RARE DISEASE
Moyamoya disease
Moyamoya disease
Moyamoya disease
Synonyms: Idiopathic Moyamoya disease
Synonyms: Idiopathic Moyamoya disease
Synonyms: Idiopathic Moyamoya disease
Drug discovery
4
drugs
With orphan designations
Overview
Moyamoya disease is a rare, progressive cerebrovascular disorder characterized by bilateral stenosis of the internal carotid arteries and compensatory collateral vessel formation ("puff of smoke" appearance). It causes ischemic strokes in children (58% initial presentation) and hemorrhagic strokes in adults (16-42% presentation), with transient ischemic attacks, seizures, and cognitive decline as common manifestations [1][4][8][12]. Surgical revascularization remains the primary intervention to prevent stroke progression [3][15][17].
Therapies
Direct bypass: Superficial temporal artery-to-middle cerebral artery anastomosis (preferred in adults) [3][11][16]
Indirect revascularization: Pial synangiosis or burr holes (effective in children) [3][9][17]
Medical management: Antiplatelets (aspirin), calcium channel blockers, and seizure control as adjuncts [7][17][18]
Categories: rare genetic diseases, rare neurological diseases
Research Papers
1,998 drug discovery papers about Moyamoya disease, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,998 drug discovery papers about Moyamoya disease, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-14 | Endovascular treatment of an inaccessible aneurysm in moyamoya‑like vessels using the floating‑coil technique.
In moyamoya disease (MMD), moyamoya‑like vessels develop at the base of the brain. A ruptured aneurysm originating from these vessels is challenging to manage with endovascular treatment (EVT). When direct catheterization is infeasible, parent artery occlusion (PAO) may be the last resort. However, if liquid embolic agents are unsafe due to a short reflux distance, deploying floating coils into the parent artery to occlude or trap the aneurysm offers a viable alternative. This maneuver, termed the "floating‑coil technique," has not been previously described. A 60‑year‑old man with subarachnoid hemorrhage (Hunt-Hess grade II) had MMD and an aneurysm in moyamoya-like vessels arising from the posterior cerebral artery. During EVT, neither the Marathon nor the Echelon‑10 microcatheter could be navigated into the parent artery because of an acute angulation. The floating-coil technique was used: first, an Axium Prime 1 mm × 2 cm coil was pushed out, detached, and floated into the parent artery. Then, 3 Axium Prime 1 mm × 1 cm coils were similarly deployed to occlude the parent artery of the aneurysm. Post‑EVT angiography showed disappearance of the aneurysm and occlusion of moyamoya‑like vessels. The patient had no new deficits and recovered well, with a modified Rankin Scale score of 0 at the 2‑month follow‑up. Thus, the "floating‑coil technique" is a valid choice for inaccessible aneurysms in moyamoya‑like vessels.
2026-08-13 | Computed Tomography Angiography Recognition of a Hemorrhagic Moyamoya Pattern May Alter Acute Blood Pressure Management.
Moyamoya disease (MMD) is a rare progressive cerebrovascular occlusive disorder characterized by stenosis of the terminal internal carotid arteries and the development of fragile lenticulostriate collateral vessels. In adults, MMD can manifest as intracranial hemorrhage (ICH), carrying significant morbidity and a high risk of recurrent bleeding. When hemorrhagic MMD coexists with bilateral large vessel occlusion, acute management becomes exceptionally complex, as the standard imperative to aggressively lower blood pressure following ICH directly conflicts with the hemodynamic requirements of collateral-dependent cerebral perfusion. A 52-year-old Caucasian woman with hypertension and treated hypothyroidism, recently started on aspirin for TIA-like symptoms, presented with acute-onset left hemiplegia and a National Institutes of Health Stroke Scale (NIHSS) score of 11. Hypertension was her sole conventional atherosclerotic risk factor, and thyroid autoantibodies obtained previously had been negative. Non-contrast computed tomography (CT) identified a 2.3 × 1.9 × 2.5 cm right gangliocapsular intraparenchymal hemorrhage with a concurrent small right thalamic hemorrhage. Computed tomography angiography (CTA) demonstrated bilateral M1 segment occlusions with distal M2 reconstitution, a pattern that immediately raised concern for MMD and led directly to the recognition that mechanical thrombectomy was not indicated. The neurosurgical team concurred with a clinical and radiographic diagnosis of moyamoya vasculopathy on hospital day two. Rather than applying standard post-ICH targets, the team individualized blood pressure management to a permissive systolic range of 120 to 160 mmHg, chosen to balance limiting hematoma expansion against preserving collateral-dependent perfusion. Intravenous nicardipine was successfully weaned by hospital day three. The diagnosis was considered probable and imaging-based. Formal cerebral angiography for Suzuki staging and revascularization planning was appropriately deferred during the acute admission and planned on an outpatient basis; the patient was discharged to an inpatient rehabilitation facility on hospital day five but was subsequently lost to follow-up, so digital subtraction angiography (DSA) was never performed. Bilateral M1 occlusion with distal M2 reconstitution on CTA in the setting of gangliocapsular hemorrhage should raise suspicion for MMD and may inform both interventional and hemodynamic decision-making. Recognition of the characteristic CTA pattern supported the decision not to pursue mechanical thrombectomy and prompted individualized blood pressure targets to preserve collateral-dependent cerebral perfusion. Because DSA was not obtained, intracranial atherosclerosis could not be formally excluded, and the diagnosis remains probable rather than definitive.
2026-08-06 | Transarterial embolization of ruptured distal choroidal artery aneurysm in Moyamoya disease: A case series and literature review.
Moyamoya disease (MMD) is characterized by the compensatory development of collateral vasculature. Aneurysm formation on collaterals is common. The rupture of these aneurysms is associated with a poor prognosis, which presents significant treatment challenges. We encountered two cases of distal choroidal artery aneurysm rupture in MMD. The first case experienced re-rupture and underwent superselective embolization. However, this case was complicated by an intraoperative rupture and subsequent hydrocephalus. The second case underwent parent artery occlusion without complications. These cases highlight both efficacy and the risks involved. Lesion accessibility is crucial. A careful evaluation of collaterals and precise planning are required.
2026-08-03 | Ruptured artery of Percheron aneurysm in moyamoya disease with thalamic hemorrhage and acute hydrocephalus: illustrative case.
In moyamoya disease, fragile collateral networks such as periventricular anastomoses are associated with an increased risk of hemorrhage, particularly in the posterior circulation. Peripheral aneurysms arising from these vessels are rare, and those involving the artery of Percheron are exceptionally uncommon. A 55-year-old patient with a history of thalamic hemorrhage presented with headache and impaired consciousness. CT revealed a right thalamic hemorrhage with intraventricular extension and acute hydrocephalus. Emergency ventricular drainage was performed. Subsequent angiography identified a ruptured peripheral aneurysm arising from the artery of Percheron originating from the left P1 segment, along with right-dominant moyamoya vascular architecture. The aneurysm was successfully treated with N-butyl cyanoacrylate embolization to prevent rebleeding. Due to insufficient clearance of intraventricular hematoma, endoscopic evacuation was performed. The patient experienced no rebleeding, and follow-up angiography confirmed durable obliteration of the aneurysm. Peripheral aneurysms arising from the artery of Percheron in moyamoya disease are extremely rare but should be considered in cases of deep hemorrhage with intraventricular extension. Prompt endovascular embolization using liquid embolic agents, combined with endoscopic hematoma evacuation, may provide an effective and minimally invasive treatment strategy. https://thejns.org/doi/10.3171/CASE26356.
2026-07-09 | Effects of intraoperative inhalational versus intravenous anesthesia on perioperative neurological outcomes and long-term prognosis in patients with moyamoya disease undergoing revascularization surgery: a systematic review and meta-analysis.
Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by progressive stenosis of intracranial carotid arteries and abnormal collateral network formation. Surgical revascularization is the standard treatment for stroke prevention, but the optimal intraoperative anesthetic strategy to minimize perioperative neurological complications remains controversial. This meta-analysis compares inhalational versus intravenous anesthesia for perioperative neurological outcomes in MMD patients undergoing revascularization. We systematically searched PubMed, Embase, Cochrane Library, and Web of Science from database inception to April 2026, including randomized controlled trials and high-quality observational studies comparing the two anesthesia regimens. Two investigators independently completed literature screening, data extraction, and risk of bias assessment. Random-effects models were applied to pool effect sizes. Primary outcomes included postoperative transient neurological events (TNEs), post-anesthesia care unit (PACU) delirium, and postoperative stroke. Evidence quality was graded using the GRADE system. Eleven studies (1673 patients, 2232 procedures) were included, with 6 studies constituting the core quantitative analysis set. Outcome coverage varied: 5 studies reported TNEs, 2 reported postoperative stroke, and only 1 single-center study reported PACU delirium. Pooled results showed no significant intergroup difference in TNEs (OR = 0.87, 95% CI: 0.55-1.38, P = 0.56, I² = 61%) or postoperative stroke (OR = 1.05, 95% CI: 0.50-2.17, P = 0.91, I² = 0%). Based on limited pediatric data, inhalational anesthesia may be associated with increased PACU delirium risk in children. Qualitative evidence indicated both regimens maintained stable cerebral oxygenation, while propofol-based intravenous anesthesia had advantages in reducing intracranial pressure and improving surgical field exposure. Current low-to-very-low quality evidence shows no significant difference in major perioperative neurological complications between the two anesthetic regimens for MMD revascularization. Intravenous anesthesia has potential advantages in intraoperative cerebral physiology and surgical conditions, and may be considered preferentially for children at high delirium risk, with limited evidence strength. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251272930.
cell therapies
2026-07-02 | Clinical and CT perfusion outcomes after direct STA-MCA bypass in moyamoya and non-moyamoya steno-occlusive disease: an Indonesian single-center cohort.
Direct superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass is used for selected haemodynamic cerebrovascular disorders, but comparative data between moyamoya and non-moyamoya disease remain limited in Indonesia. Consecutive patients undergoing direct STA-MCA bypass from 2021 to 2025 were retrospectively analysed. Clinical and operative outcomes were assessed in 68 patients; paired CT perfusion data were available in 41. The cohort included 40 patients with moyamoya disease and 28 with non-moyamoya disease, predominantly intracranial atherosclerotic disease [27/28 (96%)]. Patients with moyamoya were younger [41 (29-49) vs 48 (38-59) years; p = 0.003] and had lower rates of diabetes mellitus [7% vs 29%; p = 0.041] and hypertension [42% vs 86%; p < 0.001]. Bypass patency was documented in 90% versus 100% (p = 0.226). Paired modified Rankin Scale scores improved in both cohorts: from 2.08 ± 1.51 to 1.38 ± 1.39 in moyamoya (mean difference 0.70; p < 0.001) and from 2.82 ± 1.19 to 1.86 ± 1.33 in non-moyamoya disease (mean difference 0.96; p < 0.001). M4 frontal clipping time was longer in moyamoya [33 (31-37) vs 26 (24-32) minutes; p = 0.002]. Postoperative seizure occurred in 15% versus 7% (p = 0.455), and ischaemic stroke in 0% versus 11% (p = 0.065). In the CT perfusion cohort, pre-bypass Tmax was higher in non-moyamoya disease [2.17 (1.25-3.34) vs 1.31 (1.10-1.92); p = 0.048], while infarct volume was higher in moyamoya [8.65 (1.41-17.23) vs 5.63 (3.35-7.32) mL; p = 0.034]. No follow-up CT perfusion parameter differed significantly. Direct STA-MCA bypass was followed by functional improvement in both cohorts and comparable follow-up CT perfusion profiles.
2026-06-27 | Rescue direct bypass after insufficient prior revascularization in moyamoya disease: Feasibility of using reused or preserved superficial temporal artery branches.
To describe the feasibility and short- to mid-term outcomes of rescue direct or combined revascularization using reused or preserved superficial temporal artery branches in patients with moyamoya disease after insufficient prior revascularization. We retrospectively reviewed five patients with moyamoya disease who underwent repeat revascularization for recurrent ischemic or hemorrhagic stroke after prior revascularization. Donor suitability was assessed using digital subtraction angiography to determine whether the previous donor artery had developed effective collateralization and SPECT to identify persistent hemodynamic compromise. Three patients underwent rescue direct bypass using a previously used STA branch that had failed to develop sufficient collateralization. Two patients underwent rescue revascularization using an STA branch that had not been used during the initial operation. All patients underwent successful rescue direct or combined revascularization. Bypass patency was confirmed intraoperatively and postoperatively in all cases. No postoperative ischemic or hemorrhagic complications occurred, and no patient experienced recurrent stroke during follow-up. Rescue direct or combined bypass using reused or preserved STA branches may be feasible in carefully selected patients with recurrent stroke after prior revascularization. Preoperative angiographic confirmation of donor suitability and perfusion imaging are essential for selecting the appropriate rescue strategy.
2026-06-17 | Implications for a Deeper Clinical Understanding of Moyamoya Disease: Temporal Evolution of Suzuki Staging.
Moyamoya disease (MMD) is a rare cerebrovascular disorder discovered in Japan, characterized by progressive internal carotid artery stenosis and fragile collateral vessel formation. Diagnosis relies on imaging, with Suzuki staging commonly used to classify disease severity. There is limited literature on MMD in non-Asian, non-White populations. This study evaluated clinical factors associated with disease presentation, severity, treatment, and progression, with a novel focus on longitudinal changes in Suzuki stage. A retrospective cohort study was conducted using electronic medical records. Clinical data, including demographics, Suzuki stages, surgical interventions, stroke frequency, and outcomes, were collected and analyzed. Of 114 patients diagnosed with MMD, 89 were from underrepresented populations in Moyamoya literature. Imaging from 91 patients showed Suzuki scores following a bell-curve distribution. Higher initial Suzuki scores were significantly associated with an increased likelihood of surgery (P < .001). In a subcohort of 71 patients with at least 2 Suzuki scores 1 year apart, scores remained largely stable, although a weak, nonsignificant trend toward worsening was seen in nonsurgical patients (P = .14). Notably, Mann-Whitney U analysis revealed a significant difference in Suzuki stage changes, with nonsurgical patients showing greater radiographic progression and surgically treated patients exhibiting stability or improvement (P < .05). No significant correlation was found between changes in Suzuki stage and functional outcomes or stroke events. This study expands understanding of MMD in a diverse, non-Asian population and supports Suzuki staging as a reliable tool for disease assessment and surgical planning. Surgical intervention appears to slow radiographic progression, supporting its role in management. Further prospective studies are needed to refine Suzuki staging in monitoring disease trajectory and guiding treatment.
2026-06-11 | AI-Guided Patient-Derived Endothelial Modeling Identifies a Reversible Moyamoya-Specific miRNA Deficiency Corrected by Stem Cell-Extracellular Vesicles.
Moyamoya disease (MMD) is a progressive cerebrovascular disorder characterized by abnormal vascular remodeling and impaired angiogenesis. We profiled plasma extracellular vesicle (EV)-derived microRNAs (miRNAs) from MMD patients and healthy controls and generated patient-specific induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) to investigate disease-associated molecular alterations and therapeutic reversibility. Both plasma EVs and iPSC-ECs from MMD patients showed significant depletion of angiogenesis-related miRNAs. Small RNA sequencing data revealed mesenchymal stem cell-derived EVs (MSC-EVs) contain a miRNA repertoire that substantially overlaps with miRNAs deficient in MMD. Treatment of MMD iPSC-ECs with MSC-EVs restored the majority of the depleted miRNAs to normal levels, normalized predicted target mRNA expression, and rescued angiogenic function in a dose-dependent manner, as demonstrated by tube formation assays. To improve identification of biologically relevant miRNA-mRNA interactions, we developed an artificial intelligence-based framework integrating experimentally validated databases, endothelial-focused literature mining, and large language model (LLM)-assisted mechanistic scoring. Incorporation of LLM-derived contextual features modestly improved prediction performance compared with conventional sequence-based models (baseline AUROC ~ 0.51; LLM-enhanced AUROC ~ 0.72), suggesting that literature-informed biological context provides meaningful signal beyond structural target features alone. Furthermore, our findings demonstrate that MSC-EV therapy can substantially reverse molecular and functional endothelial deficits. Integrated profiling and AI-driven interaction mapping together establish a hypothesis-generating framework ("Exo-Courier") for biologically informed prioritization of EV-based therapeutic targets in vascular disorders.
2026-05-12 | Blood, Brain, and Bypass: Moyamoya Syndrome Unmasked During Hematologic Optimization in an Adult With Sickle Cell Disease.
Moyamoya syndrome is a rare, progressive cerebrovascular disorder characterized by stenosis or occlusion of the terminal internal carotid arteries with the formation of fragile collateral vessels. While classically described in pediatric patients and idiopathic Moyamoya disease, secondary Moyamoya syndrome has been reported in association with sickle cell disease (SCD). Adult presentations remain uncommon and are frequently underrecognized. We report a unique case of a 36-year-old man with sickle cell anemia who developed acute neurological deterioration following hematologic optimization with packed red blood cell transfusion and therapeutic phlebotomy during a vaso-occlusive crisis. Cerebral angiography revealed complete occlusion of the left internal carotid artery at its terminus, consistent with Moyamoya syndrome. The patient subsequently underwent surgical revascularization with encephaloduroarteriosynangiosis with subsequent neurological stabilization. This case illustrates how advanced but previously compensated large-vessel cerebrovascular disease in adults with SCD may become clinically manifest during physiologic perturbation, underscoring the importance of early vascular imaging and multidisciplinary management when neurologic symptoms evolve during hematologic therapy.
proteins
2026-02-09 | Angiographic outcomes after indirect revascularization in pediatric Moyamoya disease: a systematic review and Meta-analysis.
Moyamoya disease is a rare progressive cerebral vasculopathy characterized by narrowing or occlusion of the internal carotid arteries, leading to the formation of fragile collateral vessels and a high risk of ischemic events, especially in pediatric patients. Although direct revascularization techniques are commonly used, they are technically challenging in children due to vascular fragility and anatomy. Indirect revascularization techniques favor the formation of new blood vessels through alternative flow routes. Their efficacy is usually assessed using the Matsushima scale, which measures the degree of revascularization achieved. This study aims to describe postoperative angiographic outcomes of indirect revascularization techniques in pediatric patients with Moyamoya disease. A systematic review and meta-analysis was performed following PRISMA guidelines, searching six databases (PubMed, Embase, Scopus, Web of Science, CENTRAL and Google Scholar) for observational studies that evaluated indirect revascularization techniques in pediatric patients with Moyamoya disease. Seventeen studies comprising 1360 hemispheres were included. Primary outcomes were the proportions of angiographic revascularization according to grades A, B, and C of the Matsushima scale. Secondary outcomes included postoperative clinical complications such as stroke, transient ischemic attacks (TIAs), seizures, bleeding, mortality, and functional status assessed using the modified Rankin scale (mRS ≤2). Meta-analyses were performed with random-effects models in R (version 4.2.3) and risk of bias was assessed with the MINORS tool. Meta-regression was applied to explore possible predictors of outcomes. The certainty of evidence was assessed with the GRADE approach. The combined proportions of hemispheres achieving Matsushima grades A, B and C were 47.1% (95% CI: 38.4-55.9; I2 = 84.4%), 38.2% (95% CI: 32.0-44.9; I2 = 84.4%) and 12.3% (95% CI: 9.3-16.0; I2 = 47.0%), respectively. Postoperative complications were low: stroke 8.3%, TIA 7.2%, seizures 2.5%, bleeding 2.7% and mortality 0.8%. Good functional status (mRS ≤2) was achieved in 82.1% of patients. Meta-regression revealed that unilateral vs. bilateral procedures significantly predicted Matsushima grade B outcomes (p = 0.002). The risk of bias was low to moderate. The certainty of evidence was generally low to moderate, except for mortality which showed high certainty. Indirect revascularization techniques in pediatric Moyamoya show favorable angiographic and clinical results, with low complications and high functional independence. According to the Matsushima scale, about 47% of the hemispheres achieved grade A, 38% grade B and 12% grade C. Pial synangiosis and EDAMS were more effective in grade A, whereas EDAS showed a lower proportion in grade A and slightly more in grade C. Postoperative complications were low and most patients achieved good functional status (mRS ≤2). These findings suggest the safe and effective use of indirect techniques, although the high heterogeneity and methodological limitations evidence the need for randomized studies to validate and optimize these results in the long term.
2025-09-17 | Short Stature in Moyamoya Disease: A Systematic Review of Potential Mechanisms and Clinical Outcomes.
Background: Moyamoya disease (MMD) is a complex cerebrovascular disorder. While its neurological manifestations are well documented, the association between MMD and short stature remains underrecognized. This review explores potential mechanisms linking MMD with growth impairment, with a focus on endocrine and syndromic contributors. Methods: A systematic review was conducted in accordance with PRISMA guidelines using PubMed and Scopus databases. Studies reporting cases of MMD with short stature or growth impairment were included. Data were extracted on patient demographics, endocrine findings, genetic mutations, neuroimaging, management, and outcomes. A narrative synthesis approach was used due to heterogeneity in study designs. Results: Across 25 studies, 30 individuals with MMD and clinically significant short stature were identified, predominantly pediatric (2.5-52 years). Presentations frequently included seizures (n = 21), TIAs (n = 8), hemiparesis (n = 7), cognitive impairment (n = 8), and headaches (n = 3); in many, growth failure predated neurological events. Height deficits ranged from -2.13 to -23.7 SDS. Endocrine involvement was common: growth hormone deficiency (n ≈ 6), delayed bone age (n = 3), and other pituitary-thyroid-gonadal disturbances; a rare pituitary stalk duplication was reported. Management varied. Indirect revascularization in selected cases reduced recurrent ischemia; growth hormone therapy improved height velocity. Antiplatelets were commonly used; anticoagulation occasionally led to complications. Outcomes were heterogeneous; four deaths occurred, typically in patients with severe multisystem disease. Conclusion: Growth retardation in MMD is generally a manifestation of hypothalamic-pituitary dysfunction, chronic cerebral hypoxia, or genetic syndromes. The observations in the present study suggest that MMD may be part of a more generalized multisystemic disorder in some patients and needs multisystemic assessment and management.
2025-07-08 | Machine learning identifies KRT8 dysregulation and endothelial remodeling in Moyamoya disease.
Moyamoya disease (MMD) is a rare occlusive cerebrovascular disease, and its pathological mechanism remains unclear at present. The abnormal vascular remodeling may be involved in vascular endothelial cells. In this study, RNA seq was performed on the superficial temporal arteries of 10 patients with MMD. Integrated analysis was conducted by combining validation set with training set. Key genes were identified through differential analysis and WGCNA. The functions of potential biomarkers were explored by methods such as correlation analysis, KEGG analysis, PPI network, and tube formation experiments. Integrated analysis of three cohorts (43 MMD vs. 26 controls) identified 19 shared DEGs, including upregulated KRT8/KRT18 and downregulated NT5C2 (P < 0.001). Enrichment revealed dysregulation in circadian rhythm, calcium signaling, and metabolic pathways (P < 0.05). Immune infiltration showed elevated pro-inflammatory cells (neutrophils, M1 macrophages) and reduced Tregs/NK cells (P < 0.05). Machine learning (SVM-RFE, Boruta, LASSO) prioritized KRT8 as diagnostic markers (AUC > 0.96). KRT8 overexpression enhanced angiogenesis in HBMECs (1.5-fold tube formation, P < 0.01). This omics approach delineates MMD's molecular interplay between inflammation, metabolism, and vascular remodeling. KRT8 may promote vascular remodeling in MMD by regulating the tube-forming ability of endothelial cells. This could be a highlight of therapeutic targets for MMD and shed light on the mechanism research of MMD.
2025-02-07 | Reinforcement of Transdural Angiogenesis: A Novel Approach to Treating Ischemic Stroke With Cerebral Perfusion Impairment.
Cerebral hypoperfusion plays a critical role in early neurological deterioration and long-term outcomes in patients with acute ischemic stroke, which remains a major global health challenge. This review explored transdural angiogenesis as a promising therapeutic strategy to restore cerebral perfusion in patients with ischemic stroke. The multiple burr hole procedure has been preliminarily used as an indirect revascularization method to induce transdural arteriogenesis. Theoretically, its efficacy could be enhanced by combining it with angiogenic boosters, such as erythropoietin. Recent clinical and preclinical studies have revealed that this combination therapy promotes angiogenesis and arteriogenesis, leading to successful revascularization across the dura mater and improved cerebral blood flow. This strategy may be particularly beneficial for high-risk patients with recurrent ischemic events, such as those with moyamoya disease or intracranial arterial occlusion, representing an effective strategy when conventional medical treatments are insufficient. This review highlights the potential of transdural angiogenesis enhancement as a novel intervention for ischemic stroke, offering an alternative to thrombolysis or endovascular treatment, particularly in acute stroke patients with impaired cerebral perfusion. This approach has the potential to bridge the treatment gap for patients outside the therapeutic window for acute stroke interventions. Although further research is required to refine this technique and validate its efficacy in broader clinical settings, early results have revealed promising outcomes at reducing stroke-related complications and improving patient prognosis. This review indicates that this novel strategy may offer hope for managing ischemic stroke and related conditions associated with significant cerebral hypoperfusion.
2025-01-07 | Multiple burr hole and erythropoietin combination therapy: optimal early surgical intervention for patients with acute stroke episode of moyamoya disease or moyamoya syndrome.
The optimal timing of bypass surgery for patients with moyamoya disease (MMD) or moyamoya syndrome (MMS) following an acute stroke episode remains unclear, mainly owing to the risk of postoperative complications. In this study, we aim to validate the safety and efficacy of early intervention using multiple burr hole (MBH) and erythropoietin (EPO) therapy, thereby refining the management strategy for patients with acute stroke episode of MMD or MMS. We retrospectively analyzed data from 70 patients with MMD or MMS who underwent MBH and EPO therapy. The cohort was divided based on the time interval between the latest neurological deterioration and surgery: early (<30 days) and later (≥30 days) groups. We evaluated and compared perioperative clinical parameters and the extent of neovascularization on a 6-month postoperative angiography. Long-term clinical outcomes, including transient ischemic attack (TIA), infarction, hemorrhage, and seizure, were also analyzed during the follow-up period. In the cohort, 36 patients (51.4%) were in the early group, whereas 34 (48.6%) were in the later group. The 6-month follow-up angiography demonstrated that 34/47 hemispheres (72.3%) in the early group exhibited successful neovascularization (≥2/3 of MCA territories) compared with the 19/44 (43.2%) hemispheres in the later group (odds ratio [OR] = 3.44; 95% confidence interval [CI]: 1.46-8.45; p < 0.01). In addition, a notable reduction (≥50%) in basal moyamoya vessels was observed in 30/47 hemispheres (63.8%) from the early group vs. 12/44 (27.3%) hemispheres from the later group (OR = 4.71; 95% CI: 1.97-11.82; p < 0.001). During the average follow-up of 56.5 months, only six patients experienced infarction or hemorrhage. Our dataset suggests that MBH and EPO combination therapy is an effective, minimally invasive, and acceptable treatment, even in the early period of patients with MMD or MMS following an acute stroke episode.
gene therapies
2026-02-13 | Delineating the Genetic Basis of RNF213-related vasculopathies: The association of PKHD1 variants with bilateral cerebral vasculopathy.
Moyamoya disease (MMD) is an idiopathic cerebrovascular disorder characterized by progressive stenosis of the internal carotid artery termini and the formation of an abnormal network of fragile perforators. Although the RNF213 gene has been implicated as a susceptibility factor for MMD, the precise genetic basis of the disease remains elusive. This study aimed to investigate other genetic factors contributing to differences in disease manifestation and vascular phenotypes. We conducted whole-exome sequencing of patients with RNF213-related vasculopathy and healthy controls. In total, 122 patients (comprising 69 with bilateral MMD, 13 with unilateral MMD, and 40 with intracranial artery stenosis [ICAS]) and 458 controls were enrolled. Following appropriate quality control measures, case-control analysis and in-case analysis (bilateral MMD vs. unilateral MMD and ICAS) were conducted using single-variant association testing and gene-based aggregation testing. Although no significant locus or gene was found in the case-control analysis, the PKHD1 gene emerged as a top candidate associated with bilateral MMD in the in-case analysis. Two rare damaging variants, p.Ile2364Asn and p.Ser3210Cys, were significantly more prevalent in the bilateral MMD group and were further validated in an independent cohort of 216 individuals. Publicly available single-cell transcriptome data of mouse cerebrovascular and perivascular cells revealed that Pkhd1 expression was significantly higher in specific endothelial-cell clusters. Despite some limitations, our study provides new insights into the potential role of the PKHD1 gene in bilateral MMD, highlighting the need for further investigation of endothelial gene expression in patients with RNF213 and PKHD1 mutations.
2025-12-02 | MicroRNA-29b-3p promotes endothelial cell inflammation via NTRK2/PI3K/NLRP3 pathway in Moyamoya disease.
Moyamoya disease (MMD) is a rare chronic progressive vascular anomaly of the skull base whose molecular regulatory mechanisms remain poorly understood. We therefore aimed to analyze the molecular mechanisms involved in the development of MMD from the perspective of miRNA regulation of mRNA. Raw gene expression profiles (GSE178501, GSE157628 and GSE189993) were downloaded from the Gene Expression Omnibus database and used to identify differentially expressed genes and perform functional enrichment analysis. Differentially expressed miRNAs and their predicted target genes were validated by RT-qPCR. Oxygen glucose deprivation was applied to induce an inflammatory injury cell model in human brain microvascular endothelial cells (BMEC). 973 differentially expressed mRNAs and 3 differentially expressed miRNAs were identified in three sets of gene expression profiles. RT-qPCR confirmed that the miR-29b-3p was upregulated in leukocytes of MMD and that the expression of NTRK2 was downregulated. Dual-luciferase reporter assay indicated that NTRK2 was the direct target of miR-29b-3p. Overexpression of NTRK2 improved the viability of BMEC and increased the protein levels of NTRK2 and pPI3K, while suppressed the expression of NLRP3, IL1β, and TNF-α. miR-29b-3p treatment partially abolished the protective effect of NTRK2 and diminished the effect of NTRK2 on PI3K/NLRP3 pathway. In conclusion, this study provided a novel insight into the pathophysiological mechanisms of MMD and demonstrated that the miR-29b-3p/NTRK2/PI3K/NLRP3 axis plays a pivotal role in the progression of MMD.
2024-10-05 | Whole-exome sequencing reveals the genetic causes and modifiers of moyamoya syndrome.
Moyamoya vasculopathy secondary to various genetic disorders is classified as moyamoya syndrome (MMS). Recent studies indicate MMS occurs due to a combination of genetic modifiers and causative mutations for the primary genetic disorders. We performed whole-exome sequencing (WES) in 13 patients with various genetic disorders who developed MMS. WES successfully revealed the genetic diagnoses of neurofibromatosis type 1 (NF-1), Down syndrome, multisystemic smooth muscle dysfunction syndrome, Noonan syndrome, and alpha thalassemia. The previously reported modifier genes, RNF213 and MRVI1, were confirmed in the NF-1 and Down syndrome cases. Further analysis revealed rare hypomorphic variants in the causative genes of the primary disorders underlying MMS, such as Alagille syndrome and Rasopathies, conferred susceptibility to MMS. Genes involved in the development of pulmonary arterial hypertension (PAH), such as ABCC8 and BMPR2, were also identified as potential modifiers. The rare variants in the MMS and PAH genes were significantly enriched in the eight Japanese patients with MMS compared with the 104 Japanese individuals from the 1000 Genomes Project. Disease genes associated with the arterial occlusive conditions represented by those of Rasopathies and PAH may provide novel diagnostic markers and future therapeutic targets for MMS as well as moyamoya disease with an unknown cause.
2024-09-24 | HAPLN3 p.T34A contributes to incomplete penetrance of moyamoya disease in Chinese carrying RNF213 p.R4810K.
The penetrance of the RNF213 p.R4810K, a founder mutation of moyamoya disease (MMD), is estimated to be only 1/150-1/300. However, the factors affecting its penetrance remain unclear. Therefore, our study aims to identify modifier genes associated with the incomplete penetrance of this founder mutation. Whole-exome sequencing (WES) was performed on 36 participants, including 22 MMD patients and 14 non-MMD controls with RNF213 p.R4810K mutation. Fisher's exact test was used to assess the presence of genetic variants that differed significantly between MMD patients and non-MMD controls. In order to exclude false-positive results, another 55 carriers were included to perform Fisher's exact test for the selected sites in the WES discovery stage. Subsequently, human brain microvascular endothelial cells were transfected with wild-type and mutant HAPLN3 for tube formation assays and western blotting to explore the impact of candidate genes on angiogenesis. Analysis of variants from WES data revealed a total of 12 non-synonymous variants. Through bioinformatics analysis, the focus was on the HAPLN3 p.T34A variant with a significant p value of 0.00731 in Fisher's exact test. Validation through Sanger sequencing confirmed the presence of this variant in the WES data. In vitro experiments revealed that silencing HAPLN3 and transfecting HAPLN3 p.T34A significantly enhanced tube formation and increased the relative protein expression of vascular endothelial growth factor in endothelial cells. These results suggest that HAPLN3 may function as a modifier gene of RNF213 p.R4810K, promoting the development of MMD and contributing to the incomplete penetrance of MMD founder mutations.
2024-08-13 | Comprehensive Analysis and In Vitro Verification of Endothelial-Mesenchymal Transition-Related Genes in Moyamoya Disease.
Moyamoya disease (MMD) is a rare, chronic, and progressive cerebrovascular disorder with unclear underlying causes and mechanisms. Previous studies suggest a potential involvement of endothelial-mesenchymal transition (EndMT) in the pathogenesis of MMD. This study aimed to explore the contribution of EndMT-related genes (ERGs) in MMD. Two datasets, GSE141022 and GSE157628, were integrated as the training set after batch effects removal. Differentially expressed ERGs were identified between MMD and control groups. Functional enrichment analysis and immune infiltration analysis were further performed. LASSO regression was used for hub MMD-related ERG selection. Consensus clustering was used for MMD subtype classification based on these hub MMD-related ERGs. Molecular characteristics between MMD subtypes were analyzed using WGCNA. PPI network was used to illuminate the genetic relationship. The hub MMD-related ERGs were validated in an independent testing set, GSE189993. The nomogram model was constructed and evaluated using ROC curves and calibration plots. Additionally, CCK-8, EdU, wound healing, and western blot were performed to confirm the function of the hub MMD-related ERGs. A total of 107 DE-ERGs were identified. Functional enrichment analysis showed these genes were associated with EndMT and immune response. The infiltrating levels of immune cells were commonly higher in the MMD group. LASSO regression identified 12 hub MMD-related ERGs, leading to the identification of two MMD subtypes. Four ERGs emerged as the final hub MMD-related ERGs after validation in the testing set, including CCL21, CEBPA, KRT18, and TNFRSF11A. The nomogram model exhibited excellent discrimination ability. In vitro experiments showed that CCL21, CEBPA, KRT18, and TNFRSF11A could promote proliferation, migration, and EndMT. This study investigated the potential role of EndMT in MMD and identified four hub MMD-related ERGs, providing potential therapeutic targets for MMD treatment.
other
2026-07-25 | Integrated Serum Multiomics Reveal Subtype-Specific Immune Dysregulation and Sex-Dimorphic Pathophysiology in Moyamoya Disease.
Moyamoya disease (MMD) is a rare cerebrovascular disorder with unknown pathogenesis, partly due to limited access to human cerebral vascular tissue and suitable animal models. Using a large biobank of frozen serum samples, this study aimed to explore molecular signatures of ischemic and hemorrhagic MMD. Serum from 30 patients with MMD (18 ischemic, 12 hemorrhagic) and 30 matched healthy controls underwent proteomic and metabolomic profiling. Data were analyzed for differential expression, pathway enrichment, and protein-metabolite networks, with adjustment for age, sex, and body mass index. In a separate large Chinese cohort (n=6167), female patients had a higher proportion of hemorrhagic MMD (19.9% versus 16.9%) and a higher prevalence of anterior choroidal artery dilation (15.1% versus 13.2%) than male patients (both P<0.05). At the molecular level, ischemic MMD showed complement C4-B deficiency and disrupted natural killer cell cytotoxicity; both subtypes shared immunoglobulin perturbations (eg, decreased heavy-chain variable regions). Sex-specific alterations included anti-folate-binding protein, serum amyloid A2, glycolithocholic acid, and estradiol. All omics data are publicly accessible. Integrated serum multiomics defines distinct immune-related signatures for ischemic and hemorrhagic MMD and reveals sex-dimorphic molecular pathways. These findings, together with clinical sex differences in disease subtype and vascular anatomy, provide a framework for personalized, sex-aware management of MMD.
2026-07-03 | Proteomic landscape and molecular mechanisms of encephalomyosynangiosis in a rodent model of chronic cerebral hypoperfusion.
The purpose of the present study was to establish a reproducible 2-vessel occlusion (2VO) rat model combined with encephalomyosynangiosis (EMS) to investigate angiogenic and proteomic mechanisms of indirect cerebral revascularization as a basis for further study in order to improve angiogenesis and cognition. Fifteen rats underwent 2VO of the bilateral common carotid arteries 1 week apart. At the time of the second occlusion, 10 animals underwent EMS while 5 animals received a sham surgery. Adequate hypoperfusion was considered established if the cerebral blood flow decreased to 40% of baseline. Six weeks after surgery, reperfusion outcomes were assessed with the Longa model, novel object recognition, immunohistochemical analysis, and proteomic analysis. Animals that underwent EMS surgery demonstrated minimal neurological deficits on the Longa model, and EMS animals spent more time with both the old (mean 16.08 seconds vs 8.07 seconds) and novel (18.21 seconds vs 10.84 seconds) objects, suggesting that the EMS animals overall spent more time exploring in both scenarios compared to the 2VO animals that were more sedentary. Immunohistochemical analysis revealed evidence of increased angiogenesis in tissue specimens collected from the experimental cohort. Proteomic analysis showed that the EMS mechanism of action likely alters metabolism, notably by stimulating aerobic respiration, reducing neutrophil-mediated neuroinflammation, altering synapses, reorganizing cytoskeletal protein binding, and activating MAPK/ERK signaling through L1CAM activation. Establishing a 2VO and EMS rat model lays the groundwork for future research across laboratories to explore novel strategies for enhancing neovascularization, ultimately contributing to improved therapeutic approaches for patients with moyamoya disease and other vaso-occlusive cerebrovascular disorders.
2025-10-24 | The orbital grading system in pediatric moyamoya: an interrater reliability analysis of angiographic outcomes.
The Matsushima grading system is widely used to evaluate angiographic revascularization outcomes after pial synangiosis for moyamoya vasculopathy by quantifying collateral ingrowth. The authors hypothesized that the orbital grading system (OGS), a new scale developed for adults to measure collateral ingrowth, would provide greater consistency and interrater reliability. They aimed to compare the performance of these scales for the first time in the pediatric population. The authors performed a retrospective analysis of patients with moyamoya vasculopathy with follow-up catheter angiography after indirect revascularization at a single major pediatric center from 2006 to 2023. An interrater reliability analysis was performed using 5 raters with varying levels of training, who provided scores for 30 blinded cases. Fleiss' kappa coefficient (κ) was calculated as a measure of agreement beyond chance. A total of 101 patients with a median age of 9 years, of predominantly female sex (56.4%) who were mostly affected by moyamoya disease (71.3%) were included. A total of 158 cerebral hemispheres were treated with pial synangiosis (57 patients had bilateral surgeries). Most hemispheres were categorized as Suzuki stage 3 or above (82.9%). At a median of 12.4 months postoperatively, collateral growth was classified as Matsushima grade A in 57.6%, B in 24.1%, C in 14.6%, and as borderline grades in 3.8%. The OGS scores were grade 0 in 7.0%, grade 1 in 8.9%, grade 2 in 43.7%, and grade 3 in 40.5%. Interrater agreement evaluation revealed that the OGS had a superior κ value compared with the Matsushima scale (0.51 vs 0.15, p < 0.001). The OGS had higher interrater agreement rates than the Matsushima scale for identifying postoperative collateral ingrowth in children after pial synangiosis. This scale provides a more consistent method for evaluating angiographic outcomes after indirect revascularization in the pediatric population.
2025-07-30 | Unraveling the links between intracranial artery stenosis, cerebral perfusion, and white matter hyperintensity in moyamoya disease.
White matter hyperintensity (WMH) is commonly observed in patients with intracranial artery stenosis (ICAS), such as atherosclerosis or moyamoya disease (MMD). However, the relationships between ICAS, cerebral blood flow (CBF), and WMH remain unclear. We aimed to investigate whether reduced CBF mediated the relationship between ICAS and WMH in MMD. We retrospectively analyzed prospectively collected data of patients with MMD who underwent 3T-MRI between June 2020 and July 2023. CBF in the territories of anterior cerebral artery (ACA), middle cerebral artery (MCA) and posterior cerebral artery (PCA) was quantified using arterial spin labeling, and the stage of ICAS was evaluated by MRA. We pooled the data from each hemisphere together. Sixty-five patients were included, with WMH mainly distributed within the MCA territory. Among 124 hemispheres with WMH, WMH volume increased with the increased stage of ICAS (p < 0.001). CBF in each arterial territory showed a negative correlation with WMH volume (ACA: r = -0.364; MCA: r = -0.406; PCA: r = -0.309; all p < 0.001). Linear mixed-effects models revealed that ICAS stage (β = 0.132, p = 0.026) and CBF in the MCA territory (β = -0.026, p = 0.019) were significantly associated with WMH volume. Mediation analysis showed that decreased CBF in the MCA territory mediated 40% of the effect of ICAS on WMH volume. Hypoperfusion in the MCA territory partially mediated the association between ICAS and WMH, suggesting that enhancing perfusion could be a potential treatment strategy for WMH in MMD. Question Whether cerebral blood flow mediates the relationship between intracranial artery stenosis and white matter hyperintensity remains unclear. Findings In patients with moyamoya disease, cerebral blood flow in the middle cerebral artery territory mediates 40% of the effect of arterial stenosis on white matter hyperintensity. Clinical relevance Improvement of cerebral blood flow in the middle cerebral artery territory could be a potential treatment strategy for white matter hyperintensity in moyamoya disease, thereby alleviating clinical manifestations such as cognitive dysfunction in patients.
2025-03-11 | Integrated bulk RNA sequencing and mass cytometry analysis reveal the circulating immune landscape in ischemic and hemorrhagic Moyamoya disease.
Moyamoya disease (MMD) is increasingly recognized as being influenced by chronic inflammation, with circulating immune cells playing a role in its progression. However, research on the immune characteristics of different MMD subtypes is limited. This study aims to compare the peripheral immune profiles of ischemic and hemorrhagic MMD patients. Peripheral immune profiles were analyzed using transcriptome sequencing and mass cytometry. Data preprocessing was followed by functional and gene set enrichment analyses, as well as the construction of immune-related gene sets and protein-protein interaction networks. High-dimensional data analysis was performed using the PhenoGraph and t-SNE algorithms. The study involved 9 ischemic and 6 hemorrhagic MMD patients for transcriptome analysis, and 20 ischemic and 16 hemorrhagic patients for mass cytometry. Hemorrhagic MMD patients exhibited upregulated genes associated with inflammation, hypoxia, and bacterial responses and downregulated genes related to immune response regulation. The results of mass cytometry analysis showed that, compared to ischemic MMD, patients with hemorrhagic MMD had reduced CD3 expression levels in T cells and their specific subsets, as well as impaired chemotactic capacity of DPT cells. The function of the B03 subset in B cells was diminished, while the proportion of NK cells increased and that of monocytes decreased. Additionally, the proportions of the D03 and D07 subsets in dendritic cells (DCs) were elevated. This study reveals distinct immune profiles in ischemic and hemorrhagic MMD, emphasizing the need for subtype-specific therapeutic strategies.
small molecules
2026-08-14 | Endovascular treatment of an inaccessible aneurysm in moyamoya‑like vessels using the floating‑coil technique.
In moyamoya disease (MMD), moyamoya‑like vessels develop at the base of the brain. A ruptured aneurysm originating from these vessels is challenging to manage with endovascular treatment (EVT). When direct catheterization is infeasible, parent artery occlusion (PAO) may be the last resort. However, if liquid embolic agents are unsafe due to a short reflux distance, deploying floating coils into the parent artery to occlude or trap the aneurysm offers a viable alternative. This maneuver, termed the "floating‑coil technique," has not been previously described. A 60‑year‑old man with subarachnoid hemorrhage (Hunt-Hess grade II) had MMD and an aneurysm in moyamoya-like vessels arising from the posterior cerebral artery. During EVT, neither the Marathon nor the Echelon‑10 microcatheter could be navigated into the parent artery because of an acute angulation. The floating-coil technique was used: first, an Axium Prime 1 mm × 2 cm coil was pushed out, detached, and floated into the parent artery. Then, 3 Axium Prime 1 mm × 1 cm coils were similarly deployed to occlude the parent artery of the aneurysm. Post‑EVT angiography showed disappearance of the aneurysm and occlusion of moyamoya‑like vessels. The patient had no new deficits and recovered well, with a modified Rankin Scale score of 0 at the 2‑month follow‑up. Thus, the "floating‑coil technique" is a valid choice for inaccessible aneurysms in moyamoya‑like vessels.
2026-08-13 | Computed Tomography Angiography Recognition of a Hemorrhagic Moyamoya Pattern May Alter Acute Blood Pressure Management.
Moyamoya disease (MMD) is a rare progressive cerebrovascular occlusive disorder characterized by stenosis of the terminal internal carotid arteries and the development of fragile lenticulostriate collateral vessels. In adults, MMD can manifest as intracranial hemorrhage (ICH), carrying significant morbidity and a high risk of recurrent bleeding. When hemorrhagic MMD coexists with bilateral large vessel occlusion, acute management becomes exceptionally complex, as the standard imperative to aggressively lower blood pressure following ICH directly conflicts with the hemodynamic requirements of collateral-dependent cerebral perfusion. A 52-year-old Caucasian woman with hypertension and treated hypothyroidism, recently started on aspirin for TIA-like symptoms, presented with acute-onset left hemiplegia and a National Institutes of Health Stroke Scale (NIHSS) score of 11. Hypertension was her sole conventional atherosclerotic risk factor, and thyroid autoantibodies obtained previously had been negative. Non-contrast computed tomography (CT) identified a 2.3 × 1.9 × 2.5 cm right gangliocapsular intraparenchymal hemorrhage with a concurrent small right thalamic hemorrhage. Computed tomography angiography (CTA) demonstrated bilateral M1 segment occlusions with distal M2 reconstitution, a pattern that immediately raised concern for MMD and led directly to the recognition that mechanical thrombectomy was not indicated. The neurosurgical team concurred with a clinical and radiographic diagnosis of moyamoya vasculopathy on hospital day two. Rather than applying standard post-ICH targets, the team individualized blood pressure management to a permissive systolic range of 120 to 160 mmHg, chosen to balance limiting hematoma expansion against preserving collateral-dependent perfusion. Intravenous nicardipine was successfully weaned by hospital day three. The diagnosis was considered probable and imaging-based. Formal cerebral angiography for Suzuki staging and revascularization planning was appropriately deferred during the acute admission and planned on an outpatient basis; the patient was discharged to an inpatient rehabilitation facility on hospital day five but was subsequently lost to follow-up, so digital subtraction angiography (DSA) was never performed. Bilateral M1 occlusion with distal M2 reconstitution on CTA in the setting of gangliocapsular hemorrhage should raise suspicion for MMD and may inform both interventional and hemodynamic decision-making. Recognition of the characteristic CTA pattern supported the decision not to pursue mechanical thrombectomy and prompted individualized blood pressure targets to preserve collateral-dependent cerebral perfusion. Because DSA was not obtained, intracranial atherosclerosis could not be formally excluded, and the diagnosis remains probable rather than definitive.
2026-08-06 | Transarterial embolization of ruptured distal choroidal artery aneurysm in Moyamoya disease: A case series and literature review.
Moyamoya disease (MMD) is characterized by the compensatory development of collateral vasculature. Aneurysm formation on collaterals is common. The rupture of these aneurysms is associated with a poor prognosis, which presents significant treatment challenges. We encountered two cases of distal choroidal artery aneurysm rupture in MMD. The first case experienced re-rupture and underwent superselective embolization. However, this case was complicated by an intraoperative rupture and subsequent hydrocephalus. The second case underwent parent artery occlusion without complications. These cases highlight both efficacy and the risks involved. Lesion accessibility is crucial. A careful evaluation of collaterals and precise planning are required.
2026-08-03 | Ruptured artery of Percheron aneurysm in moyamoya disease with thalamic hemorrhage and acute hydrocephalus: illustrative case.
In moyamoya disease, fragile collateral networks such as periventricular anastomoses are associated with an increased risk of hemorrhage, particularly in the posterior circulation. Peripheral aneurysms arising from these vessels are rare, and those involving the artery of Percheron are exceptionally uncommon. A 55-year-old patient with a history of thalamic hemorrhage presented with headache and impaired consciousness. CT revealed a right thalamic hemorrhage with intraventricular extension and acute hydrocephalus. Emergency ventricular drainage was performed. Subsequent angiography identified a ruptured peripheral aneurysm arising from the artery of Percheron originating from the left P1 segment, along with right-dominant moyamoya vascular architecture. The aneurysm was successfully treated with N-butyl cyanoacrylate embolization to prevent rebleeding. Due to insufficient clearance of intraventricular hematoma, endoscopic evacuation was performed. The patient experienced no rebleeding, and follow-up angiography confirmed durable obliteration of the aneurysm. Peripheral aneurysms arising from the artery of Percheron in moyamoya disease are extremely rare but should be considered in cases of deep hemorrhage with intraventricular extension. Prompt endovascular embolization using liquid embolic agents, combined with endoscopic hematoma evacuation, may provide an effective and minimally invasive treatment strategy. https://thejns.org/doi/10.3171/CASE26356.
2026-07-09 | Effects of intraoperative inhalational versus intravenous anesthesia on perioperative neurological outcomes and long-term prognosis in patients with moyamoya disease undergoing revascularization surgery: a systematic review and meta-analysis.
Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by progressive stenosis of intracranial carotid arteries and abnormal collateral network formation. Surgical revascularization is the standard treatment for stroke prevention, but the optimal intraoperative anesthetic strategy to minimize perioperative neurological complications remains controversial. This meta-analysis compares inhalational versus intravenous anesthesia for perioperative neurological outcomes in MMD patients undergoing revascularization. We systematically searched PubMed, Embase, Cochrane Library, and Web of Science from database inception to April 2026, including randomized controlled trials and high-quality observational studies comparing the two anesthesia regimens. Two investigators independently completed literature screening, data extraction, and risk of bias assessment. Random-effects models were applied to pool effect sizes. Primary outcomes included postoperative transient neurological events (TNEs), post-anesthesia care unit (PACU) delirium, and postoperative stroke. Evidence quality was graded using the GRADE system. Eleven studies (1673 patients, 2232 procedures) were included, with 6 studies constituting the core quantitative analysis set. Outcome coverage varied: 5 studies reported TNEs, 2 reported postoperative stroke, and only 1 single-center study reported PACU delirium. Pooled results showed no significant intergroup difference in TNEs (OR = 0.87, 95% CI: 0.55-1.38, P = 0.56, I² = 61%) or postoperative stroke (OR = 1.05, 95% CI: 0.50-2.17, P = 0.91, I² = 0%). Based on limited pediatric data, inhalational anesthesia may be associated with increased PACU delirium risk in children. Qualitative evidence indicated both regimens maintained stable cerebral oxygenation, while propofol-based intravenous anesthesia had advantages in reducing intracranial pressure and improving surgical field exposure. Current low-to-very-low quality evidence shows no significant difference in major perioperative neurological complications between the two anesthetic regimens for MMD revascularization. Intravenous anesthesia has potential advantages in intraoperative cerebral physiology and surgical conditions, and may be considered preferentially for children at high delirium risk, with limited evidence strength. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251272930.
cell therapies
2026-07-02 | Clinical and CT perfusion outcomes after direct STA-MCA bypass in moyamoya and non-moyamoya steno-occlusive disease: an Indonesian single-center cohort.
Direct superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass is used for selected haemodynamic cerebrovascular disorders, but comparative data between moyamoya and non-moyamoya disease remain limited in Indonesia. Consecutive patients undergoing direct STA-MCA bypass from 2021 to 2025 were retrospectively analysed. Clinical and operative outcomes were assessed in 68 patients; paired CT perfusion data were available in 41. The cohort included 40 patients with moyamoya disease and 28 with non-moyamoya disease, predominantly intracranial atherosclerotic disease [27/28 (96%)]. Patients with moyamoya were younger [41 (29-49) vs 48 (38-59) years; p = 0.003] and had lower rates of diabetes mellitus [7% vs 29%; p = 0.041] and hypertension [42% vs 86%; p < 0.001]. Bypass patency was documented in 90% versus 100% (p = 0.226). Paired modified Rankin Scale scores improved in both cohorts: from 2.08 ± 1.51 to 1.38 ± 1.39 in moyamoya (mean difference 0.70; p < 0.001) and from 2.82 ± 1.19 to 1.86 ± 1.33 in non-moyamoya disease (mean difference 0.96; p < 0.001). M4 frontal clipping time was longer in moyamoya [33 (31-37) vs 26 (24-32) minutes; p = 0.002]. Postoperative seizure occurred in 15% versus 7% (p = 0.455), and ischaemic stroke in 0% versus 11% (p = 0.065). In the CT perfusion cohort, pre-bypass Tmax was higher in non-moyamoya disease [2.17 (1.25-3.34) vs 1.31 (1.10-1.92); p = 0.048], while infarct volume was higher in moyamoya [8.65 (1.41-17.23) vs 5.63 (3.35-7.32) mL; p = 0.034]. No follow-up CT perfusion parameter differed significantly. Direct STA-MCA bypass was followed by functional improvement in both cohorts and comparable follow-up CT perfusion profiles.
2026-06-27 | Rescue direct bypass after insufficient prior revascularization in moyamoya disease: Feasibility of using reused or preserved superficial temporal artery branches.
To describe the feasibility and short- to mid-term outcomes of rescue direct or combined revascularization using reused or preserved superficial temporal artery branches in patients with moyamoya disease after insufficient prior revascularization. We retrospectively reviewed five patients with moyamoya disease who underwent repeat revascularization for recurrent ischemic or hemorrhagic stroke after prior revascularization. Donor suitability was assessed using digital subtraction angiography to determine whether the previous donor artery had developed effective collateralization and SPECT to identify persistent hemodynamic compromise. Three patients underwent rescue direct bypass using a previously used STA branch that had failed to develop sufficient collateralization. Two patients underwent rescue revascularization using an STA branch that had not been used during the initial operation. All patients underwent successful rescue direct or combined revascularization. Bypass patency was confirmed intraoperatively and postoperatively in all cases. No postoperative ischemic or hemorrhagic complications occurred, and no patient experienced recurrent stroke during follow-up. Rescue direct or combined bypass using reused or preserved STA branches may be feasible in carefully selected patients with recurrent stroke after prior revascularization. Preoperative angiographic confirmation of donor suitability and perfusion imaging are essential for selecting the appropriate rescue strategy.
2026-06-17 | Implications for a Deeper Clinical Understanding of Moyamoya Disease: Temporal Evolution of Suzuki Staging.
Moyamoya disease (MMD) is a rare cerebrovascular disorder discovered in Japan, characterized by progressive internal carotid artery stenosis and fragile collateral vessel formation. Diagnosis relies on imaging, with Suzuki staging commonly used to classify disease severity. There is limited literature on MMD in non-Asian, non-White populations. This study evaluated clinical factors associated with disease presentation, severity, treatment, and progression, with a novel focus on longitudinal changes in Suzuki stage. A retrospective cohort study was conducted using electronic medical records. Clinical data, including demographics, Suzuki stages, surgical interventions, stroke frequency, and outcomes, were collected and analyzed. Of 114 patients diagnosed with MMD, 89 were from underrepresented populations in Moyamoya literature. Imaging from 91 patients showed Suzuki scores following a bell-curve distribution. Higher initial Suzuki scores were significantly associated with an increased likelihood of surgery (P < .001). In a subcohort of 71 patients with at least 2 Suzuki scores 1 year apart, scores remained largely stable, although a weak, nonsignificant trend toward worsening was seen in nonsurgical patients (P = .14). Notably, Mann-Whitney U analysis revealed a significant difference in Suzuki stage changes, with nonsurgical patients showing greater radiographic progression and surgically treated patients exhibiting stability or improvement (P < .05). No significant correlation was found between changes in Suzuki stage and functional outcomes or stroke events. This study expands understanding of MMD in a diverse, non-Asian population and supports Suzuki staging as a reliable tool for disease assessment and surgical planning. Surgical intervention appears to slow radiographic progression, supporting its role in management. Further prospective studies are needed to refine Suzuki staging in monitoring disease trajectory and guiding treatment.
2026-06-11 | AI-Guided Patient-Derived Endothelial Modeling Identifies a Reversible Moyamoya-Specific miRNA Deficiency Corrected by Stem Cell-Extracellular Vesicles.
Moyamoya disease (MMD) is a progressive cerebrovascular disorder characterized by abnormal vascular remodeling and impaired angiogenesis. We profiled plasma extracellular vesicle (EV)-derived microRNAs (miRNAs) from MMD patients and healthy controls and generated patient-specific induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) to investigate disease-associated molecular alterations and therapeutic reversibility. Both plasma EVs and iPSC-ECs from MMD patients showed significant depletion of angiogenesis-related miRNAs. Small RNA sequencing data revealed mesenchymal stem cell-derived EVs (MSC-EVs) contain a miRNA repertoire that substantially overlaps with miRNAs deficient in MMD. Treatment of MMD iPSC-ECs with MSC-EVs restored the majority of the depleted miRNAs to normal levels, normalized predicted target mRNA expression, and rescued angiogenic function in a dose-dependent manner, as demonstrated by tube formation assays. To improve identification of biologically relevant miRNA-mRNA interactions, we developed an artificial intelligence-based framework integrating experimentally validated databases, endothelial-focused literature mining, and large language model (LLM)-assisted mechanistic scoring. Incorporation of LLM-derived contextual features modestly improved prediction performance compared with conventional sequence-based models (baseline AUROC ~ 0.51; LLM-enhanced AUROC ~ 0.72), suggesting that literature-informed biological context provides meaningful signal beyond structural target features alone. Furthermore, our findings demonstrate that MSC-EV therapy can substantially reverse molecular and functional endothelial deficits. Integrated profiling and AI-driven interaction mapping together establish a hypothesis-generating framework ("Exo-Courier") for biologically informed prioritization of EV-based therapeutic targets in vascular disorders.
2026-05-12 | Blood, Brain, and Bypass: Moyamoya Syndrome Unmasked During Hematologic Optimization in an Adult With Sickle Cell Disease.
Moyamoya syndrome is a rare, progressive cerebrovascular disorder characterized by stenosis or occlusion of the terminal internal carotid arteries with the formation of fragile collateral vessels. While classically described in pediatric patients and idiopathic Moyamoya disease, secondary Moyamoya syndrome has been reported in association with sickle cell disease (SCD). Adult presentations remain uncommon and are frequently underrecognized. We report a unique case of a 36-year-old man with sickle cell anemia who developed acute neurological deterioration following hematologic optimization with packed red blood cell transfusion and therapeutic phlebotomy during a vaso-occlusive crisis. Cerebral angiography revealed complete occlusion of the left internal carotid artery at its terminus, consistent with Moyamoya syndrome. The patient subsequently underwent surgical revascularization with encephaloduroarteriosynangiosis with subsequent neurological stabilization. This case illustrates how advanced but previously compensated large-vessel cerebrovascular disease in adults with SCD may become clinically manifest during physiologic perturbation, underscoring the importance of early vascular imaging and multidisciplinary management when neurologic symptoms evolve during hematologic therapy.
proteins
2026-02-09 | Angiographic outcomes after indirect revascularization in pediatric Moyamoya disease: a systematic review and Meta-analysis.
Moyamoya disease is a rare progressive cerebral vasculopathy characterized by narrowing or occlusion of the internal carotid arteries, leading to the formation of fragile collateral vessels and a high risk of ischemic events, especially in pediatric patients. Although direct revascularization techniques are commonly used, they are technically challenging in children due to vascular fragility and anatomy. Indirect revascularization techniques favor the formation of new blood vessels through alternative flow routes. Their efficacy is usually assessed using the Matsushima scale, which measures the degree of revascularization achieved. This study aims to describe postoperative angiographic outcomes of indirect revascularization techniques in pediatric patients with Moyamoya disease. A systematic review and meta-analysis was performed following PRISMA guidelines, searching six databases (PubMed, Embase, Scopus, Web of Science, CENTRAL and Google Scholar) for observational studies that evaluated indirect revascularization techniques in pediatric patients with Moyamoya disease. Seventeen studies comprising 1360 hemispheres were included. Primary outcomes were the proportions of angiographic revascularization according to grades A, B, and C of the Matsushima scale. Secondary outcomes included postoperative clinical complications such as stroke, transient ischemic attacks (TIAs), seizures, bleeding, mortality, and functional status assessed using the modified Rankin scale (mRS ≤2). Meta-analyses were performed with random-effects models in R (version 4.2.3) and risk of bias was assessed with the MINORS tool. Meta-regression was applied to explore possible predictors of outcomes. The certainty of evidence was assessed with the GRADE approach. The combined proportions of hemispheres achieving Matsushima grades A, B and C were 47.1% (95% CI: 38.4-55.9; I2 = 84.4%), 38.2% (95% CI: 32.0-44.9; I2 = 84.4%) and 12.3% (95% CI: 9.3-16.0; I2 = 47.0%), respectively. Postoperative complications were low: stroke 8.3%, TIA 7.2%, seizures 2.5%, bleeding 2.7% and mortality 0.8%. Good functional status (mRS ≤2) was achieved in 82.1% of patients. Meta-regression revealed that unilateral vs. bilateral procedures significantly predicted Matsushima grade B outcomes (p = 0.002). The risk of bias was low to moderate. The certainty of evidence was generally low to moderate, except for mortality which showed high certainty. Indirect revascularization techniques in pediatric Moyamoya show favorable angiographic and clinical results, with low complications and high functional independence. According to the Matsushima scale, about 47% of the hemispheres achieved grade A, 38% grade B and 12% grade C. Pial synangiosis and EDAMS were more effective in grade A, whereas EDAS showed a lower proportion in grade A and slightly more in grade C. Postoperative complications were low and most patients achieved good functional status (mRS ≤2). These findings suggest the safe and effective use of indirect techniques, although the high heterogeneity and methodological limitations evidence the need for randomized studies to validate and optimize these results in the long term.
2025-09-17 | Short Stature in Moyamoya Disease: A Systematic Review of Potential Mechanisms and Clinical Outcomes.
Background: Moyamoya disease (MMD) is a complex cerebrovascular disorder. While its neurological manifestations are well documented, the association between MMD and short stature remains underrecognized. This review explores potential mechanisms linking MMD with growth impairment, with a focus on endocrine and syndromic contributors. Methods: A systematic review was conducted in accordance with PRISMA guidelines using PubMed and Scopus databases. Studies reporting cases of MMD with short stature or growth impairment were included. Data were extracted on patient demographics, endocrine findings, genetic mutations, neuroimaging, management, and outcomes. A narrative synthesis approach was used due to heterogeneity in study designs. Results: Across 25 studies, 30 individuals with MMD and clinically significant short stature were identified, predominantly pediatric (2.5-52 years). Presentations frequently included seizures (n = 21), TIAs (n = 8), hemiparesis (n = 7), cognitive impairment (n = 8), and headaches (n = 3); in many, growth failure predated neurological events. Height deficits ranged from -2.13 to -23.7 SDS. Endocrine involvement was common: growth hormone deficiency (n ≈ 6), delayed bone age (n = 3), and other pituitary-thyroid-gonadal disturbances; a rare pituitary stalk duplication was reported. Management varied. Indirect revascularization in selected cases reduced recurrent ischemia; growth hormone therapy improved height velocity. Antiplatelets were commonly used; anticoagulation occasionally led to complications. Outcomes were heterogeneous; four deaths occurred, typically in patients with severe multisystem disease. Conclusion: Growth retardation in MMD is generally a manifestation of hypothalamic-pituitary dysfunction, chronic cerebral hypoxia, or genetic syndromes. The observations in the present study suggest that MMD may be part of a more generalized multisystemic disorder in some patients and needs multisystemic assessment and management.
2025-07-08 | Machine learning identifies KRT8 dysregulation and endothelial remodeling in Moyamoya disease.
Moyamoya disease (MMD) is a rare occlusive cerebrovascular disease, and its pathological mechanism remains unclear at present. The abnormal vascular remodeling may be involved in vascular endothelial cells. In this study, RNA seq was performed on the superficial temporal arteries of 10 patients with MMD. Integrated analysis was conducted by combining validation set with training set. Key genes were identified through differential analysis and WGCNA. The functions of potential biomarkers were explored by methods such as correlation analysis, KEGG analysis, PPI network, and tube formation experiments. Integrated analysis of three cohorts (43 MMD vs. 26 controls) identified 19 shared DEGs, including upregulated KRT8/KRT18 and downregulated NT5C2 (P < 0.001). Enrichment revealed dysregulation in circadian rhythm, calcium signaling, and metabolic pathways (P < 0.05). Immune infiltration showed elevated pro-inflammatory cells (neutrophils, M1 macrophages) and reduced Tregs/NK cells (P < 0.05). Machine learning (SVM-RFE, Boruta, LASSO) prioritized KRT8 as diagnostic markers (AUC > 0.96). KRT8 overexpression enhanced angiogenesis in HBMECs (1.5-fold tube formation, P < 0.01). This omics approach delineates MMD's molecular interplay between inflammation, metabolism, and vascular remodeling. KRT8 may promote vascular remodeling in MMD by regulating the tube-forming ability of endothelial cells. This could be a highlight of therapeutic targets for MMD and shed light on the mechanism research of MMD.
2025-02-07 | Reinforcement of Transdural Angiogenesis: A Novel Approach to Treating Ischemic Stroke With Cerebral Perfusion Impairment.
Cerebral hypoperfusion plays a critical role in early neurological deterioration and long-term outcomes in patients with acute ischemic stroke, which remains a major global health challenge. This review explored transdural angiogenesis as a promising therapeutic strategy to restore cerebral perfusion in patients with ischemic stroke. The multiple burr hole procedure has been preliminarily used as an indirect revascularization method to induce transdural arteriogenesis. Theoretically, its efficacy could be enhanced by combining it with angiogenic boosters, such as erythropoietin. Recent clinical and preclinical studies have revealed that this combination therapy promotes angiogenesis and arteriogenesis, leading to successful revascularization across the dura mater and improved cerebral blood flow. This strategy may be particularly beneficial for high-risk patients with recurrent ischemic events, such as those with moyamoya disease or intracranial arterial occlusion, representing an effective strategy when conventional medical treatments are insufficient. This review highlights the potential of transdural angiogenesis enhancement as a novel intervention for ischemic stroke, offering an alternative to thrombolysis or endovascular treatment, particularly in acute stroke patients with impaired cerebral perfusion. This approach has the potential to bridge the treatment gap for patients outside the therapeutic window for acute stroke interventions. Although further research is required to refine this technique and validate its efficacy in broader clinical settings, early results have revealed promising outcomes at reducing stroke-related complications and improving patient prognosis. This review indicates that this novel strategy may offer hope for managing ischemic stroke and related conditions associated with significant cerebral hypoperfusion.
2025-01-07 | Multiple burr hole and erythropoietin combination therapy: optimal early surgical intervention for patients with acute stroke episode of moyamoya disease or moyamoya syndrome.
The optimal timing of bypass surgery for patients with moyamoya disease (MMD) or moyamoya syndrome (MMS) following an acute stroke episode remains unclear, mainly owing to the risk of postoperative complications. In this study, we aim to validate the safety and efficacy of early intervention using multiple burr hole (MBH) and erythropoietin (EPO) therapy, thereby refining the management strategy for patients with acute stroke episode of MMD or MMS. We retrospectively analyzed data from 70 patients with MMD or MMS who underwent MBH and EPO therapy. The cohort was divided based on the time interval between the latest neurological deterioration and surgery: early (<30 days) and later (≥30 days) groups. We evaluated and compared perioperative clinical parameters and the extent of neovascularization on a 6-month postoperative angiography. Long-term clinical outcomes, including transient ischemic attack (TIA), infarction, hemorrhage, and seizure, were also analyzed during the follow-up period. In the cohort, 36 patients (51.4%) were in the early group, whereas 34 (48.6%) were in the later group. The 6-month follow-up angiography demonstrated that 34/47 hemispheres (72.3%) in the early group exhibited successful neovascularization (≥2/3 of MCA territories) compared with the 19/44 (43.2%) hemispheres in the later group (odds ratio [OR] = 3.44; 95% confidence interval [CI]: 1.46-8.45; p < 0.01). In addition, a notable reduction (≥50%) in basal moyamoya vessels was observed in 30/47 hemispheres (63.8%) from the early group vs. 12/44 (27.3%) hemispheres from the later group (OR = 4.71; 95% CI: 1.97-11.82; p < 0.001). During the average follow-up of 56.5 months, only six patients experienced infarction or hemorrhage. Our dataset suggests that MBH and EPO combination therapy is an effective, minimally invasive, and acceptable treatment, even in the early period of patients with MMD or MMS following an acute stroke episode.
gene therapies
2026-02-13 | Delineating the Genetic Basis of RNF213-related vasculopathies: The association of PKHD1 variants with bilateral cerebral vasculopathy.
Moyamoya disease (MMD) is an idiopathic cerebrovascular disorder characterized by progressive stenosis of the internal carotid artery termini and the formation of an abnormal network of fragile perforators. Although the RNF213 gene has been implicated as a susceptibility factor for MMD, the precise genetic basis of the disease remains elusive. This study aimed to investigate other genetic factors contributing to differences in disease manifestation and vascular phenotypes. We conducted whole-exome sequencing of patients with RNF213-related vasculopathy and healthy controls. In total, 122 patients (comprising 69 with bilateral MMD, 13 with unilateral MMD, and 40 with intracranial artery stenosis [ICAS]) and 458 controls were enrolled. Following appropriate quality control measures, case-control analysis and in-case analysis (bilateral MMD vs. unilateral MMD and ICAS) were conducted using single-variant association testing and gene-based aggregation testing. Although no significant locus or gene was found in the case-control analysis, the PKHD1 gene emerged as a top candidate associated with bilateral MMD in the in-case analysis. Two rare damaging variants, p.Ile2364Asn and p.Ser3210Cys, were significantly more prevalent in the bilateral MMD group and were further validated in an independent cohort of 216 individuals. Publicly available single-cell transcriptome data of mouse cerebrovascular and perivascular cells revealed that Pkhd1 expression was significantly higher in specific endothelial-cell clusters. Despite some limitations, our study provides new insights into the potential role of the PKHD1 gene in bilateral MMD, highlighting the need for further investigation of endothelial gene expression in patients with RNF213 and PKHD1 mutations.
2025-12-02 | MicroRNA-29b-3p promotes endothelial cell inflammation via NTRK2/PI3K/NLRP3 pathway in Moyamoya disease.
Moyamoya disease (MMD) is a rare chronic progressive vascular anomaly of the skull base whose molecular regulatory mechanisms remain poorly understood. We therefore aimed to analyze the molecular mechanisms involved in the development of MMD from the perspective of miRNA regulation of mRNA. Raw gene expression profiles (GSE178501, GSE157628 and GSE189993) were downloaded from the Gene Expression Omnibus database and used to identify differentially expressed genes and perform functional enrichment analysis. Differentially expressed miRNAs and their predicted target genes were validated by RT-qPCR. Oxygen glucose deprivation was applied to induce an inflammatory injury cell model in human brain microvascular endothelial cells (BMEC). 973 differentially expressed mRNAs and 3 differentially expressed miRNAs were identified in three sets of gene expression profiles. RT-qPCR confirmed that the miR-29b-3p was upregulated in leukocytes of MMD and that the expression of NTRK2 was downregulated. Dual-luciferase reporter assay indicated that NTRK2 was the direct target of miR-29b-3p. Overexpression of NTRK2 improved the viability of BMEC and increased the protein levels of NTRK2 and pPI3K, while suppressed the expression of NLRP3, IL1β, and TNF-α. miR-29b-3p treatment partially abolished the protective effect of NTRK2 and diminished the effect of NTRK2 on PI3K/NLRP3 pathway. In conclusion, this study provided a novel insight into the pathophysiological mechanisms of MMD and demonstrated that the miR-29b-3p/NTRK2/PI3K/NLRP3 axis plays a pivotal role in the progression of MMD.
2024-10-05 | Whole-exome sequencing reveals the genetic causes and modifiers of moyamoya syndrome.
Moyamoya vasculopathy secondary to various genetic disorders is classified as moyamoya syndrome (MMS). Recent studies indicate MMS occurs due to a combination of genetic modifiers and causative mutations for the primary genetic disorders. We performed whole-exome sequencing (WES) in 13 patients with various genetic disorders who developed MMS. WES successfully revealed the genetic diagnoses of neurofibromatosis type 1 (NF-1), Down syndrome, multisystemic smooth muscle dysfunction syndrome, Noonan syndrome, and alpha thalassemia. The previously reported modifier genes, RNF213 and MRVI1, were confirmed in the NF-1 and Down syndrome cases. Further analysis revealed rare hypomorphic variants in the causative genes of the primary disorders underlying MMS, such as Alagille syndrome and Rasopathies, conferred susceptibility to MMS. Genes involved in the development of pulmonary arterial hypertension (PAH), such as ABCC8 and BMPR2, were also identified as potential modifiers. The rare variants in the MMS and PAH genes were significantly enriched in the eight Japanese patients with MMS compared with the 104 Japanese individuals from the 1000 Genomes Project. Disease genes associated with the arterial occlusive conditions represented by those of Rasopathies and PAH may provide novel diagnostic markers and future therapeutic targets for MMS as well as moyamoya disease with an unknown cause.
2024-09-24 | HAPLN3 p.T34A contributes to incomplete penetrance of moyamoya disease in Chinese carrying RNF213 p.R4810K.
The penetrance of the RNF213 p.R4810K, a founder mutation of moyamoya disease (MMD), is estimated to be only 1/150-1/300. However, the factors affecting its penetrance remain unclear. Therefore, our study aims to identify modifier genes associated with the incomplete penetrance of this founder mutation. Whole-exome sequencing (WES) was performed on 36 participants, including 22 MMD patients and 14 non-MMD controls with RNF213 p.R4810K mutation. Fisher's exact test was used to assess the presence of genetic variants that differed significantly between MMD patients and non-MMD controls. In order to exclude false-positive results, another 55 carriers were included to perform Fisher's exact test for the selected sites in the WES discovery stage. Subsequently, human brain microvascular endothelial cells were transfected with wild-type and mutant HAPLN3 for tube formation assays and western blotting to explore the impact of candidate genes on angiogenesis. Analysis of variants from WES data revealed a total of 12 non-synonymous variants. Through bioinformatics analysis, the focus was on the HAPLN3 p.T34A variant with a significant p value of 0.00731 in Fisher's exact test. Validation through Sanger sequencing confirmed the presence of this variant in the WES data. In vitro experiments revealed that silencing HAPLN3 and transfecting HAPLN3 p.T34A significantly enhanced tube formation and increased the relative protein expression of vascular endothelial growth factor in endothelial cells. These results suggest that HAPLN3 may function as a modifier gene of RNF213 p.R4810K, promoting the development of MMD and contributing to the incomplete penetrance of MMD founder mutations.
2024-08-13 | Comprehensive Analysis and In Vitro Verification of Endothelial-Mesenchymal Transition-Related Genes in Moyamoya Disease.
Moyamoya disease (MMD) is a rare, chronic, and progressive cerebrovascular disorder with unclear underlying causes and mechanisms. Previous studies suggest a potential involvement of endothelial-mesenchymal transition (EndMT) in the pathogenesis of MMD. This study aimed to explore the contribution of EndMT-related genes (ERGs) in MMD. Two datasets, GSE141022 and GSE157628, were integrated as the training set after batch effects removal. Differentially expressed ERGs were identified between MMD and control groups. Functional enrichment analysis and immune infiltration analysis were further performed. LASSO regression was used for hub MMD-related ERG selection. Consensus clustering was used for MMD subtype classification based on these hub MMD-related ERGs. Molecular characteristics between MMD subtypes were analyzed using WGCNA. PPI network was used to illuminate the genetic relationship. The hub MMD-related ERGs were validated in an independent testing set, GSE189993. The nomogram model was constructed and evaluated using ROC curves and calibration plots. Additionally, CCK-8, EdU, wound healing, and western blot were performed to confirm the function of the hub MMD-related ERGs. A total of 107 DE-ERGs were identified. Functional enrichment analysis showed these genes were associated with EndMT and immune response. The infiltrating levels of immune cells were commonly higher in the MMD group. LASSO regression identified 12 hub MMD-related ERGs, leading to the identification of two MMD subtypes. Four ERGs emerged as the final hub MMD-related ERGs after validation in the testing set, including CCL21, CEBPA, KRT18, and TNFRSF11A. The nomogram model exhibited excellent discrimination ability. In vitro experiments showed that CCL21, CEBPA, KRT18, and TNFRSF11A could promote proliferation, migration, and EndMT. This study investigated the potential role of EndMT in MMD and identified four hub MMD-related ERGs, providing potential therapeutic targets for MMD treatment.
other
2026-07-25 | Integrated Serum Multiomics Reveal Subtype-Specific Immune Dysregulation and Sex-Dimorphic Pathophysiology in Moyamoya Disease.
Moyamoya disease (MMD) is a rare cerebrovascular disorder with unknown pathogenesis, partly due to limited access to human cerebral vascular tissue and suitable animal models. Using a large biobank of frozen serum samples, this study aimed to explore molecular signatures of ischemic and hemorrhagic MMD. Serum from 30 patients with MMD (18 ischemic, 12 hemorrhagic) and 30 matched healthy controls underwent proteomic and metabolomic profiling. Data were analyzed for differential expression, pathway enrichment, and protein-metabolite networks, with adjustment for age, sex, and body mass index. In a separate large Chinese cohort (n=6167), female patients had a higher proportion of hemorrhagic MMD (19.9% versus 16.9%) and a higher prevalence of anterior choroidal artery dilation (15.1% versus 13.2%) than male patients (both P<0.05). At the molecular level, ischemic MMD showed complement C4-B deficiency and disrupted natural killer cell cytotoxicity; both subtypes shared immunoglobulin perturbations (eg, decreased heavy-chain variable regions). Sex-specific alterations included anti-folate-binding protein, serum amyloid A2, glycolithocholic acid, and estradiol. All omics data are publicly accessible. Integrated serum multiomics defines distinct immune-related signatures for ischemic and hemorrhagic MMD and reveals sex-dimorphic molecular pathways. These findings, together with clinical sex differences in disease subtype and vascular anatomy, provide a framework for personalized, sex-aware management of MMD.
2026-07-03 | Proteomic landscape and molecular mechanisms of encephalomyosynangiosis in a rodent model of chronic cerebral hypoperfusion.
The purpose of the present study was to establish a reproducible 2-vessel occlusion (2VO) rat model combined with encephalomyosynangiosis (EMS) to investigate angiogenic and proteomic mechanisms of indirect cerebral revascularization as a basis for further study in order to improve angiogenesis and cognition. Fifteen rats underwent 2VO of the bilateral common carotid arteries 1 week apart. At the time of the second occlusion, 10 animals underwent EMS while 5 animals received a sham surgery. Adequate hypoperfusion was considered established if the cerebral blood flow decreased to 40% of baseline. Six weeks after surgery, reperfusion outcomes were assessed with the Longa model, novel object recognition, immunohistochemical analysis, and proteomic analysis. Animals that underwent EMS surgery demonstrated minimal neurological deficits on the Longa model, and EMS animals spent more time with both the old (mean 16.08 seconds vs 8.07 seconds) and novel (18.21 seconds vs 10.84 seconds) objects, suggesting that the EMS animals overall spent more time exploring in both scenarios compared to the 2VO animals that were more sedentary. Immunohistochemical analysis revealed evidence of increased angiogenesis in tissue specimens collected from the experimental cohort. Proteomic analysis showed that the EMS mechanism of action likely alters metabolism, notably by stimulating aerobic respiration, reducing neutrophil-mediated neuroinflammation, altering synapses, reorganizing cytoskeletal protein binding, and activating MAPK/ERK signaling through L1CAM activation. Establishing a 2VO and EMS rat model lays the groundwork for future research across laboratories to explore novel strategies for enhancing neovascularization, ultimately contributing to improved therapeutic approaches for patients with moyamoya disease and other vaso-occlusive cerebrovascular disorders.
2025-10-24 | The orbital grading system in pediatric moyamoya: an interrater reliability analysis of angiographic outcomes.
The Matsushima grading system is widely used to evaluate angiographic revascularization outcomes after pial synangiosis for moyamoya vasculopathy by quantifying collateral ingrowth. The authors hypothesized that the orbital grading system (OGS), a new scale developed for adults to measure collateral ingrowth, would provide greater consistency and interrater reliability. They aimed to compare the performance of these scales for the first time in the pediatric population. The authors performed a retrospective analysis of patients with moyamoya vasculopathy with follow-up catheter angiography after indirect revascularization at a single major pediatric center from 2006 to 2023. An interrater reliability analysis was performed using 5 raters with varying levels of training, who provided scores for 30 blinded cases. Fleiss' kappa coefficient (κ) was calculated as a measure of agreement beyond chance. A total of 101 patients with a median age of 9 years, of predominantly female sex (56.4%) who were mostly affected by moyamoya disease (71.3%) were included. A total of 158 cerebral hemispheres were treated with pial synangiosis (57 patients had bilateral surgeries). Most hemispheres were categorized as Suzuki stage 3 or above (82.9%). At a median of 12.4 months postoperatively, collateral growth was classified as Matsushima grade A in 57.6%, B in 24.1%, C in 14.6%, and as borderline grades in 3.8%. The OGS scores were grade 0 in 7.0%, grade 1 in 8.9%, grade 2 in 43.7%, and grade 3 in 40.5%. Interrater agreement evaluation revealed that the OGS had a superior κ value compared with the Matsushima scale (0.51 vs 0.15, p < 0.001). The OGS had higher interrater agreement rates than the Matsushima scale for identifying postoperative collateral ingrowth in children after pial synangiosis. This scale provides a more consistent method for evaluating angiographic outcomes after indirect revascularization in the pediatric population.
2025-07-30 | Unraveling the links between intracranial artery stenosis, cerebral perfusion, and white matter hyperintensity in moyamoya disease.
White matter hyperintensity (WMH) is commonly observed in patients with intracranial artery stenosis (ICAS), such as atherosclerosis or moyamoya disease (MMD). However, the relationships between ICAS, cerebral blood flow (CBF), and WMH remain unclear. We aimed to investigate whether reduced CBF mediated the relationship between ICAS and WMH in MMD. We retrospectively analyzed prospectively collected data of patients with MMD who underwent 3T-MRI between June 2020 and July 2023. CBF in the territories of anterior cerebral artery (ACA), middle cerebral artery (MCA) and posterior cerebral artery (PCA) was quantified using arterial spin labeling, and the stage of ICAS was evaluated by MRA. We pooled the data from each hemisphere together. Sixty-five patients were included, with WMH mainly distributed within the MCA territory. Among 124 hemispheres with WMH, WMH volume increased with the increased stage of ICAS (p < 0.001). CBF in each arterial territory showed a negative correlation with WMH volume (ACA: r = -0.364; MCA: r = -0.406; PCA: r = -0.309; all p < 0.001). Linear mixed-effects models revealed that ICAS stage (β = 0.132, p = 0.026) and CBF in the MCA territory (β = -0.026, p = 0.019) were significantly associated with WMH volume. Mediation analysis showed that decreased CBF in the MCA territory mediated 40% of the effect of ICAS on WMH volume. Hypoperfusion in the MCA territory partially mediated the association between ICAS and WMH, suggesting that enhancing perfusion could be a potential treatment strategy for WMH in MMD. Question Whether cerebral blood flow mediates the relationship between intracranial artery stenosis and white matter hyperintensity remains unclear. Findings In patients with moyamoya disease, cerebral blood flow in the middle cerebral artery territory mediates 40% of the effect of arterial stenosis on white matter hyperintensity. Clinical relevance Improvement of cerebral blood flow in the middle cerebral artery territory could be a potential treatment strategy for white matter hyperintensity in moyamoya disease, thereby alleviating clinical manifestations such as cognitive dysfunction in patients.
2025-03-11 | Integrated bulk RNA sequencing and mass cytometry analysis reveal the circulating immune landscape in ischemic and hemorrhagic Moyamoya disease.
Moyamoya disease (MMD) is increasingly recognized as being influenced by chronic inflammation, with circulating immune cells playing a role in its progression. However, research on the immune characteristics of different MMD subtypes is limited. This study aims to compare the peripheral immune profiles of ischemic and hemorrhagic MMD patients. Peripheral immune profiles were analyzed using transcriptome sequencing and mass cytometry. Data preprocessing was followed by functional and gene set enrichment analyses, as well as the construction of immune-related gene sets and protein-protein interaction networks. High-dimensional data analysis was performed using the PhenoGraph and t-SNE algorithms. The study involved 9 ischemic and 6 hemorrhagic MMD patients for transcriptome analysis, and 20 ischemic and 16 hemorrhagic patients for mass cytometry. Hemorrhagic MMD patients exhibited upregulated genes associated with inflammation, hypoxia, and bacterial responses and downregulated genes related to immune response regulation. The results of mass cytometry analysis showed that, compared to ischemic MMD, patients with hemorrhagic MMD had reduced CD3 expression levels in T cells and their specific subsets, as well as impaired chemotactic capacity of DPT cells. The function of the B03 subset in B cells was diminished, while the proportion of NK cells increased and that of monocytes decreased. Additionally, the proportions of the D03 and D07 subsets in dendritic cells (DCs) were elevated. This study reveals distinct immune profiles in ischemic and hemorrhagic MMD, emphasizing the need for subtype-specific therapeutic strategies.
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Drug Discovery Landscape
4 orphan drug designations for Moyamoya disease.
4 orphan drug designations for Moyamoya disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Red blood cell-derived microparticles | — | FDA | 2023-02-09 | — | RxMP Therapeutics, Inc. |
Glyburide | — | FDA | 2017-01-12 | — | Remedy Pharmaceuticals, Inc. |
recombinant activated Factor X variant | — | FDA | 2015-03-03 | — | Pfizer, Inc. |
Theranost 68 Ga RGD | oligonucleotides | FDA | 2014-10-01 | — | Advanced Imaging Projects, LLC (AIP) |
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