The effectiveness of various stroke treatments depends on the anatomical variability of the cerebral vasculature, particularly the collateral blood vessel network. Collaterals at the level of the Circle of Willis and distal collaterals, such as the leptomeningeal arteries, serve as alternative avenues of flow when the primary pathway is obstructed during an ischemic stroke. Stroke treatment typically involves catheterization of the primary pathway, and the potential risk of further flow reduction to the affected brain area during this treatment has not been previously investigated. To address this clinical question, we derived the lumped parameters for catheterized blood vessels and implemented a corresponding distributed compartment (0D) model. This 0D model was validated against an experimental model and benchmark test cases solved using a 1D model. Additionally, we compared various off-center catheter trajectories modeled using a 3D solver to this 0D model. The differences between them were minimal, validating the simplifying assumption of the central catheter placement in the 0D model. The 0D model was then used to simulate blood flows in realistic cerebral arterial networks with different collateralization characteristics. Ischemic strokes were modeled by occlusion of the M1 segment of the middle cerebral artery in these networks. Catheters of different diameters were inserted up to the obstructed segment and flow alterations in the network were calculated. Results showed up to 45% maximum blood flow reduction in the affected brain region. These findings suggest that catheterization during stroke treatment may have a further detrimental effect for some patients with poor collateralization.

Stroke management employs a variety of diagnostic imaging modalities, image processing and analysis methods, and treatment procedures. This work categorizes methods for stroke imaging, image processing and analysis, and treatment, and provides their taxonomies illustrated by a state-of-the-art review. Imaging plays a critical role in stroke management, and the most frequently employed modalities are computed tomography (CT) and magnetic resonance (MR). CT includes unenhanced non-contrast CT as the first-line diagnosis, CT angiography, and CT perfusion. MR is the most complete method to examine stroke patients. MR angiography is useful to evaluate the severity of artery stenosis, vascular occlusion, and collateral flow. Diffusion-weighted imaging is the gold standard for evaluating ischemia. MR perfusion-weighted imaging assesses the penumbra. The stroke image processing methods are divided into non-atlas/template-based and atlas/template-based. The non-atlas/template-based methods are subdivided into intensity and contrast transformations, local segmentation-related, anatomy-guided, global density-guided, and artificial intelligence/deep learning-based. The atlas/template-based methods are subdivided into intensity templates and atlases with three atlas types: anatomy atlases, vascular atlases, and lesion-derived atlases. The treatment procedures for arterial and venous strokes include intravenous and intraarterial thrombolysis and mechanical thrombectomy. This work captures the state-of-the-art in stroke management summarized in the form of comprehensive and straightforward taxonomy diagrams. All three introduced taxonomies in diagnostic imaging, image processing and analysis, and treatment are widely illustrated and compared against other state-of-the-art classifications.

The presence of an intracranial tumour is a relative or absolute contraindication to stroke thrombolysis by most guidelines across the world. This is based on the risk of iatrogenic symptomatic intracranial haemorrhage related to the tumour. We present a patient where the decision to proceed with thrombolysis was complicated by an incidental finding of an intracranial tumour. The decision was made to proceed with thrombolysis. The patient had excellent functional recovery in the hours after administration and didn\'t suffer any intracranial haemorrhage. The evidence around excluding this patient group from thrombolysis is scant and mostly of low quality. Original randomised controlled trials or stroke thrombolysis excluded this patient group and there have been none since. Published case reports and series are heterogeneous in their conclusions regarding the risk of symptomatic haemorrhage following thrombolysis in patients with intra-axial and extra-axial neoplasms. Further studies may clarify guidelines.

Acute ischemic stroke is a critical health condition that requires timely intervention. Following admission, clinicians typically use perfusion imaging to facilitate treatment decision-making. While deep learning models leveraging perfusion data have demonstrated the ability to predict post-treatment tissue infarction for individual patients, predictions are often represented as binary or probabilistic masks that are not straightforward to interpret or easy to obtain. Moreover, these models typically rely on large amounts of subjectively segmented data and non-standard perfusion analysis techniques. To address these challenges, we propose a novel deep learning approach that directly predicts follow-up computed tomography images from full spatio-temporal 4D perfusion scans through a temporal compression. The results show that this method leads to realistic follow-up image predictions containing the infarcted tissue outcomes. The proposed compression method achieves comparable prediction results to using perfusion maps as inputs but without the need for perfusion analysis or arterial input function selection. Additionally, separate models trained on 45 patients treated with thrombolysis and 102 treated with thrombectomy showed that each model correctly captured the different patient-specific treatment effects as shown by image difference maps. The findings of this work clearly highlight the potential of our method to provide interpretable stroke treatment decision support without requiring manual annotations.

Acute ischemic stroke (AIS) is the second leading cause of death globally. No Food and Drug Administration (FDA) approved therapies exist that target cerebroprotection following stroke. Our group recently reported significant cerebroprotection with the adenosine A1/A3 receptor agonist, AST-004, in a transient stroke model in non-human primates (NHP) and in a preclinical mouse model of traumatic brain injury (TBI). However, the specific receptor pathway activated was only inferred based on in vitro binding studies. The current study investigated the underlying mechanism of AST-004 cerebroprotection in two independent models of AIS: permanent photothrombotic stroke in mice and transient middle cerebral artery occlusion (MCAO) in rats. AST-004 treatments across a range of doses were cerebroprotective and efficacy could be blocked by A3R antagonism, indicating a mechanism of action that does not require A1R agonism. The high affinity A3R agonist MRS5698 was also cerebroprotective following stroke, but not the A3R agonist Cl-IB-MECA under our experimental conditions. AST-004 efficacy was blocked by the astrocyte specific mitochondrial toxin fluoroacetate, confirming an underlying mechanism of cerebroprotection that was dependent on astrocyte mitochondrial metabolism. An increase in A3R mRNA levels following stroke suggested an intrinsic cerebroprotective response that was mediated by A3R signaling. Together, these studies confirm that certain A3R agonists, such as AST-004, may be exciting new therapeutic avenues to develop for AIS.

BACKGROUND: Although results from in vitro studies and small randomized controlled trials have shown positive effects of Dazhu hongjingtian injection (DZHJTI) on acute ischemic stroke (AIS), their generalizability to routine clinical practice remains to be established.
OBJECTIVE: The primary aim of this study is to evaluate the effectiveness of DZHJTI treatment for AIS with regard to changes in the stroke-related neurological deficit from baseline to outpatient follow-up, mortality, subsequent vascular events, disability, and traditional Chinese medicine syndrome in real-world clinical settings. By monitoring for adverse events or significant changes in vital signs and laboratory parameters, we also aim to assess the safety of DZHJTI.
METHODS: This prospective, multicenter cohort study plans to enroll 2000 patients with AIS within 14 days of symptom onset from 30 hospitals across China. Eligible patients will be followed up for 6 months after initiating medication treatments. The primary outcome will be the change in the National Institute of Health Stroke Scale score from baseline to outpatient follow-up. The secondary outcomes include overall mortality, stroke recurrence, new-onset major vascular events, global disability, and improvement of traditional Chinese medicine syndrome in 6 months. Adverse events or clinically significant changes in vital signs and laboratory parameters, regardless of the severity, will be recorded during the trial to assess the safety of DZHJTI. An augmented inverse propensity weighted estimator will be used to reduce variability and improve accuracy in average treatment effects estimation.
RESULTS: The clinical trial registration was approved in October 2022, and the recruitment and enrollment of participants started in November 2022. The study\'s outcomes are expected to be published in 2025 in reputable, peer-reviewed health-related research journals.
CONCLUSIONS: This real-world cohort study is the first to assess the effectiveness and safety of DZHJTI in treating AIS. It may provide additional clinical evidence, including the duration of response, long-term drug effectiveness, and subgroup efficacy data. The study results will be valuable for clinicians and patients seeking optimal treatment for AIS and could lead to better use of DZHJTI and improved patient outcomes.
BACKGROUND: ITMCTR ITMCTR2022000005; http://tinyurl.com/554ns8m5.
UNASSIGNED: DERR1-10.2196/52447.

BACKGROUND: Door-to-needle time (DNT) is an established predictor of outcome in acute ischemic stroke (AIS) patients treated with intravenous thrombolysis (IVT). Several strategies have been proposed to streamline in-hospital pathways, among which treatment at CT/MR bed.
OBJECTIVE: To explore the impact of treatment at CT/MR bed, here defined as imaging area (IA), on functional outcome in stroke patients treated with IVT alone.
METHODS: All AIS patients treated with IVT alone at our center in 2020, 2021, and 2022 were included. Patients with any previous disability were excluded. The cohort was divided into two groups, depending on the treatment site. One group received IVT at IA, the other at emergency room or stroke unit (non-IA). Regression analysis assessed the association between treatment site and 3-month outcome.
RESULTS: A total of 327 patients who received IVT alone were included in the analysis. One hundred thirty-three (40.7%) were in the IA group and 194 (59.3%) in the non-IA group. The groups showed similar baseline characteristics. In the IA group, DNT was 45 min shorter. Despite similar rates of functional independence (mRS 0-2), the IA group showed higher rates of excellent outcome (mRS 0-1) compared to the non-IA group (60.1% vs 42.8%, p<0.01). Immediate treatment at IA was independently associated to excellent outcome (OR 1.78 [1.03-3.08]).
CONCLUSIONS: Thrombolytic treatment at IA lowers DNT and is an independent predictor of excellent outcome after AIS. Our study emphasizes the importance of immediate thrombolytic treatment at IA, soon after radiological eligibility is confirmed. Immediate treatment at IA should be a standard-of-care for AIS.

Stroke, a debilitating condition often leading to long-term disability, poses a substantial global concern and formidable challenge. The increasing incidence of stroke has drawn the attention of medical researchers and neurologists worldwide. Circadian rhythms have emerged as pivotal factors influencing stroke\'s onset, pathogenesis, treatment, and outcomes. To gain deeper insights into stroke, it is imperative to explore the intricate connection between circadian rhythms and stroke, spanning from molecular mechanisms to pathophysiological processes. Despite existing studies linking circadian rhythm to stroke onset, there remains a paucity of comprehensive reviews exploring its role in pathogenesis, treatment, and prognosis. This review undertakes a narrative analysis of studies investigating the relationship between circadian variation and stroke onset. It delves into the roles of various physiological factors, including blood pressure, coagulation profiles, blood cells, catecholamines, cortisol, and the timing of antihypertensive medication, which contribute to variations in circadian-related stroke risk. At a molecular level, the review elucidates the involvement of melatonin, circadian genes, and glial cells in the pathophysiology. Furthermore, it provides insights into the diverse factors influencing stroke treatment and outcomes within the context of circadian variation. The review underscores the importance of considering circadian rhythms when determining the timing of stroke interventions, emphasizing the necessity for personalized stroke management strategies that incorporate circadian rhythms. It offers valuable insights into potential molecular targets and highlights areas that require further exploration to enhance our understanding of the underlying pathophysiology. In comparison to the published literature, this manuscript distinguishes itself through its coverage of circadian rhythms\' impact on stroke across the entire clinical spectrum. It presents a unique synthesis of epidemiological, clinical, molecular, and cellular evidence, underscoring their collective significance.

BIIB131, a small molecule, is currently in Phase 2 for the treatment of acute ischemic stroke. Safety and metabolism of BIIB131 were evaluated following intravenous administration to rats and monkeys. Exposure increased dose-proportionally in rats up to 60 mg/kg and more than dose-proportionally in monkeys at greater than 10 mg/kg accompanied by prolonged half-life and safety findings. The BIIB131 was poorly metabolized in microsomes with no inhibition of CYPs. BIIB131-glucuronide, formed by UGT1A1, accounted for 21.5% metabolism in human hepatocytes and 28-40% in rat bile. In rats, excretion was primarily via the bile. BIIB131 inhibited the hERG and Nav1.5 cardiac channels by 39% but showed no effect on cardiovascular parameters in monkeys. Toxicology findings were limited to reversable hematuria, changes in urinary parameters and local effects. A MTD of 30 mg/kg was established in monkeys, the most sensitive species, at total plasma Cmax and AUC of 6- and 14-fold, respectively, greater than the NOAEL. The Phase 1 study started with intravenous 0.05 mg/kg and ascended to 6.0 mg/kg which corresponded to safety margins of 147- to 0.9-fold (for Cmax) within the linear drug exposure. Thus, the preclinical profile of BIIB131 has been appropriately characterized and supports its further clinical development.

Circulatory models can significantly help develop new ways to alleviate the burden of stroke on society. However, it is not always easy to know what hemodynamics conditions to impose on a numerical model or how to simulate porous media, which ineluctably need to be addressed in strokes. We propose a validated open-source, flexible, and publicly available lattice-Boltzmann numerical framework for such problems and present its features in this chapter. Among them, we propose an algorithm for imposing pressure boundary conditions. We show how to use the method developed by Walsh et al. (Comput Geosci 35(6):1186-1193, 2009) to simulate the permeability law of any porous medium. Finally, we illustrate the features of the framework through a thrombolysis model.