Changes in the Proteome of the Circle of Willis during Aging Reveal Signatures of Vascular Disease.

Approximately 70% of all strokes occur in patients over 65 years old, and stroke increases the risk of developing dementia. The circle of Willis (CoW), the ring of arteries at the base of the brain, links the intracerebral arteries to one another to maintain adequate cerebral perfusion. The CoW proteome is affected in cerebrovascular and neurodegenerative diseases, but changes related to aging have not been described. Here, we report on a quantitative proteomics analysis comparing the CoW from five young (2-3-month-old) and five aged male (18-20-month-old) mice using gene ontology (GO) enrichment, ingenuity pathway analysis (IPA), and iPathwayGuide tools. This revealed 242 proteins that were significantly dysregulated with aging, among which 189 were upregulated and 53 downregulated. GO enrichment-based analysis identified blood coagulation as the top biological function that changed with age and integrin binding and extracellular matrix constituents as the top molecular functions. Consistent with these findings, iPathwayGuide-based impact analysis revealed associations between aging and the complement and coagulation, platelet activation, ECM-receptor interaction, and metabolic process pathways. Furthermore, IPA analysis revealed the enrichment of 97 canonical pathways that contribute to inflammatory responses, as well as 59 inflammation-associated upstream regulators including 39 transcription factors and 20 cytokines. Thus, aging-associated changes in the CoW proteome in male mice demonstrate increases in metabolic, thrombotic, and inflammatory processes.

Hemodynamics regulate spatiotemporal artery muscularization in the developing circle of Willis.

Vascular smooth muscle cells (VSMCs) envelop vertebrate brain arteries and play a crucial role in regulating cerebral blood flow and neurovascular coupling. The dedifferentiation of VSMCs is implicated in cerebrovascular disease and neurodegeneration. Despite its importance, the process of VSMC differentiation on brain arteries during development remains inadequately characterized. Understanding this process could aid in reprogramming and regenerating dedifferentiated VSMCs in cerebrovascular diseases. In this study, we investigated VSMC differentiation on zebrafish circle of Willis (CoW), comprising major arteries that supply blood to the vertebrate brain. We observed that arterial specification of CoW endothelial cells (ECs) occurs after their migration from cranial venous plexus to form CoW arteries. Subsequently, acta2+ VSMCs differentiate from pdgfrb+ mural cell progenitors after they were recruited to CoW arteries. The progression of VSMC differentiation exhibits a spatiotemporal pattern, advancing from anterior to posterior CoW arteries. Analysis of blood flow suggests that earlier VSMC differentiation in anterior CoW arteries correlates with higher red blood cell velocity and wall shear stress. Furthermore, pulsatile flow induces differentiation of human brain PDGFRB+ mural cells into VSMCs, and blood flow is required for VSMC differentiation on zebrafish CoW arteries. Consistently, flow-responsive transcription factor klf2a is activated in ECs of CoW arteries prior to VSMC differentiation, and klf2a knockdown delays VSMC differentiation on anterior CoW arteries. In summary, our findings highlight blood flow activation of endothelial klf2a as a mechanism regulating initial VSMC differentiation on vertebrate brain arteries.

The effect of circle of willis anatomy and scanning practices on outcomes for blunt cerebrovascular injuries.

BACKGROUND: Limited research has explored the effect of Circle of Willis (CoW) anatomy among blunt cerebrovascular injuries (BCVI) on outcomes. It remains unclear if current BCVI screening and scanning practices are sufficient in identification of concomitant COW anomalies and how they affect outcomes. METHODS: This retrospective cohort study included adult traumatic BCVIs at 17 level I-IV trauma centers (08/01/2017-07/31/2021). The objectives were to compare screening criteria, scanning practices, and outcomes among those with and without COW anomalies. RESULTS: Of 561 BCVIs, 65% were male and the median age was 48 y/o. 17% (n = 93) had a CoW anomaly. Compared to those with normal CoW anatomy, those with CoW anomalies had significantly higher rates of any strokes (10% vs. 4%, p = 0.04), ICHs (38% vs. 21%, p = 0.001), and clinically significant bleed (CSB) before antithrombotic initiation (14% vs. 3%, p < 0.0001), respectively. Compared to patients with a normal CoW, those with a CoW anomaly also had ischemic strokes more often after antithrombotic interruption (13% vs. 2%, p = 0.02).Patients with CoW anomalies were screened significantly more often because of some other head/neck indication not outlined in BCVI screening criteria than patients with normal CoW anatomy (27% vs. 18%, p = 0.04), respectively. Scans identifying CoW anomalies included both the head and neck significantly more often (53% vs. 29%, p = 0.0001) than scans identifying normal CoW anatomy, respectively. CONCLUSIONS: While previous studies suggested universal scanning for BCVI detection, this study found patients with BCVI and CoW anomalies had some other head/neck injury not identified as BCVI scanning criteria significantly more than patients with normal CoW which may suggest that BCVI screening across all patients with a head/neck injury may improve the simultaneous detection of CoW and BCVIs. When screening for BCVI, scans including both the head and neck are superior to a single region in detection of concomitant CoW anomalies. Worsened outcomes (strokes, ICH, and clinically significant bleeding before antithrombotic initiation) were observed for patients with CoW anomalies when compared to those with a normal CoW. Those with a CoW anomaly experienced strokes at a higher rate than patients with normal CoW anatomy specifically when antithrombotic therapy was interrupted. This emphasizes the need for stringent antithrombotic therapy regimens among patients with CoW anomalies and may suggest that patients CoW anomalies would benefit from more varying treatment, highlighting the need to include the CoW anatomy when scanning for BCVI. LEVEL OF EVIDENCE: Level III, Prognostic/Epidemiological.

Establishing the distribution of cerebrovascular resistance using computational fluid dynamics and 4D flow MRI.

Cerebrovascular resistance (CVR) regulates blood flow in the brain, but little is known about the vascular resistances of the individual cerebral territories. We present a method to calculate these resistances and investigate how CVR varies in the hemodynamically disturbed brain. We included 48 patients with stroke/TIA (29 with symptomatic carotid stenosis). By combining flow rate (4D flow MRI) and structural computed tomography angiography (CTA) data with computational fluid dynamics (CFD) we computed the perfusion pressures out from the circle of Willis, with which CVR of the MCA, ACA, and PCA territories was estimated. 56 controls were included for comparison of total CVR (tCVR). CVR were 33.8 ± 10.5, 59.0 ± 30.6, and 77.8 ± 21.3 mmHg s/ml for the MCA, ACA, and PCA territories. We found no differences in tCVR between patients, 9.3 ± 1.9 mmHg s/ml, and controls, 9.3 ± 2.0 mmHg s/ml (p = 0.88), nor in territorial CVR in the carotid stenosis patients between ipsilateral and contralateral hemispheres. Territorial resistance associated inversely to territorial brain volume (p < 0.001). These resistances may work as reference values when modelling blood flow in the circle of Willis, and the method can be used when there is need for subject-specific analysis.

Establishment of a novel protocol for assessing the severity of subarachnoid hemorrhage in circle Willis perforation mouse model.

The Circle of Willis perforation (cWp) mouse model is a key tool in subarachnoid hemorrhage (SAH) research; however, inconsistent bleeding volumes can challenge experimental reliability. To address this issue, we introduced the ROB Scoring System, a novel protocol integrating Rotarod Tests (RT), Open-field Tests (OT) video analysis, and daily Body Weight Loss (BWL) monitoring to precisely categorize SAH severity. Forty C57BL/6 mice underwent cWp SAH induction, categorized by ROB into severity subgroups (severe, moderate, mild). Validation compared ROB trends in subgroups, and ROB outcomes with autopsy results on postoperative days three and seven for acute and sub-acute evaluations. Mortality rates were analyzed via the survival log-rank test, revealing a significant difference among SAH subgroups (P < 0.05). Strong correlations between ROB grades and autopsy findings underscored its precision. Notably, the severe group exhibited 100% mortality within 4 days post SAH onset. Single parameters (RT, OT, BWL) were insufficient for distinguishing SAH severity levels. The ROB score represents a significant advancement, offering an objective method for precise categorization and addressing inherent bleeding variations in the cWp SAH model. This standardized protocol enhances the reliability and effectiveness of the SAH translational research, providing a valuable tool for future investigations into this critical area.

Investigation of 3D vessel reconstruction under Doppler imaging with phantoms: Towards reconstruction of the Circle of Willis.

BACKGROUND: Stroke is the second leading cause of death across the globe. Early screening and risk detection could provide early intervention and possibly prevent its incidence. Imaging modalities, including 1D-Transcranial Doppler Ultrasound (1D-TCD) or Transcranial Color-code sonography (TCCS), could only provide low spatial resolution or 2D image information, respectively. Notably, 3D imaging modalities including CT have high radiation exposure, whereas MRI is expensive and cannot be adopted in patients with implanted devices. This study proposes an alternative imaging solution for reconstructing 3D Doppler ultrasound geared towards providing a screening tool for the 3D vessel structure of the brain. METHODS: The system comprises an ultrasound phased array attached to a servo motor, which can rotate 180˚ at a speed of 2˚/s. We extracted the color Doppler ROI from the image before reconstructing it into a 3D view using a customized pixel-based algorithm. Different vascular diameters, flow velocity, and depth were tested using a vascular phantom with a pumped flow to confirm the system for imaging blood flow. These variables were set to mimic the vessel diameter, flow speed, and depth of the Circle of Willis (CoW) during a transcranial screening. RESULTS AND CONCLUSIONS: The lower values of absolute error and ratio were found in the larger vascular channels, and vessel diameter overrepresentation was observed. Under different flow velocities, such diameter overrepresentation in the reconstructed flow did not change much; however, it did change with different depths. Meanwhile, the setting of the velocity scale and the color gain affected the dimension of reconstructed objectives. Moreover, we presented a 3D image of CoW from a subject to demonstrate its potential. The findings of this work can provide a good reference for further studies on the reconstruction of the CoW or other blood vessels using Doppler imaging.

Midterm follow-up after embolization of intracranial aneurysms proximal to the circle of Willis with the Silk Vista flow diverter: the I-MAMA registry.

PURPOSE: The aim of this registry was to assess technical success, procedural safety and mid- to long-term follow-up results of the Silk Vista "Mama" (SVM) flow diverter (BALT, Montmorency, France) for the treatment of proximal intracranial aneurysms. METHODS: Between August 2020 and March 2022, data from nine Italian neurovascular centres were collected. Data included patients' clinical presentation, aneurysms' size, location and status, technical details, overall complications and mid- to long-term angiographic follow-up. RESULTS: Forty-eight aneurysms in 48 patients were treated using the SVM. Most aneurysms were small (≤ 10 mm: no. 29, 60%) and unruptured (no. 31, 65%); 13 aneurysms were recurrent after coiling or clipping. 37/48 aneurysms involved the internal carotid artery (77%). Optimal opening and complete wall apposition of the device were achieved in 46 out of 48 cases (96%). Four intra- or periprocedural complications occurred (two thrombotic complications successfully resolved, one cerebellar ischemia, one perirenal hematoma), without new neurological deficit. No significant intra-stent stenosis or stent displacement was observed during follow-up. No FD-related morbidity nor mortality was reported. At midterm (6-12 months) to long-term (> 12 months) follow-up, complete aneurysm occlusion (OKM D) was achieved in 76% of cases. Eighty-eight percent of patients had complete aneurysm occlusion or entry remnant (OKM D + C). CONCLUSIONS: Our experience suggests that the new generation of low-profile SVM flow diverter for the treatment of proximal intracranial aneurysms is safe and effective, with low rates of intraprocedural complications and acceptable mid- to long-term occlusion rate.

A Computational Pipeline to Investigate Longitudinal Blood Flow Changes in the Circle of Willis of Patients with Stable and Growing Aneurysms.

Changes in cerebral blood flow are often associated with the initiation and development of different life-threatening medical conditions including aneurysm rupture and ischemic stroke. Nevertheless, it is not fully clear how haemodynamic changes in time across the Circle of Willis (CoW) are related with intracranial aneurysm (IA) growth. In this work, we introduced a novel reduced-order modelling strategy for the systematic quantification of longitudinal blood flow changes across the whole CoW in patients with stable and unstable/growing aneurysm. Magnetic Resonance Angiography (MRA) images were converted into one-dimensional (1-D) vessel networks through a semi-automated procedure, with a level of geometric reconstruction accuracy controlled by user-dependent parameters. The proposed pipeline was used to systematically analyse longitudinal haemodynamic changes in seven different clinical cases. Our preliminary simulation results indicate that growing aneurysms are not necessarily associated with significant changes in mean flow over time. A concise sensitivity analysis also shed light on which modelling aspects need to be further characterized to have reliable patient-specific predictions. This study poses the basis for investigating how time-dependent changes in the vasculature affect the haemodynamics across the whole CoW in patients with stable and growing aneurysms.

Influence of circle of Willis modeling on hemodynamic parameters in anterior communicating artery aneurysms and recommendations for model selection.

Computational fluid dynamics (CFD) has been utilized to calculate hemodynamic parameters in anterior communicating artery aneurysm (AComA), which is located at a junction between left and right A1 and A2 segments. However, complete or half circle of Willis (CoW) models are used indiscriminately. This study aims to suggest recommendations for determining suitable CoW model. Five patient-specific CoW models with AComA were used, and each model was divided into complete, left-half, and right-half models. After validating the CFD using a flow experiment, the hemodynamic parameters and flow patterns in five AComAs were compared. In four out of five cases, inflow from one A1 side had a dominant influence on the AComA, while both left and right A1 sides affected the AComA in the remaining case. Also, the average difference in time-averaged wall shear stress between the complete and half models for four cases was 4.6%, but it was 62% in the other case. The differences in the vascular resistances of left and right A1 and A2 segments greatly influenced the flow patterns in the AComA. These results may help to enhance clinicians' understanding of blood flow in the brain, leading to improvements in diagnosis and treatment of cerebral aneurysms.

A patient-specific circle of Willis blood flow model in predicting outcomes of balloon test occlusion.

BACKGROUND AND PURPOSE: Balloon test occlusion (BTO) evaluates cerebral ischemic tolerance before internal carotid artery (ICA) sacrifice but carries risks like dissection and thrombosis. This study introduces a new approach using a patient-specific circle of Willis (COW) blood flow model, based on non-invasive quantitative MR angiography (qMRA) measurements, to predict the outcomes of BTO. METHODS: We developed individualized COW blood flow models for 43 patients undergoing BTO. These models simulated blood flow and pressure under normal conditions and with the ICA occlusion. We then compared the model's predictions of blood flow changes due to the simulated ICA occlusion to actual qMRA measurements before the BTO. RESULTS: For all 31 BTO failures, the ipsilateral hemisphere showed an average flow decrease of 15 ± 10% (mean ± standard deviation), compared to 3 ± 2% in the contralateral hemisphere. In all 12 BTO passes, these figures were 6 ± 3% and 1 ± 0.8%, respectively. Notably, all BTO passes had less than a 10% reduction in the ipsilateral hemisphere. In contrast, 65% of BTO failures and 67% single-photon emission computed tomography (SPECT) failures exhibited a decrease of 10% or more in the same region. CONCLUSION: Blood flow reduction exceeding 10% in the ipsilateral hemisphere during BTO is a strong predictor of failure in both BTO and SPECT. Our patient-specific COW blood flow models, incorporating detailed flow and arterial geometry data, offered valuable insights for predicting BTO outcomes. These models are especially beneficial for situations where conducting BTO or SPECT is clinically impractical.

Exploring the anatomical configurations of the cerebral arteries in a cohort of South African patients.

The cerebral arteries, specifically the anterior cerebral artery (ACA) and posterior cerebral artery (PCA), work together with the smaller calibre arteries to provide effective communication between the anterior and posterior circuits of the brain via the circle of Willis (CoW). Morphologic variations of the cerebral arteries and the CoW may alter blood flow to the brain, resulting in intracranial vascular disorders associated with stroke, and aneurysms. This study aimed to document the morphology of the cerebral arteries and the CoW in the South African population. Two hundred and thirty-nine computed tomography angiography scans were assessed. Cerebral arteries and CoW normal morphology and variations were classified as complete, absent, or hypoplastic. The ACA A1 was absent in 4.91%, hypoplastic in 30.40%, fenestrated in 1.06%, and typical in 63.6%. The ACA A2 was absent in 0.42%, hypoplastic in 26.28%, and typical in 69.44%. We found triple ACA A2 in 2.98%, azygos in 1.28% and fenestrated in 1.28%. The middle cerebral artery (MCA) was hypoplastic in 7.35% and typical in 92.64%. The PCA was hypoplastic in 28.74% and typical in 71.25%. Knowledge of the configuration of the CoW plays a significant role in guiding therapeutic decision-making in treating various neurovascular pathologies.

Neurovascular description in the South American plains vizcacha, Lagostomus maximus (Chinchilloidea, Caviomorpha). A study involving evolutionarily related species of Caviomorpha and Muroidea.

Oxygenated blood is required for the adequate metabolic activity of the brain. This is supplied by the circle of Willis (CoW) and the vertebrobasilar and carotid systems. The CoW ensures blood flow in case of arterial stenosis or occlusion. Different animal models have been explored for the CoW morphological and functional study. This work aims to characterize the vascular architecture of the CoW of the plains vizcacha, Lagostomus maximus (Suborder: Hystricomorpha), and to compare it with evolutionarily related species of Caviomorpha and Muroidea. The blood supply in adult plains vizcachas was studied using latex cerebrovascular casts and angiography. A caudo-rostral flow direction was determined, beginning in the spinal and vertebral arteries and converging in the basilar artery which bifurcates in the carotid-basilar communication in the caudal communicating arteries. In the first third of its course, the caudal cerebral arteries project laterally, and the middle and rostral cerebral arteries bifurcate from their rostral terminal segment, supplying the temporo-parietal and frontal cortex. The CoW architecture is mainly conserved between rodent species. Likewise, the small neurovascular variations observed could be considered phylogenetic morphological variations more than evolutionary adaptations. The absence of the rostral communicating artery that generates the rostral open architecture of the CoW in the vizcacha as in the other analyzed species, supports the need for a revision of the CoW classical function as a security system. Finally, this work supports the importance of expanding our understanding of brain anatomy among species, which may contribute to a better understanding of functional neuroanatomy.

Trend of cerebral aneurysms over the past two centuries: need for early screening.

OBJECTIVE: Cerebral aneurysms (CAs) are linked to variations in the cerebral basal arterial network (CBAN). This study aimed to find the optimal age for screening to detect brain arterial variations and predict aneurysms before rupture. DESIGN: An observational, quantitative and retrospective research. SETTING: The study analysed 1127 cases of CAs published from 1761 to 1938. Additionally, CT angiography images of 173-patients at the Royal Adelaide Hospital (RAH), South Australia between 2011 and 2019 were examined for the presence and the location of aneurysms in CBAN. PARTICIPANTS: The data were collected from patients at RAH and 407 published sources, including males and females across the entire age range, up to 100 years old. OUTCOME MEASURES AND RESULTS: Data, CAs cases, from 1761 to 1938 included (526 males, 573 females and 28 unknown sexes). The age of these patients varied from 18 months to 89 years (mean age=42, SD=18). Approximately 11.5% of the CAs occurred in patients aged <20 years. Among the 1078 aneurysms whose location was reported, 76% were located in the internal carotid (IC), middle cerebral (MC) and anterior communicating artery complex (AcomAC) regions, while the remaining 24% were in the vertebrobasilar region. Among 173 patients from RAH aged between 18 and 100 years (male=83 and female=90, mean age=60, SD=16), 94% of the CAs were found in the IC, MC and AcomAC regions. The pattern of aneurysm occurrence, as indicated by values at the 25th, 50th and 75th percentiles, along with the minimum and maximum patient ages, has remained consistent from 1761 to 2019. CONCLUSION: The distribution pattern of CAs in relation to sex, age and locations in the CBAN, remained steady over the last 260 years resulting in risk of strokes early in life. Therefore, early screening for CBAN segment variations is advised for stroke prevention if possible.

Chemotherapy-associated hemorrhagic posterior reversible encephalopathy syndrome (PRES) with considerations for circle of Willis variants on cerebral blood flow and autoregulation: A case report.

RATIONALE: Hodgkin lymphoma, a lymphatic system cancer, is treated by chemotherapy, radiation therapy, and hematopoietic stem cell transplantation. Posterior reversible encephalopathy syndrome (PRES) is a rare neurotoxic effect associated with several drugs and systemic conditions. This case study emphasizes the potential risks of intensive chemotherapy regimens and postulates the impact of the circle of Willis variants on the heterogeneity of hemispheric lesions in PRES. PATIENT CONCERNS: A 42-year-old woman diagnosed with stage IIA nodular sclerosing Hodgkin lymphoma and chronic thrombocytopenia presented after 6 years of initial diagnosis and 4 years post-haploidentical transplant. She underwent planned chemotherapy with ifosfamide, carboplatin, and etoposide. DIAGNOSES: She developed an alteration in her mental status. A computerized tomography scan and angiogram of the head and neck revealed findings consistent with PRES and a left fetal-type posterior cerebral artery with an aplastic A1 segment of the left anterior cerebral artery. One hour later she was found comatose with clinical sequelae of an uncal herniation. INTERVENTIONS: Subsequent events led to emergent intubation, and administration of 23.4% hypertonic saline. A repeat computerized tomography scan showed a right intraparenchymal hemorrhage with fluid-fluid levels measuring up to 4.7 cm, bilateral subarachnoid hemorrhage, right uncal herniation, and 15 mm of leftward midline shift. She emergently underwent a right decompressive hemi-craniectomy. OUTCOMES: An magnetic resonance imaging of the brain demonstrated bilateral cytotoxic edema involving the parieto-occipital lobes. Despite interventions, the patient's neurological condition deteriorated, leading to a declaration of brain death on the 8th day. LESSONS: This case underscores the importance of recognizing the severe neurological complications, including PRES, associated with chemotherapeutic treatments in Hodgkin lymphoma. PRES may also be exacerbated by coagulopathies such as thrombocytopenia in this case. The circle of Willis variants may influence cerebral blood flow, autoregulation, and other factors of hemodynamics, leading to increased susceptibility to both radiographic lesion burden and the worst clinical outcomes.

Development of the Circle of Willis Score (COWS) to help guide decision making during acute tandem occlusion treatment: Preliminary analysis.

BACKGROUND: Acute tandem occlusions (TOs) are challenging to treat. Although acute carotid stenting of the proximal lesion is well tolerated, there are certain situations when the practitioner may be wary of acute stenting (bleeding concerns). OBJECTIVE: The purpose of this study was to retrospectively study patients with tandem occlusions who had re-occlusion of the extracranial ICA and develop a Circle of Willis Score (COWS) to help predict which patients could forego acute stenting. METHODS: This is a retrospective review of TO patients with a persistent proximal occlusion following intervention (either expected or unexpected). Pre intervention CTA and intraoperative DSA were reviewed, and each patient was assigned a score 2 (complete COW), 1a (patent A1-Acomm-A1), 1p (patent Pcomm), or 0 (incomplete COW). Findings from the DSA took precedence over the CTA. Two cohorts were created, the complete COW cohort (COWS 2) versus the incomplete COW cohort (COWS 1a,1p, or 0). Angiographic outcomes were assessed using the mTICI score (2b-3) and clinical outcomes were assessed using discharge mRS (good outcome mRS 0-3). RESULTS: Of 68 TO cases, 12 had persistent proximal occlusions. There were 5/12 (42 %) patients in the complete COW cohort, and 7/12 (58 %) in the incomplete COW cohort (5/12 with scores of 1a/1p and 2/12 with a score of 0). In the complete COW cohort, there were 2 ICA-ICA and 3 ICA-MCA occlusions. In the incomplete COW cohort, there was one ICA-ICA occlusion and 6 ICA-MCA occlusions. LKW-puncture was shorter in the complete COW cohort (208 min vs. 464 min, p = 0.16). Successful reperfusion was higher in the complete COW cohort (100 % vs. 71 %). There was a trend toward better clinical outcomes in the complete COW cohort (80 % vs 29 %, p = 0.079). CONCLUSION: The COWS is a simple score that may help predict a successful clinical outcome without proximal revascularization when concerned about performing an acute carotid stent during TO treatment. Evaluation in larger TO cohort is warranted.

Anatomical differences of intracranial arteries according to sex: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Intracranial aneurysms are more common in women than in men. Some anatomical variants of the circle of Willis (CoW) are associated with a higher risk of developing intracranial aneurysms. We hypothesized that variations of the CoW are sex dependent which may partly explain why intracranial aneurysms are more common in women. We systematically reviewed and meta-analyzed the literature to compare the presence of anatomical variations of the CoW between women and men in the general population. MATERIAL AND METHODS: A systematic search in Pubmed and EMBASE using predefined criteria, following the PRISMA guidelines was performed. The presence of different CoW anatomical variants and a complete CoW was compared between women and men using an inverse variance weighted random effects meta-analysis to calculate relative risks (RR) with 95% confidence intervals (95% CIs). RESULTS: Fourteen studies were included reporting on 5478 healthy participants (2511 women, 2967 men). Bilateral fetal type posterior cerebral arteries (RR 2.79; 95%CI 1.65-4.72, I2=0%), and a complete CoW (RR 1.24, 95%CI 1.13-1.36; I2=0%) were more prevalent in women than in men. The variants absence or hypoplasia of one of the anterior cerebral arteries (RR 0.58, 95%CI 0.38-0.88, I2=57%) and hypoplasia or absence of both posterior communicating arteries (RR 0.79, 95%CI 0.71-0.87, I2=0%) were more prevalent in men. CONCLUSIONS: Several anatomical variations of the CoW are sex dependent, with some variants being more common in women while others in men. Future research should assess how these sex-specific CoW variants relate to the sex-specific occurrence of intracranial aneurysms.