Single-Cell Analysis in Cerebrovascular Research: Primed for Breakthroughs and Clinical Impact.

Data generated using single-cell RNA-sequencing has the potential to transform understanding of the cerebral circulation and advance clinical care. However, the high volume of data, sometimes generated and presented without proper pathophysiological context, can be difficult to interpret and integrate into current understanding of the cerebral circulation and its disorders. Furthermore, heterogeneity in the representation of brain regions and vascular segments makes it difficult to compare results across studies.

Single-nucleus RNA sequencing of human periventricular white matter in vascular dementia.

Vascular dementia (VaD) refers to a variety of dementias driven by cerebrovascular disease and is the second leading cause of dementia globally. VaD may be caused by ischemic strokes, intracerebral hemorrhage, and/or cerebral small vessel disease, commonly identified as white matter hyperintensities on MRI. The mechanisms underlying these white matter lesions in the periventricular brain are poorly understood.

Polygenic Risk of Epilepsy and Poststroke Epilepsy.

Background: Epilepsy is highly heritable, with numerous known genetic risk loci. However, the genetic predisposition's role in poststroke epilepsy (PSE) remains understudied. This study assesses whether a higher genetic predisposition to epilepsy raises poststroke survivor's risk of PSE.

Deep learning for prediction of post-thrombectomy outcomes based on admission CT angiography in large vessel occlusion stroke.

Purpose: Computed Tomography Angiography (CTA) is the first line of imaging in the diagnosis of Large Vessel Occlusion (LVO) strokes. We trained and independently validated end-to-end automated deep learning pipelines to predict 3-month outcomes after anterior circulation LVO thrombectomy based on admission CTAs.

Methods: We split a dataset of 591 patients into training/cross-validation (n = 496) and independent test set (n = 95).

An Approach to Successful Development of Clinician-Scientists in Neurology: The NINDS R25 Experience.

Objective: Training clinician-scientists is a primary objective of many academic neurology departments, as these individuals are uniquely positioned to perform insightful clinical or laboratory-based research informed both by clinical knowledge and their own experiences caring for patients. Despite its importance, training clinician-scientists has perhaps never been so challenging. The National Institute of Neurologic Disorders and Stroke (NINDS) R25 program was designed in an attempt to support these individuals, decrease the time needed to obtain National Institutes of Health K awards, and to help educate a cohort of trainees preparing for a career in academic neurology.

Biological and Procedural Predictors of Outcome in the Stroke Preclinical Assessment Network (SPAN) Trial.

Background: The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo.

Automated detection of early signs of irreversible ischemic change on CTA source images in patients with large vessel occlusion.

Purpose: To create and validate an automated pipeline for detection of early signs of irreversible ischemic change from admission CTA in patients with large vessel occlusion (LVO) stroke.

Methods: We retrospectively included 368 patients for training and 143 for external validation. All patients had anterior circulation LVO stroke, endovascular therapy with successful reperfusion, and follow-up diffusion-weighted imaging (DWI).

StrokeClassifier: ischemic stroke etiology classification by ensemble consensus modeling using electronic health records.

Determining acute ischemic stroke (AIS) etiology is fundamental to secondary stroke prevention efforts but can be diagnostically challenging. We trained and validated an automated classification tool, StrokeClassifier, using electronic health record (EHR) text from 2039 non-cryptogenic AIS patients at 2 academic hospitals to predict the 4-level outcome of stroke etiology adjudicated by agreement of at least 2 board-certified vascular neurologists' review of the EHR. StrokeClassifier is an ensemble consensus meta-model of 9 machine learning classifiers applied to features extracted from discharge summary texts by natural language processing.

Radiomics-Based Prediction of Collateral Status from CT Angiography of Patients Following a Large Vessel Occlusion Stroke.

Background: A major driver of individual variation in long-term outcomes following a large vessel occlusion (LVO) stroke is the degree of collateral arterial circulation. We aimed to develop and evaluate machine-learning models that quantify LVO collateral status using admission computed tomography angiography (CTA) radiomics.

Methods: We extracted 1116 radiomic features from the anterior circulation territories from admission CTAs of 600 patients experiencing an acute LVO stroke.

VEGF-C prophylaxis favors lymphatic drainage and modulates neuroinflammation in a stroke model.

Meningeal lymphatic vessels (MLVs) promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelial growth factor-C (VEGF-C) regulates MLV development and maintenance and has therapeutic potential for treating neurological disorders. Herein, we investigated the effects of VEGF-C overexpression on brain fluid drainage and ischemic stroke outcomes in mice.

Association of Neighborhood-Level Socioeconomic Factors With Delay to Hospital Arrival in Patients With Acute Stroke.

Background And Objectives: Delivery of acute ischemic stroke (AIS) therapies is contingent on the duration from last known well (LKW) to emergency department arrival time (EDAT). One reason for treatment ineligibility is delay in presentation to the hospital. We evaluate patient and neighborhood characteristics associated with time from LKW to EDAT.

Characterization of CSF inflammatory markers after hemorrhagic stroke and their relationship to disease severity.

Background: The inflammatory response within the central nervous system is a key driver of secondary brain injury after hemorrhagic stroke, both in patients with intracerebral hemorrhage (ICH) and aneurysmal subarachnoid hemorrhage (aSAH). In this study, we aimed to characterize inflammatory molecules in the blood and cerebrospinal fluid (CSF) of patients within 72 hours of hemorrhage to understand how such molecules vary across disease types and disease severity.

Methods: Biological samples were collected from patients admitted to a single-center Neurosciences Intensive Care Unit with a diagnosis of ICH or aSAH between 2014 and 2022.

Trained immunity induced by high-salt diet impedes stroke recovery.

A high-salt diet (HSD) elicits sustained sterile inflammation and worsens tissue injury. However, how this occurs after stroke, a leading cause of morbidity and mortality, remains unknown. Here, we report that HSD impairs long-term brain recovery after intracerebral hemorrhage, a severe form of stroke, despite salt withdrawal prior to the injury.

Ischemic Stroke Etiology Classification by Ensemble Consensus Modeling Using Electronic Health Records.

Determining the etiology of an acute ischemic stroke (AIS) is fundamental to secondary stroke prevention efforts but can be diagnostically challenging. We trained and validated an automated classification machine intelligence tool, , using electronic health record (EHR) text data from 2,039 non-cryptogenic AIS patients at 2 academic hospitals to predict the 4-level outcome of stroke etiology determined by agreement of at least 2 board-certified vascular neurologists' review of the stroke hospitalization EHR. is an ensemble consensus meta-model of 9 machine learning classifiers applied to features extracted from discharge summary texts by natural language processing.

Clinical Trial Protocol for BEACH: A Phase 2a Study of MW189 in Patients with Acute Nontraumatic Intracerebral Hemorrhage.

Patients with acute spontaneous intracerebral hemorrhage (ICH) develop secondary neuroinflammation and cerebral edema that can further damage the brain and lead to increased risk of neurologic complications. Preclinical studies in animal models of acute brain injury have shown that a novel small-molecule drug candidate, MW01-6-189WH (MW189), decreases neuroinflammation and cerebral edema and improves functional outcomes. MW189 was also safe and well tolerated in phase 1 studies in healthy adults.

Polygenic Risk of Epilepsy and Post-Stroke Epilepsy.

Background And Aims: Epilepsy is highly heritable, with numerous known genetic risk loci. However, the genetic predisposition's role in post-acute brain injury epilepsy remains understudied. This study assesses whether a higher genetic predisposition to epilepsy raises post-stroke or Transient Ischemic Attack (TIA) survivor's risk of Post-Stroke Epilepsy (PSE).

Radiomic markers of intracerebral hemorrhage expansion on non-contrast CT: independent validation and comparison with visual markers.

Objective: To devise and validate radiomic signatures of impending hematoma expansion (HE) based on admission non-contrast head computed tomography (CT) of patients with intracerebral hemorrhage (ICH).

Methods: Utilizing a large multicentric clinical trial dataset of hypertensive patients with spontaneous supratentorial ICH, we developed signatures predictive of HE in a discovery cohort ( = 449) and confirmed their performance in an independent validation cohort ( = 448). In addition to = 1,130 radiomic features, = 6 clinical variables associated with HE, = 8 previously defined visual markers of HE, the BAT score, and combinations thereof served as candidate variable sets for signatures.

Common Pathways of Epileptogenesis in Patients With Epilepsy Post-Brain Injury: Findings From a Systematic Review and Meta-analysis.

Background And Objectives: Epilepsy may result from various brain injuries, including stroke (ischemic and hemorrhagic), traumatic brain injury, and infections. Identifying shared common biological pathways and biomarkers of the epileptogenic process initiated by the different injuries may lead to novel targets for preventing the development of epilepsy. We systematically reviewed biofluid biomarkers to test their association with the risk of post-brain injury epilepsy.

VEGF-C promotes brain-derived fluid drainage, confers neuroprotection, and improves stroke outcomes.

Unlabelled: Meningeal lymphatic vessels promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelium growth factor-C (VEGF-C) is essential for meningeal lymphatic development and maintenance and has therapeutic potential for treating neurological disorders, including ischemic stroke. We have investigated the effects of VEGF-C overexpression on brain fluid drainage, single cell transcriptome in the brain, and stroke outcomes in adult mice.

Targeted drug delivery to the brain endothelium dominates over passive delivery via vascular leak in experimental intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is one of the most common causes of fatal stroke, yet has no specific drug therapies. Many attempts at passive intravenous (IV) delivery in ICH have failed to deliver drugs to the salvageable area around the hemorrhage. The passive delivery method assumes vascular leak through the ruptured blood-brain barrier will allow drug accumulation in the brain.

Polygenic Susceptibility to Hypertension and Blood Pressure Control in Stroke Survivors.

Background And Objectives: Blood pressure (BP) is often not at goal in stroke survivors, leaving individuals vulnerable to additional vascular events. Given that BP is a highly heritable trait, we hypothesize that a higher polygenic susceptibility to hypertension (PSH) leads to worse BP control in stroke survivors.

Methods: We conducted a study within the UK Biobank evaluating persons of European ancestry who survived an ischemic or hemorrhagic stroke.

Embracing Heterogeneity in The Multicenter Stroke Preclinical Assessment Network (SPAN) Trial.

The Stroke Preclinical Assessment Network (SPAN) is a multicenter preclinical trial platform using rodent models of transient focal cerebral ischemia to address translational failure in experimental stroke. In addition to centralized randomization and blinding and large samples, SPAN aimed to introduce heterogeneity to simulate the heterogeneity embodied in clinical trials for robust conclusions. Here, we report the heterogeneity introduced by allowing the 6 SPAN laboratories to vary most of the biological and experimental model variables and the impact of this heterogeneity on middle cerebral artery occlusion (MCAo) performance.