GABAergic neurons differentiated from BDNF- and Dlx2-modified neural stem cells restore disrupted neural circuits in brainstem stroke.

BACKGROUND: Brainstem stroke causes severe and persistent neurological impairment. Due to the limited spontaneous recovery and regeneration of the disrupted neural circuits, transplantation of exogenous neural stem cells (NSCs) was an alternative, while there were limitations for primitive NSCs. METHODS: We established a mouse model of brainstem stroke by injecting endothelin in the right pons. Brain-derived neurotrophic factor (BDNF)- and distal-less homeobox 2 (Dlx2)-modified NSCs were transplanted to treat brainstem stroke. Transsynaptic viral tracking, immunostaining, magnetic resonance imaging, behavioral testing, and whole-cell patch clamp recordings were applied to probe the pathophysiology and therapeutic prospects of BDNF- and Dlx2-modified NSCs. RESULTS: GABAergic neurons were predominantly lost after the brainstem stroke. No endogenous NSCs were generated in situ or migrated from the neurogenesis niches within the brainstem infarct region. Co-overexpressions of BDNF and Dlx2 not only promoted the survival of NSCs, but also boosted the differentiation of NSCs into GABAergic neurons. Results from transsynaptic virus tracking, immunostaining, and evidence from whole-cell patch clamping revealed the morphological and functional integration of the grafted BDNF- and Dlx2-modified NSCs-derived neurons with the host neural circuits. Neurological function was improved by transplantation of BDNF- and Dlx2-modified NSCs in brainstem stroke. CONCLUSIONS: These findings demonstrated that BDNF- and Dlx2-modified NSCs differentiated into GABAergic neurons, integrated into and reconstituted the host neural networks, and alleviated the ischemic injury. It thus provided a potential therapeutic strategy for brainstem stroke.

Influence of renal impairment on clinical outcomes after endovascular recanalization in vertebrobasilar artery occlusions.

BACKGROUND: Renal impairment (RI) is associated with worse outcomes in the treatment of intravenous thrombolysis and emergent endovascular treatment (EVT) in anterior circulation stroke. The objective of this study was to investigate the association of RI with short-term and long-term outcomes in patients with vertebrobasilar artery occlusions (VBAO) who received EVT. METHODS: Consecutive patients with VBAO receiving EVT involving 21 stroke centers were retrospectively included. Multivariate regression analyses were used to evaluate the association of RI with mortality and symptomatic intracranial hemorrhage (sICH) during the hospital stay, and also mortality, favorable functional outcome (modified Rankin Scale (mRS) score of 0-3), and functional improvement (shift in mRS score) at 3 months and 1 year follow-up. The association between RI and the risk of recurrent stroke was evaluated with multivariate competing-risk regression analyses. RESULTS: After adjustment for potential confounders, RI was independently associated with sICH (OR 3.30, 95% CI 1.55 to 7.18), as well as mortality (OR 2.54, 95% CI 1.47 to 4.38; OR 3.07, 95% CI 1.72 to 8.08), favorable functional outcome (OR 0.33, 95% CI 0.17 to 0.66; OR 0.25, 95% CI 0.12 to 0.51), and functional improvement (OR 0.45, 95% CI 0.28 to 0.74; OR 0.35, 95% CI 0.21 to 0.60) at 3 months and 1 year follow-up, respectively, but RI was not associated with in-hospital mortality. Additionally, there was no significant association between RI and recurrent stroke within 1 year. CONCLUSIONS: Our findings suggest that RI is associated with a higher risk of sICH in hospital and a decrease in survival, favorable functional outcome, and functional improvement at 90 days and 1 year follow-up. TRIAL REGISTRATION NUMBER: URL: http://www.chictr.org.cn/; Unique identifier: ChiCTR2000033211.

Blood Pressure After Endovascular Thrombectomy and Malignant Cerebral Edema in Large Vessel Occlusion Stroke.

Background: Elevated blood pressure (BP) can cause blood-brain barrier disruption and facilitates brain edema formation. We aimed to investigate the association of BP level after thrombectomy with the development of malignant cerebral edema (MCE) in patients treated with endovascular thrombectomy (EVT). Methods: Consecutive patients who underwent EVT for an anterior circulation ischemic stroke were enrolled from three comprehensive stroke centers. BP was measured hourly during the first 24 h after thrombectomy. MCE was defined as swelling causing a midline shift on the follow-up imaging within 5 days after EVT. Associations of various BP parameters, including mean BP, maximum BP (BPmax), and BP variability (BPV), with the development of MCE were analyzed. Results: Of the 498 patients (mean age 66.9 ± 11.7 years, male 58.2%), 97 (19.5%) patients developed MCE. Elevated mean systolic BP (SBP) (OR, 1.035; 95% CI, 1.006-1.065; P = 0.017) was associated with a higher likelihood of MCE. The best SBPmax threshold that predicted the development of MCE was 165 mmHg. Additionally, increases in BPV, as evaluated by SBP standard deviation (OR, 1.061; 95% CI, 1.003-1.123; P = 0.039), were associated with higher likelihood of MCE. Interpretation: Elevated mean SBP and BPV were associated with a higher likelihood of MCE. Having a SBPmax > 165 mm Hg was the best threshold to discriminate the development of MCE. These results suggest that continuous BP monitoring after EVT could be used as a non-invasive predictor for clinical deterioration due to MCE. Randomized clinical studies are warranted to address BP goal after thrombectomy.

Genetically Predicted Coffee Consumption and Risk of Alzheimer's Disease and Stroke.

BACKGROUND: Observational studies have reported that coffee consumption was associated with Alzheimer's disease (AD) and stroke risk. However, the results are inconclusive. OBJECTIVE: We aimed to evaluate whether genetically predicted coffee consumption is associated with AD and stroke using Mendelian randomization (MR) design. METHODS: Summary-level data for AD (n = 54,162), ischemic stroke (n = 440,328), and intracerebral hemorrhage (ICH, n = 3,026) were adopted from publicly available databases. Summary-level data for coffee consumption were obtained from two genome-wide association studies, comprising up to 375,833 subjects. RESULTS: Genetically predicted coffee consumption (cups/day) was associated with an increased risk of AD (OR = 1.26, 95%CI = 1.05-1.51). Moreover, genetically predicted 50%increase of coffee consumption was associated with an increased risk of ICH (OR: 2.27, 95%CI: 1.08-4.78) but a decreased risk of small vessel stroke (OR: 0.71, 95%CI: 0.51-0.996). Estimate for AD and ICH in FinnGen consortium is directionally consistent. Combined analysis of different databases further confirmed that genetically predicted coffee consumption was associated with an increased risk of AD and ICH. In the multivariable MR analysis, genetically predicted coffee consumption retained a stable effect with AD and ICH when adjusting for smoking (p < 0.05), while the association with AD attenuated when adjusting for alcohol use. CONCLUSION: Our results indicate that genetically predicted coffee consumption may be associated with an increased risk of AD and ICH. The underlying biological mechanisms warrant further study.

Infarct morphology assessment in patients with carotid artery/middle cerebral artery occlusion using fast fluid-attenuated inversion recovery (FLAIR) vascular hyperintensity (FVH).

We aim to evaluate the value of fast fluid-attenuated inversion recovery (FLAIR) vascular hyperintensity (FVH) in assessing infarct morphology in patients with symptomatic internal carotid artery (ICA) or middle cerebral artery (MCA) occlusions. Magnetic resonance (MR) diffusion-weighted imaging (DWI) FLAIR sequences, and carotid/cerebral magnetic resonance angiography of 102 patients with symptomatic ICA or MCA occlusions were evaluated. The location and score of FVH were determined using Olindo's method; patients were classified as having Low or High FVHs based on FVH score, and either Distal or Proximal FVH based on FVH location. The differences between infarct morphologies were analyzed. FVH were detectable in 62 patients with High FVH and in 40 patients with Low FVHs based on the Olindo's scale. There were no statistically significant differences in age, gender, hypertension, diabetes, hyperlipidemia, smoking history, and vascular occlusive site between High and Low FVHs patients, except for infarct morphology (P<0.01). Patients with Distal FVH presented with significant (P<0.01) perforating artery and border zone infarcts, whereas those with Proximal FVH had significant (P<0.01) large territorial infarcts. The scores and locations of FVH could be a predictive imaging marker for infarct morphology in patients with symptomatic ICA or MCA occlusion.