A single-cell atlas of the normal and malformed human brain vasculature.

Cerebrovascular diseases are a leading cause of death and neurologic disability. Further understanding of disease mechanisms and therapeutic strategies requires a deeper knowledge of cerebrovascular cells in humans. We profiled transcriptomes of 181,388 cells to define a cell atlas of the adult human cerebrovasculature, including endothelial cell molecular signatures with arteriovenous segmentation and expanded perivascular cell diversity. By leveraging this reference, we investigated cellular and molecular perturbations in brain arteriovenous malformations, which are a leading cause of stroke in young people, and identified pathologic endothelial transformations with abnormal vascular patterning and the ontology of vascularly derived inflammation. We illustrate the interplay between vascular and immune cells that contributes to brain hemorrhage and catalog opportunities for targeting angiogenic and inflammatory programs in vascular malformations.

The Rist radial access system: a multicenter study of 152 patients.

BACKGROUND: Transradial access (TRA) for neurointervention is becoming increasingly popular as experience with the technique grows. Despite reasonable efficacy using femoral catheters off-label, conversion to femoral access occurs in approximately 8.6-10.3% of TRA cases, due to an inability of the catheter to track into the vessel of interest, lack of support, or radial artery spasm. METHODS: This is a multicenter, retrospective case series of patients undergoing neurointerventions using the Rist Radial Access System. We also present our institutional protocol for using the system. RESULTS: 152 patients were included in the cohort. The most common procedure was flow diversion (28.3%). The smallest radial diameter utilized was 1.9 mm, and 44.1% were performed without an intermediate catheter. A majority of cases (96.1%) were completed successfully; 3 (1.9%) required conversion to a different radial catheter, 2 (1.3%) required conversion to femoral access, and 1 (0.7%) was aborted. There was 1 (0.7%) minor access site complication and 4 (2.6%) neurological complications. CONCLUSIONS: The Rist catheter is a safe and effective tool for a wide range of complex neurointerventions, with lower conversion rates than classically reported.

Somatic mosaicism in the MAPK pathway in sporadic brain arteriovenous malformation and association with phenotype.

OBJECTIVE: Sporadic brain arteriovenous malformation (BAVM) is a tangled vascular lesion characterized by direct artery-to-vein connections that can cause life-threatening intracerebral hemorrhage (ICH). Recently, somatic mutations in KRAS have been reported in sporadic BAVM, and mutations in other mitogen-activated protein kinase (MAPK) signaling pathway genes have been identified in other vascular malformations. The objectives of this study were to systematically evaluate somatic mutations in MAPK pathway genes in patients with sporadic BAVM lesions and to evaluate the association of somatic mutations with phenotypes of sporadic BAVM severity. METHODS: The authors performed whole-exome sequencing on paired lesion and blood DNA samples from 14 patients with sporadic BAVM, and 295 genes in the MAPK signaling pathway were evaluated to identify genes with somatic mutations in multiple patients with BAVM. Digital droplet polymerase chain reaction was used to validate KRAS G12V and G12D mutations and to assay an additional 56 BAVM samples. RESULTS: The authors identified a total of 24 candidate BAVM-associated somatic variants in 11 MAPK pathway genes. The previously identified KRAS G12V and G12D mutations were the only recurrent mutations. Overall, somatic KRAS G12V was present in 14.5% of BAVM lesions and G12D was present in 31.9%. The authors did not detect a significant association between the presence or allelic burden of KRAS mutation and three BAVM phenotypes: lesion size (maximum diameter), age at diagnosis, and age at ICH. CONCLUSIONS: The authors confirmed the high prevalence of somatic KRAS mutations in sporadic BAVM lesions and identified several candidate somatic variants in other MAPK pathway genes. These somatic variants may contribute to understanding of the etiology of sporadic BAVM and the clinical characteristics of patients with this condition.

Air Pollution Particulate Matter Exposure and Chronic Cerebral Hypoperfusion and Measures of White Matter Injury in a Murine Model.

BACKGROUND: Exposure to ambient air pollution particulate matter (PM) is associated with increased risk of dementia and accelerated cognitive loss. Vascular contributions to cognitive impairment are well recognized. Chronic cerebral hypoperfusion (CCH) promotes neuroinflammation and blood-brain barrier weakening, which may augment neurotoxic effects of PM. OBJECTIVES: This study examined interactions of nanoscale particulate matter (nPM; fine particulate matter with aerodynamic diameter ≤200 nm) and CCH secondary to bilateral carotid artery stenosis (BCAS) in a murine model to produce white matter injury. Based on other air pollution interactions, we predicted synergies of nPM with BCAS. METHODS: nPM was collected using a particle sampler near a Los Angeles, California, freeway. Mice were exposed to 10 wk of reaerosolized nPM or filtered air (FA) for 150 h. CCH was induced by BCAS surgery. Mice (C57BL/6J males) were randomized to four exposure paradigms: a) FA, b) nPM, c) FA + BCAS, and d) nPM + BCAS. Behavioral outcomes, white matter injury, glial cell activation, inflammation, and oxidative stress were assessed. RESULTS: The joint nPM + BCAS group exhibited synergistic effects on white matter injury (2.3× the additive nPM and FA + BCAS scores) with greater loss of corpus callosum volume on T2 magnetic resonance imaging (MRI) (30% smaller than FA group). Histochemical analyses suggested potential microglial-specific inflammatory responses with synergistic effects on corpus callosum C5 immunofluorescent density and whole brain nitrate concentrations (2.1× and 3.9× the additive nPM and FA + BCAS effects, respectively) in the joint exposure group. Transcriptomic responses (RNA-Seq) showed greater impact of nPM + BCAS than individual additive effects, consistent with changes in proinflammatory pathways. Although nPM exposure alone did not alter working memory, the nPM + BCAS cohort demonstrated impaired working memory when compared to the FA + BCAS group. DISCUSSION: Our data suggest that nPM and CCH contribute to white matter injury in a synergistic manner in a mouse model. Adverse neurological effects may be aggravated in a susceptible population exposed to air pollution. https://doi.org/10.1289/EHP8792.

Carotid artery occlusion and revascularization in the management of meningioma.

As the carotid artery courses through the skull base and into the subarachnoid space, it lies in close proximity to regions notorious for meningioma growth. Although infrequent, the growth of these tumors can compromise blood flow through the artery, putting the downstream territory at risk for stroke. In other scenarios, removal of these tumors sometimes requires planning to accomplish both tumor removal and revascularization in the same procedure when then the tumor invades the artery. Since revascularization (bypass surgery) is best performed on a nonemergent basis, it should be given consideration in the preoperative setting. Crisis situations related to intraoperative iatrogenic injury are managed methodically by determining the site of vessel injury and then deciding whether a primary repair or bypass procedure is necessary. The mainstays of revascularization procedures of the carotid artery include flow augmentation and flow replacement, with the superficial temporal artery and external carotid artery being the donor sites, respectively. Although tumor control or cure can be accomplished with surgical, radiosurgical, or combined methods, attention to vascular structures and ensuring blood flow preservation as part of the treatment plan is an important tenet in meningioma surgery.

Failure of Flow Diverter Therapy: Predictors and Management Strategies.

Flow diversion is a safe and effective treatment for many types of brain aneurysms. Even so, there remain some aneurysms that persist despite initial treatment. In studies with the longest follow-up (5 yr), at least 5% of aneurysms persist with this treatment modality. As the cumulative experience and clinical indications for flow diversion continue to expand, the anatomic and functional characteristics that are associated with aneurysm persistence are increasingly described. Identification of these factors preoperatively can help to guide initial treatment decisions, enhance monitoring protocols in the follow-up period, and establish best practices for re-treatment when necessary. Herein, we review published clinical series and provide examples to highlight variables implicated in aneurysm persistence after treatment with flow diversion.

Comparison of predictive grading systems for procedural risk in endovascular treatment of brain arteriovenous malformations: analysis of 104 consecutive patients.

OBJECTIVE: Several grading systems for procedural risk in the endovascular treatment of brain arteriovenous malformations (AVMs) have been proposed, including the Buffalo, Puerto Rico, and AVM embocure scoring systems. The authors sought to validate these systems in an independent patient cohort and compare each system to the established Spetzler-Martin (SM) scale. METHODS: One hundred four consecutive patients underwent adjunctive endovascular embolization of brain AVMs between 2002 and 2016 with the goal of reducing the surgical or hemorrhagic risk before definitive radiosurgical treatment. Baseline clinical and AVM characteristics, complications, and degree of AVM nidus reduction were obtained retrospectively. Univariate and multivariate comparisons and receiver operating characteristic (ROC) curve analyses were performed. RESULTS: Ten major (9.6%) and 16 minor (15.4%) complications were encountered in 24 patients (23.1%). An arterial pedicle size < 1 mm (p = 0.001) and a greater number of pedicles (p = 0.039) were predictors of complication occurrence. Only the Buffalo score predicted the complication rate on univariate (p = 0.039) and multivariate (p = 0.001) analyses. ROC curve analysis revealed a greater area under the curve (AUC) of the Buffalo score (0.703) compared to the Puerto Rico score (p = 0.028), AVM embocure score (AVMES; p = 0.010), and SM grade (SMG; p = 0.030). The Buffalo score, Puerto Rico score, and AVMES but not the SMG predicted > 85% nidus reduction. The AUCs for the different scoring systems were not significantly different. CONCLUSIONS: The major complication rate of 9.6% is within the range of rates reported in the literature and emphasizes that brain AVM embolization is not a low-risk procedure. The Buffalo score but not the Puerto Rico score, AVMES, or SMG predicted the endovascular procedural risk. All three endovascular scores but not the SMG predicted a > 85% nidus reduction rate in this cohort embolized as part of a multimodal AVM treatment.

The Continued Role and Value of Imaging for Acute Ischemic Stroke.

Advances in neuroimaging in the last 2 decades have revolutionized the management of acute ischemic stroke (AIS). Here we review the development of computed tomography (CT) and magnetic resonance imaging (MRI) modalities used to guide treatment of patients with AIS characterized by large vessel occlusion. In particular, we highlight recent randomized trials and their patient selection methodologies to detail the progression of these selection paradigms. With advanced imaging, distinction between at-risk penumbra and ischemic core in AIS may be performed using either CT or MRI. While limitations exist for methodologies to quantify core and penumbra, commercially available fully automated software packages provide useful information to guide treatment decisions. Randomized controlled trials implementing perfusion imaging to patient selection algorithms have demonstrated marked success in improving functional outcomes in patients with large vessel occlusions. As such, imaging has become a vital aspect of AIS treatment in selecting patients who may benefit from mechanical thrombectomy.

Pharmacogenomic considerations for antiplatelet agents: the era of precision medicine in stroke prevention and neurointerventional practice.

Antiplatelet drugs are widely utilized in the setting of primary stroke prevention, secondary stroke prevention, and neuroendovascular device-related stroke prevention. These medications are effective in general, although significant variability in drug activity exists between patients. Although this variation may be related in part to a multitude of factors, a growing body of evidence suggests that individual genotypes are a main contributor. The PharmGKB database was mined to prioritize genetic variants with potential clinical relevance for response to aspirin, clopidogrel, prasugrel, and ticagrelor. Although variants were reported for all drugs, the highest level of evidence was found in cytochrome P450 (CYP450) genotype variation related to clopidogrel response. Individual genetic influences have an impact on the pharmacodynamics of antiplatelet agents. Current clinical practice for stroke prevention is primarily empiric or guided by functional assays; however, there now exists a third potential pathway to base treatment decisions: genotype-guided treatment.

Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation.

Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.

Identification of a rare BMP pathway mutation in a non-syndromic human brain arteriovenous malformation via exome sequencing.

Brain arteriovenous malformations (AVMs) are abnormal connections between arteries and veins that can result in hemorrhagic stroke. A genetic basis for AVMs is suspected, and we investigated potential mutations in a 14-year-old girl who developed a recurrent brain AVM. Whole-exome sequencing (WES) of AVM lesion tissue and blood was performed accompanied by in silico modeling, protein expression observation in lesion tissue and zebrafish modeling. A stop-gain mutation (c.C739T:p.R247X) in the gene SMAD family member 9 (SMAD9) was discovered. In the human brain tissue, immunofluorescent staining demonstrated a vascular predominance of SMAD9 at the protein level. Vascular SMAD9 was markedly reduced in AVM peri-nidal blood vessels, which was accompanied by a decrease in phosphorylated SMAD4, a downstream effector protein of the bone morphogenic protein signaling pathway. Zebrafish modeling (Tg kdrl:eGFP) of the morpholino splice site and translation-blocking knockdown of SMAD9 resulted in abnormal cerebral artery-to-vein connections with morphologic similarities to human AVMs. Orthogonal trajectories of evidence established a relationship between the candidate mutation discovered in SMAD9 via WES and the clinical phenotype. Replication in similar rare cases of recurrent AVM, or even more broadly sporadic AVM, may be informative in building a more comprehensive understanding of AVM pathogenesis.

Surgical management of superior petrosal sinus dural arteriovenous fistulae with dominant internal carotid artery supply.

Background While technological advances have improved the efficacy of endovascular techniques for tentorial dural arteriovenous fistulae (DAVF), superior petrosal sinus (SPS) DAVF with dominant internal carotid artery (ICA) supply frequently require surgical intervention to achieve a definitive cure. Methods To compare the angiographic and clinical outcomes of endovascular and surgical interventions in patients with SPS DAVF, the records of all patients with tentorial DAVF from August 2010 to November 2015 were reviewed. Results Within this cohort, eight patients with nine SPS DAVF were eligible for evaluation. Five DAVF were initially treated with endovascular embolization, while four underwent surgical occlusion without embolization. Of the SPS DAVF treated with embolization, two (40%) remained occluded on follow-up, while the remaining three (60%) persisted/recurred and required surgical intervention for definitive closure. Of the four SPS DAVF treated with primary surgical occlusion, all four (100%) remained closed on follow-up. In addition, of the three SPS DAVF that persisted/recurred following embolization and required subsequent surgical closure, all three (100%) remained occluded on follow-up. Two (100%) SPS DAVF that were successfully treated with embolization had major or minor external carotid artery supply, while the three (100%) persistent lesions had major ICA supply via the meningohypophyseal trunk (MHT). Three (75%) of the four SPS DAVF treated with primary surgical occlusion had dominant MHT supply. Conclusion Complete endovascular closure of SPS DAVF with dominant ICA supply via the MHT may be difficult to achieve, while upfront surgical intervention is associated with a high rate of complete occlusion.

Reductions in brain pericytes are associated with arteriovenous malformation vascular instability.

OBJECTIVEBrain arteriovenous malformations (bAVMs) are rupture-prone tangles of blood vessels with direct shunting of blood flow between arterial and venous circulations. The molecular and/or cellular mechanisms contributing to bAVM pathogenesis and/or destabilization in sporadic lesions have remained elusive. Initial insights into AVM formation have been gained through models of genetic AVM syndromes. And while many studies have focused on endothelial cells, the contributions of other vascular cell types have yet to be systematically studied. Pericytes are multifunctional mural cells that regulate brain angiogenesis, blood-brain barrier integrity, and vascular stability. Here, the authors analyze the abundance of brain pericytes and their association with vascular changes in sporadic human AVMs.METHODSTissues from bAVMs and from temporal lobe specimens from patients with medically intractable epilepsy (nonvascular lesion controls [NVLCs]) were resected. Immunofluorescent staining with confocal microscopy was performed to quantify pericytes (platelet-derived growth factor receptor-beta [PDGFRß] and aminopeptidase N [CD13]) and extravascular hemoglobin. Iron-positive hemosiderin deposits were quantified with Prussian blue staining. Syngo iFlow post-image processing was used to measure nidal blood flow on preintervention angiograms.RESULTSQuantitative immunofluorescent analysis demonstrated a 68% reduction in the vascular pericyte number in bAVMs compared with the number in NVLCs (p < 0.01). Additional analysis demonstrated 52% and 50% reductions in the vascular surface area covered by CD13- and PDGFRß-positive pericyte cell processes, respectively, in bAVMs (p < 0.01). Reductions in pericyte coverage were statistically significantly greater in bAVMs with prior rupture (p < 0.05). Unruptured bAVMs had increased microhemorrhage, as evidenced by a 15.5-fold increase in extravascular hemoglobin compared with levels in NVLCs (p < 0.01). Within unruptured bAVM specimens, extravascular hemoglobin correlated negatively with pericyte coverage (CD13: r = -0.93, p < 0.01; PDGFRß: r = -0.87, p < 0.01). A similar negative correlation was observed with pericyte coverage and Prussian blue-positive hemosiderin deposits (CD13: r = -0.90, p < 0.01; PDGFRß: r = -0.86, p < 0.01). Pericyte coverage positively correlated with the mean transit time of blood flow or the time that circulating blood spends within the bAVM nidus (CD13: r = 0.60, p < 0.05; PDGFRß: r = 0.63, p < 0.05). A greater reduction in pericyte coverage is therefore associated with a reduced mean transit time or faster rate of blood flow through the bAVM nidus. No correlations were observed with time to peak flow within feeding arteries or draining veins.CONCLUSIONSBrain pericyte number and coverage are reduced in sporadic bAVMs and are lowest in cases with prior rupture. In unruptured bAVMs, pericyte reductions correlate with the severity of microhemorrhage. A loss of pericytes also correlates with a faster rate of blood flow through the bAVM nidus. This suggests that pericytes are associated with and may contribute to vascular fragility and hemodynamic changes in bAVMs. Future studies in animal models are needed to better characterize the role of pericytes in AVM pathogenesis.

Neuroprotective strategies following intraparenchymal hemorrhage.

Intracerebral hemorrhage and, more specifically, intraparenchymal hemorrhage, are devastating disease processes with poor clinical outcomes. Primary injury to the brain results from initial hematoma expansion while secondary hemorrhagic injury occurs from blood-derived products such as hemoglobin, heme, iron, and coagulation factors that overwhelm the brains natural defenses. Novel neuroprotective treatments have emerged that target primary and secondary mechanisms of injury. Nonetheless, translational application of neuroprotectants from preclinical to clinical studies has yet to show beneficial clinical outcomes. This review summarizes therapeutic agents and neuroprotectants in ongoing clinical trials aimed at targeting primary and secondary mechanisms of injury after intraparenchymal hemorrhage.