Endovascular thrombectomy plus medical care versus medical care alone for large ischaemic stroke: 1-year outcomes of the SELECT2 trial.

BACKGROUND: Multiple randomised trials have shown efficacy and safety of endovascular thrombectomy in patients with large ischaemic stroke. The aim of this study was to evaluate long-term (ie, at 1 year) evidence of benefit of thrombectomy for these patients. METHODS: SELECT2 was a phase 3, open-label, international, randomised controlled trial with blinded endpoint assessment, conducted at 31 hospitals in the USA, Canada, Spain, Switzerland, Australia, and New Zealand. Patients aged 18-85 years with ischaemic stroke due to proximal occlusion of the internal carotid artery or of the first segment of the middle cerebral artery, showing large ischaemic core on non-contrast CT (Alberta Stroke Program Early Computed Tomographic Score of 3-5 [range 0-10, with lower values indicating larger infarctions]) or measuring 50 mL or more on CT perfusion and MRI, were randomly assigned, within 24 h of ischaemic stroke onset, to thrombectomy plus medical care or to medical care alone. The primary outcome for this analysis was the ordinal modified Rankin Scale (range 0-6, with higher scores indicating greater disability) at 1-year follow-up in an intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT03876457) and is completed. FINDINGS: The trial was terminated early for efficacy at the 90-day follow-up after 352 patients had been randomly assigned (178 to thrombectomy and 174 to medical care only) between Oct 11, 2019, and Sept 9, 2022. Thrombectomy significantly improved the 1-year modified Rankin Scale score distribution versus medical care alone (Wilcoxon-Mann-Whitney probability of superiority 0·59 [95% CI 0·53-0·64]; p=0·0019; generalised odds ratio 1·43 [95% CI 1·14-1·78]). At the 1-year follow-up, 77 (45%) of 170 patients receiving thrombectomy had died, compared with 83 (52%) of 159 patients receiving medical care only (1-year mortality relative risk 0·89 [95% CI 0·71-1·11]). INTERPRETATION: In patients with ischaemic stroke due to a proximal occlusion and large core, thrombectomy plus medical care provided a significant functional outcome benefit compared with medical care alone at 1-year follow-up. FUNDING: Stryker Neurovascular.

Targeting SRSF3 restores immune mRNA translation in microglia/macrophages following cerebral ischemia.

We recently described a novel ribosome-based regulatory mechanism/checkpoint that controls innate immune gene translation and microglial activation in non-sterile inflammation orchestrated by RNA binding protein SRSF3. Here we describe a role of SRSF3 in the regulation of microglia/macrophage activation phenotypes after experimental stroke. Using a model-system for analysis of the dynamic translational state of microglial ribosomes we show that 24 h after stroke highly upregulated immune mRNAs are not translated resulting in a marked dissociation of mRNA and protein networks in activated microglia/macrophages. Next, microglial activation after stroke was characterized by a robust increase in pSRSF3/SRSF3 expression levels. Targeted knockdown of SRSF3 using intranasal delivery of siRNA 24 h after stroke caused a marked knockdown of endogenous protein. Further analyses revealed that treatment with SRSF3-siRNA alleviated translational arrest of selected genes and induced a transient but significant increase in innate immune signaling and IBA1+ immunoreactivity peaking 5 days after initial injury. Importantly, delayed SRSF3-mediated increase in immune signaling markedly reduced the size of ischemic lesion measured 7 days after stroke. Together, our findings suggest that targeting SRSF3 and immune mRNA translation may open new avenues for molecular/therapeutic reprogramming of innate immune response after ischemic injury.

A2 reactive astrocyte-derived exosomes alleviate cerebral ischemia-reperfusion injury by delivering miR-628.

Ischemia and hypoxia activate astrocytes into reactive types A1 and A2, which play roles in damage and protection, respectively. However, the function and mechanism of A1 and A2 astrocyte exosomes are unknown. After astrocyte exosomes were injected into the lateral ventricle, infarct volume, damage to the blood-brain barrier (BBB), apoptosis and the expression of microglia-related proteins were measured. The dual luciferase reporter assay was used to detect the target genes of miR-628, and overexpressing A2-Exos overexpressed and knocked down miR-628 were constructed. qRT-PCR, western blotting and immunofluorescence staining were subsequently performed. A2-Exos obviously reduced the infarct volume, damage to the BBB and apoptosis and promoted M2 microglial polarization. RT-PCR showed that miR-628 was highly expressed in A2-Exos. Dual luciferase reporter assays revealed that NLRP3, S1PR3 and IRF5 are target genes of miR-628. After miR-628 was overexpressed or knocked down, the protective effects of A2-Exos increased or decreased, respectively. A2-Exos reduced pyroptosis and BBB damage and promoted M2 microglial polarization through the inhibition of NLRP3, S1PR3 and IRF5 via the delivery of miR-628. This study explored the mechanism of action of A2-Exos and provided new therapeutic targets and concepts for treating cerebral ischemia.

Cathodal bilateral transcranial direct-current stimulation regulates selenium to confer neuroprotection after rat cerebral ischaemia-reperfusion injury.

Non-invasive transcranial direct-current stimulation (tDCS) is a safe ischaemic stroke therapy. Cathodal bilateral tDCS (BtDCS) is a modified tDCS approach established by us recently. Because selenium (Se) plays a crucial role in cerebral ischaemic injury, we investigated whether cathodal BtDCS conferred neuroprotection via regulating Se-dependent signalling in rat cerebral ischaemia-reperfusion (I/R) injury. We first showed that the levels of Se and its transport protein selenoprotein P (SEPP1) were reduced in the rat cortical penumbra following I/R, whereas cathodal BtDCS prevented the reduction of Se and SEPP1. Interestingly, direct-current stimulation (DCS) increased SEPP1 level in cultured astrocytes subjected to oxygen-glucose deprivation reoxygenation (OGD/R) but had no effect on SEPP1 level in OGD/R-insulted neurons, indicating that DCS may increase Se in ischaemic neurons by enhancing the synthesis and secretion of SEPP1 in astrocytes. We then revealed that DCS reduced the number of injured mitochondria in OGD/R-insulted neurons cocultured with astrocytes. DCS and BtDCS prevented the reduction of the mitochondrial quality-control signalling, vesicle-associated membrane protein 2 (VAMP2) and syntaxin-4 (STX4), in OGD/R-insulted neurons cocultured with astrocytes and the ischaemic brain respectively. Under the same experimental conditions, downregulation of SEPP1 blocked DCS- and BtDCS-induced upregulation of VAMP2 and STX4. Finally, we demonstrated that cathodal BtDCS increased Se to reduce infract volume following I/R. Together, the present study uncovered a molecular mechanism by which cathodal BtDCS confers neuroprotection through increasing SEPP1 in astrocytes and subsequent upregulation of SEPP1/VAMP2/STX4 signalling in ischaemic neurons after rat cerebral I/R injury. KEY POINTS: Cathodal bilateral transcranial direct-current stimulation (BtDCS) prevents the reduction of selenium (Se) and selenoprotein P in the ischaemic penumbra. Se plays a crucial role in cerebral ischaemia injury. Direct-current stimulation reduces mitochondria injury and blocks the reduction of vesicle-associated membrane protein 2 (VAMP2) and syntaxin-4 (STX4) in oxygen-glucose deprivation reoxygenation-insulted neurons following coculturing with astrocytes. Cathodal BtDCS regulates Se/VAMP2/STX4 signalling to confer neuroprotection after ischaemia.

What Is a Meaningful Difference When Using Infarct Volume as the Primary Outcome?: Results From the HERMES Database.

BACKGROUND: Ischemic stroke lesion volume at follow-up is an important surrogate outcome for acute stroke trials. We aimed to assess which differences in 48-hour lesion volume translate into meaningful clinical differences. METHODS: We used pooled data from 7 trials investigating the efficacy of endovascular treatment for anterior circulation large vessel occlusion in acute ischemic stroke. We assessed 48-hour lesion volume follow-up computed tomography or magnetic resonance imaging. The primary outcome was a good functional outcome, defined as modified Rankin Scale (mRS) scores of 0 to 2. We performed multivariable logistic regression to predict the probability of achieving mRS scores of 0 to 2 and determined the differences in 48-hour lesion volume that correspond to a change of 1%, 5%, and 10% in the adjusted probability of achieving mRS scores of 0 to 2. RESULTS: In total, 1665/1766 (94.2%) patients (median age, 68 [interquartile range, 57-76] years, 781 [46.9%] female) had information on follow-up ischemic lesion volume. Computed tomography was used for follow-up imaging in 83% of patients. The median 48-hour lesion volume was 41 (interquartile range, 14-120) mL. We observed a linear relationship between 48-hour lesion volume and mRS scores of 0 to 2 for adjusted probabilities between 65% and 20%/volumes <80 mL, although the curve sloped off for lower mRS scores of 0-2 probabilities/higher volumes. The median differences in 48-hour lesion volume associated with a 1%, 5%, and 10% increase in the probability of mRS scores of 0 to 2 for volumes <80 mL were 2 (interquartile range, 2-3), 10 (9-11), and 20 (18-23) mL, respectively. We found comparable associations when assessing computed tomography and magnetic resonance imaging separately. CONCLUSIONS: A difference of 2, 10, and 20 mL in 48-hour lesion volume, respectively, is associated with a 1%, 5%, and 10% absolute increase in the probability of achieving good functional outcome. These results can inform the design of future stroke trials that use 48-hour lesion volume as the primary outcome.

Expanding the Treatable Imaging Profile in Patients With Large Ischemic Stroke: Subanalysis From a Randomized Clinical Trial.

BACKGROUND: We aimed to examine the boundary of the ischemic core volume in patients undergoing endovascular thrombectomy (EVT) versus those receiving medical management to determine the minimum optimal size for favorable treatment outcomes. METHODS: This is a prespecified substudy of the RESCUE-Japan LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism-Japan Large Ischemic Core Trial). Patients with large vessel occlusion were enrolled between November 2018 and September 2021 with a National Institutes of Health Stroke Scale score of at least 6 on admission and an Alberta Stroke Program Early Computed Tomography Score value of 3 to 5. We investigated the correlation between optimal quantified ischemic core volume, assessed solely using magnetic resonance diffusion-weighted imaging, and functional outcomes (modified Rankin Scale score, 0-3) at 90 days by predictive marginal plots. Final infarct volume and safety outcomes (symptomatic intracerebral hemorrhage and mortality) were also assessed. RESULTS: Of the 203 cases, 168 patients (85 in the EVT group versus 83 in the medical management group) were included. The median (interquartile range) core volume was 94 (65-160) mL in patients with EVT and 115 (71-141) mL in the medical management group (P=0.72). The predictive marginal probabilities of the 2 groups intersected at 128 mL for estimating functional outcomes. Symptomatic intracerebral hemorrhage and mortality within 90 days had overlay margins through all core volumes in both groups. The median final infarct volume (interquartile range) was smaller in the EVT group (142 [80-223] mL versus 211 [123-289] mL in the medical management group; P<0.001). CONCLUSIONS: In this prespecified analysis of a randomized clinical trial involving patients with large ischemic strokes, patients with an estimated core volume of up to 128 mL on diffusion-weighted imaging benefit from EVT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03702413.

Outcomes of Bridging Intravenous Thrombolysis Versus Endovascular Therapy Alone in Late-Window Acute Ischemic Stroke.

BACKGROUND: Studies comparing bridging intravenous thrombolysis (IVT) with direct endovascular therapy (EVT) in patients with acute ischemic stroke who present late are limited. We aimed to compare the clinical outcomes and safety of bridging IVT in patients with acute ischemic stroke due to anterior circulation large vessel occlusion who underwent EVT 6 to 24 hours after time last known well. METHODS: We enrolled patients with anterior circulation large vessel occlusion stroke and a National Institutes of Health Stroke Scale score of ≥6 from 20 centers across 10 countries in the multicenter retrospective CLEAR study (CT for Late Endovascular Reperfusion) between January 2014 and May 2022. We used inverse probability of treatment weighting modeling adjusted for clinical and imaging confounders to compare functional outcomes, reperfusion success, symptomatic intracranial hemorrhage, and mortality between EVT patients with and without prior IVT. RESULTS: Of 5098 patients screened for eligibility, we included 2749 patients, of whom 549 received bridging IVT before EVT. The timing of IVT was not recorded. Witnessed stroke onset and transfer rates were higher in the bridging IVT group (25% versus 12% and 77% versus 55%, respectively, P value for both <0.0001), and time intervals between stroke onset and treatment were shorter (time last known well-start of EVT median 560 minutes [interquartile range, 432-791] versus 724 minutes [interquartile range, 544-912]; P<0.0001). After adjustment for confounders, there was no difference in functional outcome at 3 months (adjusted common odds ratio for modified Rankin Scale shift, 1.03 [95% CI, 0.89-1.19]; P=0.72) or successful reperfusion (adjusted odds ratio, 1.19 [95% CI, 0.81-1.75]; P=0.39). There were no safety concerns associated with bridging IVT versus direct EVT (symptomatic intracranial hemorrhage: adjusted odds ratio, 0.75 [95% CI, 0.38-1.48]; P=0.40; mortality: adjusted odds ratio, 1.14 [95% CI, 0.89-1.46]; P=0.31). Results were unchanged when the analysis was limited to patients who received IVT >6 hours after last known well. CONCLUSIONS: In patients with an anterior circulation large vessel occlusion stroke who underwent EVT 6 to 24 hours from last known well, bridging IVT was not associated with a difference in outcomes compared with direct EVT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04096248.

Combining Early Ischemic Change and Collateral Extent for Functional Outcomes After Endovascular Therapy: An Analysis From AcT Trial.

BACKGROUND: Early ischemic change and collateral extent are colinear with ischemic core volume (ICV). We investigated the relationship between a combined score using the Alberta Stroke Program Early Computed Tomography Score and multiphase computed tomography angiography (mCTA) collateral extent, named mCTA-ACE score, on functional outcomes in endovascular therapy-treated patients. METHODS: We performed a post hoc analysis of a subset of endovascular therapy-treated patients from the Alteplase Compared to Tenecteplase trial which was conducted between December 2019 and January 2022 at 22 centers across Canada. Ten-point mCTA collateral corresponding to M2 to M6 regions of the Alberta Stroke Program Early Computed Tomography Score grid was evaluated as 0 (poor), 1 (moderate), or 2 (normal) and additively combined with the 10-point Alberta Stroke Program Early Computed Tomography Score to produce a 20-point mCTA-ACE score. We investigated the association of mCTA-ACE score with modified Rankin Scale score ≤2 and return to prestroke level of function at 90 to 120 days using mixed-effects logistic regression. In the subset of patients who underwent baseline computed tomography perfusion imaging, we compared the mCTA-ACE score and ICV for outcome prediction. RESULTS: Among 1577 intention-to-treat population in the trial, 368 (23%; 179 men; median age, 73 years) were included, with Alberta Stroke Program Early Computed Tomography Score, mCTA collateral, and combination of both (mCTA-ACE score: median [interquartile range], 8 [7-10], 9 [8-10], and 17 [16-19], respectively). The probability of modified Rankin Scale score ≤2 and return to prestroke level of function increased for each 1-point increase in mCTA-ACE score (odds ratio, 1.16 [95% CI, 1.06-1.28] and 1.22 [95% CI, 1.06-1.40], respectively). Among 173 patients in whom computed tomography perfusion data was assessable, the mCTA-ACE score was inversely correlated with ICV (ρ=-0.46; P<0.01). The mCTA-ACE score was comparable to ICV to predict a modified Rankin Scale score ≤2 and return to prestroke level of function (C statistics 0.71 versus 0.69 and 0.68 versus 0.64, respectively). CONCLUSIONS: The mCTA-ACE score had a significant positive association with functional outcomes after endovascular therapy and had a similar predictive performance as ICV.

Research progress on immune-related therapeutic targets of brain injury caused by cerebral ischemia.

Stroke is the second leading cause of death worldwide and a leading cause of disability. The innate immune response occurs immediately after cerebral ischemia, resulting in adaptive immunity. More and more experimental evidence has proved that the immune response caused by cerebral ischemia plays an important role in early brain injury and later the recovery of brain injury. Innate immune cells and adaptive cells promote the occurrence of cerebral ischemic injury but also protect brain cells. A large number of studies have shown that cytokines and immune-related substances also have dual functions of promoting injury, reducing injury, or promoting injury recovery in the later stage of cerebral ischemia. They can be an important target for treating cerebral ischemic recovery. Therefore, this study discussed the immune cells, cytokines, and immune-related substances with dual roles in cerebral ischemia and summarized the therapeutic targets of cerebral ischemia. To explore more effective methods to treat cerebral ischemia, promote the recovery of brain function, and improve the prognosis of patients.

Sex differences in acute stroke metrics and outcome dependent on COVID status.

BACKGROUND AND PURPOSE: Biological sex is known to have an impact on quality metrics of acute stroke. We aimed to determine whether COVID positivity accentuates this effect and constitutes worse outcome. METHODS: The present analysis was based on the Global COVID-19 Stroke Registry, a retrospective, international, cohort study of consecutive ischemic stroke patients receiving intravenous thrombolysis and/or endovascular thrombectomy between 1 March 2020 and 30 June 2021. We investigated differences between the sexes in patient characteristics, acute stroke metrics as well as post-stroke outcome in COVID-positive and COVID-negative stroke patients undergoing acute revascularization procedures. RESULTS: A total of 15,128 patients from 106 centers were recorded in the Global COVID-19 Stroke Registry, 853 (5.6%) of whom were COVID-positive. Overall, COVID-positive individuals were treated significantly slower according to every acute stroke metric compared to COVID-negative patients. We were able to show that key quality indicators in acute stroke treatment were unfavorable for COVID-negative women compared to men (last-seen-well-to-door time + 11 min in women). Furthermore, COVID-negative women had worse 3-month outcomes (3-month modified Rankin Scale score [interquartile range] 3.0 [4.0] vs. 2.0 [3.0]; p < 0.01), even after adjusting for confounders. In COVID-positive individuals no such difference between the sexes, either in acute management metrics or in 3-month outcome, was seen. CONCLUSION: Known sex-related differences in acute stroke management exist and extend to times of crisis. Nevertheless, if patients were COVID-19-positive at stroke onset, women and men were treated the same, which could be attributed to structured treatment pathways.

Providing clinical context to the spatio-temporal analysis of 4D CT perfusion to predict acute ischemic stroke lesion outcomes.

Acute ischemic stroke is a leading cause of mortality and morbidity worldwide. Timely identification of the extent of a stroke is crucial for effective treatment, whereas spatio-temporal (4D) Computed Tomography Perfusion (CTP) imaging is playing a critical role in this process. Recently, the first deep learning-based methods that leverage the full spatio-temporal nature of perfusion imaging for predicting stroke lesion outcomes have been proposed. However, clinical information is typically not integrated into the learning process, which may be helpful to improve the tissue outcome prediction given the known influence of various factors (i.e., physiological, demographic, and treatment factors) on lesion growth. Cross-attention, a multimodal fusion strategy, has been successfully used to combine information from multiple sources, but it has yet to be applied to stroke lesion outcome prediction. Therefore, this work aimed to develop and evaluate a novel multimodal and spatio-temporal deep learning model that utilizes cross-attention to combine information from 4D CTP and clinical metadata simultaneously to predict stroke lesion outcomes. The proposed model was evaluated using a dataset of 70 acute ischemic stroke patients, demonstrating significantly improved volume estimates (mean error = 19 ml) compared to a baseline unimodal approach (mean error = 35 ml, p< 0.05). The proposed model allows generating attention maps and counterfactual outcome scenarios to investigate the relevance of clinical variables in predicting stroke lesion outcomes at a patient level, helping to provide a better understanding of the model's decision-making process.

Impact of temporal resolution on perfusion metrics, therapy decision, and radiation dose reduction in brain CT perfusion in patients with suspected stroke.

PURPOSE: CT perfusion of the brain is a powerful tool in stroke imaging, though the radiation dose is rather high. Several strategies for dose reduction have been proposed, including increasing the intervals between the dynamic scans. We determined the impact of temporal resolution on perfusion metrics, therapy decision, and radiation dose reduction in brain CT perfusion from a large dataset of patients with suspected stroke. METHODS: We retrospectively included 3555 perfusion scans from our clinical routine dataset. All cases were processed using the perfusion software VEOcore with a standard sampling of 1.5 s, as well as simulated reduced temporal resolution of 3.0, 4.5, and 6.0 s by leaving out respective time points. The resulting perfusion maps and calculated volumes of infarct core and mismatch were compared quantitatively. Finally, hypothetical decisions for mechanical thrombectomy following the DEFUSE-3 criteria were compared. RESULTS: The agreement between calculated volumes for core (ICC = 0.99, 0.99, and 0.98) and hypoperfusion (ICC = 0.99, 0.99, and 0.97) was excellent for all temporal sampling schemes. Of the 1226 cases with vascular occlusion, 14 (1%) for 3.0 s sampling, 23 (2%) for 4.5 s sampling, and 63 (5%) for 6.0 s sampling would have been treated differently if the DEFUSE-3 criteria had been applied. Reduction of temporal resolution to 3.0 s, 4.5 s, and 6.0 s reduced the radiation dose by a factor of 2, 3, or 4. CONCLUSION: Reducing the temporal sampling of brain perfusion CT has only a minor impact on image quality and treatment decision, but significantly reduces the radiation dose to that of standard non-contrast CT.

MRI of cerebral oedema in ischaemic stroke and its current use in routine clinical practice.

Currently, with the knowledge of the role of collateral circulation in the development of cerebral ischaemia, traditional therapeutic windows are being prolonged, with time not being the only criterion. Instead, a more personalised approach is applied to select additional patients who might benefit from active treatment. This review briefly describes the current knowledge of the pathophysiology of the development of early ischaemic changes, the capabilities of MRI to depict such changes, and the basics of the routinely used imaging techniques broadly available for the assessment of individual phases of cerebral ischaemia, and summarises the possible clinical use of routine MR imaging, including patient selection for active treatment and assessment of the outcome on the basis of imaging.

Therapeutic gene delivery by mesenchymal stem cell for brain ischemia damage: Focus on molecular mechanisms in ischemic stroke.

Cerebral ischemic damage is prevalent and the second highest cause of death globally across patient populations; it is as a substantial reason of morbidity and mortality. Mesenchymal stromal cells (MSCs) have garnered significant interest as a potential treatment for cerebral ischemic damage, as shown in ischemic stroke, because of their potent intrinsic features, which include self-regeneration, immunomodulation, and multi-potency. Additionally, MSCs are easily obtained, isolated, and cultured. Despite this, there are a number of obstacles that hinder the effectiveness of MSC-based treatment, such as adverse microenvironmental conditions both in vivo and in vitro. To overcome these obstacles, the naïve MSC has undergone a number of modification processes to enhance its innate therapeutic qualities. Genetic modification and preconditioning modification (with medications, growth factors, and other substances) are the two main categories into which these modification techniques can be separated. This field has advanced significantly and is still attracting attention and innovation. We examine these cutting-edge methods for preserving and even improving the natural biological functions and therapeutic potential of MSCs in relation to adhesion, migration, homing to the target site, survival, and delayed premature senescence. We address the use of genetically altered MSC in stroke-induced damage. Future strategies for improving the therapeutic result and addressing the difficulties associated with MSC modification are also discussed.

Anti-ferroptosis exosomes engineered for targeting M2 microglia to improve neurological function in ischemic stroke.

BACKGROUND: Stroke is a devastating disease affecting populations worldwide and is the primary cause of long-term disability. The inflammatory storm plays a crucial role in the progression of stroke. In the acute phase of ischemic stroke, there is a transient increase in anti-inflammatory M2 microglia followed by a rapid decline. Due to the abundant phospholipid in brain tissue, lipid peroxidation is a notable characteristic of ischemia/reperfusion (I/R), constituting a structural foundation for ferroptosis in M2 microglia. Slowing down the decrease in M2 microglia numbers and controlling the inflammatory microenvironment holds significant potential for enhancing stroke recovery. RESULTS: We found that the ferroptosis inhibitor can modulate inflammatory response in MCAO mice, characterizing that the level of M2 microglia-related cytokines was increased. We then confirmed that different subtypes of microglia exhibit distinct sensitivities to I/R-induced ferroptosis. Adipose-derived stem cells derived exosome (ADSC-Exo) effectively decreased the susceptibility of M2 microglia to ferroptosis via Fxr2/Atf3/Slc7a11, suppressing the inflammatory microenvironment and promoting neuronal survival. Furthermore, through plasmid engineering, a more efficient M2 microglia-targeted exosome, termed M2pep-ADSC-Exo, was developed. In vivo and in vitro experiments demonstrated that M2pep-ADSC-Exo exhibits significant targeting specificity for M2 microglia, further inhibiting M2 microglia ferroptosis and improving neurological function in ischemic stroke mice. CONCLUSION: Collectively, we illustrated a novel potential therapeutic mechanism that Fxr2 in ADSC-Exo could alleviate the M2 microglia ferroptosis via regulating Atf3/Slc7all expression, hence inhibiting the inflammatory microenvironment, improving neurofunction recovery in cerebral I/R injury. We obtained a novel exosome, M2pep-ADSC-Exo, through engineered modification, which exhibits improved targeting capabilities toward M2 microglia. This provides a new avenue for the treatment of stroke.

Chemical angioplasty vs. balloon plus chemical angioplasty for delayed cerebral ischemia: a pilot study of PbtO2 outcomes.

BACKGROUND: Delayed cerebral ischaemia (DCI) is a major cause of morbidity and mortality after aneurysmal subarachnoid haemorrhage (aSAH). Chemical angioplasty (CA) and transluminal balloon angioplasty (TBA) are used to treat patients with refractory vasospasm causing DCI. Multi-modal monitoring including brain tissue oxygenation (PbtO2) is routinely used at this centre for early detection and management of DCI following aSAH. In this single-centre pilot study, we are comparing these two treatment modalities and their effects on PbtO2. METHODS: Retrospective case series of patients with DCI who had PbtO2 monitoring as part of their multimodality monitoring and underwent either CA or TBA combined with CA. PbtO2 values were recorded from intra-parenchymal Raumedic NEUROVENT-PTO® probes. Data were continuously collected and downloaded as second-by-second data. Comparisons were made between pre-angioplasty PbtO2 and post-angioplasty PbtO2 median values (4 h before angioplasty, 4 h after and 12 h after). RESULTS: There were immediate significant improvements in PbtO2 at the start of intervention in both groups. PbtO2 then increased by 13 mmHg in the CA group and 15 mmHg in the TBA plus CA group in the first 4 h post-intervention. This improvement in PbtO2 was sustained for the TBA plus CA group but not the CA group. CONCLUSION: Combined balloon plus chemical angioplasty results in more sustained improvement in brain tissue oxygenation compared with chemical angioplasty alone. Our findings suggest that PbtO2 is a useful tool for monitoring the response to angioplasty in vasospasm.

Mechanisms by Which Electroacupuncture Alleviates Neurovascular Unit Injury after Ischemic Stroke: A Potential Therapeutic Strategy for Ischemic Brain Injury after Stroke.

Stroke is the most common cerebrovascular disease and one of the leading causes of death and disability worldwide. The current conventional treatment for stroke involves increasing cerebral blood flow and reducing neuronal damage; however, there are no particularly effective therapeutic strategies for rehabilitation after neuronal damage. Therefore, there is an urgent need to identify a novel alternative therapy for stroke. Acupuncture has been applied in China for 3000 years and has been widely utilized in the treatment of cerebrovascular diseases. Accumulating evidence has revealed that acupuncture holds promise as a potential therapeutic strategy for stroke. In our present review, we focused on elucidating the possible mechanisms of acupuncture in the treatment of ischemic stroke, including nerve regeneration after brain injury, inhibition of inflammation, increased cerebral blood flow, and subsequent rehabilitation.

Therapeutic Strategies for Ischemic Stroke: Modulating the Adult Neural Stem Cell Niche through the Wnt/ß-catenin Pathway.

Stroke is a prominent contributor to mortality and impairment on a global scale. Ischemic stroke accounts for approximately 80% of stroke cases and is caused by occlusion of cerebral blood vessels. Enhancing neurogenesis through the modulation of the neural stem cell niche in the adult brain is a promising therapeutic strategy for individuals afflicted with ischemic stroke. Neurogenesis results in the generation of newborn neurons that serve as replacements for deceased neural cells within the ischemic core, thereby playing a significant role in the process of neural restoration subsequent to cerebral ischemia. Research has shown that activation of the Wnt/ß-catenin pathway can augment neurogenesis following cerebral ischemia, suggesting that this pathway is a potentially beneficial therapeutic target for managing ischemic stroke. This review provides an extensive analysis of the current knowledge regarding the involvement of the Wnt/ß-catenin pathway in promoting neurogenesis, thereby offering a promising avenue for therapeutic intervention in the context of ischemic stroke or other neurological impairments.

Comprehensive Management of Stroke: From Mechanisms to Therapeutic Approaches.

Acute ischemic stroke (AIS) is a challenging disease, which needs urgent comprehensive management. Endovascular thrombectomy (EVT), alone or combined with iv thrombolysis, is currently the most effective therapy for patients with acute ischemic stroke (AIS). However, only a limited number of patients are eligible for this time-sensitive treatment. Even though there is still significant room for improvement in the management of this group of patients, up until now there have been no alternative therapies approved for use in clinical practice. However, there is still hope, as clinical research with novel emerging therapies is now generating promising results. These drugs happen to stop or palliate some of the underlying molecular mechanisms involved in cerebral ischemia and secondary brain damage. The aim of this review is to provide a deep understanding of these mechanisms and the pathogenesis of AIS. Later, we will discuss the potential therapies that have already demonstrated, in preclinical or clinical studies, to improve the outcomes of patients with AIS.

Post-diffusion and perfusion magnetic resonance imaging of emboli to distal territories after endovascular thrombectomy.

BACKGROUND AND PURPOSE: This study aimed to investigate the clinical outcomes of emboli to distal territories (EDT) after aspiration thrombectomy in patients with acute anterior circulation occlusion. MATERIALS AND METHODS: From January 2016 to December 2022, all eligible patients who underwent endovascular treatment (EVT) due to acute anterior circulation occlusion were retrospectively reviewed. During this period, patients with EDT after EVT underwent magnetic resonance (MR) perfusion with angiography and diffusion-weighted imaging within 12 hours from recanalization. Hypoperfusion was defined as a Tmax value > 6-second volume. RESULTS: Of the 104 eligible patients (65 males, median age 74 years), 79 (76.0 %; 2a: 19, 2b: 55, 2c: 5) had hypoperfusion on perfusion MR (PWI). Complete mismatch on diffusion-weighted imaging (DWI) of the hypoperfusion area was significantly higher in patients with successful recanalization than in patients with incomplete recanalization (58.3 % vs. 31.6 %, p = 0.0437). Of the 79 patients with hypoperfusion, 24 had EDT in the M2, 39 in the M3, and 16 in the M4. Complete mismatch on DWI and PWI was significantly higher in patients with a distal EDT (M3 or M4) than in patients with an M2 EDT (65.8 % vs. 20.8 %, p < 0.001). CONCLUSIONS: EDT to the M3 or more distal branches after EVT had a higher rate of complete DWI-PWI mismatch on early follow-up MRI than EDT to M2.