Identifying novel risk genes in intracranial aneurysm by integrating human proteomes and genetics.

Genome-wide association studies (GWAS) have become increasingly popular for detecting numerous loci associated with intracranial aneurysm (IA), but how these loci function remains unclear. In this study, we employed an integrative analytical pipeline to efficiently transform genetic associations and identify novel genes for IA. Using multidimensional high-throughput data, we integrated proteome-wide association studies (PWAS), transcriptome-wide association studies (TWAS), Mendelian randomization (MR) and Bayesian co-localization analyses to prioritize genes that can increase IA risk by altering their expression and protein abundances in the brain and blood. Moreover, single-cell RNA sequencing (scRNA-seq) of the circle of Willis was performed to enrich filtered genes in cells, and gene set enrichment analysis (GSEA) was conducted for each gene using bulk RNA-seq data for IA. No significant genes with cis-regulated plasma protein levels were proven to be associated with IA. The protein abundances of five genes in the brain were found to be associated with IA. According to cellular enrichment analysis, these five genes were expressed mainly in the endothelium, fibroblasts and vascular smooth muscle cells. Only three genes, CNNM2, GPRIN3 and UFL1, passed MR and Bayesian co-localization analyses. While UFL1 was not validated in confirmation PWAS as it was not profiled, it was validated in TWAS. GSEA suggested these three genes are associated with the cell cycle. In addition, the protein abundance of CNNM2 was found to be associated with IA rupture (based on PWAS, MR and co-localization analyses). Our findings indicated that CNNM2, GPRIN3 and UFL1 (CNNM2 correlated with IA rupture) are potential IA risk genes that may provide a broad hint for future research on possible mechanisms and therapeutic targets for IA.

Cigarette Smoking and Observed Growth of Unruptured Intracranial Aneurysms: A Systematic Literature Review and Meta-Analysis.

BACKGROUND: Smoking and observed growth of intracranial aneurysms are known risk factors for rupture. The mechanism by which smoking increases this risk is not completely elucidated. Furthermore, an association between smoking and aneurysm growth has not been clearly defined in the literature. We hypothesize that smoking is associated with aneurysm growth, which, in turn, may serve as one of the mechanisms by which smoking drives rupture risk. METHODS: We report a systematic review of the literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Using the R software, we performed a meta-analysis to investigate the association between smoking and the growth of unruptured intracranial aneurysms. Studies on familial aneurysms and genetic syndromes known to increase the risk of aneurysms were excluded. RESULTS: Eighteen observational studies were included with a total of 3535 patients and 4289 aneurysms with a mean follow-up period ranging from 17 to 226 months. The mean age among the studies ranged from 38.4 to 73.9 years; 74% of patients were female. Ever-smoking status (odds ratio, 1.10 [95% CI, 0.87-1.38]) and current smoking status (odds ratio, 1.43 [95% CI, 0.84-2.43]) did not show a statistically significant association with growth of intracranial aneurysms. Patients currently smoking did not have a statistically significant association with the growth of intracranial aneurysms (odds ratio, 1.18 [95% CI, 0.72-1.93]) compared with patients without a smoking history. No significant association was found in patients who previously smoked compared with patients who never smoked (odds ratio, 1.46 [95% CI, 0.88-2.43]). CONCLUSIONS: Smoking is not clearly associated with the growth of unruptured intracranial aneurysms, despite trends being observed, there is no statistical association. The mechanism by which smoking increases rupture risk might not be growth. In patients for whom observation is recommended, the absence of growth over time in the setting of smoking history does not, therefore, imply protection from rupture.

ARISE I Consensus Review on the Management of Intracranial Aneurysms.

BACKGROUND: Intracranial aneurysms (IAs) remain a challenging neurological diagnosis associated with significant morbidity and mortality. There is a plethora of microsurgical and endovascular techniques for the treatment of both ruptured and unruptured aneurysms. There is no definitive consensus as to the best treatment option for this cerebrovascular pathology. The Aneurysm, Arteriovenous Malformation, and Chronic Subdural Hematoma Roundtable Discussion With Industry and Stroke Experts discussed best practices and the most promising approaches to improve the management of brain aneurysms. METHODS: A group of experts from academia, industry, and federal regulators convened to discuss updated clinical trials, scientific research on preclinical system models, management options, screening and monitoring, and promising novel device technologies, aiming to improve the outcomes of patients with IA. RESULTS: Aneurysm, Arteriovenous Malformation, and Chronic Subdural Hematoma Roundtable Discussion With Industry and Stroke Experts suggested the incorporation of artificial intelligence to capture sequential aneurysm growth, identify predictors of rupture, and predict the risk of rupture to guide treatment options. The consensus strongly recommended nationwide systemic data collection of unruptured IA radiographic images for the analysis and development of machine learning algorithms for rupture risk. The consensus supported centers of excellence for preclinical multicenter trials in areas such as genetics, cellular composition, and radiogenomics. Optical coherence tomography and magnetic resonance imaging contrast-enhanced 3T vessel wall imaging are promising technologies; however, more data are needed to define their role in IA management. Ruptured aneurysms are best managed at large volume centers, which should include comprehensive patient management with expertise in microsurgery, endovascular surgery, neurology, and neurocritical care. CONCLUSIONS: Clinical and preclinical studies and scientific research on IA should engage high-volume centers and be conducted in multicenter collaborative efforts. The future of IA diagnosis and monitoring could be enhanced by the incorporation of artificial intelligence and national radiographic and biologic registries. A collaborative effort between academic centers, government regulators, and the device industry is paramount for the adequate management of IA and the advancement of the field.

Higher Risk of Mental Illness in Patients With Diagnosed and Untreated Unruptured Intracranial Aneurysm: Findings From a Nationwide Cohort Study.

BACKGROUND: We aimed to investigate the association between a diagnosis of untreated unruptured intracranial aneurysms (UIAs) and the development of mental illness. METHODS: This retrospective, propensity-score-matched cohort study was based on the nationwide South Korean database. The UIA diagnosis group included participants newly diagnosed with UIA between 2011 and 2019. For a well-matched control group, patients diagnosed with an acute upper respiratory infection but without UIA during the same period were selected through 1:4 matching based on propensity scores, which were calculated using age, sex, economic status, and comorbidities. The study's outcome measure encompassed the incidence of mental illnesses over a 10-year period, using International Classification of Diseases-Tenth Revision codes for anxiety, stress, depressive, bipolar, and eating disorders, insomnia, and alcohol or drug misuse. RESULTS: After propensity score matching, 85 438 participants with untreated UIAs (50.75% male; average age, 56.41 [±13.82] years; follow-up, 4.21 [±2.56] years) and 331 123 controls (49.44% males; average age, 56.69 [±12.92] years; follow-up, 7.48 [±2.12] years) were compared. Incidence rate of mental illness was higher in the UIA group (113.07 versus 90.41 per 1000 person-years; hazard ratio, 1.104 [95% CI, 1.089-1.119]). The risk of mental illness varied slightly by sex (males: hazard ratio, 1.131 [95% CI, 1.108-1.155]; females: hazard ratio, 1.082 [95% CI, 1.063-1.103]). Hazard ratios showed a U-shaped relationship with age, peaking in younger age groups, decreasing in middle-aged groups, and slightly increasing in older age groups, especially in patients with severe mental illness receiving psychotherapy. CONCLUSIONS: Our findings indicate a higher risk of mental illness in patients with UIA diagnosis in specific demographic groups, suggesting a possible psychological burden associated with UIAs. Clinicians treating cerebral aneurysms should be aware that the psychological burden caused by the diagnosis of UIA itself could contribute to mental illness and strive to provide comprehensive care for these patients.

Multiomics integrated analysis and experimental validation identify TLR4 and ALOX5 as oxidative stress-related biomarkers in intracranial aneurysms.

BACKGROUND: Intracranial aneurysm (IA) is a severe cerebrovascular disease, and effective gene therapy and drug interventions for its treatment are still lacking. Oxidative stress (OS) is closely associated with the IA, but the key regulatory genes involved are still unclear. Through multiomics analysis and experimental validation, we identified two diagnostic markers for IA associated with OS. METHODS: In this study, we first analyzed the IA dataset GSE75436 and conducted a joint analysis of oxidative stress-related genes (ORGs). Differential analysis, functional enrichment analysis, immune infiltration, WGCNA, PPI, LASSO, and other methods were used to identify IA diagnostic markers related to OS. Next, the functions of TLR4 and ALOX5 expression in IA and their potential targeted therapeutic drugs were analyzed. We also performed single-cell sequencing of patient IA and control (superficial temporal artery, STA) tissues. 23,342 cells were captured from 2 IA and 3 STA samples obtained from our center. Cell clustering and annotation were conducted using R software to observe the distribution of TLR4 and ALOX5 expression in IAs. Finally, the expression of TLR4 and ALOX5 were validated in IA patients and in an elastase-induced mouse IA model using experiments such as WB and immunofluorescence. RESULTS: Through bioinformatics analysis, we identified 16 key ORGs associated with IA pathogenesis. Further screening revealed that ALOX5 and TLR4 were highly expressed to activate a series of inflammatory responses and reduce the production of myocytes. Methotrexate (MTX) may be a potential targeted drug. Single-cell analysis revealed a notable increase in immune cells in the IA group, with ALOX5 and TLR4 primarily localized to monocytes/macrophages. Validation through patient samples and mouse models confirmed high expression of ALOX5 and TLR4 in IAs. CONCLUSIONS: Bioinformatics analysis indicated that ALOX5 and TLR4 are the most significant ORGs associated with the pathogenesis of IA. Single-cell sequencing and experiments revealed that the high expression of ALOX5 and TLR4 are closely related to IA. These two genes are promising new targets for IA therapy.

Nanoarchitectonic Engineering of Thermal-Responsive Magnetic Nanorobot Collectives for Intracranial Aneurysm Therapy.

Stent-assisted coiling is a main treatment modality for intracranial aneurysms (IAs) in clinics, but critical challenges remain to be overcome, such as exogenous implant-induced stenosis and reliance on antiplatelet agents. Herein, an endovascular approach is reported for IA therapy without stent grafting or microcatheter shaping, enabled by active delivery of thrombin (Th) to target aneurysms using innovative phase-change material (PCM)-coated magnetite-thrombin (Fe3O4-Th@PCM) FTP nanorobots. The nanorobots are controlled by an integrated actuation system of dynamic torque-force hybrid magnetic fields. With robust intravascular navigation guided by real-time ultrasound imaging, nanorobotic collectives can effectively accumulate and retain in model aneurysms constructed in vivo, followed by controlled release of the encapsulated Th for rapid occlusion of the aneurysm upon melting the protective PCM (thermally responsive in a tunable manner) through focused magnetic hyperthermia. Complete and stable aneurysm embolization is confirmed by postoperative examination and 2-week postembolization follow-up using digital subtraction angiography (DSA), contrast-enhanced ultrasound (CEUS), and histological analysis. The safety of the embolization therapy is assessed through biocompatibility evaluation and histopathology assays. This strategy, seamlessly integrating secure drug packaging, agile magnetic actuation, and clinical interventional imaging, avoids possible exogenous implant rejection, circumvents cumbersome microcatheter shaping, and offers a promising option for IA therapy.

The SNHG12/microRNA-15b-5p/MYLK axis regulates vascular smooth muscle cell phenotype to affect intracranial aneurysm formation.

OBJECTIVE: This research was dedicated to investigating the impact of the SNHG12/microRNA (miR)-15b-5p/MYLK axis on the modulation of vascular smooth muscle cell (VSMC) phenotype and the formation of intracranial aneurysm (IA). METHODS: SNHG12, miR-15b-5p and MYLK expression in IA tissue samples from IA patients were tested by RT-qPCR and western blot. Human aortic vascular smooth muscle cells (VSMCs) were cultivated with H2O2 to mimic IA-like conditions in vitro, and the cell proliferation and apoptosis were measured by MTT assay and Annexin V/PI staining. IA mouse models were established by induction with systemic hypertension combined with elastase injection. The blood pressure in the tail artery of mice in each group was assessed and the pathological changes in arterial tissues were observed by HE staining and TUNEL staining. The expression of TNF-α and IL-1ß, MCP-1, iNOS, caspase-3, and caspase-9 in the arterial tissues were tested by RT-qPCR and ELISA. The relationship among SNHG12, miR-15b-5p and MYLK was verified by bioinformatics, RIP, RNA pull-down, and luciferase reporter assays. RESULTS: The expression levels of MYLK and SNHG12 were down-regulated and that of miR-15b-5p was up-regulated in IA tissues and H2O2-treated human aortic VSMCs. Overexpressed MYLK or SNHG12 mitigated the decrease in proliferation and increase in apoptosis of VSMCs caused by H2O2 induction, and overexpression of miR-15b-5p exacerbated the decrease in proliferation and increase in apoptosis of VSMCs caused by H2O2 induction. Overexpression of miR-15b-5p reversed the H2O2-treated VSMC phenotypic changes caused by SNHG12 up-regulation, and overexpression of MYLK reversed the H2O2-treated VSMC phenotypic changes caused by up-regulation of miR-15b-5p. Overexpression of SNHG12 reduced blood pressure and ameliorated arterial histopathological damage and VSMC apoptosis in IA mice. The mechanical analysis uncovered that SNHG12 acted as an endogenous RNA that competed with miR-15b-5p, thus modulating the suppression of its endogenous target, MYLK. CONCLUSION: Decreased expression of SNHG12 in IA may contribute to the increasing VSMC apoptosis via increasing miR-15b-5p expression and subsequently decreasing MYLK expression. These findings provide potential new strategies for the clinical treatment of IA.

Hemodynamic Parameters in the Parent Arteries of Unruptured Intracranial Aneurysms Depend on Aneurysm Size and Are Different Compared to Contralateral Arteries: A 7 Tesla 4D Flow MRI Study.

BACKGROUND: Different Circle of Willis (CoW) variants have variable prevalences of aneurysm development, but the hemodynamic variation along the CoW and its relation to presence and size of unruptured intracranial aneurysms (UIAs) are not well known. PURPOSE: Gain insight into hemodynamic imaging markers of the CoW for UIA development by comparing these outcomes to the corresponding contralateral artery without an UIA using 4D flow magnetic resonance imaging (MRI). STUDY TYPE: Retrospective, cross-sectional study. SUBJECTS: Thirty-eight patients with an UIA, whereby 27 were women and a mean age of 62 years old. FIELD STRENGTH/SEQUENCE: Four-dimensional phase-contrast (PC) MRI with a 3D time-resolved velocity encoded gradient echo sequence at 7 T. ASSESSMENT: Hemodynamic parameters (blood flow, velocity pulsatility index [vPI], mean velocity, distensibility, and wall shear stress [peak systolic (WSSMAX ), and time-averaged (WSSMEAN )]) in the parent artery of the UIA were compared to the corresponding contralateral artery without an UIA and were related to UIA size. STATISTICAL TESTS: Paired t-tests and Pearson Correlation tests. The threshold for statistical significance was P < 0.05 (two-tailed). RESULTS: Blood flow, mean velocity, WSSMAX , and WSSMEAN were significantly higher, while vPI was lower, in the parent artery relative to contralateral artery. The WSSMAX of the parent artery significantly increased linearly while the WSSMEAN decreased linearly with increasing UIA size. CONCLUSIONS: Hemodynamic parameters and WSS differ between parent vessels of UIAs and corresponding contralateral vessels. WSS correlates with UIA size, supporting a potential hemodynamic role in aneurysm pathology. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Enhanced vessel wall magnetic resonance imaging in the follow-up of intracranial aneurysms treated with flow diversion.

OBJECTIVE: This study aimed to compare the efficacy of enhanced 3D T1-weighted black-blood fast-spin-echo vessel wall magnetic resonance imaging (eVW-MRI) and time-of-flight magnetic resonance angiography (TOF MRA) for follow-up evaluation of aneurysms treated with flow diversion (FD). METHODS: Our study enrolled 77 patients harboring 84 aneurysms treated with FD. Follow-up was by MRI (eVW-MRI and TOF MRA) and digital subtraction angiography (DSA). Two radiologists, blinded to DSA examination results, independently evaluated the images of aneurysm occlusion and parent artery patency using the Kamran-Byrne Scale. Interobserver diagnostic agreement and intermodality diagnostic agreement were acquired. Pretreatment and follow-up aneurysm wall enhancement (AWE) patterns were collected. RESULTS: Based on the Kamran-Byrne Scale, the intermodality agreement between eVW-MRI and DSA was better than TOF MRA versus DSA for aneurysm remnant detection (weighted ĸ = 0.891 v. 0.553) and parent artery patency (ĸ = 0.950 v. 0.221). Even with the coil artifact, the consistency of eVW-MRI with DSA for aneurysm remnant detection was better than that of TOF MRA (weighted ĸ = 0.891 v. 0.511). The artifact of adjunctive coils might be more likely to affect the accuracy in evaluating parent artery patency with TOF MRA than with eVW-MRI (ĸ = 0.077 v. 0.788). The follow-up AWE patterns were not significantly associated with pretreatment AWE patterns and aneurysm occlusion. CONCLUSIONS: The eVW-MRI outperforms TOF MRA as a reliable noninvasive and nonionizing radioactive imaging method for evaluating aneurysm remnants and parent artery patency after FD. The significance of enhancement patterns on eVW-MRI sequences needs more exploration. CLINICAL RELEVANCE STATEMENT: The application of enhanced vessel wall magnetic resonance imaging has proven to be a promising tool to depict aneurysm remnant and parent artery stenosis in order to tailor the antiplatelet therapy strategy in patients after flow diversion. KEY POINTS: • Enhanced vessel wall magnetic resonance imaging has an emerging role in depicting aneurysm remnant and parent artery patency after flow diversion. • With or without the artifact from adjunctive coils, enhanced vessel wall magnetic resonance imaging was better than TOF MRA in detecting aneurysm residual and parent artery stenosis by using DSA imaging as the standard. • Enhanced vessel wall magnetic resonance imaging holds potential to be used as an alternative to DSA for routine aneurysm follow-up after flow diversion.

Gadolinium-enhanced intracranial aneurysm wall imaging and risk of aneurysm growth and rupture: a multicentre longitudinal cohort study.

OBJECTIVES: In patients with an unruptured intracranial aneurysm, gadolinium enhancement of the aneurysm wall is associated with growth and rupture. However, most previous studies did not have a longitudinal design and did not adjust for aneurysm size, which is the main predictor of aneurysm instability and the most important determinant of wall enhancement. We investigated whether aneurysm wall enhancement predicts aneurysm growth and rupture during follow-up and whether the predictive value was independent of aneurysm size. MATERIALS AND METHODS: In this multicentre longitudinal cohort study, individual patient data were obtained from twelve international cohorts. Inclusion criteria were as follows: 18 years or older with ≥ 1 untreated unruptured intracranial aneurysm < 15 mm; gadolinium-enhanced aneurysm wall imaging and MRA at baseline; and MRA or rupture during follow-up. Patients were included between November 2012 and November 2019. We calculated crude hazard ratios with 95%CI of aneurysm wall enhancement for growth (≥ 1 mm increase) or rupture and adjusted for aneurysm size. RESULTS: In 455 patients (mean age (SD), 60 (13) years; 323 (71%) women) with 559 aneurysms, growth or rupture occurred in 13/194 (6.7%) aneurysms with wall enhancement and in 9/365 (2.5%) aneurysms without enhancement (crude hazard ratio 3.1 [95%CI: 1.3-7.4], adjusted hazard ratio 1.4 [95%CI: 0.5-3.7]) with a median follow-up duration of 1.2 years. CONCLUSIONS: Gadolinium enhancement of the aneurysm wall predicts aneurysm growth or rupture during short-term follow-up, but not independent of aneurysm size. CLINICAL RELEVANCE STATEMENT: Gadolinium-enhanced aneurysm wall imaging is not recommended for short-term prediction of growth and rupture, since it appears to have no additional value to conventional predictors. KEY POINTS: • Although aneurysm wall enhancement is associated with aneurysm instability in cross-sectional studies, it remains unknown whether it predicts risk of aneurysm growth or rupture in longitudinal studies. • Gadolinium enhancement of the aneurysm wall predicts aneurysm growth or rupture during short-term follow-up, but not when adjusting for aneurysm size. • While gadolinium-enhanced aneurysm wall imaging is not recommended for short-term prediction of growth and rupture, it may hold potential for aneurysms smaller than 7 mm.

Wall permeability on magnetic resonance imaging is associated with intracranial aneurysm symptoms and wall enhancement.

OBJECTIVES: Wall remodeling and inflammation accompany symptomatic unruptured intracranial aneurysms (UIAs). The volume transfer constant (Ktrans) of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) reflects UIA wall permeability. Aneurysmal wall enhancement (AWE) on vessel wall MRI (VWI) is associated with inflammation. We hypothesized that Ktrans is related to symptomatic UIAs and AWE. METHODS: Consecutive patients with UIAs were prospectively recruited for 3-T DCE-MRI and VWI from January 2018 to March 2023. UIAs were classified as asymptomatic and symptomatic if associated with sentinel headache or oculomotor nerve palsy. Ktrans and AWE were assessed on DCE-MRI and VWI, respectively. AWE was evaluated using the AWE pattern and wall enhancement index (WEI). Spearman's correlation coefficient and univariate and multivariate analyses were used to assess correlations between parameters. RESULTS: We enrolled 82 patients with 100 UIAs (28 symptomatic and 72 asymptomatic). The median Ktrans (2.1 versus 0.4 min-1; p < 0.001) and WEI (1.5 versus 0.4; p < 0.001) were higher for symptomatic aneurysms than for asymptomatic aneurysms. Ktrans (odds ratio [OR]: 1.60, 95% confidence interval [95% CI]: 1.01-2.52; p = 0.04) and WEI (OR: 3.31, 95% CI: 1.05-10.42; p = 0.04) were independent risk factors for symptomatic aneurysms. Ktrans was positively correlated with WEI (Spearman's coefficient of rank correlation (rs) = 0.41, p < 0.001). The combination of Ktrans and WEI achieved an area under the curve of 0.81 for differentiating symptomatic from asymptomatic aneurysms. CONCLUSIONS: Ktrans may be correlated with symptomatic aneurysms and AWE. Ktrans and WEI may provide an additional value than the PHASES score for risk stratification of UIAs. CLINICAL RELEVANCE STATEMENT: The volume transfer constant (Ktrans) from DCE-MRI perfusion is associated with symptomatic aneurysms and provides additional value above the clinical PHASES score for risk stratification of intracranial aneurysms. KEY POINTS: • The volume transfer constant is correlated with intracranial aneurysm symptoms and aneurysmal wall enhancement. • Dynamic contrast-enhanced and vessel wall MRI facilitates understanding of the pathophysiological characteristics of intracranial aneurysm walls. • The volume transfer constant and wall enhancement index perform better than the traditional PHASES score in differentiating symptomatic aneurysms.

Optimizing timing for quantification of intracranial aneurysm enhancement: a multi-phase contrast-enhanced vessel wall MRI study.

OBJECTIVES: Aneurysm wall enhancement (AWE) on high-resolution contrast-enhanced vessel wall MRI (VWMRI) is an emerging biomarker for intracranial aneurysms (IAs) stability. Quantification methods of AWE in the literature, however, are variable. We aimed to determine the optimal post-contrast timing to quantify AWE in both saccular and fusiform IAs. MATERIALS AND METHODS: Consecutive patients with unruptured IAs were prospectively recruited. VWMRI was acquired on 1 pre-contrast and 4 consecutive post-contrast phases (each phase was 9 min). Signal intensity values of cerebrospinal fluid (CSF) and aneurysm wall on pre- and 4 post-contrast phases were measured to determine the aneurysm wall enhancement index (WEI). AWE was also qualitatively analyzed on post-contrast images using previous grading criteria. The dynamic changes of AWE grade and WEI were analyzed for both saccular and fusiform IAs. RESULTS: Thirty-four patients with 42 IAs (27 saccular IAs and 15 fusiform IAs) were included. The changes in AWE grade occurred in 8 (30%) saccular IAs and 6 (40%) in fusiform IAs during the 4 post-contrast phases. The WEI of fusiform IAs decreased 22.0% over time after contrast enhancement (p = 0.009), while the WEI of saccular IAs kept constant during the 4 post-contrast phases (p > 0.05). CONCLUSIONS: When performing quantitative analysis of AWE, acquiring post-contrast VWMRI immediately after contrast injection achieves the strongest AWE for fusiform IAs. While the AWE degree is stable for 36 min after contrast injection for saccular IAs. CLINICAL RELEVANCE STATEMENT: The standardization of imaging protocols and analysis methods for AWE will be helpful for imaging surveillance and further treatment decisions of patients with unruptured IAs. KEY POINTS: Imaging protocols and measurements of intracranial aneurysm wall enhancement are reported heterogeneously. Aneurysm wall enhancement for fusiform intracranial aneurysms (IAs) is strongest immediately post-contrast, and stable for 36 min for saccular IAs. Future multi-center studies should investigate aneurysm wall enhancement as an emerging marker of aneurysm growth and rupture.

Early and delayed blood-brain barrier permeability predicts delayed cerebral ischemia and outcomes following aneurysmal subarachnoid hemorrhage.

OBJECTIVES: This study aimed to monitor blood-brain barrier permeability within 24 h and during the delayed cerebral ischemia (DCI) time window (DCITW) spanning 4-14 days after aneurysmal subarachnoid hemorrhage (aSAH) and to investigate its correlation with both DCI occurrence and outcomes at three months. METHODS: A total of 128 patients were stratified based on the DCI occurrence and three-month modified Rankin scale scores. Comparison of Ktrans at admission (admission Ktrans) and during DCITW (DCITW Ktrans) was conducted between DCI and non-DCI groups, as well as between groups with good and poor outcomes. Changes in Ktrans were also analyzed. Multivariate logistic regression analysis was performed to identify independent predictors of DCI and poor outcomes. RESULTS: Admission Ktrans (0.58 ± 0.18 vs 0.47 ± 0.12, p = 0.002) and DCITW Ktrans (0.54 ± 0.19 vs 0.41 ± 0.14, p < 0.001) were significantly higher in the DCI group compared with the non-DCI group. Although both were higher in the poor outcome group than the good outcome group, the difference was not statistically significant at admission (0.53 ± 0.18 vs 0.49 ± 0.14, p = 0.198). Ktrans in the non-DCI group (0.47 ± 0.12 vs 0.41 ± 0.14, p = 0.004) and good outcome group (0.49 ± 0.14 vs 0.41 ± 0.14, p < 0.001) decreased significantly from the admission to DCITW. Multivariate analysis identified DCITW Ktrans and admission Ktrans as independent predictors of poor outcomes (OR = 1.73, 95%CI: 1.24-2.43, p = 0.001) and DCI (OR = 1.75, 95%CI: 1.25-2.44, p = 0.001), respectively. CONCLUSION: Elevated Ktrans at admission is associated with the occurrence of DCI. Continuous monitoring of Ktrans from admission to DCITW can accurately identify reversible and irreversible changes and can predict outcomes at 3 months. CLINICAL RELEVANCE STATEMENT: Ktrans measured with CT perfusion is a valuable tool for predicting both delayed cerebral ischemia and three-month outcomes following aneurysmal subarachnoid hemorrhage. Monitoring changes in Ktrans from admission to time window of delayed cerebral ischemia can guide treatment and management decisions for aneurysmal subarachnoid hemorrhage patients. KEY POINTS: • Ktrans measured at admission and during the delayed cerebral ischemia time window (4-14 days) holds distinct clinical significance following aneurysmal subarachnoid hemorrhage. • Admission Ktrans serves as a predictor for delayed cerebral ischemia, while continuous assessment of Ktrans from admission to the delayed cerebral ischemia time window can predict three-month outcomes. • Monitoring Ktrans at different stages improves instrumental in enhancing decision-making and treatment planning for patients with aneurysmal subarachnoid hemorrhage.

Scanxiety and quality of life around follow-up imaging in patients with unruptured intracranial aneurysms: a prospective cohort study.

OBJECTIVES: Patients with an unruptured intracranial aneurysm (UIA) may experience scanxiety around follow-up imaging. We studied the prevalence and temporal pattern of scanxiety, and compared quality of life (QoL) outcomes in patients with and without scanxiety. METHODS: We performed a prospective cohort study in a tertiary referral center in the Netherlands between October 2021 and November 2022. We sent questionnaires to patients ≥ 18 years old undergoing UIA follow-up imaging 4 weeks before (T1), immediately after (T2), and 6 weeks after the scan (T3) to assess health-related QoL (HRQoL) and emotional functioning. At T3, we also assessed scanxiety with a purpose-designed questionnaire. We compared differences in QoL outcomes between respondents with and without scanxiety using mixed models. RESULTS: Of 158 eligible patients, 106 (67%) participated (mean age 61 years ± 11 [standard deviation], 84 women). Sixty of the 91 respondents (66%) who completed the purpose-designed questionnaire experienced scanxiety. Of the 49 respondents who experienced scanxiety after the scan, it resolved in 22 (45%) within a day after receiving the radiology report. HRQoL did not differ between respondents with or without scanxiety. Emotional functioning was worse for respondents with scanxiety (mean Hospital Anxiety and Depression Scale sum score difference at T1, 3.6 [95% CI, 0.9-6.3]; T2, 4.1 [95% CI, 1.5-6.8]; and T3, 4.0 [95% CI, 1.5-6.5]). CONCLUSIONS: Two-thirds of the respondents experienced scanxiety around follow-up imaging, which often resolved within a day after receiving results. Patients with scanxiety had similar HRQoL but worse emotional functioning compared to patients without scanxiety. The time between the scan and receiving the results should be minimized to decrease the duration of scanxiety. CLINICAL RELEVANCE STATEMENT: We showed that scanxiety is common in UIA patients, and negatively associated with emotional functioning. Since scanxiety often disappears immediately after receiving the radiology report, it should be communicated to the patient as early as possible to alleviate patients' distress. KEY POINTS: • Many patients with an unruptured intracranial aneurysm experience emotional distress around follow-up imaging, termed "scanxiety." • Patients with scanxiety had worse emotional functioning compared to patients without scanxiety. • Scanxiety often resolved within a day after receiving the radiology report.

Intracranial arterial calcification in patients with unruptured and ruptured intracranial aneurysms.

OBJECTIVES: Arterial calcification is thought to protect against rupture of intracranial aneurysms, but studies in a representative population of intracranial aneurysm patients have not yet been performed. The aim was to compare the prevalence of aneurysm wall calcification and intracranial carotid artery calcification (ICAC) between patients with an unruptured intracranial aneurysm (UIA) and a ruptured intracranial aneurysm (RIA). MATERIALS AND METHODS: We matched 150 consecutive UIA patients to 150 RIA patients on age and sex. Aneurysm wall calcification and ICAC were quantified on non-contrast enhanced computed tomography images with the modified Agatston score. We compared the prevalence of aneurysm wall calcification, ICAC, and severe ICAC (defined as a modified Agatston score in the fourth quartile) between UIA and RIA patients using univariate and multivariate conditional logistic regression models adjusted for aneurysm characteristics and cardiovascular risk factors. RESULTS: Aneurysm wall calcification was more prevalent in UIA compared to RIA patients (OR 5.2, 95% CI: 2.0-13.8), which persisted after adjustment (OR 5.9, 95% CI: 1.7-20.2). ICAC prevalence did not differ between the two groups (crude OR 0.9, 95% CI: 0.5-1.8). Severe ICAC was more prevalent in UIA patients (OR 2.0, 95% CI: 1.1-3.6), but not after adjustment (OR 1.0, 95% CI: 0.5-2.3). CONCLUSIONS: Aneurysm wall calcification but not ICAC was more prevalent in UIAs than in RIAs, which corresponds to the hypothesis that calcification may protect against aneurysmal rupture. Aneurysm wall calcification should be further assessed as a predictor of aneurysm stability in prospective cohort studies. CLINICAL RELEVANCE STATEMENT: Calcification of the intracranial aneurysm wall was more prevalent in unruptured than ruptured intracranial aneurysms after adjustment for cardiovascular risk factors. Calcification may therefore protect the aneurysm against rupture, and aneurysm wall calcification is a candidate predictor of aneurysm stability. KEY POINTS: Aneurysm wall calcification was more prevalent in patients with unruptured than ruptured aneurysms, while internal carotid artery calcification was similar. Aneurysm wall calcification but not internal carotid artery calcification is a candidate predictor of aneurysm stability. Cohort studies are needed to assess the predictive value of aneurysm wall calcification for aneurysm stability.

Analysis of aneurysmal subarachnoid hemorrhage as a multistep process.

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (ASAH) is a complex disease with higher incidence in women compared to men and in Japan compared to other countries. It was hypothesized that ASAH is consistent with a multistep model of disease. The following assessments were made: (1) the number of steps needed for the disease to occur and (2) whether this number may be different in female versus male and in Japanese versus non-Japanese patients. METHODS: Incidence data were generated from a meta-analysis on ASAH incidence until 2017, which was supplemented with a literature search from 2017 to April 2023. Age- and sex-adjusted incidences per 10-year age groups were calculated and the logarithm of age-specific incidence against the logarithm of age was regressed with least-squares regression. RESULTS: In 2317 ASAH patients a linear relationship between logarithm of incidence and logarithm of age was found with a slope estimate of 3.13 (95% confidence interval 2.60-3.65), consistent with a four-step process. Similar estimates were found for female, male, Japanese and non-Japanese patients. CONCLUSIONS: Our results suggest that ASAH is a four-step process, also in subgroups with higher ASAH incidence. Elucidation of the exact nature of these steps can provide important clues for identification of disease mechanisms underlying ASAH.

Prevalence of pre-eclampsia in 265 patients with an intracranial aneurysm, 393 female relatives versus a control cohort: A case-control study.

BACKGROUND AND OBJECTIVES: There is emerging evidence on the connection between pre-eclampsia and saccular intracranial aneurysms (sIAs). Our aim was to study the prevalence of pre-eclampsia in sIA patients, their female relatives, and matched controls, and to examine familial sIA disease and familial pre-eclampsia in sIA patients' families. METHODS: We included all female sIA patients in the Kuopio Intracranial Aneurysm Patient and Family Database from 1995 to 2018. First, we identified the sIA patients, their female relatives, and matched population controls with the first birth in 1987 or later and studied the prevalence of pre-eclampsia. Second, all female sIA patients and all female relatives were analyzed for familial sIA disease and familial pre-eclampsia. Using the Finnish nationwide health registries, we obtained data on drug purchases, hospital diagnoses, and causes of death. RESULTS: In total, 265 sIA patients, 57 daughters, 167 sisters, 169 nieces, and 546 matched controls had the first birth in 1987 or later. Among them, 29 (11%) sIA patients, 5 (9%) daughters, 10 (6%) sisters, 10 (6%) nieces, and 32 (6%) controls had pre-eclampsia. Of all the 1895 female sIA patients and 12,141 female relatives, 68 sIA patients and 375 relatives had pre-eclampsia, including 32 families with familial pre-eclampsia. CONCLUSIONS: Pre-eclampsia was significantly more common in the sIA patients than in their matched controls. Familial sIA disease and familial pre-eclampsia co-occurred in seven families. Further studies of the mechanisms by which pre-eclampsia could affect the walls of brain arteries and increase the rupture risk in sIA disease are indicated.

Causal association between circulating inflammatory cytokines and intracranial aneurysm and subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The causal association between inflammatory cytokines and the development of intracranial aneurysm (IA), unruptured IA (uIA) and subarachnoid hemorrhage (SAH) lacks clarity. METHODS: The summary-level datasets for inflammatory cytokines were extracted from a genome-wide association study of the Finnish Cardiovascular Risk in Young Adults Study and the FINRISK survey. The summary statistics datasets related to IA, uIA and SAH were obtained from the genome-wide association study meta-analysis of the International Stroke Genetics Consortium and FinnGen Consortium. The primary method employed for analysis was inverse variance weighting (false discovery rate), supplemented by sensitivity analyses to address pleiotropy and enhance robustness. RESULTS: In the International Stroke Genetics Consortium, 10, six and eight inflammatory cytokines exhibited a causal association with IA, uIA and SAH, respectively (false discovery rate, p < 0.05). In FinnGen datasets, macrophage Inflammatory Protein-1 Alpha (MIP_1A), MIP_1A and interferon γ-induced protein 10 (IP_10) were verified for IA, uIA and SAH, respectively. In the reverse Mendelian randomization analysis, the common cytokines altered by uIA and SAH were vascular endothelial growth factor (VEGF), MIP_1A, IL_9, IL_10 and IL_17, respectively. The meta-analysis results show that MIP_1A and IP_10 could be associated with the decreased risk of IA, and MIP_1A and IP_10 were associated with the decreased risk of uIA and SAH, respectively. Notably, the levels of VEGF, MIP_1A, IL_9, IL_10 and TNF_A were increased with uIA. Comprehensive heterogeneity and pleiotropy analyses confirmed the robustness of these results. CONCLUSION: Our study unveils a bidirectional association between inflammatory cytokines and IA, uIA and SAH. Further investigations are essential to validate their relationship and elucidate the underlying mechanisms.

Dietary Iron Restriction Protects against Aneurysm Rupture in a Mouse Model of Intracranial Aneurysm.

INTRODUCTION: Iron accumulation in vessel walls induces oxidative stress and inflammation, which can cause cerebrovascular damage, vascular wall degeneration, and intracranial aneurysmal formation, growth, and rupture. Subarachnoid hemorrhage from intracranial aneurysm rupture results in significant morbidity and mortality. This study used a mouse model of intracranial aneurysm to evaluate the effect of dietary iron restriction on aneurysm formation and rupture. METHODS: Intracranial aneurysms were induced using deoxycorticosterone acetate-salt-induced hypertension and a single injection of elastase into the cerebrospinal fluid of the basal cistern. Mice were fed an iron-restricted diet (n = 23) or a normal diet (n = 25). Aneurysm rupture was detected by neurological symptoms, while the presence of intracranial aneurysm with subarachnoid hemorrhage was confirmed by post-mortem examination. RESULTS: The aneurysmal rupture rate was significantly lower in iron-restricted diet mice (37%) compared with normal diet mice (76%; p < 0.05). Serum oxidative stress, iron accumulation, macrophage infiltration, and 8-hydroxy-2'-deoxyguanosine in the vascular wall were lower in iron-restricted diet mice (p < 0.01). The areas of iron positivity were similar to the areas of CD68 positivity and 8-hydroxy-2'-deoxyguanosine in both normal diet and iron-restricted diet mouse aneurysms. CONCLUSIONS: These findings suggest that iron is involved in intracranial aneurysm rupture via vascular inflammation and oxidative stress. Dietary iron restriction may have a promising role in preventing intracranial aneurysm rupture.

Pitfalls of single-study external validation illustrated with a model predicting functional outcome after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Prediction models are often externally validated with data from a single study or cohort. However, the interpretation of performance estimates obtained with single-study external validation is not as straightforward as assumed. We aimed to illustrate this by conducting a large number of external validations of a prediction model for functional outcome in subarachnoid hemorrhage (SAH) patients. METHODS: We used data from the Subarachnoid Hemorrhage International Trialists (SAHIT) data repository (n = 11,931, 14 studies) to refit the SAHIT model for predicting a dichotomous functional outcome (favorable versus unfavorable), with the (extended) Glasgow Outcome Scale or modified Rankin Scale score, at a minimum of three months after discharge. We performed leave-one-cluster-out cross-validation to mimic the process of multiple single-study external validations. Each study represented one cluster. In each of these validations, we assessed discrimination with Harrell's c-statistic and calibration with calibration plots, the intercepts, and the slopes. We used random effects meta-analysis to obtain the (reference) mean performance estimates and between-study heterogeneity (I2-statistic). The influence of case-mix variation on discriminative performance was assessed with the model-based c-statistic and we fitted a "membership model" to obtain a gross estimate of transportability. RESULTS: Across 14 single-study external validations, model performance was highly variable. The mean c-statistic was 0.74 (95%CI 0.70-0.78, range 0.52-0.84, I2 = 0.92), the mean intercept was -0.06 (95%CI -0.37-0.24, range -1.40-0.75, I2 = 0.97), and the mean slope was 0.96 (95%CI 0.78-1.13, range 0.53-1.31, I2 = 0.90). The decrease in discriminative performance was attributable to case-mix variation, between-study heterogeneity, or a combination of both. Incidentally, we observed poor generalizability or transportability of the model. CONCLUSIONS: We demonstrate two potential pitfalls in the interpretation of model performance with single-study external validation. With single-study external validation. (1) model performance is highly variable and depends on the choice of validation data and (2) no insight is provided into generalizability or transportability of the model that is needed to guide local implementation. As such, a single single-study external validation can easily be misinterpreted and lead to a false appreciation of the clinical prediction model. Cross-validation is better equipped to address these pitfalls.