Effects of transplantation with bone marrow-derived mesenchymal stem cells modified by Survivin on experimental stroke in rats

<p>Abstract</p> <p>Background</p> <p>This study was performed to determine whether injury induced by cerebral ischemia could be further improved by transplantation with bone marrow-derived mesenchymal stem cells (MSCs) modified by Survivin (SVV).</p> <p>Methods</p> <p>MSCs derived from bone marrow of male Sprague-Dawley rats were infected by the self-inactive lentiviral vector GCFU carrying green fluorescent protein (GFP) gene and SVV recombinant vector (GCFU-SVV). In vitro, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were detected in infected MSCs supernatants under hypoxic conditions by ELSIA. In vivo, experiments consisted of three groups, one receiving intravenous injection of 500 μl of phosphate-buffered saline (PBS) without cells (control group) and two groups administered the same volume solution with either three million GFP-MSCs (group GFP) or SVV/GFP-MSCs (group SVV). All animals were submitted to 2-hour middle cerebral artery occlusion (MCAO) and then reperfusion. Differentiation and survival of the transplanted MSCs were determined by confocal microscope. Western blot was used to detect the expression of VEGF and bFGF in ischemic tissue. A 2,3,5-triphenyltetrazolium chloride (TTC) staining was used to assess the infarct volume. Evaluation of neurological function was performed using a modified Neurological Severity Score (mNSS).</p> <p>Results</p> <p>In vitro, modification with SVV further increased secretion of VEGF and bFGF under hypoxic condition. In vivo, only very few transplantated cells co-expressed GFP and NeuN. The survival transplanted cells in the group SVV was 1.3-fold at 4 days after transplantation and 3.4-fold higher at 14 days after transplantation, respectively, when compared with group GFP. Expression of VEGF and bFGF in the ischemic tissue were further up-regulated by modification with SVV. Moreover, modification with SVV further reduced the cerebral infarct volume by 5.2% at 4 days after stroke and improved post-stroke neurological function at 14 days after transplantation.</p> <p>Conclusion</p> <p>Modification with SVV could further enhance the therapeutic effects of MSCs possibly through improving the MSCs survival capacity and up-regulating the expression of protective cytokines in the ischemic tissue.</p

Association between Perivascular Spaces Burden and Future Stroke Risk in Ischemic Stroke and Transient Ischemic Attack: A Systematic Review and Meta-Analysis

Introduction: This meta-analysis aimed to explore the association of perivascular spaces (PVS) burden with the risks of future stroke events and mortality in patients with ischemic stroke and transient ischemic attack (TIA). Methods: We systematically searched PubMed, Embase, and Cochrane database from inception to December 31, 2023. We included eligible studies that reported adjusted estimated effects for future intracranial hemorrhage (ICH), ischemic stroke, and mortality with baseline PVS burden in patients with ischemic stroke and TIA. Data were pooled using an inverse-variance method for the fixed effects (FE) model and a restricted maximum likelihood method for the random effects (RE) model. Results: Thirteen observational studies (5 prospective, 8 retrospective) were included, comprising 20,256 patients. Compared to 0–10 PVS at basal ganglia (BG-PVS), a higher burden (>10) of BG-PVS was significantly associated with an increased risk of future ICH (adjusted hazards ratio [aHR] 2.79, 95% confidence interval [CI]: 1.16–6.73, RE model; aHR 2.14, 95% CI: 1.34–3.41, FE model; I2 = 64%, n = 17,084 from four studies) followed up for at least 1 year. There was no significant association between >10 BG-PVS and ICH within 7 days after reperfusion therapy (adjusted odds ratio [aOR] 1.69, 95% CI: 0.74–3.88, RE model; aOR 1.43, 95% CI: 0.89–2.88, FE model; I2 = 67%, n = 1,176 from four studies). We did not detect a significant association of recurrent ischemic stroke, mortality, or disability with BG-PVS burden. Neither >10 PVS at centrum semiovale (CSO-PVS) nor increasing CSO-PVS burden was significantly associated with the risk of future intracranial hemorrhage or ischemic stroke recurrence. Conclusions: Current evidence suggests that a higher BG-PVS burden may be associated with an increased risk of future ICH in patients with ischemic stroke and TIA

Total Cerebral Small Vessel Disease Score and Cerebral Bleeding Risk in Patients With Acute Stroke Treated With Intravenous Thrombolysis

OBJECTIVE: The aim of this study was to investigate the association of total cerebral small vessel disease (cSVD) score with the risk of intracerebral hemorrhage (ICH) in patients with acute ischemic stroke who received intravenous thrombolysis (IVT) using recombinant tissue-plasminogen activator (rt-PA). METHODS: We retrospectively reviewed clinical data from two stroke registries of patients with acute ischemic stroke treated with IVT. We assessed the baseline magnetic resonance (MR) visible cSVD markers and total cSVD score (ranging from 0 to 4) between patients with and without ICH after IVT. Logistic regression analysis was used to determine the association of total cSVD score with the risk of ICH after IVT, adjusted for cofounders selected by least absolute shrinkage and selection operator (LASSO). We additionally performed an E-value analysis to fully explain away a specific exposure-outcome association. Receiver operating characteristic (ROC) curve analysis was used to quantify the predictive potential of the total cSVD score for any ICH after IVT. RESULTS: Among 271 eligible patients, 55 (20.3%) patients experienced any ICH, 16 (5.9%) patients experienced a symptomatic ICH (sICH), and 5 (1.85%) patients had remote intracranial parenchymal hemorrhage (rPH). Logistic regression analysis showed that the risk of any ICH increased with increasing cSVD score [per unit increase, adjusted odds ratio (OR) 2.03, 95% CI 1.22–3.41, P = 0.007]. Sensitivity analyses using E-value revealed that it would need moderately robust unobserved confounding to render the exposure-outcome (cSVD-any ICH) association null. ROC analysis showed that compared with the National Institutes of Health Stroke Scale (NIHSS) score alone, a combination of cSVD and NIHSS score had a larger area under the curve for any ICH (0.811, 95% CI 0.756–0.866 vs. 0.784, 95% CI 0.723–0.846, P = 0.0004). CONCLUSION: The total cSVD score is associated with an increased risk of any ICH after IVT and improves prediction for any ICH compared with NIHSS alone

Association of enlarged perivascular spaces and anticoagulant-related intracranial hemorrhage

Objective: To investigate whether enlarged perivascular spaces within the basal ganglia or deep cerebral white matter are risk factors for intracranial hemorrhage in patients taking oral anticoagulants (OAC), independent of established clinical and radiological risk factors, we conducted a post hoc analysis of CROMIS-2 (AF), a prospective inception cohort study. Methods: Patients with atrial fibrillation and recent TIA or ischaemic stroke underwent standardised MR imaging prior to starting OAC. We rated basal ganglia (BGPVS) and centrum semiovale (CSOPVS) perivascular spaces, cerebral microbleeds (CMBs), white matter hyperintensities and lacunes. We dichotomized the PVS rating using a threshold of &gt;10 PVS in the relevant region of either cerebral hemisphere. The primary outcome was symptomatic intracranial hemorrhage (sICH). We identified risk factors for sICH using Cox regression. Results: 1386 participants with available clinical and imaging variables were followed up for a mean of 2.34 years. 14 sICH occurred (11 intracerebral). In univariable analysis, diabetes, CMB presence, lacune presence and &gt;10 BGPVS, but not CSOPVS, were associated with sICH. In a multivariable model incorporating all variables with significant associations in univariable analysis, &gt;10 BGPVS (HR 8.96, 95% CI 2.41 – 33.4, p = 0.001) and diabetes (HR 3.91, 95% CI 1.34 – 11.4) remained significant risk factors for sICH. Conclusion: Enlarged BGPVS might be a novel risk factor for OAC-related ICH. The strength of this association and potential use in predicting ICH in clinical practice should be investigated in larger cohorts

Clinical associations and prognostic value of MRI-visible perivascular spaces in patients with ischemic stroke or TIA: a pooled analysis

BACKGROUND AND OBJECTIVES: Visible perivascular spaces are an MRI marker of cerebral small vessel disease and might predict future stroke. However, results from existing studies vary. We aimed to clarify this through a large collaborative multicenter analysis. METHODS: We pooled individual patient data from a consortium of prospective cohort studies. Participants had recent ischemic stroke or transient ischemic attack (TIA), underwent baseline MRI, and were followed up for ischemic stroke and symptomatic intracranial hemorrhage (ICH). Perivascular spaces in the basal ganglia (BGPVS) and perivascular spaces in the centrum semiovale (CSOPVS) were rated locally using a validated visual scale. We investigated clinical and radiologic associations cross-sectionally using multinomial logistic regression and prospective associations with ischemic stroke and ICH using Cox regression. RESULTS: We included 7,778 participants (mean age 70.6 years; 42.7% female) from 16 studies, followed up for a median of 1.44 years. Eighty ICH and 424 ischemic strokes occurred. BGPVS were associated with increasing age, hypertension, previous ischemic stroke, previous ICH, lacunes, cerebral microbleeds, and white matter hyperintensities. CSOPVS showed consistently weaker associations. Prospectively, after adjusting for potential confounders including cerebral microbleeds, increasing BGPVS burden was independently associated with future ischemic stroke (versus 0-10 BGPVS, 11-20 BGPVS: HR 1.19, 95% CI 0.93-1.53; 21+ BGPVS: HR 1.50, 95% CI 1.10-2.06; = 0.040). Higher BGPVS burden was associated with increased ICH risk in univariable analysis, but not in adjusted analyses. CSOPVS were not significantly associated with either outcome. DISCUSSION: In patients with ischemic stroke or TIA, increasing BGPVS burden is associated with more severe cerebral small vessel disease and higher ischemic stroke risk. Neither BGPVS nor CSOPVS were independently associated with future ICH

Association between atrial cardiopathy and stroke severity in acute ischemic stroke

Abstract In this hospital-based cross-sectional analytic study, we retrospectively reviewed clinical data of patients with acute ischemic stroke (AIS) between January 2017 and April 2023. Atrial cardiopathy was defined as any presence of the following: left atrial diameter ≥ 52 mm (males) or ≥ 47 mm (females), elevated P-wave terminal force in V1 > 5000 μV ms, or serum N terminal pro B type natriuretic peptide > 250 pg/ml. Initial stroke severity was defined by the National Institutes of Health Stroke Scale (NIHSS; moderate-to-severe, ≥ 5; and severe, ≥ 15). Univariate and multivariate binary logistic regression analyses were performed to assess the association between atrial cardiopathy and stroke severity. Among 662 AIS patients (mean age 70 years [interquartile range 61–78], 31.3% women), 303 (45.8%) had atrial cardiopathy. Multivariable logistic regression analysis showed that the presence of atrial cardiopathy was significantly associated with a higher odd of moderate-to-severe stroke (adjusted odds ratio [OR] 2.16, 95% confidence interval [CI] 1.46–3.20, p < 0.001) and severe stroke (adjusted OR 4.89, 95%CI 2.45–9.76, p < 0.001). This association remained significant in a sensitivity analysis excluding those with atrial fibrillation or coronary artery disease. Findings of the current study revealed that the association of atrial cardiopathy was with initial stroke severity independent of atrial fibrillation and was even confirmed in patients without atrial fibrillation; future studies to explore improved stroke prevention strategies for patients with atrial cardiopathy are needed

Atrial Fibrillation and Clinical Outcomes of Endovascular Thrombectomy for Acute Ischemic Stroke: A Meta‐Analysis of Adjusted Effect Estimates

Background The impact of atrial fibrillation (AF) on the clinical outcomes in patients with acute ischemic stroke (AIS) who received endovascular thrombectomy remains unclear. We aimed to perform a meta‐analysis of adjusted effect estimates to examine the association between the presence of AF and the clinical outcomes in patients with AIS who received endovascular thrombectomy. Methods and Results We searched PubMed, Embase, and the Cochrane database between January 1, 2013 and July 10, 2023. Data were meta‐analyzed to compare the outcomes among patients with AIS with and without AF who received endovascular thrombectomy. Our primary outcome was 90‐day functional independence defined as a modified Rankin Scale score of 0 to 2. Secondary outcomes included excellent independence (90‐day modified Rankin Scale score of 0–1), 90‐day mortality, symptomatic intracranial hemorrhage, and any intracranial hemorrhage. Eighteen observational studies comprising 16 096 patients with AIS (mean age, 70.1 years; women, 48.2%; 6862 with AF versus 9234 without AF) were included. There were no statistically significant differences for modified Rankin Scale score of 0 to 2 (pooled odds ratio [OR], 1.14 [95% CI, 0.95–1.37]; [95% prediction interval [PI], 0.72–1.80]), mortality (OR, 0.92 [95% CI, 0.79–1.08]; [95% PI, 0.77–1.11]), symptomatic intracranial hemorrhage (OR, 0.97 [95% CI, 0.71–1.32]; [95% PI, 0.43–2.17]), and any intracranial hemorrhage (OR, 1.08 [95% CI, 0.91–1.28]; [95% PI, 0.74–1.58]) among patients with AIS with and without AF. Conclusions This meta‐analysis detected no significant differences in 90‐day functional outcomes, mortality, and intracerebral hemorrhage risk after endovascular thrombectomy in patients with AIS with and without AF. Registration URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD 42021293511

Netrin-1 Prevents Rat Primary Cortical Neurons from Apoptosis via the DCC/ERK Pathway

In the nervous system, Netrin-1 serves as a neural guide, mediating the neuronal development. However, it remains blurred whether Netrin-1 can protect neurons from apoptosis induced by cerebral stroke. In the current study, the cultured rat primary cortical neurons were transfected with Netrin-1-encoding lentivirus before the oxygen-glucose-deprivation (OGD) treatment. Cell death and apoptosis were evaluated by lactate dehydrogenase (LDH) release and flow cytometry. We found that Netrin-1 attenuated OGD-induced cell death and neuronal apoptosis at 24 h after OGD treatment, and that the overexpression of Netrin-1 activated the ERK signaling pathway. These effects were partly abolished by blocking its receptor deleted in colorectal cancer (DCC) or U0126, an inhibitor of the ERK signaling pathway. Netrin-1 overexpression in neurons elevated the expression of DCC, on mRNA level and protein level. Netrin-1 also reduced DNA damage. Taken together, our findings suggest that Netrin-1 attenuates cell death and neuronal apoptosis via the DCC/ERK signaling pathway in the cultured primary cortical neurons after OGD injury, which may involve the mediation of DNA damage in the neurons