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Purpose: Renal impairment (RI) has been regarded as a risk factor for unfavorable neurologic outcomes after mechanical thrombectomy (MT) in acute ischemic stroke. However, most of the previous studies were conducted on patients with anterior circulation stroke. Accordingly, the influence of RI on MT outcomes has not been well elucidated in detail in acute vertebrobasilar stroke. Methods: Consecutive stroke patients with MT due to acute vertebrobasilar artery occlusion between March 2015 and December 2020 at four institutions were included. Multivariable logistic regression analysis was conducted to assess the associations between RI and outcomes and mortality at 3 months, and the development of intracerebral hemorrhage (ICH) after the procedure. Additionally, the multivariable Cox proportional hazards model was performed to determine the influence of RI on survival probability after patient discharge. Results: A total of 110 patients were included in the final analysis. The presence of RI (OR = 0.268, 95% CI: 0.077–0.935), National Institute of Health Stroke Scale scores (OR = 0.849, 95% CI: 0.791–0.910), and puncture-to-recanalization time (OR = 0.981, 95% CI: 0.966–0.997) were related to outcomes. There was no significant association between RI and 3-month mortality or ICH. The cumulative survival probability after adjusting for relevant risk factors demonstrated that RI remained significantly associated with poorer survival after MT compared to patients without RI (HR = 2.111, 95% CI: 0.919–4.847). Conclusion: RI was an independent risk factor for poor 3-month neurologic outcomes and survival probability after MT in patients with acute vertebrobasilar stroke. [ABSTRACT FROM AUTHOR]

Background and purpose Transarterial access to dural arteriovenous fistulas (dAVFs) has been popularized by device improvements and novel embolic materials. However, this approach is limited in the cavernous sinus (CS) because of related complications and low cure rates. Although a transvenous approach, via ipsilateral inferior petrosal sinus (IPS), may be more suitable for CS-dAVFs, microcatheter delivery is occasionally impeded by ipsilateral IPS occlusion. Described herein is a microguidewire looping method to breach such occlusions, thus enabling access to CS lesions. Methods A microcatheter is initially advanced into the IPS orifice, and a microguidewire is passed into the occluded IPS. Looping is easily achieved through the resistance met. With greater support of the guiding catheter, the microguidewire (still looped) is then advanced into the CS. When nearing the CS, the microcatheter is further reinforced, and it is navigated along the microguidewire into the CS. Results This technique was applied in 10 instances of CS-dAVF with ipsilateral IPS occlusion, enabling ipsilateral access to the CS. In eight cases (80%), microdevice advancement was successful, culminating in effective transvenous coil embolization. Clinical and radiologic outcomes in all patients were excellent, with no delayed post-procedural cranial palsies. Conclusion This microguidewire looping technique enables safe and effective entry into the CS during transvenous coil embolization of CS-dAVFs with ipsilateral IPS occlusion. [ABSTRACT FROM AUTHOR]

The prognostic value of copeptin in subarachnoid hemorrhage (SAH) has been reported, but the prognosis was largely affected by the initial clinical severity. Thus, the previous studies are not very useful in predicting delayed cerebral ischemia (DCI) in poor-grade SAH patients. Here, we first investigated the feasibility of predicting DCI in poor-grade SAH based on consecutive measurements of plasma copeptin. We measured copeptin levels of 86 patients on days 1, 3, 5, 7, 9, 11, and 13 using ELISA. The primary outcome was the association between consecutive copeptin levels and DCI development. The secondary outcomes were comparison of copeptin with C-reactive protein (CRP) in predicting DCI. Additionally, we compared the prognostic value of transcranial Doppler ultrasonography (TCD) with copeptin using TCD alone to predict DCI. Increased copeptin (OR = 1.022, 95% CI: 1.008–1.037) and modified Fisher scale IV (OR = 2.841; 95% CI: 0.998–8.084) were closely related to DCI. Consecutive plasma copeptin measurements showed significant differences between DCI and non-DCI groups (p < 0.001). Higher CRP and DCI appeared to show a correlation, but it was not statistically significant. Analysis of copeptin changes with TCD appeared to predict DCI better than TCD alone with AUCROC differences of 0.072. Consecutive measurements of plasma copeptin levels facilitate the screening of DCI in poor-grade SAH patients. [ABSTRACT FROM AUTHOR]

The assessment of rupture probability is crucial to identifying at risk intracranial aneurysms (IA) in patients harboring multiple aneurysms. We aimed to develop a computer-assisted detection system for small-sized aneurysm ruptures using a convolutional neural network (CNN) based on images of three-dimensional digital subtraction angiography. A retrospective data set, including 368 patients, was used as a training cohort for the CNN using the TensorFlow platform. Aneurysm images in six directions were obtained from each patient and the region-of-interest in each image was extracted. The resulting CNN was prospectively tested in 272 patients and the sensitivity, specificity, overall accuracy, and receiver operating characteristics (ROC) were compared to a human evaluator. Our system showed a sensitivity of 78.76% (95% CI: 72.30%–84.30%), a specificity of 72.15% (95% CI: 60.93%–81.65%), and an overall diagnostic accuracy of 76.84% (95% CI: 71.36%–81.72%) in aneurysm rupture predictions. The area under the ROC (AUROC) in the CNN was 0.755 (95% CI: 0.699%–0.805%), better than that obtained from a human evaluator (AUROC: 0.537; p < 0.001). The CNN-based prediction system was feasible to assess rupture risk in small-sized aneurysms with diagnostic accuracy superior to human evaluators. Additional studies based on a large data set are necessary to enhance diagnostic accuracy and to facilitate clinical application. [ABSTRACT FROM AUTHOR]

We aimed to investigate whether mitochondrial dysfunction in extracellular cerebrospinal fluid (CSF), which is associated with autophagy and mitophagy, might be involved in neurological outcomes in adult patients with hemorrhagic moyamoya disease (MMD) whose pathogenesis related to poor outcomes is not well-known. CSF samples were collected from 43 adult MMD patients and analyzed according to outcomes at 3 months. Fluorescence-activated cell sorter analysis (FACS) and the JC-1 red/green ratio were used to assess mitochondrial cells and intact mitochondrial membrane potential (MMP). We performed quantitative real-time polymerase chain reaction and Western blotting analyses of autophagy and mitophagy-related markers, including HIF1α, ATG5, pBECN1, BECN1, BAX, BNIP3L, DAPK1, and PINK1. Finally, FACS analysis with specific fluorescence-conjugated antibodies was performed to evaluate the potential cellular origin of CSF mitochondrial cells. Twenty-seven females (62.8%) with a mean age of 47.4 ± 9.7 years were included in the study. Among 43 patients with hemorrhagic MMD, 23 (53.5%) had poor outcomes. The difference in MMP was evident between the two groups (2.4 ± 0.2 in patients with poor outcome vs. 3.5 ± 0.4 in patients with good outcome; p = 0.02). A significantly higher expression (2–ΔCt) of HIF1α, ATG5, DAPK1 followed by BAX and BNIP3L mRNA and protein was also observed in poor-outcome patients compared to those with good outcomes. Higher percentage of vWF-positive mitochondria, suggesting endothelial cell origins, was observed in patients with good outcome compared with those with poor outcome (25.0 ± 1.4% in patients with good outcome vs. 17.5 ± 1.5% in those with poor outcome; p < 0.01). We observed the association between increased mitochondrial dysfunction concomitant with autophagy and mitophagy in CSF cells and neurological outcomes in adult patients with hemorrhagic MMD. Further prospective multicenter studies are needed to determine whether it has a diagnostic value for risk prediction. [ABSTRACT FROM AUTHOR]

There are no effective treatments for relieving neuronal dysfunction after mild traumatic brain injury (TBI). Here, we evaluated therapeutic efficacy of human embryonic stem cell-derived cerebral organoids (hCOs) in a mild TBI model, in terms of repair of damaged cortical regions, neurogenesis, and improved cognitive function. Male C57BL/6 J mice were randomly divided into sham-operated, mild TBI, and mild TBI with hCO groups. hCOs cultured at 8 weeks were used for transplantation. Mice were sacrificed at 7 and 14 days after transplantation followed by immunofluorescence staining, cytokine profile microarray, and novel object recognition test. 8W-hCOs transplantation significantly reduced neuronal cell death, recovered microvessel density, and promoted neurogenesis in the ipsilateral subventricular zone and dentate gyrus of hippocampus after mild TBI. In addition, increased angiogenesis into the engrafted hCOs was observed. Microarray results of hCOs revealed neuronal differentiation potential and higher expression of early brain development proteins associated with neurogenesis, angiogenesis and extracellular matrix remodeling. Ultimately, 8W-hCO transplantation resulted in reconstruction of damaged cortex and improvement in cognitive function after mild TBI. hCO transplantation may be feasible for treating mild TBI-related neuronal dysfunction via reconstruction of damaged cortex and neurogenesis in the hippocampus. • Cerebral organoids (COs) consist of early neural cells that make up the brain. • COs at 8weeks was considered to be an appropriate time point for mild TBI. • Transplantation of COs could restore cognitive function after TBI. [ABSTRACT FROM AUTHOR]

Object. We aimed to investigate the association of Haptoglobin (Hp) phenotypes with perihematomal edema (PHE) and neurological outcomes after intracerebral hemorrhage (ICH). Methods. This prospective multicenter study enrolled patients that suffered ICH from March 2017 to February 2020. Hp phenotypes were determined using Western blotting; relative α1 intensity was calculated in patients with Hp2-1. A multivariable logistic regression analysis was then conducted to identify risk factors for increased relative PHE at 96 h and 3-month poor outcomes. Results. In total, 120 patients were ultimately enrolled: Hp1-1 (n = 15, 12.5%); Hp2-1 (n = 51, 42.5%); and Hp2-2 (n = 54, 45.0%). Hp phenotype was significantly associated with PHE (p = 0.028). With Hp1-1 as a reference value, Hp2-2 significantly increased the likelihood of increased rPHE (OR = 6.294, 95% CI: 1.283–30.881), while Hp2-1 did not (OR = 2.843, 95% CI: 0.566–14.284). Poor outcomes were found to be closely associated with hematoma volume at admission (OR = 1.057, 95% CI: 1.015–1.101) and surgical treatment (OR = 5.340, 95% CI: 1.665–17.122) but not Hp phenotypes (p = 0.190). Further, a high level of relative α1 intensity was identified to be significantly associated with decreased rPHE (OR = 0.020, 95% CI: 0.001–0.358). However, the relative α1 intensity was not associated with poor outcomes (OR = 0.057, 95% CI: 0.001–11.790). Conclusions: ICH patients with Hp2-2 exhibited a higher likelihood of increased rPHE than those with Hp1-1. Higher relative α1 intensities were identified to be closely associated with rPHE in patients with Hp2-1. [ABSTRACT FROM AUTHOR]

Polygenic risk scores (PRSs) have an important relevance to approaches for clinical usage in intracranial aneurysm (IA) patients. Hence, we aimed to develop IA-predicting PRS models including the genetic basis shared with acute ischemic stroke (AIS) in Korean populations. We applied a weighted PRS (wPRS) model based on a previous genome-wide association study (GWAS) of 250 IA patients in a hospital-based multicenter cohort, 222 AIS patients in a validation study, and 296 shared controls. Risk predictability was analyzed by the area under the receiver operating characteristic curve (AUROC). The best-fitting risk models based on wPRSs were stratified into tertiles representing the lowest, middle, and highest risk groups. The weighted PRS, which included 29 GWASs (p < 5×10−8) and two reported genetic variants (p < 0.01), showed a high predictability in IA patients (AUROC = 0.949, 95% CI: 0.933–0.966). This wPRS was significantly validated in AIS patients (AUROC = 0.842, 95% CI: 0.808–0.876; p < 0.001). Two-stage risk models stratified into tertiles showed an increased risk for IA (OR = 691.25, 95% CI: 241.77–1976.35; p = 3.1×10−34; sensitivity/specificity = 0.728/0.963), which was replicated in AIS development (OR = 39.76, 95% CI: 16.91–93.49; p = 3.1×10−17; sensitivity/specificity = 0.284/0.963). A higher wPRS for IA may be associated with an increased risk of AIS in the Korean population. These findings suggest that IA and AIS may have a shared genetic architecture and should be studied further to generate a precision medicine model for use in personalized diagnosis and treatment. [ABSTRACT FROM AUTHOR]

In addition to conventional genome-wide association studies (GWAS), a fine-mapping analysis is increasingly used to identify the genetic function of variants associated with disease susceptibilities. Here, we used a fine-mapping approach to evaluate candidate variants based on a previous GWAS involving patients with intracranial aneurysm (IA). A fine-mapping analysis was conducted based on the chromosomal data provided by a GWAS of 250 patients diagnosed with IA and 296 controls using posterior inclusion probability (PIP) and log10 transformed Bayes factor (log10BF). The narrow sense of heritability (h2) explained by each candidate variant was estimated. Subsequent gene expression and functional network analyses of candidate genes were used to calculate transcripts per million (TPM) values. Twenty single-nucleotide polymorphisms (SNPs) surpassed a genome-wide significance threshold for creditable evidence (log10BF > 6.1). Among them, four SNPs, rs75822236 (GBA; log10BF = 15.06), rs112859779 (TCF24; log10BF = 12.12), rs79134766 (OLFML2A; log10BF = 14.92), and rs371331393 (ARHGAP32; log10BF = 20.88) showed a completed PIP value in each chromosomal region, suggesting a higher probability of functional candidate variants associated with IA. On the contrary, these associations were not shown clearly under different replication sets. Our fine-mapping analysis suggested that four functional candidate variants of GBA, TCF24, OLFML2A, and ARHGAP32 were linked to IA susceptibility and pathogenesis. However, this approach could not completely replace replication sets based on large-scale data. Thus, caution is required when interpreting results of fine-mapping analysis. [ABSTRACT FROM AUTHOR]

Decreased mitochondrial membrane potential in cerebrospinal fluid (CSF) was observed in patients with subarachnoid hemorrhage (SAH) accompanied by delayed cerebral ischemia (DCI). However, whether abnormal mechanisms of mitochondria are associated with the development of DCI has not been reported yet. Under cerebral ischemia, mitochondria can transfer into the extracellular space. Mitochondrial dysfunction can aggravate neurologic complications. The objective of this study was to evaluate whether mitochondrial dysfunction might be associated with autophagy and mitophagy in CSF cells to provide possible insight into DCI pathogenesis. CSF samples were collected from 56 SAH patients (DCI, n = 21; and non-DCI, n = 35). We analyzed CSF cells using autophagy and mitophagy markers (DAPK1, BNIP3L, BAX, PINK1, ULK1, and NDP52) via qRT-PCR and western blotting of proteins (BECN1, LC3, and p62). Confocal microscopy and immunogold staining were performed to demonstrate the differentially expression of markers within dysfunctional mitochondria. Significant induction of autophagic flux with accumulation of autophagic vacuoles, increased expression of BECN1, LC3-II, and p62 degradation were observed during DCI. Compared to non-DCI patients, DCI patients showed significantly increased mRNA expression levels (2−ΔCt) of DAPK1, BNIP3L, and PINK1, but not BAX, ULK1, or NDP52. Multivariable logistic regression analysis revealed that Hunt and Hess grade ≥ IV (p = 0.023), DAPK1 (p = 0.003), and BNIP3L (p = 0.039) were related to DCI. Increased mitochondrial dysfunction associated with autophagy and mitophagy could play an important role in DCI pathogenesis. [ABSTRACT FROM AUTHOR]

Auto-detection of cerebral aneurysms via convolutional neural network (CNN) is being increasingly reported. However, few studies to date have accurately predicted the risk, but not the diagnosis itself. We developed a multi-view CNN for the prediction of rupture risk involving small unruptured intracranial aneurysms (UIAs) based on three-dimensional (3D) digital subtraction angiography (DSA). The performance of a multi-view CNN-ResNet50 in accurately predicting the rupture risk (high vs. non-high) of UIAs in the anterior circulation measuring less than 7 mm in size was compared with various CNN architectures (AlexNet and VGG16), with similar type but different layers (ResNet101 and ResNet152), and single image-based CNN (single-view ResNet50). The sensitivity, specificity, and overall accuracy of risk prediction were estimated and compared according to CNN architecture. The study included 364 UIAs in training and 93 in test datasets. A multi-view CNN-ResNet50 exhibited a sensitivity of 81.82 (66.76–91.29)%, a specificity of 81.63 (67.50–90.76)%, and an overall accuracy of 81.72 (66.98–90.92)% for risk prediction. AlexNet, VGG16, ResNet101, ResNet152, and single-view CNN-ResNet50 showed similar specificity. However, the sensitivity and overall accuracy were decreased (AlexNet, 63.64% and 76.34%; VGG16, 68.18% and 74.19%; ResNet101, 68.18% and 73.12%; ResNet152, 54.55% and 72.04%; and single-view CNN-ResNet50, 50.00% and 64.52%) compared with multi-view CNN-ResNet50. Regarding F1 score, it was the highest in multi-view CNN-ResNet50 (80.90 (67.29–91.81)%). Our study suggests that multi-view CNN-ResNet50 may be feasible to assess the rupture risk in small-sized UIAs. [ABSTRACT FROM AUTHOR]

Little is known about the epigenetic changes associated with delayed cerebral ischemia (DCI) pathogenesis after subarachnoid hemorrhage (SAH). Here, we investigated genome-wide DNA methylation profiles specifically associated with DCI, which is a major contributor to poor clinical outcomes. An epigenome-wide association study (EWAS) and quantitative real-time PCR (qRT-PCR) were conducted in 40 SAH patients (DCI, n = 13; non-DCI, n = 27). A replication study using bisulfite modification and methylation-specific PCR was further performed in 36 patients (DCI, n = 12; non-DCI, n = 24). The relative degree of methylation was described as the median and 25th–75th percentile. No significant differences in clinical characteristics between DCI and non-DCI groups were observed. Among the top 10 differentially methylated genes analyzed via EWAS, two aberrantly methylated CpG sites of cg00441765 (INSR gene) and cg11464053 (CDHR5 gene) were associated with decreased mRNA expression (2−ΔCt). They include INSR [0.00020 (0.00012–0.00030) in DCI vs. 0.00050 (0.00030–0.00068) in non-DCI] and CDHR5 [0.114 (0.053–0.143) in DCI vs. 0.170 (0.110–0.212) in non-DCI]. Compared with non-DCI cases, patients with DCI exhibited an increased degree of methylation in the replication study: INSR, 0.855 (0.779–0.913) in DCI vs. 0.582 (0.565–0.689) in non-DCI; CDHR5, 0.786 (0.708–0.904) in DCI vs. 0.632 (0.610–0.679) in non-DCI. Hypermethylation of two novel genes, INSR and CDHR5 may serve as a biomarker for early detection of DCI following SAH. [ABSTRACT FROM AUTHOR]

Objectives: To estimate long-term durability in coiled aneurysms completely occluded at 6-month follow-up imaging, focusing on late recanalization rate and the risk factors involved.Methods: A cohort of 620 patients harbouring 698 completely occluded coiled aneurysms at 6-month follow-up was subjected to extended monitoring (mean, 24.5 ± 7.9 months). Cumulative recanalization rate and related risk factors were analysed using Cox proportional hazards regression and Kaplan-Meier product-limit estimator.Results: Forty-three aneurysms (6.2 %) occluded completely at 6-months displayed recanalization (3.02 % per aneurysm-year) during continued surveillance (1425.5 aneurysm-years), with 26 (60.5 %) surfacing in another 6 months, 15 (34.9 %) within 18 months and 2 (4.6 %) within 30 months. Cumulative survival rates without recanalization were significantly lower in subjects with aneurysms >7 mm (p = 0.014), with bifurcation aneurysms (p = 0.009) and with subarachnoid haemorrhage (SAH) at presentation (p < 0.001). Multivariate analysis indicated that aneurysms >7 mm (HR = 2.37, p = 0.02) and bifurcation aneurysms (HR = 2.70, p = 0.03) were significant factors in late recanalization, whereas a link with SAH at presentation was marginal (HR = 1.92, p = 0.06) and stent placement fell short of statistical significance (HR = 0.47; p = 0.12).Conclusion: Most (93.8 %) coiled aneurysms showing complete occlusion at 6 months post-procedure were stable in long-term monitoring. However, aneurysms >7 mm and bifurcation aneurysms were predisposed to late recanalization.Key Points: • Most coiled aneurysms showing complete occlusion at 6 months were stable. • Forty-three aneurysms (6.2 %) occluded completely at 6-month follow-up displayed late recanalization. • Late recanalization rate was 3.02 % per aneurysm-year during follow-up of 1425.5 aneurysm-years. • Aneurysms over 7 mm and bifurcation aneurysms were predisposed to late recanalization. [ABSTRACT FROM AUTHOR]