Single-cell atlas of the human brain vasculature across development, adulthood and disease.

A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood1. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell-cell interaction analyses predict substantial endothelial-to-perivascular cell ligand-receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.

Defining the Role of Oral Pathway Inhibitors as Targeted Therapeutics in Arteriovenous Malformation Care.

Arteriovenous malformations (AVMs) are vascular malformations that are prone to rupturing and can cause significant morbidity and mortality in relatively young patients. Conventional treatment options such as surgery and endovascular therapy often are insufficient for cure. There is a growing body of knowledge on the genetic and molecular underpinnings of AVM development and maintenance, making the future of precision medicine a real possibility for AVM management. Here, we review the pathophysiology of AVM development across various cell types, with a focus on current and potential druggable targets and their therapeutic potentials in both sporadic and familial AVM populations.

Embolization techniques of spontaneous direct carotid-cavernous fistulae: a single-center experience.

PURPOSE: Spontaneous direct carotid-cavernous fistula (CCF) are usually caused by a ruptured carotid cavernous aneurysm. We studied treatment of spontaneous direct CCFs in a single-center cohort of a high-volume tertiary referral center, reporting anatomical details, technical approaches of treatment, and outcomes. METHODS: Adult patients with a spontaneous direct CCF treated between 2010-2022 with follow-up MRI and/or DSA imaging available were retrospectively analyzed. We studied age, sex, clinical presentation, angiographic findings, treatment techniques, outcomes, and complications. RESULTS: Out of 80 patients with CCFs, twelve patients were treated for a non-traumatic direct CCF (15%) in 13 sessions. Median age was 65 years. Two patients had an underlying connective tissue disorder. In 10 cases, the direct CCF was caused by a ruptured cavernous carotid aneurysm. The direct CCFs were treated by endovascular transarterial embolization (10 cases), transvenous embolization (1 case), or surgery (1 case). Selective closure of the shunt was possible in 10 patients. Two patients were treated with parent vessel occlusion (PVO; one endovascular; one surgical, with bypass). Complications occurred in 2 / 12 patients (17%), with permanent morbidity in two patients (17%): trigeminal neuralgia after PVO and new infarct after surgical PVO and bypass. Selective closure of CCF resulted in no morbidity. There was no mortality in our series. CONCLUSION: Spontaneous direct CCFs are caused by rupture of a cavernous carotid aneurysm in most cases. Selective closure of the shunt, usually feasible transarterially with coils, achieves good results. Reconstructive endovascular techniques are preferred to minimize treatment related neurological complications.

The expansion of liquid biopsies to vascular care: an overview of existing principles, techniques and potential applications to vascular malformation diagnostics.

Vascular malformations are congenital lesions that occur due to mutations in major cellular signalling pathways which govern angiogenesis, cell proliferation, motility, and cell death. These pathways have been widely studied in oncology and are substrates for various small molecule inhibitors. Given their common molecular biology, there is now a potential to repurpose these cancer drugs for vascular malformation care; however, a molecular diagnosis is required in order to tailour specific drugs to the individual patient's mutational profile. Liquid biopsies (LBs), emerging as a transformative tool in the field of oncology, hold significant promise in this feat. This paper explores the principles and technologies underlying LBs and evaluates their potential to revolutionize the management of vascular malformations. The review begins by delineating the fundamental principles of LBs, focusing on the detection and analysis of circulating biomarkers such as cell-free DNA, circulating tumor cells, and extracellular vesicles. Subsequently, an in-depth analysis of the technological advancements driving LB platforms is presented. Lastly, the paper highlights the current state of research in applying LBs to various vascular malformations, and uses the aforementioned principles and techniques to conceptualize a liquid biopsy framework that is unique to vascular malformation research and clinical care.

Effect of Cobalt-60 Treatment Dose Rate on Arteriovenous Malformation Obliteration After Stereotactic Radiosurgery With Gamma Knife.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) marginal dose is associated with successful obliteration of cerebral arteriovenous malformations (AVM). SRS dose rate-how old the cobalt-60 sources are-is known to influence outcomes for some neurological conditions and benign tumors. The objective of this study was to determine the association between cobalt-60 treatment dose rate and cerebral AVM obliteration in patients treated with SRS. METHODS: We performed a retrospective cohort study of 361 patients undergoing 411 AVM-directed SRS treatments between 2005 and 2019 at a single institution. Lesion characteristics, SRS details, obliteration dates, and post-treatment toxicities were recorded. Univariate and multivariate regression analyses of AVM outcomes regarding SRS dose rate (range 1.3-3.7 Gy, mean = 2.4 Gy, median = 2.5 Gy) were performed. RESULTS: At 10 years post-SRS, 68% of AVMs were obliterated on follow-up imaging. Dose rates >2.9 Gy/min were found to be significantly associated with AVM obliteration compared with those <2.1 Gy/min ( P = .034). AVM size, biologically effective dose, and SRS marginal dose were also associated with obliteration, with obliteration more likely for smaller lesions, higher biologically effective dose, and higher marginal dose. Higher dose rates were not associated with the development of post-SRS radiological or symptomatic edema, although larger AVM volume was associated with both types of edema. CONCLUSION: Patients with cerebral AVMs treated with higher SRS dose rates (from newer cobalt-60 sources) experience higher incidences of obliteration without a significant change in the risk of post-treatment edema.

Disconnection of a jugular foramen dural arteriovenous fistula with cortical venous reflux via an intradural retrosigmoid approach: illustrative case.

BACKGROUND: Jugular foramen dural arteriovenous fistulas (DAVFs) are rare and challenging lesions. Described methods of treatment include embolization and microsurgical disconnection through a far lateral transcondylar approach. The authors present the case of a Borden type III jugular foramen DAVF, which was treated with a novel, less invasive retrosigmoid approach with intradural skeletonization and packing of the sigmoid sinus. OBSERVATIONS: The patient presented with headache and visual field deficit. Neuroimaging demonstrated a right temporal intracerebral hematoma with mass effect. This was due to a Borden type III jugular foramen DAVF with cortical venous reflux into the vein of Labbe secondary to recanalization of a previously thrombosed sigmoid sinus. Microsurgical disconnection was performed via a retrosigmoid approach, in which the sigmoid sinus was identified intradurally at the jugular foramen. The sigmoid sinus was isolated by drilling at the pre- and retrosigmoid spaces to permit packing and clip ligation. Postoperative angiography revealed complete occlusion of the DAVF. LESSONS: Jugular foramen DAVFs are rare entities, which have been traditionally treated through a far lateral transcondylar approach. An intradural retrosigmoid approach is a safe, less invasive alternative, which involves less soft tissue and bony dissection and does not have the associated morbidity of craniocervical instability and hypoglossal neuropathy.

Utilisation of the Scepter Mini dual-lumen balloon - An illustrative series.

BACKGROUND: Dual-lumen balloon microcatheters can aid in the safety and efficacy of endovascular embolisation of cerebrospinal vascular malformations. The Scepter Mini dual-lumen balloon is a novel device with a smaller profile than previous balloon microcatheters, opening up new indications not only in the treatment of cerebrospinal malformations but in various other neurovascular therapeutic and diagnostic scenarios. METHODS: Following institutional ethics review board approval, a retrospective review of our prospectively maintained database of cases employing the Scepter Mini dual-lumen microballoon catheter was conducted. Five cases in particular were highlighted, demonstrating utilisation of this device, which may be of interest to the Neurointerventionalist. Patient demographics, procedure details, complications and clinical outcome data were reviewed. RESULTS: Five cases employing the Scepter Mini dual-lumen microballoon catheter are presented; trans-arterial embolisation of cerebral AVM, pre-operative tumour embolisation, diagnostic angiography, trans-venous embolisation of cerebral AVM and trans-arterial embolisation of DAVF. No intraprocedural complications were recorded, one patient had a delayed haemorrhage. CONCLUSION: Potential utilisation of the Scepter Mini lies not only in the trans-arterial embolisation of cerebrospinal vascular malformations, but in a range of other diagnostic and therapeutic indications as demonstrated.

Intraoperative intraarterial indocyanine green video-angiography for disconnection of a perimedullary arteriovenous fistula: illustrative case.

BACKGROUND: Intraarterial (IA) indocyanine green (ICG) angiography is an intraoperative imaging technique offering special and temporal characterization of vascular lesions with very fast dye clearance. The authors' aim is to demonstrate the use of IA ICG angiography to aid in the surgical treatment of a perimedullary thoracic arteriovenous fistula (AVF) in a hybrid operating room (OR). OBSERVATIONS: A 31-year-old woman with a known history of spinal AVF presented with 6 weeks of lower-extremity weakness, gait imbalance, and bowel/bladder dysfunction. Magnetic resonance imaging revealed an extensive series of flow voids across the thoracic spine, most notably at T11-12. After partial embolization, she was taken for surgical disconnection in a hybrid OR. Intraoperative spinal digital subtraction angiography was performed to identify feeding vessels. When the target arteries were catheterized, 0.05 mg of ICG in 2 mL of saline was injected, and the ICG flow in each artery was recorded using the microscope. With an improved surgical understanding of the contributing feeding arteries, the authors achieved complete in situ disconnection of the AVF. LESSONS: IA ICG angiography can be used in hybrid OR settings to illustrate the vascular anatomy of multifeeder perimedullary AVFs and confirm its postoperative disconnection with a fast dye clearance.

Difference in Clinical Phenotype, Mutation Position, and Structural Change of RNF213 Rare Variants Between Pediatric and Adult Japanese Patients with Moyamoya Disease.

It is unclear how rare RNF213 variants, other than the p.R4810K founder variant, affect the clinical phenotype or the function of RNF213 in moyamoya disease (MMD). This study included 151 Japanese patients with MMD. After performing targeted resequencing for all coding exons in RNF213, we investigated the clinical phenotype and statistically analyzed the genotype-phenotype correlation. We mapped RNF213 variants on a three-dimensional (3D) model of human RNF213 and analyzed the structural changes due to variants. The RNF213 p.R4810K homozygous variant, p.R4810K heterozygous variant, and wild type were detected in 10 (6.6%), 111 (73.5%), and 30 (19.9%) MMD patients, respectively. In addition, 15 rare variants were detected in 16 (10.6%) patients. In addition to the influence of the p.R4810K homozygous variant, the frequency of cerebral infarction at disease onset was higher in pediatric patients with other rare variants (3/6, 50.0%, P = 0.006) than in those with only the p.R4810K heterozygous variant or with no variants (2/51, 3.9%). Furthermore, on 3D modelling of RNF213, the majority of rare variants found in pediatric patients were located in the E3 module and associated with salt bridge loss, contrary to the results for adult patients. The clinical phenotype of rare RNF213 variants, mapped mutation position, and their predicted structural change differed between pediatric and adult patients with MMD. Rare RNF213 variants, in addition to the founder p.R4810K homozygous variant, can influence MMD clinical phenotypes or structural change which may contribute to the destabilization of RNF213.

Anatomical considerations regarding a high-flow arteriovenous fistula below the conus medullaris in a patient with hereditary hemorrhagic telangiectasia: Case report.

BACKGROUND AND IMPORTANCE: Cauda equina radicular arteriovenous fistulas are rare "low flow" shunting lesions characterized by direct communication between the radicular artery and vein of a cauda equina nerve root. None have been associated with hereditary hemorrhagic telangiectasia and a high-flow cauda equina radicular arteriovenous fistula has never been reported. We present a unique case of a high-flow cauda equina radicular arteriovenous fistula in a patient with hereditary hemorrhagic telangiectasia. Marked flow-induced vascular remodeling posed significant diagnostic and therapeutic challenges which will be highlighted in this report. CLINICAL PRESENTATION: A 39-year-old female with genetically confirmed hereditary hemorrhagic telangiectasia presented with progressive thoracic myelopathy secondary to a high-flow single-hole arteriovenous fistula below the conus. The feeding artery, arising from the anterior spinal artery, and draining vein had a paramedian course, favoring the diagnosis of a cauda equina radicular arteriovenous fistula (supplied by a proximal radicular artery) over a filum terminale arteriovenous fistula. Transarterial embolization was attempted but significant elongation and tortuosity of the anterior spinal artery precluded microcatheter access to the fistulous point. Surgical disconnection was successfully performed. The intraoperative findings supported the diagnosis of cauda equina radicular arteriovenous fistula. Delayed neurologic deterioration secondary to overshooting venous thrombosis was observed. She recovered after the initiation of therapeutic anticoagulation. CONCLUSION: To the best of our knowledge, we hereby report the first high-flow cauda equina radicular arteriovenous fistula. The accurate differentiation of cauda equina radicular arteriovenous fistula from filum terminale arteriovenous fistulas, while challenging, is important to avoid treatment-related complications. Careful preoperative planning, the use of specialized endovascular and surgical techniques, and meticulous postoperative care can ensure the safe and complete disconnection of high-flow cauda equina radicular arteriovenous fistulas.

Complication of Middle Cerebral Artery Aneurysm Surgery: An M2 Tear at the Neck, Managed with a Salvage M2-to-M2 In Situ Bypass.

An unexpected rupture at the aneurysm neck, with or without adjacent arterial injury or compromise of distal branches during microsurgical clipping, can be a challenging surgical problem to resolve. In this presented case of a neurologically intact 65-year-old woman, elective clipping of an unruptured right middle cerebral artery bifurcation aneurysm was complicated by an unexpected M2 tear at the neck, involving the origin of the frontal M2. Attempts to seal the tear directly, using various techniques, failed; therefore, it was ultimately managed with sacrifice of the vessel and a salvage side-to-side M2-to-M2 in situ bypass. Six months after surgery, the patient demonstrated moderate disability but was able to ambulate with a cane.

A dual-center validation of the PIRAMD scoring system for assessing the severity of ischemic Moyamoya disease.

Background: Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD) is a recently proposed imaging-based scoring system that incorporates the severity of disease and its impact on parenchymal hemodynamics in order to better support clinical management and evaluate response to intervention. In particular, PIRAMD may have merit in identifying symptomatic patients that may benefit most from revascularization. Our aim was to validate the PIRAMD scoring system. Methods: Patients with ischemic Moyamoya disease, who underwent catheter angiographic [modified Suzuki Score (mSS) and collateralization status], morphological MRI and a parenchymal hemodynamic evaluation with blood oxygenation-level dependent cerebrovascular reactivity (BOLD-CVR) at two transatlantic centers, were retrospectively included. The primary outcome was the presence of neurological symptoms. The diagnostic capacity of each PIRAMD feature alone was evaluated, as well as combined and the inter-institutional differences of each parameter were evaluated. Results: Seventy-two hemispheres of 38 patients were considered for analysis, of which 39 (54%) were classified as symptomatic. The presence of a prior infarct had the highest odds ratio [odds ratio (OR) =24; 95% CI: 6.7-87.2] for having neurological symptoms, followed by impaired CVR (OR =17; 95% CI: 5-62). No inter-institutional differences in the odds ratios or area under the curve (AUC) were found for any study parameter. The PIRAMD score had an AUC of 0.88 (95% CI: 0.80-0.96) with a similar AUC for the PIRAMD grading score. Conclusions: Our multicentric validation of the recently published PIRAMD scoring system was highly effective in rating the severity of ischemic Moyamoya disease with excellent inter-institutional agreement. Future studies should investigate the prognostic value of this novel imaging-based score in symptomatic patients with Moyamoya disease.

Shaping the brain vasculature in development and disease in the single-cell era.

The CNS critically relies on the formation and proper function of its vasculature during development, adult homeostasis and disease. Angiogenesis - the formation of new blood vessels - is highly active during brain development, enters almost complete quiescence in the healthy adult brain and is reactivated in vascular-dependent brain pathologies such as brain vascular malformations and brain tumours. Despite major advances in the understanding of the cellular and molecular mechanisms driving angiogenesis in peripheral tissues, developmental signalling pathways orchestrating angiogenic processes in the healthy and the diseased CNS remain incompletely understood. Molecular signalling pathways of the 'neurovascular link' defining common mechanisms of nerve and vessel wiring have emerged as crucial regulators of peripheral vascular growth, but their relevance for angiogenesis in brain development and disease remains largely unexplored. Here we review the current knowledge of general and CNS-specific mechanisms of angiogenesis during brain development and in brain vascular malformations and brain tumours, including how key molecular signalling pathways are reactivated in vascular-dependent diseases. We also discuss how these topics can be studied in the single-cell multi-omics era.

Nucleolin promotes angiogenesis and endothelial metabolism along the oncofetal axis in the human brain vasculature.

Glioblastomas are among the deadliest human cancers and are highly vascularized. Angiogenesis is dynamic during brain development, almost quiescent in the adult brain but reactivated in vascular-dependent CNS pathologies, including brain tumors. The oncofetal axis describes the reactivation of fetal programs in tumors, but its relevance in endothelial and perivascular cells of the human brain vasculature in glial brain tumors is unexplored. Nucleolin is a regulator of cell proliferation and angiogenesis, but its roles in the brain vasculature remain unknown. Here, we studied the expression of Nucleolin in the neurovascular unit in human fetal brains, adult brains, and human gliomas in vivo as well as its effects on sprouting angiogenesis and endothelial metabolism in vitro. Nucleolin is highly expressed in endothelial and perivascular cells during brain development, downregulated in the adult brain, and upregulated in glioma. Moreover, Nucleolin expression correlated with glioma malignancy in vivo. In culture, siRNA-mediated Nucleolin knockdown reduced human brain endothelial cell (HCMEC) and HUVEC sprouting angiogenesis, proliferation, filopodia extension, and glucose metabolism. Furthermore, inhibition of Nucleolin with the aptamer AS1411 decreased brain endothelial cell proliferation in vitro. Mechanistically, Nucleolin knockdown in HCMECs and HUVECs uncovered regulation of angiogenesis involving VEGFR2 and of endothelial glycolysis. These findings identify Nucleolin as a neurodevelopmental factor reactivated in glioma that promotes sprouting angiogenesis and endothelial metabolism, characterizing Nucleolin as an oncofetal protein. Our findings have potential implications in the therapeutic targeting of glioma.

Vascular malformations: An overview of their molecular pathways, detection of mutational profiles and subsequent targets for drug therapy.

Vascular malformations are anomalies in vascular development that portend a significant risk of hemorrhage, morbidity and mortality. Conventional treatments with surgery, radiosurgery and/or endovascular approaches are often insufficient for cure, thereby presenting an ongoing challenge for physicians and their patients. In the last two decades, we have learned that each type of vascular malformation harbors inherited germline and somatic mutations in two well-known cellular pathways that are also implicated in cancer biology: the PI3K/AKT/mTOR and RAS/RAF/MEK pathways. This knowledge has led to recent efforts in: (1) identifying reliable mechanisms to detect a patient's mutational burden in a minimally-invasive manner, and then (2) understand how cancer drugs that target these mutations can be repurposed for vascular malformation care. The idea of precision medicine for vascular pathologies is growing in potential and will be critical in expanding the clinician's therapeutic armamentarium.

Thoracolumbar spinal dural arteriovenous fistulae present with longer arteriovenous transit compared to cranial and cervical dural fistulae.

BACKGROUND: Thoraco-lumbar spinal dural arteriovenous fistulae represent a rare subset of central nervous system vascular malformations. One of the unique features of spinal dural arteriovenous fistulae is their extremely low propensity to cause hemorrhage (either parenchymal or subarachnoid), with a distinct clinical presentation of myelopathy secondary to spinal venous congestion. The exact mechanism for this unique presentation is still unclear. METHODS: Following institutional review board approval, we retrospectively analyzed our prospectively maintained database of spinal dural arteriovenous fistulae and cranial (cr) DAVF cases presenting between 2008 and 2021. For all cases, angiograms were reviewed and arteriovenous transit times were calculated. Patient demographics, angiographic features, and clinical and radiological outcomes were assessed. RESULTS: In total, 66 patients presenting with confirmed thoracolumbar spinal dural arteriovenous fistulaes were identified and compared to patients presenting with cervical spinal dural arteriovenous fistulaes (n = 10), ruptured crDAVFs (n = 32) and unruptured crDAVFs (n = 20). Mean age in the target group was 66 ± 13 versus 57-62 in the other groups, p < 0.05 on one-way analysis of variance; with 80% males versus 50%-65% in other groups. Mean arteriovenous transit time in the thoracolumbar group measured 1.98 s ± 0.96 versus 0.25-0.5 s range in other groups (p < 0.0001 on one-way analysis of variance). CONCLUSION: Prolonged arteriovenous transit times may represent a distinct feature of thoracolumbar spinal dural arteriovenous fistulaes. This may, amongst other factors, play a role in the observed lesser likelihood of hemorrhagic complications compared to other dural arteriovenous shunts.

Occipital Interhemispheric Transtentorial Approach for Microsurgical Resection of a Ruptured Vermian Arteriovenous Malformation: Three-Dimensional Operative Video.

Cerebellar arteriovenous malformations (AVMs) are associated with higher risk of rupture compared with cerebral AVMs.1 Microsurgical resection of a ruptured AVM, measuring 3 cm in its largest dimension, within the cerebellar vermis and right parasagittal cerebellar lobe is demonstrated in Video 1. Cerebral angiography showed major supply from both superior cerebellar arteries and minor supply from a right anterior inferior cerebellar artery-posterior inferior cerebellar artery variant. Venous drainage was through a single ectatic vermian vein draining toward the torcula. Intraoperatively, a second, thrombosed, draining vein connected to the vein of Galen was identified. A right interhemispheric occipital transtentorial approach was elected over the supracerebellar infratentorial approach for early access to the superior cerebellar artery feeding arteries and for an orthogonal rather than a tangential view. The patient was positioned in an ipsilateral lateral position with the head turned 45° toward the floor allowing for gravity retraction of the ipsilateral occipital lobe. An external ventricular drain was also inserted to allow for further relaxation of the occipital lobe. Under neuronavigation guidance, the tentorium was opened allowing immediate visualization of the AVM with early control of the superior cerebellar artery arterial feeders. The AVM was removed using standard microsurgical technique, and hematoma was evacuated. Postoperative cerebral angiography demonstrated no AVM residual. The patient was discharged to a rehabilitation institute with minor residual cerebellar deficits. The patient provided written informed consent for the procedure, video recording, and publication.

Minimally Invasive and Outpatient Aneurysm Surgery: New Concepts.

Anterior circulation aneurysms have classically been treated using the pterional (PT) craniotomy. Minimally invasive alternatives to the PT craniotomy have been successfully used to treat vascular pathologies of the anterior circulation. These approaches offer smaller incisions and reduced tissue dissection, resulting in shorter hospital stay, improved cosmetic results, and comparable outcomes for aneurysm treatment compared with classic open approaches. The supraorbital, lateral supraorbital (LSO), mini-PT, minimal interhemispheric, and endoscopic transpterional port approach (ETPA) are each best suited for different aneurysm targets. Outpatient aneurysm surgery has been possible with the use of minimally invasive approaches.