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 development of MIAs.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 development of MIAs.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
1. Single‐cell RNA sequencing, mass cytometry and RNA‐sequencing were used to compares immune profiles in MMD patients and healthy controls.
2. 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 Tregs.
3. Disrupted circulating immunity might play a role in the aetiology of MMD.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The role of methionine (Met) cycle in the pathogenesis and progression of cardiovascular and cerebrovascular diseases has been established, but its association with moyamoya disease (MMD) has rarely ...been studied. This study aimed to analyze the levels of Met cycle-related metabolites and constructed a risk model to explore its association with the risk of MMD.
In this prospective study, a total of 302 adult MMD patients and 88 age-matched healthy individuals were consecutively recruited. The serum levels of Met cycle-related metabolites were quantified by liquid chromatography-mass spectrometry (LC-MS). Participants were randomly divided into training set and testing set at a ratio of 1:1. The training set was used to construct the risk score model by LASSO regression. The association between Met cycle-related risk score and the risk of MMD was analyzed using logistic regression and assessed by ROC curves. The testing set was used for validation.
The levels of methionine sulfoxide and homocysteine were significantly increased, while the levels of betaine and choline were significantly decreased in MMD and its subtypes compared to healthy controls (p < 0.05 for all). The training set was used to construct the risk model and the risk score of each participant has been calculated. After adjusting for potential confounders, the risk score was independently associated with the risk of MMD and its subtypes (p < 0.05 for all). We then divided the participants into low-risk and high-risk groups, the high-risk score was significantly associated with the risk of MMD and its subtypes (p < 0.05 for all). The risk scores were further assessed as tertiles, the highest tertile was significantly associated with a higher risk of MMD and its subtypes compared to the lowest (p < 0.05 for all). The results were validated in the testing set.
This study has constructed and validated a risk model based on Met cycle-related metabolites, which was independently associated with the risk of MMD and its subtypes. The findings provided a new perspective on the risk evaluation and prevention of MMD.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Moyamoya disease (MMD) is a cerebrovascular disorder marked by progressive arterial narrowing, categorized into six stages known as Suzuki stages based on angiographic features. Growing evidence ...indicates a pivotal role of systemic immune and inflammatory responses in the initiation and advancement of MMD. This study employs high-dimensional mass cytometry to reveal the immunophenotypic characteristics of peripheral blood immune cells (PBMCs) at various Suzuki stages, offering insights into the progression of MMD. PBMC samples from eight patients with early-stage MMD (Suzuki stages II and III) and eight patients with later-stage MMD (Suzuki stages IV, V, and VI) were analyzed using high-dimensional mass cytometry to evaluate the frequency and phenotype of immune cell subtypes. We identified 15 cell clusters and found that the immunological features of early-stage MMD and later-stage MMD are composed of cluster variations. In this study, we confirmed that, compared to later-stage MMD, the early-stage MMD group exhibits an increase in non-classical monocytes. As the Suzuki stage level increases, the proportions of plasmacytoid DCs and monocyte-derived DCs decrease. Furthermore, T cells, monocytes, DCs, and PMN-MDSCs in the early-stage MMD group show activation of the canonical NF-κB signaling pathway. We summarized and compared the similarities and differences between early-stage MMD patients and later-stage MMD patients. There is a potential role of circulating immune dysfunction and inflammatory responses in the onset and development of MMD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
At present, there is limited research on the mechanisms underlying moyamoya disease (MMD). Herein, we aimed to determine the role of glutamine in MMD pathogenesis, and 360 adult patients were ...prospectively enrolled. Human brain microvascular endothelial cells (HBMECs) were subjected to Integrin Subunit Beta 4 (ITGB4) overexpression or knockdown and atorvastatin. We assessed factors associated with various signaling pathways in the context of the endothelial‐to‐mesenchymal transition (EndMT), and the expression level of related proteins was validated in the superficial temporal arteries of patients. We found glutamine levels were positively associated with a greater risk of stroke (OR = 1.599, p = 0.022). After treatment with glutamine, HBMECs exhibited enhanced proliferation, migration, and EndMT, all reversed by ITGB4 knockdown. In ITGB4‐transfected HBMECs, the MAPK–ERK–TGF–β/BMP pathway was activated, with Smad4 knockdown reversing the EndMT. Furthermore, atorvastatin suppressed the EndMT by inhibiting Smad1/5 phosphorylation and promoting Smad4 ubiquitination in ITGB4‐transfected HBMECs. We also found the protein level of ITGB4 was upregulated in the superficial temporal arteries of patients with MMD. In conclusion, our study suggests that glutamine may be an independent risk factor for hemorrhage or infarction in patients with MMD and targeting ITGB4 could potentially be therapeutic approaches for MMD.
Glutamine levels were positively associated with a greater risk of stroke (OR = 1.599, p = 0.022). After treatment with glutamine, HBMECs exhibited enhanced proliferation, migration, and EndMT, all reversed by ITGB4 knockdown. In ITGB4‐transfected HBMECs, the MAPK–ERK–TGF–β/BMP pathway was activated, with Smad4 knockdown reversing the EndMT. Furthermore, atorvastatin suppressed the EndMT by inhibiting Smad1/5 phosphorylation and promoting Smad4 ubiquitination in ITGB4‐transfected HBMECs. Finally, ITGB4 upregulation was confirmed in the superficial temporal arteries of patients with MMD.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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 (
= 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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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.
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, Aβ40, Aβ42, and Aβ42/Aβ40) 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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
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.
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.
In this paper we present a drift-correcting template update strategy for precisely tracking a feature point in 2D image sequences. The proposed strategy greatly complements one of the latest ...published template update strategies by incorporating a robust non-rigid image registration step. Previous strategies use the first template to correct drifts in the current template; however, the drift still builds up when the first template becomes different from the current one particularly in a long image sequence. In our strategy the first template is updated timely when it is revealed to be quite different from the current template and henceforth the updated first template is used to correct template drifts in subsequent frames. Our method runs fast on a 3.0
GHz desktop PC, using about 0.03 s on average to track a feature point in a frame (under the assumption of a general affine transformation model, 61
×
61 pixels in template size) and less than 0.1 s to update the first template. The proposed template update strategy can be implemented either serially or in parallel. Quantitative evaluation results show the proposed method in precision tracking of a distinctive feature point whose appearance is constantly changing. Qualitative evaluation results show that the proposed method has a more sustained ability to track a feature point than two previous template update strategies. We also revealed the limitations of the proposed template update strategy by tracking feature points on a human’s face.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
