation was evaluated. Among the 116 patients with MMD enrolled in this study, 73 were women and 43 were men. The average age of the patients was 33.8 ± 15.2 years. The EPC count of the patients with MMD was 0.071% ± 0.050% (expressed as percentage of the peripheral blood mononuclear cells). The EPC count in the good postoperative collateral circulation group was significantly higher (0.085% ± 0.054%) than that in the poor collateral circulation group (0.048% ± 0.034%) (P = 0.000). The age, modified Suzuki-Mugikura grade, and EPC count were significantly correlated with the good collateral circulation post-EDAS in the multivariate analysis (P = 0.018, P = 0.007, and P = 0.003, respectively). The formation of collateral vessels by EDAS is primarily driven by angiogenesis. The EPC count may be the most critical factor for collateral circulation. The therapeutic effect of EDAS is more likely to benefit younger or severe ischemic patients with MMD.