The impact of regular aspirin use on aneurysm recanalization rates after endovascular coiling.

OBJECTIVE: Intracranial aneurysms (IAs) pose a significant health risk, often leading to subarachnoid hemorrhage and severe neurological outcomes. Endovascular coiling has been a principal treatment method, but it comes with the challenge of high recanalization rates. Aspirin has recently emerged as a potential agent to reduce these rates. In this study, the authors aimed to investigate the impact of regular aspirin use on aneurysm recanalization rates following endovascular coiling in a 10-year single-institution study. METHODS: A retrospective analysis was conducted on a dataset of 2236 aneurysms treated by a single neurosurgeon over a period of 10 years. The primary outcome measure was aneurysm recanalization, defined by a change in the Raymond-Roy Occlusion Classification of at least one grade. RESULTS: A total of 525 aneurysms were coiled, 109 of which involved patients who reported regular use of aspirin. The recanalization rate was significantly lower in the aspirin group (9.2%) compared with the control group (23.6%) (OR 0.33, 95% CI 0.15-0.66; p = 0.001). On analysis of the specific mechanisms of recanalization, aneurysm sac growth was less frequent in the aspirin group (5.5%) compared with the control group (18%) (OR 0.265, 95% CI 0.09-0.63; p = 0.002). Additionally, patients in the control group had a higher retreatment rate (18%) than patients in the aspirin group (5.5%) (OR 0.265, 95% CI 0.09-0.63; p = 0.002). CONCLUSIONS: Regular use of aspirin appears to be associated with reduced rates of aneurysm recanalization after endovascular coiling. However, caution is advised in interpretation of these results given the retrospective nature of this study. Further randomized controlled trials are needed to confirm these findings.

Efficacy and safety of tranexamic acid in the management of chronic subdural hematoma: a systematic review and meta-analysis.

OBJECTIVE: Chronic subdural hematoma (CSDH) is a prevalent neurosurgical condition, particularly among the elderly. Various treatment options exist, but recurrence rates remain high. This systematic review and meta-analysis aims to assess the efficacy and safety of tranexamic acid (TXA) in the management of CSDH. METHODS: The authors conducted a comprehensive literature search adhering to the 2020 PRISMA guidelines, involving three primary databases (Scopus, PubMed, and Web of Science) that were searched for articles compiled from inception until October 20, 2023. The primary outcome was recurrence of CSDH, and secondary outcomes included complications and SDH volume following TXA treatment. The mean difference and odds ratios with 95% confidence intervals were calculated using the random-effects model. RESULTS: A total of 5 studies, involving 643 patients in the TXA group and 736 patients in the non-TXA group, met the inclusion criteria. The meta-analysis revealed that TXA use led to a significantly lower CSDH recurrence (OR 0.35, 95% CI 0.23-0.53; p < 0.01) without increasing complications (OR 1.84, 95% CI 0.43-7.95; p = 0.42). Additionally, TXA users had a significantly lower CSDH volume compared to the non-TXA group at 3-month follow-up (mean difference -4.56, 95% CI -8.76 to -0.36; p = 0.03). CONCLUSIONS: The findings suggest that TXA might be a promising agent for reducing the risk of CSDH recurrence without elevating the risk of complications. However, these results should be interpreted cautiously due to the limited number of studies included and the methodological heterogeneity. Further large-scale randomized controlled trials are needed to confirm these findings.

Antithrombotic Therapy in Cerebral Cavernous Malformations: A Systematic Review, Meta-Analysis, and Network Meta-Analysis.

BACKGROUND: Cerebral cavernous malformations are complex vascular anomalies in the central nervous system associated with a risk of intracranial hemorrhage. Traditional guidelines have been cautious about the use of antithrombotic therapy in this patient group, citing concerns about potential bleeding risk. However, recent research posits that antithrombotic therapy may actually be beneficial. This study aims to clarify the association between antithrombotic therapy, including antiplatelet and anticoagulant medications, and the risk of intracranial hemorrhage in patients with cerebral cavernous malformations. METHODS AND RESULTS: A comprehensive literature search was conducted in PubMed, Web of Science, and Scopus databases, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Nine single-center, nonrandomized cohort studies involving 2709 patients were included. Outcomes were analyzed using random-effects model, and a network meta-analysis was conducted for further insight. Of the 2709 patients studied, 388 were on antithrombotic therapy. Patients on antithrombotic therapy had a lower risk of presenting with intracranial hemorrhage (odds ratio [OR], 0.56 [95% CI, 0.45-0.7]; P<0.0001). In addition, the use of antithrombotic therapy was associated with lower risk of intracranial hemorrhage from a cerebral cavernous malformation on follow-up (OR, 0.21 [95% CI, 0.13-0.35]; P<0.0001). A network meta-analysis revealed a nonsignificant OR of 0.73 (95% CI, 0.23-2.56) when antiplatelet therapy was compared with anticoagulant therapy. CONCLUSIONS: Our study explores the potential benefits of antithrombotic therapy in cerebral cavernous malformations. Although the analysis suggests a possible role for antithrombotic agents, it is critical to note that the evidence remains preliminary. Fundamental biases in study design, such as ascertainment and assignment bias, limit the weight of our conclusions. Therefore, our findings should be considered hypothesis-generating and not definitive for clinical practice change.

Balloon-mounting stent versus balloon angioplasty for intracranial arterial stenosis: A systematic review and meta-analysis.

BACKGROUND: Intracranial artery atherosclerotic stenosis (ICAS) is a major cause of stroke, especially in Asian countries. Current treatment options, including balloon-mounted stent (BMS) and balloon angioplasty (BA), lack sufficient evidence to determine a preferred approach. This systematic review and meta-analysis aimed to compare the efficacy and safety of BMS and BA in treating ICAS. METHODS: Following PRISMA 2020 guidelines, we conducted a comprehensive search in PubMed, Web of Science, and Scopus up to December 1, 2023. Eligible studies compared BMS with BA in patients diagnosed with ICAS. Primary outcomes included the success rate and occurrence of stroke (ischemic or hemorrhagic). Secondary outcomes were perforator occlusion, in-stent thrombosis, death, and restenosis. Statistical analysis was conducted using R software version 4.3.1, employing a random-effects model. RESULTS: Five high-quality studies involving 707 patients (515 males, 192 females) were included. BMS had a significantly higher success rate compared to BA (Risk Ratio [RR]: 1.13; CI: 1.03 to 1.24, p < 0.01; I2 = 14 %). The overall risk for stroke (ischemic and hemorrhagic) was significantly higher in BMS (RR: 2.97; CI: 1.32 to 6.67, p < 0.01; I2 = 0 %). However, no significant difference was found between BMS and BA regarding ischemic stroke (RR: 2.33; CI: 0.80 to 6.74, p = 0.12; I2 = 0 %). Additionally, no significant differences were observed in terms of perforator occlusion, in-stent thrombosis, dissection, minor and major strokes, and mortality rates. BMS was associated with a lower risk of restenosis (RR: 0.31; 95 % CI: 0.12 to 0.83, p = 0.02; I2 = 0 %). CONCLUSION: Our results indicate that BMS might be associated with higher success and lower restenosis rates than BA in the treatment of ICAS but with an increased overall risk of stroke. No significant differences were observed in ischemic stroke, perforator occlusion, in-stent thrombosis, dissection, minor and major strokes, and mortality rates. The choice of treatment should consider these findings, alongside the technical challenges and desired angiographic outcomes. Future randomized controlled trials are necessary to further elucidate these results.

Comparative outcomes of middle meningeal artery embolization with statins versus embolization alone in the treatment of chronic subdural hematoma: a systematic review and meta-analysis.

Chronic subdural hematoma (cSDH) is common among the elderly, with surgical evacuation as a prevalent treatment, facing recurrence rates up to 30%. Recently, middle meningeal artery embolization (MMAE) has emerged as a promising approach, offering reduced treatment failures and recurrence rates. Additionally, statins, known for their anti-inflammatory properties, have been considered as a potential adjunctive or sole treatment for cSDH. However, the combination of MMAE with statins remains understudied. This systematic review and meta-analysis aims to evaluate the comparative outcomes of MMAE with statins versus MMAE alone in the treatment of cSDH. A comprehensive systematic search of the PubMed, Web of Science, and SCOPUS databases was conducted. Inclusion criteria were: studies published in English between the dates of inception of each database and August 2023, studies comparing the treatment of cSDH with either MMAE + statin or MMAE alone were included. Main outcome measures were complete resolution of the hematoma at follow-up and the recurrence rates. Two studies comprising 715 patients were included; 408 patients underwent MMAE + statin; and 307 underwent MMAE alone. MMAE + statin was not significantly superior to MMAE alone in achieving complete resolution of the hematoma at follow-up (RR: 0.99; CI: 0.91 to 1.07, P = 0.84), nor was it a significant difference in rates of recurrence (RR: 1.35; CI: 0.83 to 2.17, P = 0.21) between the two groups. MMAE + statin did not demonstrate significant superiority over MMAE alone for achieving complete resolution and decreasing the recurrence rates in cSDH patients. Further research with larger, randomized studies may be required to fully elucidate the potential synergistic effects of MMAE and statins in this patient population.

Assessment of clinical continuity strategies offered by dual-degree training programs in the USA.

Background: Integration of clinical skills during graduate training in dual-degree programs remains a challenge. The present study investigated the availability and self-perceived efficacy of clinical continuity strategies for dual-degree trainees preparing for clinical training. Methods: Survey participants were MD/DO-PhD students enrolled in dual-degree-granting institutions in the USA. The response rate was 95% of 73 unique institutions surveyed, representing 56% of the 124 MD-PhD and 7 DO-PhD recognized training programs. Respondents were asked to indicate the availability and self-perceived efficacy of each strategy. Results: Reported available clinical continuity strategies included clinical volunteering (95.6%), medical grand rounds (86.9%), mentored clinical experiences (84.2%), standardized patients/ practice Objective Structured Clinical Examinations (OSCEs) (70.3%), clinical case reviews (45.9%), clinical journal clubs (38.3%), and preclinical courses/review sessions (37.2%). Trainees rated standardized patients (µ = 6.98 ± 0.356), mentored clinical experiences (µ = 6.94 ± 0.301), clinical skills review sessions (µ = 6.89 ± 0.384), preclinical courses/review sessions (µ = 6.74 ± 0.482), and clinical volunteering (µ = 6.60 ± 0.369), significantly (p < 0.050) higher than clinical case review (µ = 5.34 ± 0.412), clinical journal club (µ = 4.75 ± 0.498), and medicine grand rounds (µ = 4.45 ± 0.377). Further, 84.4% of respondents stated they would be willing to devote at least 0.5-1 hour per week to clinical continuity opportunities during graduate training. Conclusion: Less than half of the institutions surveyed offered strategies perceived as the most efficacious in preparing trainees for clinical reentry, such as clinical skills review sessions. Broader implementation of these strategies could help better prepare dual-degree students for their return to clinical training.

Principles for the design of multicellular engineered living systems.

Remarkable progress in bioengineering over the past two decades has enabled the formulation of fundamental design principles for a variety of medical and non-medical applications. These advancements have laid the foundation for building multicellular engineered living systems (M-CELS) from biological parts, forming functional modules integrated into living machines. These cognizant design principles for living systems encompass novel genetic circuit manipulation, self-assembly, cell-cell/matrix communication, and artificial tissues/organs enabled through systems biology, bioinformatics, computational biology, genetic engineering, and microfluidics. Here, we introduce design principles and a blueprint for forward production of robust and standardized M-CELS, which may undergo variable reiterations through the classic design-build-test-debug cycle. This Review provides practical and theoretical frameworks to forward-design, control, and optimize novel M-CELS. Potential applications include biopharmaceuticals, bioreactor factories, biofuels, environmental bioremediation, cellular computing, biohybrid digital technology, and experimental investigations into mechanisms of multicellular organisms normally hidden inside the "black box" of living cells.

Recycled Translation: Repurposing Drugs for Stroke.

Stroke, which continues to be a leading cause of death and long-term disability worldwide, has often been described as a clinical graveyard. While multiple small molecule therapeutics have undergone clinical trials in stroke, currently only one Food and Drug Administration (FDA)-approved medication exists for the treatment of stroke, the biological, recombinant tissue plasminogen activator (rt-PA). Repurposing of therapeutics which have previously gained FDA approval for alternative indications serves as a prospective option for stroke therapeutic translation. In contrast to de novo drug development, repurposing strategies have patient-centered and economic advantages. These include increased safety, increased chance of approval, decreased time to approval, and decreased capital investment. Presently, 37 active stroke clinical trials utilize repurposed therapeutics with various initial indications and dosing paradigms. The currently studied repurposed therapeutics fall into six mechanistic categories: (1) anticoagulation; (2) vasculature integrity, response, or red blood cell (RBC) alterations; (3) immune system regulation; (4) neurotransmission; and (5) neuroprotection. Directed hypothesis-driven computational investigation utilizing drug databases, in silico drug-protein interaction modeling, genomic data, and consensus methodology can determine if the current mechanistic repurposing categories have the highest chance of translational success or if other mechanistic avenues should be explored. With this increased focus on repurposed therapeutic strategies over de novo strategies, evolution and optimization of regulatory protections are needed to incentivize innovators and investigators.

The Immunomodulatory Capacity of Induced Pluripotent Stem Cells in the Post-stroke Environment.

Inflammation has proven to be a key contributing factor to the pathogenesis of ischemic and hemorrhagic stroke. This sequential and progressive response, marked by proliferation of resident immune cells and recruitment of peripheral immune populations, results in increased oxidative stress, and neuronal cell death. Therapeutics aimed at quelling various stages of this post-stroke inflammatory response have shown promise recently, one of which being differentiated induced pluripotent stem cells (iPSCs). While direct repopulation of damaged tissues and enhanced neurogenesis are hypothesized to encompass some of the therapeutic potential of iPSCs, recent evidence has demonstrated a substantial paracrine effect on neuroinflammation. Specifically, investigation of iPSCs, iPSC-neural progenitor cells (iPSC-NPCs), and iPSC-neuroepithelial like stem cells (iPSC-lt-NESC) has demonstrated significant immunomodulation of proinflammatory signaling and endogenous inflammatory cell populations, such as microglia. This review aims to examine the mechanisms by which iPSCs mediate neuroinflammation in the post-stroke environment, as well as delineate avenues for further investigation.

Exploring the predictive value of lesion topology on motor function outcomes in a porcine ischemic stroke model.

Harnessing the maximum diagnostic potential of magnetic resonance imaging (MRI) by including stroke lesion location in relation to specific structures that are associated with particular functions will likely increase the potential to predict functional deficit type, severity, and recovery in stroke patients. This exploratory study aims to identify key structures lesioned by a middle cerebral artery occlusion (MCAO) that impact stroke recovery and to strengthen the predictive capacity of neuroimaging techniques that characterize stroke outcomes in a translational porcine model. Clinically relevant MRI measures showed significant lesion volumes, midline shifts, and decreased white matter integrity post-MCAO. Using a pig brain atlas, damaged brain structures included the insular cortex, somatosensory cortices, temporal gyri, claustrum, and visual cortices, among others. MCAO resulted in severely impaired spatiotemporal gait parameters, decreased voluntary movement in open field testing, and higher modified Rankin Scale scores at acute timepoints. Pearson correlation analyses at acute timepoints between standard MRI metrics (e.g., lesion volume) and functional outcomes displayed moderate R values to functional gait outcomes. Moreover, Pearson correlation analyses showed higher R values between functional gait deficits and increased lesioning of structures associated with motor function, such as the putamen, globus pallidus, and primary somatosensory cortex. This correlation analysis approach helped identify neuroanatomical structures predictive of stroke outcomes and may lead to the translation of this topological analysis approach from preclinical stroke assessment to a clinical biomarker.

Tethered brain: disentangling unintentional brain-mesh interfaces. Illustrative case.

BACKGROUND: Surgical meshes have found widespread use in neurosurgical practice. While commonly recognized risks of synthetic mesh include infection, exposure of mesh implants, and foreign body reaction, the risk of mesh tethering to neural structures is often overlooked. OBSERVATIONS: The authors presented the first case, to their knowledge, of the disentanglement of mesh interfaced to cortical tissue. The patient, a 68-year-old woman, presented with severe intractable seizure disorder and worsening left hand function and incoordination after meningioma resection and cranioplasty 9 years earlier. Magnetic resonance imaging (MRI) demonstrated interval progression of macrocystic encephalomalacia involving the right supplementary motor area, with fluid-attenuated inversion recovery signal extending posteriorly into the right primary motor cortex. Both computed tomography and MRI suggested potential tethering of the cortex to the overlying cranioplasty mesh. Because of the progressive nature of her condition, the decision was made to surgically remove the tethered mesh. LESSONS: De-tethering brain parenchyma from surgical mesh requires careful microdissection and judicious use of electrocautery to minimize further tissue damage and preserve neurological function. This inadvertent complication evinces the importance of using dural substitutes when unable to primarily repair the dura to prevent scarring and tethering of neural tissues to synthetic cranioplasty materials.

Tissue and Stem Cell Sourced Extracellular Vesicle Communications with Microglia.

Extracellular vesicles (EVs), nano- to micro- sized vesicles released from cells, have garnered attention in recent years for their role in intercellular communication. Specifically, EVs from various cell sources including stem cells, have shown to have an exacerbatory or therapeutic effect in the content of pro- and anti-inflammatory environments through their interaction with immune recipient cells. This review aims to the coalescence information surrounding EVs derived from various sources and their interaction with microglia in neutral, anti, and pro- inflammatory environments. Overall, in homeostatic environments, EVs from many CNS lineages have been shown to have specific interactions with recipient microglia. In complex inflammatory environments, such as the tumor micro-environment (TME), EVs have been shown to further influence immune dampening through transition of microglia to a more M2-like phenotype. While not advantageous in the TME, this effect can be harnessed therapeutically in proinflammatory neurological conditions such as stroke, Alzheimer's, and Parkinson's. EVs derived from various stem cell and non-stem cell derived sources were found to attenuate proinflammatory responses in microglia in in vitro and in vivo models of these conditions. EVs loaded with anti-inflammatory therapeutics furthered this anti-inflammatory effect on recipient microglia. Graphical Abstract Extracellular Vesicles (EVs) from multiple cells types modulate microglial polarization. Cartoon depicting common ways microglia are activated through inflammatory and disease processes. EVs, derived from stem and non-stem sources, have been shown to attenuate proinflammatory responses in in vitro and in vivo.

Semi-Automated Cell and Tissue Analyses Reveal Regionally Specific Morphological Alterations of Immune and Neural Cells in a Porcine Middle Cerebral Artery Occlusion Model of Stroke.

Histopathological analysis of cellular changes in the stroked brain provides critical information pertaining to inflammation, cell death, glial scarring, and other dynamic injury and recovery responses. However, commonly used manual approaches are hindered by limitations in speed, accuracy, bias, and the breadth of morphological information that can be obtained. Here, a semi-automated high-content imaging (HCI) and CellProfiler histological analysis method was developed and used in a Yucatan miniature pig permanent middle cerebral artery occlusion (pMCAO) model of ischemic stroke to overcome these limitations. Evaluation of 19 morphological parameters in IBA1+ microglia/macrophages, GFAP+ astrocytes, NeuN+ neuronal, FactorVIII+ vascular endothelial, and DCX+ neuroblast cell areas was conducted on porcine brain tissue 4 weeks post pMCAO. Out of 19 morphological parameters assessed in the stroke perilesional and ipsilateral hemisphere regions (38 parameters), a significant change in 38 38 measured IBA1+ parameters, 34 38   GFAP+ parameters, 32 38 NeuN+ parameters, 31 38 FactorVIII+ parameters, and 28 38 DCX+ parameters were observed in stroked vs. non-stroked animals. Principal component analysis (PCA) and correlation analyses demonstrated that stroke-induced significant and predictable morphological changes that demonstrated strong relationships between IBA1+, GFAP+, and NeuN+ areas. Ultimately, this unbiased, semi-automated HCI and CellProfiler histopathological analysis approach revealed regional and cell specific morphological signatures of immune and neural cells after stroke in a highly translational porcine model. These identified features can provide information of disease pathogenesis and evolution with high resolution, as well as be used in therapeutic screening applications.

Magnetic Resonance Imaging and Gait Analysis Indicate Similar Outcomes Between Yucatan and Landrace Porcine Ischemic Stroke Models.

The Stroke Therapy Academic Industry Roundtable (STAIR) has recommended that novel therapeutics be tested in a large animal model with similar anatomy and physiology to humans. The pig is an attractive model due to similarities in brain size, organization, and composition relative to humans. However, multiple pig breeds have been used to study ischemic stroke with potentially differing cerebral anatomy, architecture and, consequently, ischemic stroke pathologies. The objective of this study was to characterize brain anatomy and assess spatiotemporal gait parameters in Yucatan (YC) and Landrace (LR) pigs pre- and post-stroke using magnetic resonance imaging (MRI) and gait analysis, respectively. Ischemic stroke was induced via permanent middle cerebral artery occlusion (MCAO). MRI was performed pre-stroke and 1-day post-stroke. Structural and diffusion-tensor sequences were performed at both timepoints and analyzed for cerebral characteristics, lesion diffusivity, and white matter changes. Spatiotemporal and relative pressure gait measurements were collected pre- and 2-days post-stroke to characterize and compare acute functional deficits. The results from this study demonstrated that YC and LR pigs exhibit differences in gross brain anatomy and gait patterns pre-stroke with MRI and gait analysis showing statistical differences in the majority of parameters. However, stroke pathologies in YC and LR pigs were highly comparable post-stroke for most evaluated MRI parameters, including lesion volume and diffusivity, hemisphere swelling, ventricle compression, caudal transtentorial and foramen magnum herniation, showing no statistical difference between the breeds. In addition, post-stroke changes in velocity, cycle time, swing percent, cadence, and mean hoof pressure showed no statistical difference between the breeds. These results indicate significant differences between pig breeds in brain size, anatomy, and motor function pre-stroke, yet both demonstrate comparable brain pathophysiology and motor outcomes post-stroke. The conclusions of this study suggest pigs of these different breeds generally show a similar ischemic stroke response and findings can be compared across porcine stroke studies that use different breeds.

Neural Stem Cell Extracellular Vesicles Disrupt Midline Shift Predictive Outcomes in Porcine Ischemic Stroke Model.

Magnetic resonance imaging (MRI) is a clinically relevant non-invasive imaging tool commonly utilized to assess stroke progression in real time. This study investigated the utility of MRI as a predictive measure of clinical and functional outcomes when a stroke intervention is withheld or provided, in order to identify biomarkers for stroke functional outcome under these conditions. Fifteen MRI and ninety functional parameters were measured in a middle cerebral artery occlusion (MCAO) porcine ischemic stroke model. Multiparametric analysis of correlations between MRI measurements and functional outcome was conducted. Acute axial and coronal midline shift (MLS) at 24 h post-stroke were associated with decreased survival and recovery measured by modified Rankin scale (mRS) and were significantly correlated with 52 measured acute (day 1 post) and chronic (day 84 post) gait and behavior impairments in non-treated stroked animals. These results suggest that MLS may be an important non-invasive biomarker that can be used to predict patient outcomes and prognosis as well as guide therapeutic intervention and rehabilitation in non-treated animals and potentially human patients that do not receive interventional treatments. Neural stem cell-derived extracellular vesicle (NSC EV) was a disruptive therapy because NSC EV administration post-stroke disrupted MLS correlations observed in non-treated stroked animals. MLS was not associated with survival and functional outcomes in NSC EV-treated animals. In contrast to untreated animals, NSC EVs improved stroked animal outcomes regardless of MLS severity.

Extracellular Vesicles Mediate Neuroprotection and Functional Recovery after Traumatic Brain Injury.

The lack of effective therapies for moderate-to-severe traumatic brain injuries (TBIs) leaves patients with lifelong disabilities. Neural stem cells (NSCs) have demonstrated great promise for neural repair and regeneration. However, direct evidence to support their use as a cell replacement therapy for neural injuries is currently lacking. We hypothesized that NSC-derived extracellular vesicles (NSC EVs) mediate repair indirectly after TBI by enhancing neuroprotection and therapeutic efficacy of endogenous NSCs. We evaluated the short-term effects of acute intravenous injections of NSC EVs immediately following a rat TBI. Male NSC EV-treated rats demonstrated significantly reduced lesion sizes, enhanced presence of endogenous NSCs, and attenuated motor function impairments 4 weeks post-TBI, when compared with vehicle- and TBI-only male controls. Although statistically not significant, we observed a therapeutic effect of NSC EVs on brain lesion volume, nestin expression, and behavioral recovery in female subjects. Our study demonstrates the neuroprotective and functional benefits of NSC EVs for treating TBI and points to gender-dependent effects on treatment outcomes, which requires further investigation.

Human Neural Stem Cell Extracellular Vesicles Improve Recovery in a Porcine Model of Ischemic Stroke.

BACKGROUND AND PURPOSE: Recent work from our group suggests that human neural stem cell-derived extracellular vesicle (NSC EV) treatment improves both tissue and sensorimotor function in a preclinical thromboembolic mouse model of stroke. In this study, NSC EVs were evaluated in a pig ischemic stroke model, where clinically relevant end points were used to assess recovery in a more translational large animal model. METHODS: Ischemic stroke was induced by permanent middle cerebral artery occlusion (MCAO), and either NSC EV or PBS treatment was administered intravenously at 2, 14, and 24 hours post-MCAO. NSC EV effects on tissue level recovery were evaluated via magnetic resonance imaging at 1 and 84 days post-MCAO. Effects on functional recovery were also assessed through longitudinal behavior and gait analysis testing. RESULTS: NSC EV treatment was neuroprotective and led to significant improvements at the tissue and functional levels in stroked pigs. NSC EV treatment eliminated intracranial hemorrhage in ischemic lesions in NSC EV pigs (0 of 7) versus control pigs (7 of 8). NSC EV-treated pigs exhibited a significant decrease in cerebral lesion volume and decreased brain swelling relative to control pigs 1-day post-MCAO. NSC EVs significantly reduced edema in treated pigs relative to control pigs, as assessed by improved diffusivity through apparent diffusion coefficient maps. NSC EVs preserved white matter integrity with increased corpus callosum fractional anisotropy values 84 days post-MCAO. Behavior and mobility improvements paralleled structural changes as NSC EV-treated pigs exhibited improved outcomes, including increased exploratory behavior and faster restoration of spatiotemporal gait parameters. CONCLUSIONS: This study demonstrated for the first time that in a large animal model novel NSC EVs significantly improved neural tissue preservation and functional levels post-MCAO, suggesting NSC EVs may be a paradigm changing stroke therapeutic.

Minocycline in Acute Cerebral Hemorrhage: An Early Phase Randomized Trial.

BACKGROUND AND PURPOSE: Minocycline is under investigation as a neurovascular protective agent for stroke. This study evaluated the pharmacokinetic, anti-inflammatory, and safety profile of minocycline after intracerebral hemorrhage. METHODS: This study was a single-site, randomized controlled trial of minocycline conducted from 2013 to 2016. Adults ≥18 years with primary intracerebral hemorrhage who could have study drug administered within 24 hours of onset were included. Patients received 400 mg of intravenous minocycline, followed by 400 mg minocycline oral daily for 4 days. Serum concentrations of minocycline after the last oral dose and biomarkers were sampled to determine the peak concentration, half-life, and anti-inflammatory profile. RESULTS: A total of 16 consecutive eligible patients were enrolled, with 8 randomized to minocycline. Although the literature supports a time to peak concentration (Tmax) of 1 hour for oral minocycline, the Tmax was estimated to be at least 6 hours in this cohort. The elimination half-life (available on 7 patients) was 17.5 hours (SD±3.5). No differences were observed in inflammatory biomarkers, hematoma volume, or perihematomal edema. Concentrations remained at neuroprotective levels (>3 mg/L) throughout the dosing interval in 5 of 7 patients. CONCLUSIONS: In intracerebral hemorrhage, a 400 mg dose of minocycline was safe and achieved neuroprotective serum concentrations. However, oral administration led to delayed absorption in these critically ill patients and should not be used when rapid, high concentrations are desired. Given the safety and pharmacokinetic profile of minocycline in intracerebral hemorrhage and promising data in the treatment of ischemic stroke, intravenous minocycline is an excellent candidate for a prehospital treatment trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01805895.