Probing the Global Cellular Responses to Lipotoxicity Caused by Saturated Fatty Acids.

Excessive levels of saturated fatty acids are toxic to cells, although the basis for this lipotoxicity remains incompletely understood. Here, we analyzed the transcriptome, lipidome, and genetic interactions of human leukemia cells exposed to palmitate. Palmitate treatment increased saturated glycerolipids, accompanied by a transcriptional stress response, including upregulation of the endoplasmic reticulum (ER) stress response. A comprehensive genome-wide short hairpin RNA (shRNA) screen identified >350 genes modulating lipotoxicity. Among previously unknown genetic modifiers of lipotoxicity, depletion of RNF213, a putative ubiquitin ligase mutated in Moyamoya vascular disease, protected cells from lipotoxicity. On a broader level, integration of our comprehensive datasets revealed that changes in di-saturated glycerolipids, but not other lipid classes, are central to lipotoxicity in this model. Consistent with this, inhibition of ER-localized glycerol-3-phosphate acyltransferase activity protected from all aspects of lipotoxicity. Identification of genes modulating the response to saturated fatty acids may reveal novel therapeutic strategies for treating metabolic diseases linked to lipotoxicity.

Switching of brain networks across different cerebral perfusion states: insights from EEG dynamic microstate analyses.

The alteration of neural interactions across different cerebral perfusion states remains unclear. This study aimed to fulfill this gap by examining the longitudinal brain dynamic information interactions before and after cerebral reperfusion. Electroencephalogram in eyes-closed state at baseline and postoperative 7-d and 3-month follow-ups (moyamoya disease: 20, health controls: 23) were recorded. Dynamic network analyses were focused on the features and networks of electroencephalogram microstates across different microstates and perfusion states. Considering the microstate features, the parameters were disturbed of microstate B, C, and D but preserved of microstate A. The transition probabilities of microstates A-B and B-D were increased to play a complementary role across different perfusion states. Moreover, the microstate variability was decreased, but was significantly improved after cerebral reperfusion. Regarding microstate networks, the functional connectivity strengths were declined, mainly within frontal, parietal, and occipital lobes and between parietal and occipital lobes in different perfusion states, but were ameliorated after cerebral reperfusion. This study elucidates how dynamic interaction patterns of brain neurons change after cerebral reperfusion, which allows for the observation of brain network transitions across various perfusion states in a live clinical setting through direct intervention.

Screening of Moyamoya Disease From Retinal Photographs: Development and Validation of Deep Learning Algorithms.

BACKGROUND: Moyamoya disease (MMD) is a rare and complex pathological condition characterized by an abnormal collateral circulation network in the basal brain. The diagnosis of MMD and its progression is unpredictable and influenced by many factors. MMD can affect the blood vessels supplying the eyes, resulting in a range of ocular symptoms. In this study, we developed a deep learning model using real-world data to assist a diagnosis and determine the stage of the disease using retinal photographs. METHODS: This retrospective observational study conducted from August 2006 to March 2022 included 498 retinal photographs from 78 patients with MMD and 3835 photographs from 1649 healthy participants. Photographs were preprocessed, and an ResNeXt50 model was developed. Model performance was measured using receiver operating curves and their area under the receiver operating characteristic curve, accuracy, sensitivity, and F1-score. Heatmaps and progressive erasing plus progressive restoration were performed to validate the faithfulness. RESULTS: Overall, 322 retinal photographs from 67 patients with MMD and 3752 retinal photographs from 1616 healthy participants were used to develop a screening and stage prediction model for MMD. The average age of the patients with MMD was 44.1 years, and the average follow-up time was 115 months. Stage 3 photographs were the most prevalent, followed by stages 4, 5, 2, 1, and 6 and healthy. The MMD screening model had an average area under the receiver operating characteristic curve of 94.6%, with 89.8% sensitivity and 90.4% specificity at the best cutoff point. MMD stage prediction models had an area under the receiver operating characteristic curve of 78% or higher, with stage 3 performing the best at 93.6%. Heatmap identified the vascular region of the fundus as important for prediction, and progressive erasing plus progressive restoration result shows an area under the receiver operating characteristic curve of 70% only with 50% of the important regions. CONCLUSIONS: This study demonstrated that retinal photographs could be used as potential biomarkers for screening and staging of MMD and the disease stage could be classified by a deep learning algorithm.

Moyamoya Vasculopathy and Moyamoya-Related Systemic Vasculopathy: A Review With Histopathological and Genetic Viewpoints.

Systemic vasculopathy has occasionally been reported in cases of moyamoya disease (MMD). Since the pathological relationship between moyamoya vasculopathy (MMV) and moyamoya-related systemic vasculopathy (MMRSV) remains unclear, it was examined herein by a review of histopathologic studies in consideration of clinicopathological and genetic viewpoints. Although luminal stenosis was a common finding in MMV and MMRSV, histopathologic findings of vascular remodeling markedly differed. MMV showed intimal hyperplasia, marked medial atrophy, and redundant tortuosity of the internal elastic lamina, with outer diameter narrowing called negative remodeling. MMRSV showed hyperplasia, mainly in the intima and sometimes in the media, with disrupted stratification of the internal elastic lamina. Systemic vasculopathy has also been observed in patients with non-MMD carrying the RNF213 (ring finger protein 213) mutation, leading to the concept of RNF213 vasculopathy. RNF213 vasculopathy in patients with non-MMD was histopathologically similar to MMRSV. Cases of MMRSV have sometimes been diagnosed with fibromuscular dysplasia. Fibromuscular dysplasia is similar to MMD not only in the histopathologic findings of MMRSV but also from clinicopathological and genetic viewpoints. The significant histopathologic difference between MMV and MMRSV may be attributed to a difference in the original vascular wall structure and its resistance to pathological stress between the intracranial and systemic arteries. To understand the pathogeneses of MMD and MMRSV, a broader perspective that includes RNF213 vasculopathy and fibromuscular dysplasia as well as an examination of the 2- or multiple-hit theory consisting of genetic factors, vascular structural conditions, and vascular environmental factors, such as blood immune cells and hemodynamics, are needed.

Incidence and Outcomes of Posterior Circulation Involvement in Moyamoya Disease.

BACKGROUND: Moyamoya disease (MMD) is a progressive, occlusive disease of the internal carotid arteries and their proximal branches, with the subsequent development of an abnormal vascular network that is rupture-prone. Steno-occlusive changes in the posterior cerebral arteries (PCAs) may contribute to worsened outcomes in patients with MMD; however, there is little information on the incidence and natural history of posterior circulation MMD (PCMMD). We describe clinical PCMMD characteristics in a large cohort of patients with MMD. METHODS: We retrospectively reviewed patients with MMD treated between 1991 and 2019 at a large academic medical center. Demographics, perioperative outcomes, and radiological phenotypes were recorded for 770 patients. PCA disease was graded as either 0 (no disease), 1 (mild), 2 (moderate), or 3 (severe or occluded) based on cerebral angiography. Patients with angiographically confirmed MMD diagnosis with at least 6 months follow-up and completion of revascularization surgery were included; patients with intracranial atherosclerosis, intracranial dissection, vasculitis, and undefined inflammatory processes were excluded. The presence of stenosis/occlusion was graded radiographically to assess for disease progression and the prevalence of risk factors related to reduced progression-free survival. RESULTS: In all, 686 patients met the inclusion criteria, with PCA disease identified in 282 (41.1%) patients. Of those 282 patients with PCMMD, disease severity ranged from 99 (35.1%) with mild, 72 (25.5%) with moderate, and 111 (39.4%) with severe. The total number of postoperative complications was significantly associated with PCMMD severity (P=0.0067). Additionally, PCMMD severity correlated with worse postoperative modified Rankin Scale scores (P<0.0001). At a mean follow-up of 6.0±3.9 (range, 0.1-25.0) years, a total of 60 (12.6%) patients showed new/worsening PCMMD. The overall postoperative, progression-free survival in patients with PCMMD was 95.4% at 1 year, 82.4% at 3 years, 68.8% at 5 years, and 28.3% at 10 years, with prognostic factors for progression including preoperative PCMMD status, history of tobacco use, and hypertension (P<0.0001, P<0.001, and P<0.0001, respectively). CONCLUSIONS: PCA disease involvement in MMD is associated with higher rates of ischemic perioperative complications and worsened functional outcomes, likely due to reduced collateral flow. Ten-year progression of PCA disease is highly likely and should be monitored throughout follow-up; future studies will assess the impact of PCA disease progression on long-term outcomes.

Hemorrhagic Moyamoya Angiopathy in European Patients.

BACKGROUND: Moyamoya angiopathy (MMA) is an important cause of juvenile stroke but an overall rare disease among European populations compared with East Asian cohorts. Consecutively, hemorrhagic MMA is described well in East Asian cohorts, but knowledge in non-Asian patients is limited. Literature suggests that disease presentation may vary between those cohorts, also including hemorrhage frequencies. Hence, this article aims to analyze hemorrhagic MMA in European patients. METHODS: We screened for patients of European origin with MMA from a single-center consecutive database of a German hospital specialized on MMA. Those who had a record of intracranial hemorrhage were analyzed individually regarding the type of hemorrhage and use of antiplatelet therapy before and after bleeding onset. To identify associated factors of intracranial hemorrhage, an age- and sex-matched control group was identified from the pool of patients without a history of hemorrhage. Both groups had a comparable follow-up time and were compared in terms of disease presentation, therapeutic interventions, and imaging characteristics, using both univariate tests and multivariate logistic regression analysis. RESULTS: From a pool of 332 patients with MMA we identified 288 of European ancestry. From those, 36 had a record of intracranial hemorrhage (12.5%). Thirty-three patients presenting with 37 events were included for further analysis and case-control-comparison. Most events were intracerebral hemorrhage (n=20; 54%) and subarachnoid hemorrhage (n=11; 30%). 78% developed hemorrhage although no antiplatelet therapy was in use (n=29). Seven patients developed intracranial hemorrhage ipsilateral to prior bypass surgery (21%), while 29 of the control patients had a bypass surgery (88%; P=0.0001). There was no significant difference in terms of unilateral or bilateral disease type, history of hypertension, as well as imaging characteristics (high Suzuki stage and the presence of collateral pathways in conventional angiography, as well as ischemic defects and the presence of microbleeds on cerebral magnetic resonance imaging; P>0.05 in multivariate analysis, respectively). CONCLUSIONS: Bypass surgery was negatively associated with the development of intracranial hemorrhage in MMA in European patients. There was no difference in terms of a history of hypertension between groups, indicating that blood pressure is not the major contributor for rupture of fragile collateral vessels. The investigated imaging characteristics were not associated to hemorrhage onset and, therefore, are not suitable as a tool of screening for patients at risk.

Glymphatic System Impairment in the Advanced Stage of Moyamoya Disease.

Assessing the glymphatic system activity using diffusion tensor imaging analysis along with the perivascular space (DTI-ALPS) may be helpful to understand the pathophysiology of moyamoya disease (MMD). 63 adult patients with MMD and 20 healthy controls (HCs) were included for T1-weighted images, T2-FLAIR, pseudocontinuous arterial spin labeling, and DTI. 60 patients had digital subtraction angiography more than 6 months after combined revascularization. The Suzuki stage, postoperative Matsushima grade, periventricular anastomoses (PA), enlarged perivascular spaces (EPVS), deep and subcortical white matter hyperintensities (DSWMH), DTI-ALPS, cerebral blood flow (CBF), and cognitive scales of MMD patients were assessed. MMD patients were divided into early and advanced stage based on the Suzuki stage. We detected lower DTI-ALPS in patients with advanced stage relative to HCs (p = 0.046) and patients with early stage (p = 0.004), hemorrhagic MMD compared with ischemic MMD (p = 0.048), and PA Grade 2 compared with Grade 0 (p = 0.010). DTI-ALPS was correlated with the EPVS in basal ganglia (r = -0.686, p < 0.001), Suzuki stage (r = -0.465, p < 0.001), DSWMH (r = -0.423, p = 0.001), and global CBF (r = 0.300, p = 0.017) and cognitive scores (r = 0.343, p = 0.018). The DTI-ALPS of patients with good postoperative collateral formation was higher compared to those with poor postoperative collateral formation (p = 0.038). In conclusion, the glymphatic system was impaired in advanced MMD patients and may affected cognitive function and postoperative neoangiogenesis.

De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke.

PURPOSE: RNF213, encoding a giant E3 ubiquitin ligase, has been recognized for its role as a key susceptibility gene for moyamoya disease. Case reports have also implicated specific variants in RNF213 with an early-onset form of moyamoya disease with full penetrance. We aimed to expand the phenotypic spectrum of monogenic RNF213-related disease and to evaluate genotype-phenotype correlations. METHODS: Patients were identified through reanalysis of exome sequencing data of an unselected cohort of unsolved pediatric cases and through GeneMatcher or ClinVar. Functional characterization was done by proteomics analysis and oxidative phosphorylation enzyme activities using patient-derived fibroblasts. RESULTS: We identified 14 individuals from 13 unrelated families with (de novo) missense variants in RNF213 clustering within or around the Really Interesting New Gene (RING) domain. Individuals presented either with early-onset stroke (n = 11) or with Leigh syndrome (n = 3). No genotype-phenotype correlation could be established. Proteomics using patient-derived fibroblasts revealed no significant differences between clinical subgroups. 3D modeling revealed a clustering of missense variants in the tertiary structure of RNF213 potentially affecting zinc-binding suggesting a gain-of-function or dominant negative effect. CONCLUSION: De novo missense variants in RNF213 clustering in the E3 RING or other regions affecting zinc-binding lead to an early-onset syndrome characterized by stroke or Leigh syndrome.

Biallelic variants in NOS3 and GUCY1A3, the two major genes of the nitric oxide pathway, cause moyamoya cerebral angiopathy.

BACKGROUND: Moyamoya angiopathy (MMA) is a rare cerebrovascular condition leading to stroke. Mutations in 15 genes have been identified in Mendelian forms of MMA, but they explain only a very small proportion of cases. Our aim was to investigate the genetic basis of MMA in consanguineous patients having unaffected parents in order to identify genes involved in autosomal recessive MMA. METHODS: Exome sequencing (ES) was performed in 6 consecutive consanguineous probands having MMA of unknown etiology. Functional consequences of variants were assessed using western blot and protein 3D structure analyses. RESULTS: Causative homozygous variants of NOS3, the gene encoding the endothelial nitric oxide synthase (eNOS), and GUCY1A3, the gene encoding the alpha1 subunit of the soluble guanylate cyclase (sGC) which is the major nitric oxide (NO) receptor in the vascular wall, were identified in 3 of the 6 probands. One NOS3 variant (c.1502 + 1G > C) involves a splice donor site causing a premature termination codon and leads to a total lack of eNOS in endothelial progenitor cells of the affected proband. The other NOS3 variant (c.1942 T > C) is a missense variant located into the flavodoxine reductase domain; it is predicted to be destabilizing and shown to be associated with a reduction of eNOS expression. The GUCY1A3 missense variant (c.1778G > A), located in the catalytic domain of the sGC, is predicted to disrupt the tridimensional structure of this domain and to lead to a loss of function of the enzyme. Both NOS3 mutated probands suffered from an infant-onset and severe MMA associated with posterior cerebral artery steno-occlusive lesions. The GUCY1A3 mutated proband presented an adult-onset MMA associated with an early-onset arterial hypertension and a stenosis of the superior mesenteric artery. None of the 3 probands had achalasia. CONCLUSIONS: We show for the first time that biallelic loss of function variants in NOS3 is responsible for MMA and that mutations in NOS3 and GUCY1A3 are causing fifty per cent of MMA in consanguineous patients. These data pinpoint the essential role of the NO pathway in MMA pathophysiology.

Predictors of Stroke Outcomes in Conservatively Treated Patients With Moyamoya Disease: A Follow-up MRI Study.

BACKGROUND: Little is known about the association between stroke and imaging and clinical features in conservatively treated patients with moyamoya disease (MMD). PURPOSE: To investigate independent risk factors for stroke in conservatively treated patients with MMD during a long-term follow-up. STUDY TYPE: Prospective study. SUBJECTS: One hundred sixty conservatively managed patients with MMD (median age 46 years, 89 male). FIELD STRENGTH/SEQUENCE: Time of flight, turbo inversion recovery magnitude T1WI, turbo spin echo (TSE) T2WI, echo-planar imaging DWI, T2-fluid attenuated inversion recovery, dynamic susceptibility contrast-magnetic resonance imaging, and pre- and post-contrast 3D TSE T1WI sequences at 3.0 Tesla. ASSESSMENT: Patients were assessed at baseline and followed yearly. Ischemic and hemorrhagic stroke incidence rates were determined. Multiple demographic, clinical (modified Rankin score [mRS]), and cerebral imaging (cerebral blood volume [CBV] and concentric enhancement of arterial wall) factors at baseline were considered as potential predictors of stroke during the follow-up period. STATISTICAL TESTS: Univariable and multivariable Cox proportional hazards models to calculate the hazard ratios (HRs) and corresponding 95% confidence interval (CI) for stroke. Cumulative risk of stroke was estimated by the Kaplan-Meier product-limit method. A P value <0.05 was considered statistically significant. RESULTS: The median follow-up duration was 47 months. During the follow-up period, 18 (11.25%) patients experienced stroke events (13 [8.13%] ischemic, 5 [3.12%] hemorrhagic). Univariable analysis showed that 11 factors were significantly associated with stroke. After adjustment for clinical characteristics, multivariable analysis showed that mRS score ≥3 (HR, 1.99; 95% CI, 1.26-3.14), decreased CBV (HR, 5.31; 95% CI, 2.32-12.13), and concentric enhancement of the arterial wall (HR, 4.16; 95% CI, 1.55-11.15) were significantly associated with stroke. DATA CONCLUSION: Decreased CBV, mRS score ≥ 3, and concentric enhancement of the arterial wall were significantly associated with increased incidence of stroke in conservatively treated MMD. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 4.

Nomogram Based on High-Resolution Vessel Wall MRI Features to Differentiate Moyamoya Disease From Atherosclerosis-Associated Moyamoya Vasculopathy.

BACKGROUND: The angiographic features of moyamoya disease (MMD) and atherosclerosis-associated moyamoya vasculopathy (AS-MMV) are similar, but the etiology and clinical treatment strategies are different. Differentiating MMD from AS-MMV helps to choose the appropriate treatment. PURPOSE: To investigate the feasibility of a nomogram based on high-resolution vessel wall (HR-VWI) MRI features to differentiate MMD from AS-MMV. STUDY TYPE: Retrospective. SUBJECTS: One hundred and two patients with MMD (N = 52) or AS-MMV (N = 50) in the training cohort (9-72 years; 54 females) and 70 patients with MMD (N = 42) or AS-MMV (N = 28) in the validation cohort (7-69 years; 33 females). FIELD STRENGTH/SEQUENCE: 3-T, three-dimensional time-of-flight MR angiography (3D-TOF-MRA), spin echo high-resolution 3D T1-weighted imaging (3D-T1WI), 3D T2-weighted imaging (3D-T2WI), and contrast-enhanced 3D-T1WI. ASSESSMENT: Image assessment was performed by three neuroradiologists (with 10, 15, and 18 years of experience). Demographic characteristic and image features were evaluated and compared. Independent factors of MMD were screened to construct a nomogram model in the training cohort. The validation cohort was used to validated its generality. STATISTICAL TESTS: Interclass correlation coefficient (ICC), kappa, t-test, χ2 test, receiver operating characteristic (ROC) curve, area under the curve (AUC), calibration curve and concordance index (C-index). A P-value <0.05 was considered statistically significant. RESULTS: Significant differences were observed between MMD and AS-MMV in terms of age, vessel outer diameter, vessel wall thickening pattern, maximum thickness, dot sign, and anterior cerebral artery (ACA) involved. Age, outer diameter, dot sign, and ACA involved were independent factors. The C-index was 0.886 in the training cohort and 0.859 in the validation cohort. The ROC demonstrated high diagnostic efficacy with an AUC of 0.884 in the training cohort and 0.857 in the validation cohort. DATA CONCLUSION: A nomogram model based on age, vessel outer diameter, dot sign and ACA involved may effectively distinguish MMD from AS-MMV with good reliability and accuracy. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

SAMHD1 compound heterozygous rare variants associated with moyamoya and mitral valve disease in the absence of other features of Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome (AGS) is an autosomal recessive inflammatory syndrome that manifests as an early-onset encephalopathy with both neurologic and extraneurologic clinical findings. AGS has been associated with pathogenic variants in nine genes: TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR, IFIH1, LSM11, and RNU7-1. Diagnosis is established by clinical findings (encephalopathy and acquired microcephaly, intellectual and physical impairments, dystonia, hepatosplenomegaly, sterile pyrexia, and/or chilblains), characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes), or the identification of pathogenic/likely pathogenic variants in the known genes. One of the genes associated with AGS, SAMHD1, has also been associated with a spectrum of cerebrovascular diseases, including moyamoya disease (MMD). In this report, we describe a 31-year-old male referred to genetics for MMD since childhood who lacked the hallmark features of AGS patients but was found to have compound heterozygous SAMHD1 variants. He later developed mitral valve insufficiency due to recurrent chordal rupture and ultimately underwent a heart transplant at 37 years of age. Thus, these data suggest that SAMHD1 pathogenic variants can cause MMD without typical AGS symptoms and support that SAMHD1 should be assessed in MMD patients even in the absence of AGS features.

Optical genome mapping with genome sequencing identifies subtelomeric Xq28 deletion and inserted 7p22.3 duplication in a male with multisystem developmental disorder.

We report a 17-year-old male with supravalvular stenosis, initial failure to thrive and delayed early development, short stature, acromelia, dysmorphic facial features, hypertelorism, macrocephaly, syringomyelia, hypertension, and anxiety disorder. Fluorescent in situ hybridization (FISH), chromosomal microarray analysis (CMA), and exome sequencing (ES) were nondiagnostic. Combined optical genome mapping (OGM) and genome sequencing (GS) showed a complex rearrangement including an X chromosome with a 22.5 kb deletion in band Xq28 replaced by a 61.4 kb insertion of duplicated chromosome 7p22.3 material. The deletion removes the distal 3' untranslated region (UTR) of FUNDC2, the entire CMC4 and MTCP1, and the first five exons of BRCC3. Transcriptome analysis revealed absent expression of CMC4 and MTCP1 and BRCC3 with normal transcript level of FUNDC2. The inserted duplication includes only one known gene: UNCX. Similar overlapping Xq28 deletions have been reported to be associated with Moyamoya disease (MMD), short stature, hypergonadotropic hypogonadism (HH), and facial dysmorphism. Although he has short stature, our patient does not have signs of Moyamoya arteriopathy or hypogonadism. The structurally abnormal X chromosome was present in his mother, but not in his unaffected brother, maternal uncle, or maternal grandparents. We propose that the combination of his absent Xq28 and duplicated 7p22.3 genomic material is responsible for his phenotype. This case highlights the potential of combined OGM and GS for detecting complex structural variants compared with standard of care genetic testing such as CMA and ES.

Vessel wall MRI in moyamoya disease: arterial wall enhancement varies depending on age, arteries, and disease progression.

OBJECTIVE: To investigate the relationship of followings for patients with moyamoya disease (MMD): arterial wall enhancement on vessel wall MRI (VW-MRI), cross-sectional area (CSA), time-of-flight MR angiography (MRA), age, locations from intracranial internal carotid artery (ICA) to proximal middle cerebral artery (MCA), disease progression, and transient ischemic attack (TIA). METHODS: Patients who underwent VW-MRI between October 2018 and December 2020 were enrolled in this retrospective study. We measured arterial wall enhancement (enhancement ratio, ER) and CSA at five sections of ICA and MCA. Also, we scored MRA findings. Multiple linear regression (MLR) analysis was performed to explore the associations between ER, age, MRA score, CSA, history of TIA, and surgical revascularization. RESULTS: We investigated 102 sides of 51 patients with MMD (35 women, 16 men, mean age 31 years ± 18 [standard deviation]). ER for MRA score 2 (signal discontinuity) was higher than ER for other scores in sections D (end of ICA) and E (proximal MCA) on MLR analysis. ER in section E was significantly higher in patients for MRA score 2 with TIA history than without. ER significantly increased as CSA increased in section E, which suggests ER becomes less in decreased CSA due to negative remodeling. CONCLUSION: Arterial wall enhancement in MMD varies by age, location, and disease progression. Arterial wall enhancement may be stronger in the progressive stage of MMD. Arterial wall enhancement increases with history of TIA at proximal MCA, which may indicate the progression of the disease. CLINICAL RELEVANCE STATEMENT: Arterial wall enhancement in moyamoya disease varies by age, location of arteries, and disease progression, and arterial wall enhancement may be used as an imaging biomarker of moyamoya disease. KEY POINTS: It has not been clarified what arterial wall enhancement in moyamoya disease represents. Arterial wall enhancement in moyamoya disease varies by age, location of arteries, and disease progression. Arterial wall enhancement in moyamoya disease increases as the disease progresses.

High-resolution MRI vessel wall enhancement in moyamoya disease: risk factors and clinical outcomes.

OBJECTIVES: Intracranial vessel wall enhancement (VWE) on high-resolution magnetic resonance imaging (HRMRI) is associated with the progression and poor prognosis of moyamoya disease (MMD). This study assessed potential risk factors for VWE in MMD. METHODS: We evaluated MMD patients using HRMRI and traditional angiography examinations. The participants were divided into VWE and non-VWE groups based on HRMRI. Logistic regression was performed to compare the risk factors for VWE in MMD. The incidence of cerebrovascular events of the different subgroups according to risk factors was compared using Kaplan-Meier survival and Cox regression. RESULTS: We included 283 MMD patients, 84 of whom had VWE on HRMRI. The VWE group had higher modified Rankin Scale scores at admission (p = 0.014) and a higher incidence of ischaemia and haemorrhage (p = 0.002) than did the non-VWE group. Risk factors for VWE included the ring finger protein 213 (RNF213) p.R4810K variant (odds ratio [OR] 2.01, 95% confidence interval [CI] 1.08-3.76, p = 0.028), hyperhomocysteinaemia (HHcy) (OR 5.08, 95% CI 2.34-11.05, p < 0.001), and smoking history (OR 3.49, 95% CI 1.08-11.31, p = 0.037). During the follow-up of 63.9 ± 13.2 months (median 65 months), 18 recurrent stroke events occurred. Cox regression showed that VWE and the RNF213 p.R4810K variant were risk factors for stroke. CONCLUSION: The RNF213 p.R4810K variant is strongly associated with VWE and poor prognosis in MMD. HHcy and smoking are independent risk factors for VWE. CLINICAL RELEVANCE STATEMENT: Vessel wall enhancement in moyamoya disease is closely associated with poor prognosis, especially related to the ring finger protein 213 p.R4810K variant, hyperhomocysteinaemia, and smoking, providing crucial risk assessment information for the clinic. KEY POINTS: • The baseline presence of vessel wall enhancement is significantly associated with poor prognosis in moyamoya disease. • The ring finger protein 213 p.R4810K variant is strongly associated with vessel wall enhancement and poor prognosis in moyamoya disease. • Hyperhomocysteinaemia and smoking are independent risk factors for vessel wall enhancement in moyamoya disease.

HAPLN3 p.T34A contributes to incomplete penetrance of moyamoya disease in Chinese carrying RNF213 p.R4810K.

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Association of Cognitive Reserve and Preoperative Cognitive Function in Patients with Adult Moyamoya Disease: A Preliminary Study.

INTRODUCTION: Many patients with moyamoya disease (MMD) exhibit cognitive decline; however, the link between cognitive reserve (CR) and cognitive function in those who have not undergone revascularization remains unexplored. We aimed to evaluate preoperative cognitive impairment in such patients and to explore the relationship between CR, measured using the Cognitive Reserve Index questionnaire (CRIq), and cognitive abilities across different domains, determined using neuropsychological tests. METHODS: Demographic, clinical, CRIq, and neuropsychological assessment data were gathered from patients with MMD who underwent preoperative cognitive functional assessments at our center during 2021-2023. These patients were categorized according to their Montreal Cognitive Assessment score. Multivariable linear regression was performed to analyze the association between CRIq score and cognitive performance, both globally and in specific domains. RESULTS: In the MMD cohort of 53 patients, 49% (n = 26) of the patients exhibited a decrease in overall cognitive performance. Individuals with cognitive dysfunction had significantly lower composite CRIq scores than those with intact cognition. Although no association between overall cognitive ability and CR was observed, independent associations emerged between CR and specific cognitive functions - language (ß = 0.56, p = 0.002), verbal memory (ß = 0.45, p = 0.001), and executive function (ß = 0.35, p = 0.03). CONCLUSION: This preliminary study revealed that expressive language, verbal memory, and executive function are linked to CR in presurgical patients with MMD, highlighting the role of CR in predicting cognitive outcomes. Further research is warranted to elucidate the combined effects of CR and other risk factors on the cognitive function of patients with MMD.

Prediction of cerebral infarction after bypass surgery in adult moyamoya disease: using pulsatility index on TCD.

BACKGROUND: At present, the most effective treatment for symptomatic moyamoya disease (MMD) is surgery. However, the high incidence of postoperative complications is a serious problem plaguing the surgical treatment of MMD, especially the acute cerebral infarction. Decreased cerebrovascular reserve is an independent risk factor for ischemic infarction, and the pulsatility index (PI) of transcranial Doppler (TCD) is a common intuitive index for evaluating intracranial vascular compliance. However, the relationship between PI and the occurrence of ischemic stroke after operation is unclear. OBJECTIVE: To explore whether the PI in the middle cerebral artery (MCA) could serve as a potential predictor for the occurrence of ischemic infarction after bypass surgery in MMD. METHODS: We performed a retrospective analysis of data from 71 patients who underwent combined revascularization surgery, including superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis and encephalo-duro-myo-synangiosis (EDMS). The patients were divided into two groups according to the median of ipsilateral MCA-PI before operation, low PI group (MCA-PI < 0.614) and high PI group (MCA-PI ≥ 0.614). Univariate and multivariate regression analysis were used to explore risk factors affecting the occurrence of postoperative cerebral infarction. RESULTS: Among the 71 patients with moyamoya disease, 11 patients had cerebral infarction within one week after revascularization. Among them, 10 patients' ipsilateral MCA-PI were less than 0.614, and another one's MCA- PI is higher than 0.614. Univariate analysis showed that the lower ipsilateral MCA-PI (0.448 ± 0.109 vs. 0.637 ± 0.124; P = 0.001) and higher Suzuki stage (P = 0.025) were linked to postoperative cerebral infarction. Multivariate analysis revealed that lower ipsilateral MCA-PI was an independent risk factor for predicting postoperative cerebral infarction (adjusted OR = 14.063; 95% CI = 6.265 ~ 37.308; P = 0.009). CONCLUSIONS: A lower PI in the ipsilateral MCA may predict the cerebral infarction after combined revascularization surgery with high specificity. And combined revascularization appears to be safer for the moyamoya patients in early stages.

Dilated perivascular spaces and steno-occlusive changes in children and adults with moyamoya disease.

BACKGROUND: Dilated perivascular spaces (DPVS), known as one of imaging markers in cerebral small vessel disease, may be found in patients with moyamoya disease (MMD). However, little is known about DPVS in MMD. The purpose of this study was to investigate the distribution pattern of dPVS in children and adults with MMD and determine whether it is related to steno-occlusive changes of MMD. METHODS: DPVS was scored in basal ganglia (BG) and white matter (WM) on T2-weighted imaging, using a validated 4-point semi-quantitative score. The degree of dPVS was classified as high (score > 2) or low (score ≤ 2) grade. The steno-occlusive changes on MR angiography (MRA) was scored using a validated MRA grading. Asymmetry of DPVS and MRA grading was defined as a difference of 1 grade or higher between hemispheres. RESULTS: Fifty-one patients with MMD (mean age 24.9 ± 21.1 years) were included. Forty-five (88.2%) patients had high WM-DPVS grade (degree 3 or 4). BG-DPVS was found in 72.5% of all patients and all were low grade (degree 1 or 2). The distribution patterns of DPVS degree in BG (P = 1.000) and WM (P = 0.767) were not different between child and adult groups. The asymmetry of WM-DPVS (26%) and MRA grade (42%) were significantly correlated to each other (Kendall's tau-b = 0.604, P < 0.001). CONCLUSIONS: DPVS of high grade in MMD is predominantly found in WM, which was not different between children and adults. The correlation between asymmetry of WM-DPVS degree and MRA grade suggests that weak cerebral artery pulsation due to steno-occlusive changes may affect WM-DPVS in MMD.

Persistent trigeminal artery in a patient with moyamoya disease:a case report and literature review.

BACKGROUNDS: Persistent trigeminal artery (PTA) is a rare anastomosis between internal carotid artery (ICA) and basilar artery. In rare conditions, the PTA could be combined with others cerebrovascular anomalies, moyamoya disease (MMD) is one of them. CASE PRESENTATION: Here, we reported one rare case of MMD associated with PTA, the patient admitted to our department for severe dizziness and headache, imaging examination suggested MMD combined with right PTA, which arising from the ipsilateral cavernous portion of ICA. The patient received phased bilaterral revascularization with no any complication. In the subsequent follow-up, the patient's symptoms and intracranial vascular condition gradually improved. Moreover, we conducted a literature review of coexistence of PTA and MMD, the results of a web of science regarding such condition, and a deep discussion providing brief insight into the status of co-occurrence of PTA and MMD, including its manifestation, treatment and outcome. CONCLUSIONS: The coexistence of PTA and MMD was rarely reported, the pathogenesis of such condition remains unknown. We found that the features of the coexistence of PTA and MMD were diverse, revascularization might be a feasible for such patient.