Search Results (69)

Moyamoya disease (MMD) is primarily associated with genetic variants in RNF213. RNF213 p.R4810K (c.14429G>A, p.Arg4810Lys) is a founder variant predominantly found in East Asian populations and is strongly associated with MMD, a rare cerebrovascular condition characterized by progressive stenosis of intracranial arteries and the development of abnormal collateral networks. Recent evidence suggests that RNF213 variants are also enriched in non-moyamoya intracranial arteriopathies, such as large-artery atherosclerotic stroke and intracranial arterial stenosis/occlusion (ICASO), particularly in east Asian individuals with early-onset or cryptogenic stroke. This expanded phenotypic spectrum, termed RNF213-related vasculopathy (RRV), represents a distinct pathogenic entity that may involve unique pathogenic processes separate from traditional atherosclerosis. In this review, we synthesize current genetic, clinical, radiological, and experimental findings that delineate the unique features of RRV. Patients with RRV typically exhibit a lower burden of traditional vascular risk factors, negative vascular remodeling in the absence of atheromatous plaques, and an increased propensity for disease progression. RNF213 variants may compromise vascular resilience by impairing adaptive responses to hemodynamic stress. Furthermore, emerging cellular and animal model data indicate that RNF213 influences angiogenesis, lipid metabolism, and stress responses, offering mechanistic insights into its role in maintaining vascular integrity. Recognizing RRV as a distinct clinical entity has important implications for diagnosis, risk stratification, and the development of genome-informed therapeutic strategies. Full article

Moyamoya disease (MMD) is a rare yet clinically significant cerebrovascular disorder characterized by progressive stenosis of the distal internal carotid artery and/or its principal branches, accompanied by the development of characteristic collateral vessel networks. This disease demonstrates a complex multifactorial etiology with strong genetic determinants, as evidenced by its distinct geographical distribution patterns and familial clustering. Recent genetic researches have identified multiple pathogenic mutations contributing to MMD development through three principal mechanisms: progressive vascular stenosis, abnormal angiogenesis, and dysregulated inflammatory responses. Furthermore, moyamoya syndrome frequently occurs as a secondary vascular complication in various monogenic disorders. This review provides a comprehensive analysis of recent genetic advances in MMD in view of diverse pathogenic pathways, offering valuable perspectives on the molecular mechanisms underlying disease development and potential therapeutic targets. Full article

Moyamoya disease (MMD) is a cerebrovascular disease which can result in severe strokes. However, its etiology is still unknown. We analyzed gene expression datasets from 36 MMD patients and 24 controls to identify differentially expressed genes. Using weighted gene co-expression network analysis and databases such as KEGG, we identified hypoxia-immune-related genes. These genes were further refined through machine learning algorithms. The diagnostic value was confirmed using an external dataset, and a diagnostic nomogram was constructed. Additionally, gene set enrichment analysis was conducted, and a competitive endogenous RNA (ceRNA) network was built to predict potential therapeutic targets. Our study identified AKT1, CLDN3, ISG20, and TGFB2 as the key hypoxia-immune genes associated with MMD. These genes were implicated in epithelial–mesenchymal transition, angiogenesis, and cell adhesion, suggesting a role in MMD pathogenesis. Further, our study constructed the ceRNA network and predicted potential drug targets for MMD. We obtained the top 10 drugs in the interaction of the four key genes that might serve as potential targets for the treatment of MMD. In conclusion, this study comprehensively analyzes the role of hypoxia-immune genes in MMD, which is conducive to the development of new diagnostic and therapeutic approaches and the exploration of the potential pathogenesis of MMD. Full article

RNF213 encodes a unique protein with AAA+ ATPase and E3 ubiquitin ligase activities that are critical for its diverse roles, which range from involvement in human vasculopathies, such as Moyamoya disease, to ubiquitination of viral and bacterial pathogens. Nevertheless, its primary functions in human signaling remain unclear due to the limited identification of direct substrates. Here, we investigated the interaction between RNF213 and caveolin-1 (Cav-1), a small scaffolding protein vital for caveolae formation and the regulation of a plethora of cellular processes. Cav-1 specifically binds within the two functional AAA+ domains of RNF213 in an ATP-dependent manner, highlighting the influence of cellular energy status on this interaction. Consequently, RNF213 ubiquitinates Cav-1 at several N-terminal lysine residues through K48 and K63 linkages, although several Moyamoya disease-associated RNF213 mutations greatly reduce this polyubiquitination. Moreover, RNF213 activity inhibits phosphorylation of a key regulatory residue of Cav-1, as RNF213 knockdown under oxidative stress markedly enhances Cav-1 Tyr14 phosphorylation and modifies nitric oxide bioavailability in endothelial cells. Collectively, our results indicate that RNF213 functions as a molecular switch modulating Cav-1 signaling based on RNF213 functionality and cellular conditions. These findings offer new insights into vascular pathogenesis and the vast signal pathways along the RNF213–Cav-1 axis. Full article

Moyamoya angiopathy (MMA) is a cerebrovascular disease determining chronic progressive steno-occlusion of the supraclinoid internal carotid arteries and their main branches. The pathogenesis of MMA remains largely unknown. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system characterized by the progressive accumulation of focal demyelinating lesions, whose pathophysiology has been theorized but still incompletely understood. Beyond misdiagnoses due to mimicking features among the two disorders, MS coexisting with MMA have been previously, rarely, reported. Herein, we present two other cases of patients with MMA with a concomitant, previously missed, diagnosis of MS and discuss their overlapping features as a hint for a potentially shared pathophysiology. The finding of typical angiographic features enables MMA diagnosis, yet it does not allow us to rule out other potentially concomitant disorders affecting the CNS. The association may be easily missed if the clinical/neuroradiological picture is not carefully assessed. Cerebral spinal fluid analysis and spine neuroimaging should be suggested in all MMA patients with atypical MRI lesions. Full article

Background: Hyperintense vessels (HVs) visualized on FLAIR MRI are believed to reflect sluggish antegrade or retrograde flow in leptomeningeal collaterals that develop in response to major intracranial artery stenosis or occlusion. HV is frequently observed in conditions such as Moyamoya disease and symptomatic ICA/MCA steno-occlusion. However, the relationship between HV and cerebral hemodynamics—and the effect of STA-MCA bypass on HV—remains inadequately characterized. This study aimed to investigate the relationship between HV on FLAIR and cerebral vascular hemodynamic status, as measured by SPECT, in patients with Moyamoya disease and symptomatic ICA/MCA occlusion. The secondary goal was to assess the impact of recanalization through STA-MCA bypass surgery on the presence of HV. Methods: We retrospectively analyzed 49 patients with symptomatic ICA or MCA steno-occlusion who underwent STA-MCA bypass between 2015 and 2020. Pre- and postoperative FLAIR MRIs were evaluated, and HV presence was graded as negative (0), minimal (1), or positive (2). SPECT was utilized to assess cerebrovascular reserve (CVR) in regions exhibiting various HV intensities. Follow-up FLAIR imaging was performed 3–14 months postoperatively to correlate HV changes with hemodynamic improvements observed via SPECT. Result: HV was present in 74% (36/49) of affected hemispheres. Regions exhibiting minimal or positive HV demonstrated a significantly lower CVR compared to HV-negative areas, indicating compromised perfusion. Following bypass surgery, HV was reduced or resolved in 65% (32/49) of patients, and this regression corresponded with improved CVR as confirmed by both SPECT and perfusion MRI. Conclusions: HV presence on FLAIR imaging is associated with impaired cerebrovascular hemodynamics in patients with Moyamoya disease or symptomatic large-vessel steno-occlusion. HV-positive territories exhibit reduced CVR, while surgical revascularization via STA-MCA bypass leads to hemodynamic improvement and concurrent HV reduction. These findings support HV as a potential surrogate marker for treatment response. Full article

Hemorrhagic neurovascular diseases, with high mortality and poor outcomes, urge novel biomarker discovery and therapeutic targets. Micro-ribonucleic acids (miRNAs) are potent post-transcriptional regulators of gene expression. They have been studied in association with disease states and implicated in mechanistic gene interactions in various pathologies. Their presence and stability in circulating fluids also suggest a role as biomarkers. This review summarizes the current state of knowledge about miRNAs in the context of cerebral cavernous malformations (CCMs), a disease involving cerebrovascular dysmorphism and hemorrhage, with known genetic underpinnings. We also review common and distinct miRNAs of CCM compared to other diseases with brain vascular dysmorphism and hemorrhage. A systematic search, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline, queried all peer-reviewed articles published in English as of January 2025 and reported miRNAs associated with four hemorrhagic neurovascular diseases: CCM, arteriovenous malformations, moyamoya disease, and intracerebral hemorrhage. The PubMed systematic search retrieved 154 articles that met the inclusion criteria, reporting a total of 267 unique miRNAs identified in the literature on these four hemorrhagic neurovascular diseases. Of these 267 miRNAs, 164 were identified in preclinical studies, while 159 were identified in human subjects. Seventeen miRNAs were common to CCM and other hemorrhagic diseases. Common and unique disease-associated miRNAs in this systematic review motivate novel mechanistic hypotheses and have potential applications in diagnostic, predictive, prognostic, and therapeutic contexts of use. Much of current research can be considered hypothesis-generating, reflecting association rather than causation. Future areas of mechanistic investigation are proposed alongside approaches to analytic and clinical validations of contexts of use for biomarkers. Full article

Objectives: We conducted a retrospective study to investigate the effectiveness of angiotensin receptor blockers (ARBs) in preventing moderate-to-severe cerebral vasospasm, which may influence patient outcomes in cases of subarachnoid hemorrhage resulting from aneurysmal rupture. Methods: Between 2016 and 2020, we treated 210 patients with aneurysmal subarachnoid hemorrhage (aSAH) caused by a ruptured cerebral aneurysm. We obtained the clinical and radiological characteristics of patients through medical records and divided them into two groups: those who were administered ARBs (ARB group) and those who were not (no-ARB group). Results: A total of 181 patients aged 19 years or older with aSAH, without vascular abnormalities (including vascular malformations and moyamoya disease), were enrolled in this study. The age of the enrolled patients was 59.01 ± 12.98 (mean ± standard deviation), and the sex ratio of males to females was 66:115, with a higher proportion of females. The ARB group had 29 and the no-ARB group had 152 participants. The overall incidence of moderate-to-severe vasospasm was 33.7%. The incidence of moderate-to-severe vasospasm in each group was 13.8% (4 patients) and 37.5% (57 patients), respectively. The Fisher grade (III–IV) [odds ratio (OR) of 2.732 (95% confidence interval [CI]: 1.343–5.560; p = 0.006)] independently increases the risk of moderate-to-severe vasospasm, while older age [OR = 0.963; 95% CI: 0.938–0.989; p = 0.006] and ARB administration [OR = 0.246; 95% CI: 0.079–0.771; p = 0.016] independently decrease this risk. Conclusions: Despite the potential adverse impacts associated with hypotension, the administration of ARBs may provide therapeutic benefits in preventing moderate-to-severe vasospasm. A multicenter randomized double-blind controlled trial is needed to further investigate the efficacy and safety of ARBs in preventing moderate-to-severe vasospasm in aSAH patients who have undergone interventions and are experiencing acute hypertension. Full article

Moyamoya disease (MMD) is a rare progressive cerebrovascular disorder characterized by the stenosis or occlusion of the terminal segments of the internal carotid arteries, leading to the development of abnormal collateral vascular networks. These networks are a compensatory mechanism for reduced blood flow to the brain. Despite extensive research, the exact etiology of MMD remains unknown, although recent studies suggest that immune system dysfunction plays a critical role in its pathogenesis. In particular, the involvement of immune cells such as T cells, macrophages, and dendritic cells has been increasingly recognized. These immune cells contribute to the inflammatory process and vascular remodeling observed in MMD patients, further complicating the disease’s progression. Inflammation and immune-mediated damage to the vessel walls may accelerate the narrowing and occlusion of arteries, exacerbating ischemic events in the brain. Additionally, studies have revealed that certain genetic and environmental factors can influence immune system activation in MMD, linking these pathways to disease development. This review aims to provide a comprehensive overview of the immune mechanisms at play in MMD, focusing on how immune cells participate in vascular injury and remodeling. Understanding these immunological processes may offer new therapeutic targets to halt or reverse disease progression, potentially leading to more effective treatment strategies for MMD. Full article

Background/Objectives: Recent advances in stroke genetics have substantially enhanced our understanding of the complex genetic architecture underlying cerebral infarction and other stroke subtypes. As knowledge in this field expands, healthcare providers must remain informed about these latest developments. This review aims to provide a comprehensive overview of recent advances in stroke genetics, with a focus on cerebral infarction, and discuss their potential impact on patient care and future research directions. Methods: We reviewed recent literature about advances in stroke genetics, focusing on cerebral infarction, and discussed their potential impact on patient care and future research directions. Key developments include the identification of monogenic stroke syndromes, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy caused by mutations in the NOTCH3 and HTRA1 genes, respectively. In addition, the role of RNF213 in moyamoya disease and other cerebrovascular disorders, particularly in East Asian populations, has been elucidated. The development of polygenic risk scores for assessing genetic predisposition to stroke has demonstrated the potential to improve risk prediction beyond traditional factors. Genetic studies have also elucidated the distinct genetic architecture of stroke subtypes, including large artery atherosclerosis, small vessel disease, and cardioembolic stroke. Furthermore, the investigation of epigenetic modifications influencing stroke risk and its outcomes has revealed new research avenues, while advancements in pharmacogenomics highlight the potential for personalized stroke treatment based on individual genetic profiles. Conclusions: These genetic discoveries have important clinical implications, including improved risk stratification, targeted prevention strategies, and the development of novel therapeutic approaches. Full article

Advances in stroke genetics have highlighted the critical role of rare genetic variants in cerebrovascular diseases, with RNF213 emerging as a key player in ischemic stroke and Moyamoya disease (MMD). Initially identified as the primary susceptibility gene for MMD, RNF213—notably the p.R4810K variant—has been strongly linked to intracranial artery stenosis (ICAS) and various ischemic stroke subtypes, particularly in East Asian populations. This gene encodes an E3 ubiquitin ligase with diverse roles in angiogenesis, vascular remodeling, lipid metabolism, and cerebral blood flow regulation, yet its exact mechanisms in cerebrovascular pathology remain incompletely understood. This review synthesizes findings from genetic studies, as well as cellular and animal models, to provide a holistic understanding of RNF213’s involvement in cerebrovascular diseases. Key mechanisms by which RNF213 variants contribute to disease pathogenesis are explored, alongside discussions on their clinical utility as biomarkers and therapeutic targets. Additionally, we address the gene’s implications for disease prediction, risk assessment, and cascade screening. By integrating evidence across disciplines, this review identifies critical knowledge gaps, including the biological pathways underlying RNF213’s pathogenicity. These insights lay the groundwork for future research and underscore the potential of RNF213 in driving personalized approaches to cerebrovascular disease management. Full article

Evaluating altered mental status and suspected meningeal disorders in children often begins with imaging, typically before a lumbar puncture. The challenge is that meningeal enhancement is a common finding across a range of pathologies, making diagnosis complex. This review proposes a categorization of meningeal diseases based on their predominant imaging characteristics. It includes a detailed description of the clinical and imaging features of various conditions that lead to leptomeningeal or pachymeningeal enhancement in children and adolescents. These conditions encompass infectious meningitis (viral, bacterial, tuberculous, algal, and fungal), autoimmune diseases (such as anti-MOG demyelination, neurosarcoidosis, Guillain-Barré syndrome, idiopathic hypertrophic pachymeningitis, and NMDA-related encephalitis), primary and secondary tumors (including diffuse glioneuronal tumor of childhood, primary CNS rhabdomyosarcoma, primary CNS tumoral metastasis, extracranial tumor metastasis, and lymphoma), tumor-like diseases (Langerhans cell histiocytosis and ALK-positive histiocytosis), vascular causes (such as pial angiomatosis, ANCA-related vasculitis, and Moyamoya disease), and other disorders like spontaneous intracranial hypotension and posterior reversible encephalopathy syndrome. Despite the nonspecific nature of imaging findings associated with meningeal lesions, narrowing down the differential diagnoses is crucial, as each condition requires a tailored and specific treatment approach. Full article

Background: Concentric vessel-wall contrast enhancement (VW-CE) of the terminal carotid artery and its proximal branches may be linked to ischemic strokes, disease activity and progression in Moyamoya disease (MMD). The objective of this retrospective cohort study is to analyze the association between VW-CE and perioperative acute ischemic stroke (PAIS) occurring within 24 h after revascularization. Methods: All previously untreated MMD patients who required revascularization and who had undergone preoperative MRI with VW-CE-sequences were included. PAIS was detected by CT and/or diffusion-weighted MRI sequences within 24 h postoperatively. Results: Of the 110 patients included (female-to-male ratio: 2.7:1, median age: 45.1 (16.6–69.2); n = 247 revascularizations), a priori VW-CE was present in 67.3% (mean time from MRI to first surgery: 86 days ± 82 days). PAIS occurred in five patients undergoing primary revascularization (PAIS rate per revascularization: 2.1%), all of whom had a preoperative pathological VW-CE in the vascular segment corresponding to the stroke area. Two (40%) incidents of PAIS occurred in revascularized territory, while three (60%) occurred in non-revascularized vascular territory. In each case, the supplying artery exhibited VW-CE, indicating disease activity. No additional PAIS occurred during subsequent revascularizations in cases of multistage procedures (n = 38), such as ACA or PCA revascularization as a second step. Conclusions: Preoperative VW-CE in one or more vascular segments may be a marker for postoperative stroke in the respective vascular territory at the time of revascularization. VW-CE imaging should be routinely performed when planning revascularization in MMD. If VW-CE is found, strict perioperative monitoring of these high-risk patients should be performed to achieve the best results possible. Full article

Background: Using two case reports of adult women with moyamoya disease presenting with intracranial hemorrhage from ruptured aneurysms on moyamoya collateral vessels, we aim to demonstrate the potential for effective endovascular treatment navigated by CT angiography, digital subtraction angiography, and flat panel CT. Case 1 Presentation: A 45-year-old female patient with sudden onset of headache, followed by somnolency. CT scan showed a four-ventricle hematocephalus caused by a 27 × 31 × 17 mm hematoma located in the left basal ganglia. Angiography revealed a 3 mm aneurysm on hypertrophic lenticulostriate artery bridging the M1 occlusion. Selective catheterization and distal embolisation with acrylic glue was done. Case 2 Presentation: A 47-year-old woman was admitted for a sudden onset of severe headache, CT scan showed four-ventricle hematocephalus. A 4 mm aneurysm on the collateral vessel–anterior chorioidal artery bridging the closure of the terminal segment of the internal carotid artery was diagnosed as the source of bleeding. Selective catheterization and distal embolisation with acrylic glue was done. Conclusions: Selective embolisation of ruptured aneurysms on moya moya collaterals is a simple, effective, and safe procedure when relevant microcatheters are used with imaging software navigation such as 3D DSA, 3D road map and flat-panel CT. Full article

Moyamoya disease is a cerebrovascular pathology characterized by progressive stenosis of the internal carotid arteries and their branches, leading to ischemic and/or hemorrhagic disorders of the cerebral circulation, primarily affecting children and young adults. We present a case of a 23-year-old woman with a history of recurrent cerebrovascular accidents since childhood. Despite experiencing focal motor seizures and transient ischemic attacks, her condition remained undiagnosed until 2006, when, at the age of 7, a digital subtraction angiography revealed characteristic bilateral internal carotid artery occlusions. Subsequent diagnostic challenges and treatments preceded a worsening of symptoms in adulthood, including generalized tonic–clonic seizures. Upon presentation to our clinic, the patient exhibited upper motor neuron syndrome and occipital lobe syndrome, consistent with the disease’s pathophysiology, neuroimaging, and clinical manifestations. Imaging studies confirmed multiple ischemic lesions throughout the cerebral vasculature. Treatment adjustments were made due to the increased incidence of seizures, and the dose of her anti-seizure medication—divalproex sodium—was increased. This case underscores the diagnostic complexities and challenges in managing moyamoya disease, emphasizing the importance of early recognition and prompt intervention. Full article