Background: The pathogenic mechanisms of periventricular anastomosis (PA) in moyamoya disease remain unknown. Here, we aimed to describe the angiographic profiles of PA and their relationships with really interesting new gene (RING) finger protein 213 (RNF213) genotypes. Methods: We conducted a retrospective cohort study of moyamoya disease patients consecutively recruited between June 2019 and January 2021 in Beijing Tiantan Hospital, Capital Medical University, China. C-terminal region of RNF213 was sequenced. Angiographic characteristics of PA vessels (lenticulostriate artery, thalamotuberal artery, thalamoperforating artery, anterior choroidal artery, and posterior choroidal artery) were compared between different groups of RNF213 genotypes. The dilatation and extension of PA vessels were measured by using PA score (positive, score 1–5; negative, score 0). Multivariate regression analysis was conducted to assess variables associated with PA score. In addition, gene expression of RNF213 in human brain regions was evaluated from the Allen Human Brain Atlas. Results: Among 260 patients (484 hemispheres), 71.2% carried no RNF213 rare and novel variants, 20.0% carried p.R4810K heterozygotes, and 8.8% carried other rare and novel variants. PA scores in patients with p.R4810K and other rare and novel variants were significantly higher than in wild-type patients ( P <0.001). Age (odds ratio [OR], 0.958 [95% CI, 0.942–0.974]; P <0.001), platelet count (OR, 0.996 [95% CI, 0.992–0.999]; P =0.027), p.R4810K variant (OR, 2.653 [95% CI, 1.514–4.649]; P =0.001), other rare and novel variants (OR, 3.197 [95% CI, 1.012–10.094]; P =0.048), Suzuki stage ≥4 (OR, 1.941 [95% CI, 1.138–3.309]; P =0.015), and posterior cerebral artery involvement (OR, 1.827 [95% CI, 1.020–3.271]; P =0.043) were significantly correlated with PA score. High expression of RNF213 was detected in the periventricular area. Conclusions: RNF213 variants were confirmed to be associated with PA in moyamoya disease. Individuals with RNF213 p.R4810K heterozygotes and other C-terminal region rare variants exhibited different angiographic phenotypes, compared with wild-type patients.

Background: The mechanisms driving the progression of moyamoya disease (MMD) remain unrecognized. There is evidence suggesting that genetic and environmental factors may be associated with intracranial artery stenosis. Here, we aimed to investigate the characteristics of infectious exposure and the association of the RNF213 (RING finger protein 213) variant and infectious burden (IB) with intracranial artery stenosis of MMD. Methods and Results: We prospectively recruited 275 patients with MMD. Participants underwent RNF213 p.R4810K sequencing. Serum antibody titers of herpes simplex virus, cytomegalovirus, toxoplasma, rubella virus, and Epstein‐Barr virus were assessed and combined into an IB score. The degree of intracranial artery stenosis was measured by using the Willis narrowing score (WNS), which was then dichotomized as mild and severe. Multivariate regression analyses were performed to analyze variables associated with severe WNS. Patients with the RNF213 variant had a higher risk of severe WNS than wild‐type individuals ( P =0.003). Patients with MMD with severe WNS showed an increased level of IB score ( P <0.001). The RNF213 variant (odds ratio [OR], 2.832 [95% CI, 1.347–5.955]; P =0.006) and IB score (OR, 1.771 [95% CI, 1.286–2.439]; P <0.001) were significantly associated with severe WNS after adjusting for covariates. Furthermore, the associations between IB score and severe WNS were more prominent among patients with modifiable risk factors of elevated body mass index ( P _interaction <0.001), triglycerides ( P _interaction =0.011), and homocysteine ( P _interaction =0.016). Conclusions: This study outlined a perspective of the genetic‐environmental interactions in the progression of MMD. The RNF213 variant and increased IB were associated with intracranial artery stenosis in MMD. The study will provide novel insights into the mechanism of disease progression, which may offer opportunities for early intervention of infectious exposure in MMD.

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.

Growing evidence suggests that systemic immune and inflammatory responses may play a critical role in the formation and development of aneurysms. Exploring the differences between single intracranial aneurysm (SIA) and multiple IAs (MIAs) could provide insights for targeted therapies. However, there is a lack of comprehensive and detailed characterization of changes in circulating immune cells in MIAs. Peripheral blood mononuclear cell (PBMC) samples from patients with SIA (n = 16) or MIAs (n = 6) were analyzed using high-dimensional mass cytometry to evaluate the frequency and phenotype of immune cell subtypes. A total of 25 cell clusters were identified, revealing that the immune signature of MIAs included cluster changes. Compared to patients with SIA, patients with MIAs exhibited immune dysfunction and regulatory imbalance in T-cell clusters. They also had reduced numbers of CD8+ T cells and their subgroups CD8+ Te and CD8+ Tem cells, as well as reduced numbers of the CD4+ T-cell subgroup CD27−CD4+ Tem cells. Furthermore, compared to SIA, MIAs were associated with enhanced T-cell immune activation, with elevated expression levels of CD3, CD25, CD27, CCR7, GP130, and interleukin 10. This study provides insights into the circulating immune cell profiles in patients with MIAs, highlighting the similarities and differences between patients with SIA and those with MIAs. Furthermore, the study suggests that circulating immune dysfunction may contribute to the development of MIAs.

Background: Creatine is essential for energy storage and transfer within and outside cells. However, its relationship with cerebrovascular disease has not been fully explored. This study examined the association between serum creatine levels and postoperative cerebrovascular events, including transient ischemic attack (TIA), ischemic stroke, and hemorrhagic stroke, in patients with moyamoya disease (MMD).Methods: Serum creatine and disodium creatine phosphate levels were quantified in 352 patients with MMD using liquid chromatography–tandem mass spectrometry. Kaplan–Meier (KM) curves were used to analyze the impact of serum creatine levels on cerebrovascular event risk, whereas univariate and multivariate Cox regression analyses were used to identify predictors of postoperative outcomes. A prognostic nomogram was developed to predict stroke‐free survival at 12, 24, and 36 months postoperatively.Results: In patients with MMD, serum creatine showed a negative correlation with creatinine (r = −0.22; p < 0.001) and homocysteine (r = −0.10; p < 0.05) but not with disodium creatine phosphate (r = −0.08; p = 0.15). When patients were divided into high and low groups based on the median serum creatine concentration, KM curve analysis revealed that patients in the high concentration group had a lower relative risk of cerebrovascular events than those in the low concentration group (hazard ratio: 0.55; 95% confidence interval, 0.33–0.94; p = 0.026). Furthermore, when patients were categorized into three levels based on creatine concentration, the overall KM curve analysis showed a significant difference (p = 0.038), such that the highest creatine concentration group (third tertile) showed a significantly reduced risk compared with the lowest concentration group (first tertile; p = 0.04).Conclusion: Lower preoperative serum creatine levels were associated with a higher risk of postoperative cerebrovascular events in patients with MMD. Therefore, creatine supplementation may be an effective means of preventing adverse outcomes in patients with MMD.