Glymphatic Impairment Associated with Neurocognitive Dysfunction in Moyamoya Disease.

Glymphatic system alterations have been proved to be associated with cognitive dysfunction in neurodegenerative diseases. The glymphatic pathway has not been elucidated in moyamoya disease (MMD), which was recognized as a chronic hypoperfusion model for neurodegenerative disease. Here, we aimed to investigate the glymphatic system activity and its relation with neurocognition, and associated hallmarks in MMD. We prospectively recruited 30 MMD patients and 30 matched healthy controls (HC). Participants underwent MRI and neurocognition evaluation. The glymphatic function was assessed by diffusion tensor image analysis along perivascular space (DTI-ALPS) index. Gray matter volume (GMV) and microstructural alterations were calculated. Neurodegenerative-related serum biomarkers were examined. The mediation effect of ALPS index in the associations between variables and neurocognition were further explored. A lower ALPS index was identified in patients with MMD (P < 0.001). The decreased ALPS index was significantly correlated with declined neurocognitive performance. Moreover, the reduced ALPS index was notably linked with lower total GMV% and deep GMV% (P < 0.01). Microstructural changes in the periventricular areas were detected and associated with ALPS index in MMD. Serum neurodegenerative biomarkers (ApoE, Aß40, Aß42, and Aß42/Aß40) were significantly elevated and related to ALPS index. Additionally, the ALPS index significantly mediated the associations of microstructural alterations and ApoE level with neurocognitive dysfunction. The ALPS index was notably lower MMD in patients, suggesting the utility as a marker of potential glymphatic dysfunction. The index acted as a significant mediator in neurocognitive dysfunction. These findings indicated that glymphatic impairment may interact with MMD-related pathophysiological processes.

Circulating immune cell landscape and T-cell abnormalities in patients with moyamoya disease.

BACKGROUND: Moyamoya disease (MMD) stands as a prominent cause of stroke among children and adolescents in East Asian populations. Although a growing body of evidence suggests that dysregulated inflammation and autoimmune responses might contribute to the development of MMD, a comprehensive and detailed understanding of the alterations in circulating immune cells associated with MMD remains elusive. METHODS: In this study, we employed a combination of single-cell RNA sequencing (scRNA-seq), mass cytometry and RNA-sequencing techniques to compare immune cell profiles in peripheral blood samples obtained from patients with MMD and age-matched healthy controls. RESULTS: Our investigation unveiled immune dysfunction in MMD patients, primarily characterized by perturbations in T-cell (TC) subpopulations, including a reduction in effector TCs and an increase in regulatory TCs (Tregs). Additionally, we observed diminished natural killer cells and dendritic cells alongside heightened B cells and monocytes in MMD patients. Notably, within the MMD group, there was an augmented proportion of fragile Tregs, whereas the stable Treg fraction decreased. MMD was also linked to heightened immune activation, as evidenced by elevated expression levels of HLA-DR and p-STAT3. CONCLUSIONS: Our findings offer a comprehensive view of the circulating immune cell landscape in MMD patients. Immune dysregulation in patients with MMD was characterized by alterations in T-cell populations, including a decrease in effector T-cells and an increase in regulatory T-cells (Tregs), suggest a potential role for disrupted circulating immunity in the aetiology of MMD.

Association of lysine pathway metabolites with moyamoya disease.

BACKGROUND AND OBJECTIVE: Lysine and its pathway metabolites have been identified as novel biomarkers for metabolic and vascular diseases. The role of them in the identification of moyamoya disease (MMD) has not been elucidated. This study aimed to determine the association between lysine pathway metabolites and the presence of MMD. METHODS: We prospectively enrolled 360 MMD patients and 89 healthy controls from September 2020 to December 2021 in Beijing Tiantan Hospital. Serum levels of lysine, pipecolic acid and 2-aminoadipic acid were measured by liquid chromatography-mass spectrometry. We employed logistic regression and restricted cubic spline to explore the association between these metabolites and the presence of MMD. Stratified analyses were also conducted to test the robustness of results. RESULTS: We observed that lysine levels in MMD patients were significantly higher and pipecolic acid levels were significantly lower compared to HCs (both p < 0.001), while no difference was found in the level of 2-AAA between both groups. When comparing metabolites by quartiles, elevated lysine levels were linked to increased odds for MMD (the fourth quartile [Q4] vs the first quartile [Q1]: odds ratio, 3.48, 95%CI [1.39-8.75]), while reduced pipecolic acid levels correlated with higher odds (Q4 vs Q1: odds ratio, 0.08; 95 % CI [0.03-0.20]). The restricted cubic spline found a L-shaped relationship between pipecolic acid level and the presence of MMD, with a cutoff point at 2.52 µmol/L. Robust results were also observed across subgroups. CONCLUSION: Elevated lysine levels were correlated with increased odds of MMD presence, while lower pipecolic acid levels were associated with higher odds of the condition. These results suggest potential new biomarkers for the identification of MMD. CLINICAL TRIAL REGISTRY NUMBER: URL: https://www.chictr.org.cn/. Unique identifier: ChiCTR2200061889.

Multiomics and blood-based biomarkers of moyamoya disease: protocol of Moyamoya Omics Atlas (MOYAOMICS).

BACKGROUND: Moyamoya disease (MMD) is a rare and complex cerebrovascular disorder characterized by the progressive narrowing of the internal carotid arteries and the formation of compensatory collateral vessels. The etiology of MMD remains enigmatic, making diagnosis and management challenging. The MOYAOMICS project was initiated to investigate the molecular underpinnings of MMD and explore potential diagnostic and therapeutic strategies. METHODS: The MOYAOMICS project employs a multidisciplinary approach, integrating various omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, to comprehensively examine the molecular signatures associated with MMD pathogenesis. Additionally, we will investigate the potential influence of gut microbiota and brain-gut peptides on MMD development, assessing their suitability as targets for therapeutic strategies and dietary interventions. Radiomics, a specialized field in medical imaging, is utilized to analyze neuroimaging data for early detection and characterization of MMD-related brain changes. Deep learning algorithms are employed to differentiate MMD from other conditions, automating the diagnostic process. We also employ single-cellomics and mass cytometry to precisely study cellular heterogeneity in peripheral blood samples from MMD patients. CONCLUSIONS: The MOYAOMICS project represents a significant step toward comprehending MMD's molecular underpinnings. This multidisciplinary approach has the potential to revolutionize early diagnosis, patient stratification, and the development of targeted therapies for MMD. The identification of blood-based biomarkers and the integration of multiple omics data are critical for improving the clinical management of MMD and enhancing patient outcomes for this complex disease.

Effectiveness of indirect revascularization for adult hemorrhagic moyamoya disease: a 10-year follow-up study.

OBJECTIVE: The optimal surgical approach for hemorrhagic moyamoya disease (hMMD) continues to be a topic of debate. The authors' prior research demonstrated that both combined and indirect revascularization were efficacious. However, questions remain regarding the long-term prognosis consistency between these two treatments. Therefore, the objective of this study was to evaluate and compare the enduring effects of these surgical modalities on adult hMMD, extending the findings of the authors' previous studies. METHODS: The authors recruited patients diagnosed with hMMD between 2010 and 2015. The patients were categorized into two groups: those who underwent combined revascularization (superficial temporal artery-middle cerebral artery bypass alongside dural reverse application) and those who underwent indirect revascularization (encephaloduroarteriosynangiosis [EDAS]). The primary and secondary endpoints of this study were instances of rebleeding, confirmed with CT scan, and death resulting from rebleeding, respectively. The authors estimated rebleeding-free and death-free survival rates by utilizing the Kaplan-Meier survival method. They used Cox regression to adjust for confounders and to evaluate the effects of the varying surgical modalities on the endpoints. RESULTS: After an average follow-up period of 114 months, 35 patients (28.6%) experienced 40 rebleeding events, yielding an average annual incidence of 3.5%. Of the 79 patients who received combined revascularization, 17 (21.5%) experienced rebleeding events. Similarly, of 43 patients who underwent EDAS, 18 (41.9%) experienced rebleeding events (p = 0.018). Most rebleeding instances occurred 61-120 months after surgery (21 patients [60%]), followed by 12-60 months (11 patients [31.4%]). Multivariate survival analysis highlighted significant differences in surgical outcomes (HR 0.33, 95% CI 0.15-0.74, p = 0.007). The authors observed that 8 patients (10.1%) died of rebleeding events in the combined group, as well as 10 patients (23.3%) in the EDAS group. Despite the lack of a statistically significant difference in mortality (p = 0.051), multivariable survival analysis found a significant difference (HR 0.31, 95% CI 0.10-0.97, p = 0.044). CONCLUSIONS: High rebleeding rates persist in adult hMMD patients, even after revascularization. Combined revascularization proved superior to EDAS in preventing long-term rebleeding. In contrast, EDAS alone did not display a clear effect on reducing long-term rebleeding rates.

A novel system for evaluating collateralization of the external carotid artery after cerebral revascularization in moyamoya disease.

OBJECTIVE: The objective of this retrospective study was to establish a novel system for evaluating collateralization of the external carotid artery in patients with moyamoya disease (MMD) following direct and indirect revascularization surgeries. METHODS: The authors conducted a retrospective analysis of 456 patients diagnosed with MMD who underwent direct and indirect revascularization procedures at Beijing Tiantan Hospital, Capital Medical University, between January 2015 and May 2023. Using a newly proposed digital subtraction angiography (DSA)-based evaluation system, the authors assessed collateralization angiogenesis objectively and in a standardized manner. RESULTS: The authors' findings indicated that there was no significant difference in collateralization angiogenesis between patients undergoing direct or indirect cerebral revascularization (p = 0.702). However, after cerebral revascularization, patients with ischemic MMD exhibited significantly higher collateralization angiogenesis compared with those with hemorrhagic MMD (p = 0.007). Children with MMD demonstrated higher angiogenesis levels than adults (p < 0.001), but subgroup analysis showed age-specific variations. In adults, collateralization angiogenesis was significantly greater in those with ischemic MMD (p = 0.006), whereas in children, no significant difference was noted between ischemic and hemorrhagic MMD (p = 0.962). Furthermore, regardless of MMD type, direct and indirect revascularization methods yielded similar collateralization angiogenesis (p = 0.962 and p = 0.963, respectively). Importantly, the Matsushima grading system revealed significant differences in angiogenesis in patients with ischemic MMD (p < 0.001). CONCLUSIONS: The newly introduced DSA-based evaluation system offers an objective and standardized method for assessing collateralization angiogenesis in MMD. This study supports the efficacy of both direct and indirect revascularization surgical procedures and highlights distinct pathophysiological processes of ischemic and hemorrhagic disease subtypes. These findings contribute to a better understanding of surgical outcomes and aid in the selection of appropriate treatment strategies for patients with MMD.

Gut microbiota in adults with moyamoya disease: characteristics and biomarker identification.

Background and purpose: When it comes to the onset of moyamoya disease (MMD), environmental variables are crucial. Furthermore, there is confusion about the relationship between the gut microbiome, an environmental variable, and MMD. Consequently, to identify the particular bacteria that cause MMD, we examined the gut microbiome of MMD individuals and healthy controls (HC). Methods: A prospective case-control investigation was performed from June 2021 to May 2022. The fecal samples of patients with MMD and HC were obtained. Typically, 16S rRNA sequencing was employed to examine their gut microbiota. The QIIME and R softwares were used to examine the data. The linear discriminant analysis effect size analysis was used to determine biomarkers. Multivariate analysis by linear models (MaAsLin)2 were used to find associations between microbiome data and clinical variables. Model performance was assessed using the receiver operating characteristic curve and the decision curve analysis. Results: This investigation involved a total of 60 MMD patients and 60 HC. The MMD group's Shannon and Chao 1 indices were substantially lower than those of the HC cohort. ß-diversity was significantly different in the weighted UniFrac distances. At the phylum level, the relative abundance of Fusobacteriota/Actinobacteria was significantly higher/lower in the MMD group than that in the HC group. By MaAsLin2 analysis, the relative abundance of the 2 genera, Lachnoclostridium and Fusobacterium, increased in the MMD group, while the relative abundance of the 2 genera, Bifidobacterium and Enterobacter decreased in the MMD group. A predictive model was constructed by using these 4 genera. The area under the receiver operating characteristic curve was 0.921. The decision curve analysis indicated that the model had usefulness in clinical practice. Conclusions: The gut microbiota was altered in individuals with MMD, and was characterized by increased abundance of Lachnoclostridium and Fusobacterium and decreased abundance of Bifidobacterium and Enterobacter. These 4 genera could be used as biomarkers and predictors in clinical practice.

Association between systemic immune-inflammatory markers and the risk of moyamoya disease: a case-control study.

Background:Systemic immune-inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR) and systemic immune-inflammatory index (SII) are associated with the prognosis of many cardiovascular and neoplastic diseases. Moyamoya disease (MMD) is associated with inflammation, but the relationship between systemic immune-inflammatory markers between MMD is unclear. The aim of our study was to analyse the association between systemic immune-inflammatory markers and the risk of MMD and its subtypes.Methods:We consecutively recruited 360 patients with MMD and 89 healthy control subjects in a case-control study to calculate and analyse the association of systemic immune-inflammatory markers with the risk of MMD and its subtypes.Results:The risk of MMD increased with higher levels of NLR (OR 1.237, 95% CI [1.008, 1.520], p = .042). When NLR and SII were assessed as quartile-spaced subgroups, the third quartile grouping of NLR and SII had a higher risk of MMD than the first quartile grouping (NLR: OR 3.206, 95% CI [1.271, 8.088], p = .014; SII: OR 3.074,95% CI [1.232,7.672], p = .016). When NLR was combined with SII, the highest subgroup had a higher risk of MMD than the lowest subgroup (OR2.643, 95% CI [1.340, 5.212], p = .005). The risk of subtypes also increased with higher levels of NLR and SII. The association between the levels of NLR and SII with the staging of the Suzuki stage follows an inverted U-shape. The highest levels of NLR and SII were found in patients with MMD at Suzuki stages 3-4.Conclusion:The risk of MMD increases with elevated systemic immune-inflammatory markers. This study analysed the association of systemic immune-inflammatory markers with the risk of developing MMD and its subtypes, and identified novel inflammatory markers for MMD.

Systemic immune-inflammatory markers such as neutrophil­lymphocyte ratio and systemic immune-inflammatory index were higher in moyamoya disease (MMD) patients than in normal people.Systemic immune-inflammatory markers may be an independent risk factor for the onset of MMD.Systemic immune-inflammatory markers were associated with the progression of MMD, and their levels showed an inverted U shape with imaging stages.

The prognostic nutrition index is a predictor for long-term outcomes after revascularization in adult moyamoya disease.

BACKGROUND AND PURPOSE: The prognostic nutrition index (PNI) has been associated with the prognosis of various medical disorders. This study aimed to explore the correlation between PNI and the long-term outcomes of adult patients afflicted with moyamoya disease (MMD). METHODS: This prospective study initially employed 138 adult patients diagnosed with MMD. After excluding 15 patients who did not meet the criteria, a total of 123 patients were included. Participants were divided into three groups based on the tertile of change in the PNI score. Statistical analysis compared clinical information and lab tests among the groups. The study was conducted between July 1 and December 31, 2019. RESULTS: After adjusting for multiple variables, patients in the upper two tertiles (tertiles 2-3) exhibited a significantly lower risk of adverse long-term outcomes compared to those in the lowest tertile (tertile 1) (OR, 0.089; 95% CI, 0.009-0.895; P = 0.040). Furthermore, adding PNI tertile to traditional risk factors substantially improved predicting adverse long-term outcomes (net reclassification improvement: 98.03%, P = 0.000; integrated discrimination improvement: 4.65%, P = 0.030). However, there was no statistically significant difference between the first PNI tertile (tertile 1) and the upper two tertiles (tertiles 2-3) in the Kaplan-Meier curve of stroke incidence (log-rank test, P = 0.244). CONCLUSIONS: A higher PNI level was significantly associated with a reduced risk of unfavorable long-term outcomes. Nevertheless, the PNI score did not predict stroke recurrence during extended follow-up. This study provides insights into a potential predictor of adverse long-term outcomes after revascularization in MMD patients. REGISTRATION NUMBER: ChiCTR2000031412.

Nomogram to Predict Good Neoangiogenesis After Indirect Revascularization Surgery in Patients with Moyamoya Disease: a Case-control Study.

Indirect bypass surgery is an effective treatment for moyamoya disease (MMD), but the success of the surgery depends on the formation of spontaneous collateral vessels, which cannot be accurately predicted before surgery. Developing a prediction nomogram model for neoangiogenesis in patients after indirect revascularization surgery can aid surgeons in identifying suitable candidates for indirect revascularization surgery. This retrospective observational study enrolled patients with MMD who underwent indirect bypass surgery from a multicenter cohort between December 2010 and December 2018. Data including potential clinical and radiological predictors were obtained from hospital records. A nomogram was generated based on a multivariate logistic regression analysis identifying potential predictors of good neoangiogenesis. A total of 263 hemispheres of 241 patients (mean ± SD age 24.38 ± 15.78 years, range 1-61 years) were reviewed, including 168 (63.9%) hemispheres with good postoperative collateral formation and 95 (36.1%) with poor postoperative collateral formation. Based on multivariate analysis, a nomogram was formulated incorporating four predictors, including age at operation, abundance of ICA moyamoya vessels, onset type, and Suzuki stage. The C-index for this nomogram was 0.80. Calibration curve and decision-making analysis validated the fitness and clinical application value of this nomogram. The nomogram developed in this study exhibits high accuracy in predicting good neoangiogenesis after indirect revascularization surgery in MMD patients. This model can be very helpful for clinicians when making decisions about surgical strategies for MMD patients in clinical practice.

Plasma urea cycle metabolite levels and the risk of moyamoya disease.

Background and purpose: Urea cycle metabolites are expected to be the biomarkers for cerebrovascular diseases. However, the effects of circulating urea cycle metabolites on the risk of MMD and its subcategories remain unclear. The aim of this study was to prospectively investigate the association between plasma urea cycle metabolites and the risk of MMD and its subcategories. Methods: We measured plasma urea cycle metabolite levels for 360 adult MMD patients and 89 matched healthy controls. Clinical and laboratory characteristics were obtained from the medical record. The study was conducted from July 2020 to December 2021. Results: After multivariate adjustment, the risk of MMD increased with each increment in ornithine level (per natural log [ornithine] increment: OR, 3.893; 95% CI, 1.366-11.090). The risk of MMD decreased with each increment in arginine level (per natural log [arginine] increment: OR, 0.109; 95% CI, 0.028-0.427), urea level (per natural log [urea] increment: OR, 0.261; 95% CI, 0.072-0.940), and global arginine bioavailability ratio (GABR) level (per natural log [GABR] increment: OR, 0.189; 95% CI, 0.074-0.484). The addition of plasma arginine (integrated discrimination improvement: 1.76%, p = 0.021) or GABR (integrated discrimination improvement: 1.76%, p = 0.004) to conventional risk factors significantly improved the risk reclassification for MMD. Conclusion: Plasma ornithine levels are positively associated with the risk of MMD. By contrast, the levels of arginine, urea, and GABR are inversely related to the risk of MMD. Plasma urea cycle metabolites might be potential biomarkers for the risk of MMD.

Correlation of Serum N-Acetylneuraminic Acid with the Risk of Moyamoya Disease.

N-acetylneuraminic acid (Neu5Ac) is a functional metabolite and has been demonstrated to be a risk factor for cardiovascular diseases. It is not clear whether Neu5Ac is associated with a higher risk of cerebrovascular disorders, especially moyamoya disease (MMD). We sought to elucidate the association between serum Neu5Ac levels and MMD in a case-control study and to create a clinical risk model. In our study, we included 360 MMD patients and 89 matched healthy controls (HCs). We collected the participants' clinical characteristics, laboratory results, and serum Neu5Ac levels. Increased level of serum Neu5Ac was observed in the MMD patients (p = 0.001). After adjusting for traditional confounders, the risk of MMD (odds ratio [OR]: 1.395; 95% confidence interval [CI]: 1.141-1.706) increased with each increment in Neu5Ac level (per µmol/L). The area under the curve (AUC) values of the receiver operating characteristic (ROC) curves of the basic model plus Neu5Ac binary outcomes, Neu5Ac quartiles, and continuous Neu5Ac are 0.869, 0.863, and 0.873, respectively. Furthermore, including Neu5Ac in the model offers a substantial improvement in the risk reclassification and discrimination of MMD and its subtypes. A higher level of Neu5Ac was found to be associated with an increased risk of MMD and its clinical subtypes.

Prevalence and Procedural Risk of Intracranial Atherosclerotic Stenosis Coexisting With Unruptured Intracranial Aneurysm.

BACKGROUND: Coexistence of intracranial atherosclerotic stenosis (ICAS) and unruptured intracranial aneurysms (UIAs) is increasingly encountered in clinical practice. This study aims to determine the prevalence of ICAS in patients with UIAs and procedural ischemic risk associated with ICAS when treating UIAs. METHODS: Based on the CAIASA study (Coexistence of Atherosclerotic Intracranial Arterial Stenosis With Intracranial Aneurysms), we prospectively included patients undergoing treatment procedures for UIAs from October 2015 to December 2020 at Beijing Tiantan Hospital, China. We used computed tomography angiography or digital subtraction angiography to diagnose ICAS (stenosis≥50%). Multivariable logistic regression and propensity-score matching were performed to evaluate the risk of procedure-related ischemic stroke and unfavorable outcome associated with ICAS. The ICAS score was used to explore the association between different burden of ICAS and procedure-related ischemic risk. RESULTS: Among 3949 patients who underwent endovascular or open surgical procedures for UIAs, 245 (6.2%) had ICAS. After exclusion, 15.7% (32/204) of patients with ICAS experienced procedure-related ischemic stroke compared with 5.0% (141/2825) of patients without ICAS. From the unmatched and matched cohort, ICAS was significantly associated with increased risk of procedure-related ischemic stroke (unmatched: adjusted odds ratio=3.11 [1.89-5.11]; and matched: adjusted odds ratio=2.99 [1.38-6.48]). This association became more evident among patients not receiving antiplatelet therapy (Pinteraction=0.022). For patients undergoing different treatment modalities, similar increased risks were observed (clipping: adjusted odds ratio=3.43 [1.73-6.79]; and coiling: adjusted odds ratio=3.59 [1.94-6.65]). Higher ICAS score was correlated with higher procedural ischemic risk (Ptrend<0.001). CONCLUSIONS: The occurrence of ICAS is not infrequent in patients with UIAs. ICAS confers an ~2-fold increased procedural ischemic risk, irrespective of clipping or coiling. Previous antiplatelet therapy may decrease the risk. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02795078.

Serum Kynurenic Acid and Kynurenine Are Negatively Associated with the Risk of Adult Moyamoya Disease.

Background and aim. Kynurenine (KYN) and kynurenic acid (KYNA) are key intermediate metabolites associated with inflammation and immune responses in the kynurenine pathway. It remains unknown whether KYN or KYNA is associated with the risk of adult moyamoya disease (MMD). The aim of this study was to prospectively investigate the association between serum KYN or KYNA and the risk of adult MMD. Methods. The study was conducted from July 2020 to December 2021. We measured serum KYN and KYNA levels for 360 adult MMD patients (259 cases of ischemic MMD, 101 cases of hemorrhagic MMD) and 89 age-sex-matched healthy controls. Clinical and laboratory characteristics were collected from the medical record. Results. After multivariate adjustment, decreased serum KYNA (OR, 0.085; 95% CI, 0.035−0.206; p = 0.000) or KYN (OR, 0.430; 95% CI, 0.225−0.820; p = 0.010) levels were associated with increased risk of MMD when upper and lower tertiles were compared. In addition, a higher trend of hemorrhagic MMD was found in MMD patients in KYNA tertile 1 compared with those in tertile 2 to 3 (OR, 0.584; 95% CI, 0.345−0.987; p = 0.044). Addition of serum KYNA (net reclassification improvement: 73.24%, p = 0.000; integrated discrimination improvement: 9.60%, p = 0.000) or KYN (integrated discrimination improvement: 1.70%, p = 0.037) to conventional risk factors significantly improved the risk prediction of MMD. In the exploratory analysis, we observed an interaction between KYN and age (≥40 versus <40 years) or homocysteine levels (≥13.0 versus <13.0 µmol/L) on the risk of MMD. Conclusions. Decreased serum KYNA or KYN levels were associated with an increased risk of adult MMD, suggesting that serum KYNA or KYN may be a valuable predictive biomarker for adult MMD.

Association of circulating branched-chain amino acids with risk of moyamoya disease.

Objective: Branched-Chain Amino Acids (BCAAs) has been identified as a risk factor for circulatory disease. Nevertheless, the effects and mechanisms of BCAAs on the risk of moyamoya disease (MMD) remain unrecognized. Hence, we aimed to elucidate the association between circulating BCAAs and the risk of MMD and clinical subtypes. Methods: We conducted a case-control study of 360 adult MMD patients and 89 matched healthy controls consecutively recruited between September 2020 and December 2021. Serum level of BCAAs was quantified by liquid chromatography-mass spectrometry. The associations between BCAAs and risk of MMD were evaluated. Results: Increased level of serum BCAAs was observed in MMD patients (P < 0.001). After adjusting for traditional confounders, the elevated BCAAs level was significantly associated with the risk of MMD (Q4 vs. Q1: odds ratio, 3.10 [95% CI, 1.29-7.50]). The risk of subtypes in MMD also increased with each increment in the quartiles of BCAAs. Furthermore, BCAAs offered substantial improvement in risk reclassification and discrimination for MMD and subtypes. Conclusion: Higher level of circulating BCAAs was associated with increased risk of MMD and clinical subtypes. This study will help to elucidate the pathogenesis of MMD, which may provide the support for facilitating the treatments and preventions.

Hyperhomocysteinemia Is a Predictor for Poor Postoperative Angiogenesis in Adult Patients With Moyamoya Disease.

Background and Purposes: The risk factors of poor postoperative angiogenesis in moyamoya disease (MMD) patients remain unknown. We aimed to investigate the association between hyperhomocysteinemia (HHcy) and postoperative angiogenesis of adult patients with MMD. Methods: A total of 138 adult patients with MMD were prospectively recruited from July 1 to December 31, 2019. After excluding 10 patients accepting conservative therapy and 77 individuals without postoperative digital subtraction angiography (DSA), all 51 MMD patients were enrolled, and 28 patients received bilateral operations separately. Patients were grouped according to postoperative angiogenesis and HHcy presentation, respectively. Clinical data and laboratory examinations were compared. Potential risk factors were evaluated by univariate and multivariate logistic regression analysis. Nomogram was further performed. The biological functions of homocysteine (Hcy) were explored in vitro. Results: Comparing to the normal, patients with poor postoperative angiogenesis were higher in serum Hcy (p = 0.004), HHcy ratio (p = 0.011), creatinine (Cr) (p < 0.001), uric acid (UA) (p = 0.036), Triglyceride (p = 0.001), high-density lipoprotein cholesterol (HDL-C) (p = 0.001), low-density lipoprotein cholesterol (LDL-C) (p = 0.009), ApoA (p = 0.022), apolipoprotein B (ApoB) (p = 0.013). Furthermore, HHcy was more common in men (p = 0.003) than women. Logistic analysis results showed that Hcy (OR = 0.817, 95% CI = 0.707-0.944, p = 0.006) was an independent risk factor. HHcy and Cr were significantly associated with poor postoperative angiogenesis in MMD patients. Further, Hcy could inhibit the proliferation, migration, and tube formation of human brain microvascular endothelial cells (HBMECs), which can be reversed by vascular endothelial growth factor (VEGF). Conclusion: The HHcy was significantly correlated with poor postoperative angiogenesis in adult patients with MMD. Hcy significantly inhibits HBMECs proliferation, migration, and tube formation. Furthermore, VEGF could reverse the inhibition effect induced by Hcy. Lowering the level of Hcy may be beneficial for postoperative MMD patients. Focusing on the pathophysiology and mechanism of HHcy might help to guide postoperative clinical management.

Reorganization of the Brain Structural Covariance Network in Ischemic Moyamoya Disease Revealed by Graph Theoretical Analysis.

Objective: Ischemic moyamoya (MMD) disease could alter the cerebral structure, but little is known about the topological organization of the structural covariance network (SCN). This study employed structural magnetic resonance imaging and graph theory to evaluate SCN reorganization in ischemic MMD patients. Method: Forty-nine stroke-free ischemic MMD patients and 49 well-matched healthy controls (HCs) were examined by T1-MPRAGE imaging. Structural images were pre-processed using the Computational Anatomy Toolbox 12 (CAT 12) based on the diffeomorphic anatomical registration through exponentiated lie (DARTEL) algorithm and both the global and regional SCN parameters were calculated and compared using the Graph Analysis Toolbox (GAT). Results: Most of the important metrics of global network organization, including characteristic path length (Lp), clustering coefficient (Cp), assortativity, local efficiency, and transitivity, were significantly reduced in MMD patients compared with HCs. In addition, the regional betweenness centrality (BC) values of the bilateral medial orbitofrontal cortices were significantly lower in MMD patients than in HCs after false discovery rate (FDR) correction for multiple comparisons. The BC was also reduced in the left medial superior frontal gyrus and hippocampus, and increased in the bilateral middle cingulate gyri of patients, but these differences were not significant after FDR correlation. No differences in network resilience were detected by targeted attack analysis or random failure analysis. Conclusions: Both global and regional properties of the SCN are altered in MMD, even in the absence of major stroke or hemorrhagic damage. Patients exhibit a less optimal and more randomized SCN than HCs, and the nodal BC of the bilateral medial orbitofrontal cortices is severely reduced. These changes may account for the cognitive impairments in MMD patients.

Assessment of Surgical Outcomes in Children and Adult Ischemic Moyamoya Disease and Its Relationship with the Pre-infarction Cerebral Perfusion Status.

AIM: To clarify perfusion differences, and to determine whether children and adults respond similarly to surgical prevention and how brain perfusion stages before surgery predict outcomes in ischaemic moyamoya disease (MMD) in children and adults. MATERIAL AND METHODS: A total of 355 patients with ischaemic MMD, including 74 children and 281 adults, were enrolled in the study. Computerized tomography perfusion (CTP) scans were used to identify the perfusion status according to a novel staging system of the pre-infarction period. The perfusion status of each hemisphere between the children and adult groups was analysed. The modified Rankin scale was used during long-term follow-up as an indicator of clinical outcomes. RESULTS: The proportions of stages 0 and IV in adults were significantly higher than those in children (p=0.09 and p=0.003, respectively). Stage III was more common in the children's group (p=0.001). The stroke data showed an increasing tendency in the infarction rate from stages I to IV. Both groups in stage 0 and in the early stages had a similar highly improved ratio after surgery; the children, however, achieved significantly better clinical outcomes in stage III and late stages. CONCLUSION: There are differences in the perfusion status between child and adult patients with MMD. The pre-infarction staging system is associated with MMD-related stroke to some extent. Children have a greater chance for improvement than adults in stage III and later stages.

Treatment and prognostic factors of pituicytoma: a single-center experience and comprehensive literature review.

PURPOSE: Preoperative diagnosis of pituicytomas is difficult, and management and prognostic factors remain ambiguous. The purpose of this study was to elucidate the radiological characteristics of pituicytoma, to assess the risk factors affecting tumor progression, and to propose the optimal treatment regimen based on comprehensive analysis. METHODS: We reviewed the clinical data of 22 patients with pituicytoma confirmed pathologically in our institution. In addition, 93 cases of pituicytoma in the previous literature were recruited. The individual data of 115 patients were analyzed to evaluate the adverse factors affecting pituicytoma progression. RESULTS: In the combined cohort, 3 of 61 patients who underwent gross-total resection (GTR) developed recurrence (4.9%); of the 54 patients who received non-GTR, 19 progressed (35.2%). Univariate and multivariate Cox regression analysis verified male gender (HR 2.855, 95% CI 1.008-8.089; p = 0.048), TS (transsphenoidal surgery; HR 3.559, 95% CI 1.015-12.476; p = 0.047), and non-GTR (HR 4.388, 95%CI 1.240-15.521; p = 0.022) were independent unfavorable factors for pituicytoma progression. A multivariate logistic regression model verified that tumor diameter ≥ 1.85 cm (OR 4.859, 95% CI 1.335-17.691; p = 0.016) was independent adverse factors for GTR. Compared with TS, OT (open transcranial) is more likely to have postoperative complications (OR 3.185, 95% CI 1.020-9.944; p = 0.046), especially vision deterioration (OR 37.267, 95% CI 4.486-309.595; p = 0.001). CONCLUSION: Based on our findings, GTR was advocated as an optimal treatment for pituicytomas. However, in order to avoid damage to important structures, partial resection is acceptable. After that, adjuvant radiotherapy is recommended for male patients with high Ki-67 index, and the remaining patients can be followed up closely. When the tumor recurs or progresses, it is recommended to re-operate and remove the lesion completely as far as possible. If GTR is still not possible, postoperative radiotherapy for the residual tumor is recommended.

Assessment of blood supply of the external carotid artery in moyamoya disease using super-selective pseudo-continuous arterial spin labeling technique.

OBJECTIVES: To evaluate the diagnostic accuracy of super-selective pseudo-continuous arterial spin labeling (ss-pCASL) at depicting external carotid artery (ECA) perfusion territory in moyamoya disease (MMD). METHODS: In total, 103 patients with MMD who underwent both ss-pCASL and digital subtraction angiography (DSA, the reference standard) were included. There were 3, 184, and 19 normal, preoperative, and postoperative MMD hemispheres, respectively. The ss-pCASL results were interpreted by two different visual inspection criteria: presence or absence and definite or indefinite ECA perfusion territory. The performance of ss-pCASL at depiction of ECA perfusion territory was compared to that of DSA. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated. The κ statistic was used to assess intermodality and inter-reader agreement. RESULTS: When interpreted as presence or absence, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of ss-pCASL for depicting ECA perfusion territory were 78.3 %, 79.6 %, 92.5 %, 53.4 %, and 78.6 %, respectively, and the intermodality and inter-reader agreement were κ = 0.49 (CI: 0.43 - 0.55, p < 0.01) and 0.71 (CI: 0.66 - 0.76, p < 0.01), respectively. When interpreted as definite or indefinite, the respective values were 61.1%, 100%, 100%, 44.5%, 70.4%, κ = 0.42 (CI: 0.37 - 0.47, p < 0.01), and 0.90 (CI: 0.87 - 0.93, p < 0.01). CONCLUSION: ss-pCASL has substantial sensitivity and specificity compared with DSA for depicting the presence versus absence of ECA perfusion territory in MMD. As a noninvasive method in which no ion radiation or contrast medium is needed, ss-pCASL may potentially reduce the need for repeated DSA examination. KEY POINTS: • Super-selective pseudo-continuous arterial spin labeling (ss-pCASL) is a noninvasive vessel-selective MR technique to demonstrate perfusion territory of a single cerebral artery. • Compared with digital subtraction angiography, ss-pCASL has substantial sensitivity and specificity for depicting the perfusion territory of the external carotid artery in brain parenchyma in moyamoya disease. • ss-pCASL may potentially reduce the need for repeated DSA examination.