Botch improves cognitive impairment after cerebral ischemia associated with microglia-induced A1-type astrocyte activation.

Vascular cognitive impairment (VCI) is a clinical syndrome that arises from cerebrovascular issues and associated risk factors, resulting in difficulties in at least one area of cognitive function. VCI has emerged as the second most prevalent type of dementia following Alzheimer's disease, yet there is no effective clinical treatment. Botch, an endogenous Notch1 antagonist, demonstrates neuroprotective effects by inhibiting neuroinflammatory responses mediated through the Notch pathway. While its role in stroke-induced neuroinflammation is well-established, its involvement in VCI remains largely unexplored. This study investigates the role and potential mechanisms of Botch in a rat model of cognitive impairment caused by bilateral common carotid artery occlusion (BCCAO). Firstly, we observed that Botch levels were down-regulated in BCCAO rats, which correlated with increased release of inflammatory cytokines and neuronal damage. Microglia in BCCAO rats released interleukin-1α (IL-1α), tumor necrosis factor-α (TNF-α), and complement component 1q (C1q), leading to the activation of neurotoxic C3+ A1 reactive astrocytes. Then, the down-regulation of Botch exacerbated microglia-mediated inflammation, activated C3+ A1 astrocytes, worsened neuronal damage, and led to a decline in cognitive function. Conversely, the re-expression of Botch alleviated C3+ astrocyte activation, inhibited neuronal damage, and improved mental function. In conclusion, Botch plays a crucial role in inhibiting neuroinflammation induced by type A1 reactive astrocytes. It achieves this by blocking the activation of microglia triggered by the Notch pathway. Ultimately, it inhibits neuronal damage to play a neuroprotective role. These findings suggest that Botch may represent a novel potential target for treating VCI.

PSCK9 inhibitors reduced early recurrent stroke in patients with symptomatic intracranial atherosclerotic stenosis.

BACKGROUND: Symptomatic intracranial atherosclerotic stenosis (ICAS) is prone to cause early recurrent stroke (ERS). Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein cholesterol (LDL-C) levels and prevent cardiovascular events. This multicentre, hospital-based prospective cohort study was designed to investigate whether PCSK9 inhibitors would prevent ERS in patients with symptomatic ICAS. METHODS: From 1 October 2020 to 30 September 2022, consecutive patients with acute ischaemic stroke attributed to ICAS admitted within 1 week after onset were enrolled and followed up for 1 month. Patients were divided into two groups, the PCSK9 inhibitors group receiving PCSK9 inhibitors add-on therapy, and the control group receiving statins and/or ezetimibe. The primary outcome was ERS. Cox proportional hazard models and Kaplan-Meier survival curve were used to estimate the association between PCSK9 inhibitors and ERS. RESULTS: At the end of follow-up, the LDL-C levels were further lowered by PCSK9 inhibitors add-on therapy (n=232, from 3.06±1.16 mmol/L to 2.12±1.19 mmol/L) than statins and/or ezetimibe treatment (n=429, from 2.91±1.05 mmol/L to 2.64±0.86 mmol/L, p<0.001). The Kaplan-Meier survival curves showed that PCSK9 inhibitors add-on therapy significantly reduced ERS (5.59%, 24/429, vs 2.16%, 5/232; log-rank test, p=0.044). The multivariate Cox regression analysis revealed that, after adjusting for confounders with a p value less than 0.05 in univariate analysis or of particular importance, the HR was 0.335 (95% CI 0.114 to 0.986, p=0.047), compared with the control group. CONCLUSIONS: In our study, PCSK9 inhibitors add-on therapy further reduced LDL-C levels and ERS in patients with symptomatic ICAS.

Relationships between obesity and functional outcome after ischemic stroke: a Mendelian randomization study.

BACKGROUND AND OBJECTIVES: Most previous studies suggested obesity deteriorates the functional outcome after ischemic stroke. But there are researches claiming that obesity is associated with lower mortality, recurrence, and readmission rates, which is known as the obesity paradox. Our current research aimed to investigate the correlation between genetically obesity and the post-stroke outcome with the Mendelian randomization (MR) method. METHODS: The UK Biobank and the GIANT consortium provided instrumental variables for body mass index (BMI, 806,834 individuals) and waist-to-hip ratio (WHR, 697,734 individuals). Data of functional outcome after ischemic stroke were obtained from the Genetics of Ischemic Stroke Functional Outcome network (6012 individuals). Inverse-variance weighted approach was utilized as the primary analyses. Sensitivity analyses involved the utilization of different MR methods. The heterogeneity among genetic variants was assessed by I2 and Q value statistics. RESULTS: In univariable analysis, there was a significant connection between genetic susceptibility to WHR and worse functional outcome (modified Rankin Scale 3) after ischemic stroke (OR [95%CI] = 1.47 [1.07, 2.02], P = 0.016). Genetic liability to BMI and was not associated with post-stroke functional outcome (all P > 0.05). The overall patterns between genetic liability to WHR and functional outcome post-ischemic outcome no longer existed in the multivariable MR analysis after adjusting for BMI (OR [95%CI] = 1.26[0.76,1.67], P = 0.56). CONCLUSION: The current MR study provided evidence that WHR was correlated to unfavorable outcome post-ischemic stroke. Exploring interventions against obesity may potentially improve recovery after ischemic stroke.

Association of triglyceride-glucose index with ischemic stroke recurrence in nondiabetic patients with small vessel occlusion: a multicenter hospital-based prospective cohort study.

BACKGROUND: Triglyceride-glucose (TyG) index is a simple and reliable surrogate marker of insulin resistance. Elevated TyG index was related to stroke recurrence. This study aimed to explore the associations between TyG index with ischemic stroke recurrence in nondiabetic patients with small vessel occlusion. METHODS: From November 1, 2016 to February 28, 2021, consecutive acute ischemic stroke patients admitted within 1 week after onset were screened. The stroke mechanism was determined based on medical history, laboratory examinations, cardiac examinations, vascular examinations and neuroimaging. Nondiabetic patients with small vessel occlusion were enrolled and followed up for 1 year. The primary outcome was ischemic stroke recurrence. Logistic regression and Kaplan-Meier survival curve were used to analyze the association of the TyG index and stroke recurrence. RESULTS: A total of 6100 acute ischemic stroke patients were screened, with 1970 nondiabetic patients with small vessel occlusion included and divided into 4 groups according to the TyG index quartiles (Q1: < 8.20; Q2: 8.20-8.53; Q3: 8.54-8.92; Q4: > 8.92). There were significant differences in age, body mass index, systolic blood pression, diastolic blood pressure, lipid-lowering agents, infarct location, fasting blood glucose, total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, uric acid, and stroke recurrence among the 4 groups. In the multi-adjusted models, compared to Q1 of the TyG index, the odds ratio for Q4 of the TyG index for stroke recurrence was 3.100 (1.366-8.019). The Kaplan-Meier survival (ischemic stroke-free) curves by quartiles of the TyG index also showed statistically significant differences (log-rank test, P = 0.004). CONCLUSIONS: Our findings suggested that the TyG index was associated with ischemic stroke recurrence in nondiabetic patients with small vessel occlusion, and it could be a valuable biomarker for assessing the risk of ischemic stroke recurrence in these patients.

Total magnetic resonance imaging of cerebral small vessel disease burden predicts dysphagia in patients with a single recent small subcortical infarct.

BACKGROUND: This study was performed to identify the association between the total magnetic resonance imaging burden of small vessel disease and the occurrence of post-stroke dysphagia in patients with a single recent small subcortical infarct (RSSI). METHODS: We retrospectively identified all patients with a magnetic resonance imaging-confirmed single RSSI. The water-swallowing test and volume-viscosity swallow test were performed within the first 24 h following admission to assess swallowing. Demographic and clinical data were extracted from our stroke database. Based on brain magnetic resonance imaging, we independently rated the presence of cerebral microbleeds, lacunes, white matter hyperintensities and enlarged perivascular spaces. The presence of each small vessel disease feature was summed to determine the total small vessel disease burden, ranging from 0 to 4. RESULTS: In total, 308 patients with a single RSSI were enrolled. Overall, 54 (17.5%) were diagnosed with post-stroke dysphagia. The risk factors related to post-stroke dysphagia included the following: older age, higher National Institute of Health Stroke Scale scores, higher C-reactive protein level and higher fibrinogen level. Based on multiple logistic regression, National Institute of Health Stroke Scale scores and total small vessel disease burden were independent risk factors of post-stroke dysphagia in patients with a single RSSI, after adjusting for age, gender, history of hypertension, C-reactive protein level and fibrinogen level. CONCLUSIONS: Dysphagia in patients with a single RSSI was associated with a more severe total small vessel disease burden as reflected by MRI. Total MRI of cerebral small vessel disease burden may predict dysphagia in these patients. Furthermore, more severe total small vessel disease burden was associated with systemic inflammation.

A new nomogram for individualized prediction of the probability of hemorrhagic transformation after intravenous thrombolysis for ischemic stroke patients.

BACKGROUND: A reliable scoring tool to detect the risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis for ischemic stroke is warranted. The present study was designed to develop and validate a new nomogram for individualized prediction of the probability of hemorrhagic transformation (HT) in patients treated with intravenous (IV) recombinant tissue plasminogen activator (rt-PA). METHODS: We enrolled patients who suffered from acute ischemic stroke (AIS) with IV rt-PA treatment in our emergency green channel between August 2016 and July 2018. The main outcome was defined as any type of intracerebral hemorrhage according to the European Cooperative Acute Stroke Study II (ECASS II). All patients were randomly divided into two cohorts: the primary cohort and the validation cohort. On the basis of multivariate logistic model, the predictive nomogram was generated. The performance of the nomogram was evaluated by Harrell's concordance index (C-index) and calibration plot. RESULTS: A total of 194 patients with complete data were enrolled, of whom 131 comprised the primary cohort and 63 comprised the validation cohort, with HT rate 12.2, 9.5% respectively. The score of chronic disease scale (CDS), the global burden of cerebral small vascular disease (CSVD), National Institutes of Health Stroke Scale (NIHSS) score ≥ 13, and onset-to-treatment time (OTT) ≥ 180 were detected important determinants of ICH and included to construct the nomogram. The nomogram derived from the primary cohort for HT had C- Statistics of 0.9562 and the calibration plot revealed generally fit in predicting the risk of HT. Furthermore, we made a comparison between our new nomogram and several other risk-assessed scales for HT with receiver operating characteristic (ROC) curve analysis, and the results showed the nomogram model gave an area under curve of 0.9562 (95%CI, 0.9221-0.9904, P < 0.01) greater than HAT (Hemorrhage After Thrombolysis), SEDAN (blood Sugar, Early infarct and hyper Dense cerebral artery sign on non-contrast computed tomography, Age, and NIHSS) and SPAN-100 (Stroke Prognostication using Age and NIHSS) scores. CONCLUSIONS: This proposed nomogram based on the score of CDS, the global burden of CSVD, NIHSS score ≥ 13, and OTT ≥ 180 gives rise to a more accurate and more comprehensive prediction for HT in patients with ischemic stroke receiving IV rt-PA treatment.

Topographic location of unisolated pontine infarction.

BACKGROUND: The topographic location of acute pontine infarction is associated with clinical syndromes and prognosis. Previous studies focused on isolated pontine infarction, but the topographic location of unisolated pontine infarction has remained unclear. METHODS: This was a prospective, multicenter, longitudinal registry study. Patients with acute pontine infarction confirmed by magnetic resonance imaging (MRI) were enrolled. Based on the territory of the pontine artery, the topographic location was divided into anteromedial, anterolateral, tegmental, bilateral and unilateral multiple infarctions. RESULTS: From May 1, 2003, to Oct 31, 2017, 1003 patients were enrolled, and 330 had unisolated pontine infarction. For isolated pontine infarction, 44.9, 19.8, 16.0, 13.1 and 6.2% of patients had anteromedial, anterolateral, tegmental, bilateral and unilateral multiple pontine infarctions, respectively. For unisolated pontine infarction, 30.3, 19.7, 24.5, 15.2 and 10.3% of patients had anteromedial, anterolateral, tegmental, bilateral and unilateral multiple pontine infarctions, respectively. CONCLUSION: In this large series study, our data revealed fewer anteromedial infarctions and more tegmental and unilateral multiple infarctions in patients with unisolated pontine infarction than in patients with isolated pontine infarction.

Renal Dysfunction Associated with Symptomatic Intracranial Hemorrhage after Intravenous Thrombolysis.

BACKGROUND AND AIM: Renal dysfunction (RD) is prevalent in patients with acute ischemic stroke requiring intravenous thrombolysis. The relationship between renal function and thrombolysis related intracranial hemorrhagic (ICH) complications is contradictory according to previous studies. The current study is to clarify whether RD could increase the risk of symptomatic intracranial hemorrhage (SICH) after recombinant tissue plasminogen activator (IV rtPA) in acute ischemic stroke patients. METHODS: In this observational study, acute ischemic stroke patients who received IV rtPA within 4.5 hours of symptom onset were retrospectively analyzed. Creatinine levels on admission served to calculate glomerular filtration rate (GFR) to estimate RD. SICH was defined with National Institute of Neurological Disorder and Stroke (NINDS, SICHNINDS) or European Cooperative Acute Stroke Study II (ECASS II, SICHECASSII) criteria. Association of RD with SICH was assessed using continuous GFR or binary GFR (RD defined as GFR < 90 ml/minute/1.73 m2). RESULTS: Of 312 patients included, the incidence of SICHNINDS was 7.69%, of SICHECASSII was 5.45%. Patients with RD had higher prevalence of SICHNINDS (12.80% versus 2.03%, P < .001) and SICHECASS II (9.15% versus 1.35%, P = .002). GFR as a continuous variable was associated with SICHNINDS (ORadjust = .97, P = .003), but not with SICHECASS II. GFR less than 90 ml/minute/1.73 m2 remained independently associated with SICHNINDS (ORadjust = 4.79, P = .016), and SICHECASS II (ORadjust = 2.99, P = .032) in multiple logistic regression analysis. CONCLUSIONS: Renal function is independently associated with SICH after IV rtPA thrombolysis. RD is an independent predictor for both SICHNINDS and SICHECASS II. RD should be considered when evaluating the risk of intravenous thrombolysis with IV rtPA.

Mesenchymal stem cells protect neurons against hypoxic-ischemic injury via inhibiting parthanatos, necroptosis, and apoptosis, but not autophagy.

Cellular therapy with mesenchymal stem cells (MSCs) protects cortical neurons against hypoxic-ischemic injury of stroke. Although sorts of efforts have been made to confirm the neuroprotective effect of MSCs on neurons against hypoxic-ischemic injury, the mechanism is until now far away from clear. Here in this study, oxygen-glucose deprivation (OGD)-injured neuron model was applied to mimic the neuronal hypoxic-ischemic injury in vitro. Co-culturing with MSCs in a transwell co-culture system, the OGD injured neurons were rescued by 75.0 %. Further data demonstrated that co-culturing with MSCs protected the cortical neurons from the OGD-induced parthanatos by alleviating apoptosis-inducing factor (AIF) nuclear translocation; attenuated the neuronal necroptosis by down-regulating the expression of the two essential kinases in necroptosis, receptor interacting protein kinase1 (RIP1) and 3 (RIP3); rescued the neurons from apoptosis by deactivating caspase-3; whilst performed no significant influence on OGD-induced neuronal autophagy, according to its failed regulation on Beclin1. In conclusion, MSCs potentially protect the cortical neurons from OGD-injury in vitro, through rescuing neurons from the cell death of parthanatos, necroptosis, and apoptosis, but not autophagy, which could provide some evidence to the mechanism explanation on stem cell treatment for ischemic stroke.

Efficacy and safety outcomes of Tenecteplase versus Alteplase for thrombolysis of acute ischemic stroke: A meta-analysis of 9 randomized controlled trials.

BACKGROUND: In recent years, Tenecteplase (TNK), a genetically modified variant of alteplase, has been verified as a potential substitute for alteplase in the reperfusion therapy of acute ischemic stroke (AIS). Given the emergence of new randomized controlled trials (RCTs) of this subject, a meta-analysis was conducted to evaluate the present comparative evidence regarding the efficacy and safety outcomes of TNK and alteplase in thrombolysis for AIS. METHODS: Following predefined inclusion criteria, we searched the databases of PubMed, Web of Science, and Cochrane Library. RCTs satisfying our inclusion criteria were selected for meta-analysis. Outcome indicators were categorized into efficacy outcomes (early vessel recanalization, excellent recovery, good recovery and early neurological improvement) and safety outcomes (poor recovery, symptomatic intracerebral hemorrhage, parenchymal hemorrhage type 2(PH2) post thrombolysis, and mortality). We extracted data on efficacy outcomes and safety outcomes for patients with AIS in the TNK group at a dose of 0.25 mg/kg and the alteplase group at a dose of 0.9 mg/kg, and expressed the relative risks between the 2 groups as odds ratios (ORs) and 95% confidence intervals (CIs) using the Mantel-Haenszel method. For further insight, we performed a network meta-analysis using a Bayesian framework to compare different doses of TNK (0.1, 0.25, 0.32, and 0.4 mg/kg) with alteplase (0.9 mg/kg). RESULTS: A total of 2994 patients in 9 RCTs comparing efficacy and safety outcomes in patients with AIS treated with TNK and alteplase were included. In a pairwise analysis of TNK 0.25 mg/kg and alteplase 0.9 mg/kg, regarding efficacy outcomes, the aggregated results show that TNK 0.25 mg/kg statistically significant increased early vessel recanalization (N = 368, TNK vs. alteplase, OR: 2.07,95%CI: [1.19,3.59], I2 = 0%) and excellent recovery (N = 3548, TNK vs. alteplase, OR: 1.15,95%CI: [1.01,1.32], I2 = 0%). There was no significant difference in good recovery (N = 3486, TNK vs. alteplase, OR: 1.38,95%CI: [0.89,2.15], I2 = 84%) or early neurological improvement (N = 1686, TNK vs. alteplase, OR: 1.06,95%CI: [0.87,1.28], I2 = 24%) between the TNK 0.25 mg/kg group and the alteplase 0.9 mg/kg group. In the safety outcomes, pooled results showed no significant difference in poor recovery (N = 3548, TNK vs. alteplase, OR: 0.94,95%CI: [0.81,1.10], I2 = 0%) and symptomatic intracerebral hemorrhage (N = 3567, TNK vs. alteplase, OR: 1.06,95%CI: [0.70,1.60], I2 = 0%) and PH2(N = 3103, TNK vs. alteplase, OR: 1.26,95%CI:[0.39,4.07], I2 = 56%)and mortality (N = 3447, TNK vs. alteplase, OR: 0.99,95%CI: [0.80,1.23], I2 = 33%) between the TNK group and the alteplase group. In a network meta-analysis, competing treatments were not significantly different from one another (TNK 0.1 mg/kg, TNK 0.25 mg/kg, TNK 0.32 mg/kg, TNK 0.4 mg/kg, alteplase 0.9 mg/kg) in either efficacy outcomes or safety outcomes. CONCLUSION: In this analysis of 9 RCTs in patients with AIS, TNK 0.25 mg/kg was comparable to alteplase 0.9 mg/kg from the perspective of efficacy outcomes and safety outcomes after thrombolysis within 4.5 h of AIS occurrence.

A Review: Visuospatial Dysfunction in Patients with the Cerebral Small Vessel Disease.

Cerebral small vessel disease (CSVD) impairs visuospatial function, and this is one of the most obvious areas of cognitive impairment in CSVD. So, recognizing, monitoring, and treating visuospatial dysfunction are all important to the prognosis of CSVD. This review discussed the anatomical and pathological mechanisms, clinical recognition (scales, imaging, and biomarkers), and treatment of cognitive impairment especially visuospatial dysfunction in CSVD.

Ischemic stroke or transient ischemic attack due to cervical and intracranial large-vessel vasculitis secondary to primary Sjögren's syndrome: A case series and literature review.

Introduction: Primary Sjögren's syndrome (PSS) is a systemic autoimmune disease that mainly affects exocrine glands. Little is known about PSS associated cervical and intracranial cerebral large-vessel vasculitis outside of individual case reports. Methods: We present 5 cases of ischemic stroke or transient ischemic stroke (TIA) caused by PSS associated cervical and intracranial large-vessel vasculitis. Literature review was performed to summarize and identify the demographic, clinical features, treatment, and prognosis of this condition. Results: The review resulted in 8 included articles with 8 patients, plus our 5 new patients, leading to a total of 13 subjects included in the analysis. The median age was 43 (range, 17-69) years old, among which 69.2 % (9/13) were female, and 92.3 % (12/13) came from Asia. Among them, 84.6 % (11/13) presented with cerebral infarction and 70.0 % (7/10) with watershed infarction. Middle cerebral artery (MCA) (6/13, 46.2 %) and internal carotid artery (ICA) (6/13, 46.2 %) were the most frequently involved arteries. Remarkable vessel wall concentric thickening and enhancement was observed in 57.1 % (4/7) patients and intravascular thrombi was identified in 28.6 % (2/7) patients. Glucocorticoid combined with non-glucocorticoid immunosuppressants (8/12, 66.7 %) were the most often chosen medication therapy and 4 patients received surgical intervention. Conclusion: Asian females are the most vulnerable population to ischemic stroke or TIA due to PSS associated cervical and intracranial large-vessel vasculitis. Cerebral infarctions were characterized by recurrence and watershed pattern. Magnetic resonance vessel wall imaging (MR-VWI) helps to identify the inflammatory pathology of large vessel lesion in PSS.

Blood glucose level affects prognosis of patients who received intravenous thrombolysis after acute ischemic stroke? A meta-analysis.

Background and objectives: Intravenous recombinant tissue plasminogen activator (rtPA) thrombolysis is an effective treatment for acute ischemic stroke. Hyperglycemia is a major risk factor for the occurrence, development, and prognosis of ischemic stroke. This meta-analysis purposefully estimates the association between hyperglycemia and poor prognosis in acute ischemic stroke patients receiving intravenous rtPA thrombolytic therapy. Materials and methods: According to the predefined inclusion criteria, we searched PubMed, Web of Science, and Cochrane Library databases. The association of high blood glucose(>140mg/dl) with symptomatic intracranial hemorrhage (sICH), poor clinical outcome and mortality at 90 days post-rtPA thrombolysis was studied using both a common effects model and a random effects model. Odds ratios (ORs) were plotted on forest plots. Results: Of a total cohort of 2565 patients who received intravenous thrombolytic therapy, 721 had higher blood glucose. High glucose level significantly increased the odds of sICH (OR 1.80; 95% confidence interval(95%CI): 1.30- 2.50) and poor clinical outcome at 90 days (OR 1.82; 95%CI: 1.52-2.19), and all-cause mortality at 90 days (OR 2.51; 95%CI:1.65-3.82). Conclusions: In our meta-analysis, high blood glucose was significantly associated with sICH, poor clinical outcome and higher mortality at 90 days.

Edaravone dexborneol ameliorates cognitive impairment by regulating the NF-κB pathway through AHR and promoting microglial polarization towards the M2 phenotype in mice with bilateral carotid artery stenosis (BCAS).

Cerebral small vessel disease (CSVD) is one of the most important causes of stroke and vascular dementia, so exploring effective treatment modalities for CSVD is warranted. This study aimed to explore the anti-inflammatory effects of Edaravone dexborneol (C.EDA) in a CSVD model. Mice with CSVD showed distinct cognitive decline, as assessed by the Morris water maze (MWM). Pathological staining verified leakage across the blood‒brain barrier (BBB), microglial proliferation, neuronal loss and demyelination. Western blot analysis demonstrated that M1 microglia dominated prophase and released proinflammatory molecules; the aryl hydrocarbon receptor (AHR) was found to participate in modulating nuclear factor-kappa B (NF-κB) signalling activation through tumour necrosis factor receptor-associated factor-6 (TRAF6). C.EDA treatment resulted in the polarization of microglia from the M1 to the M2 phenotype. Mice sequentially treated with C.EDA exhibited a significant improvement in cognitive function; expression of the anti-inflammatory cytokines and modulatory proteins AHR and TRAF6 was upregulated, while the levels of pNF-κBp65 and pIΚBα were downregulated. C.EDA promoted microglial activation towards the M2 phenotype by upregulating AHR expression, which prevented TRAF6 ubiquitination, promoted NF-κB RelA/p65 protein degradation and inhibited subsequent NF-κB phosphorylation. Mechanistically, the anti-inflammatory effect of C.EDA alleviated neuronal loss and myelin damage, while at the functional level, C.EDA improved cognitive function and thus showed good application prospects.

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.

Inhibiting Cyclin B1-treated Pontine Infarction by Suppressing Proliferation of SPP1+ Microglia.

Pontine infarction is the major subtype of brainstem stroke causing severe neurological deficits. The pathophysiology and treatment of pontine infarction was rarely studied. A rat model of acute pontine infarction was established via injection of endothelin-1 in the pons. Single-cell RNA sequencing was applied to detect the cellular response in pontine infarction. Based on this finding, a potential treatment for pontine infarction targeting microglia was verified. Occlusion of penetrating artery caused by endothelin-1 led to pontine infarction. Single-cell RNA sequencing revealed a subtype of activated microglia, SPP1+ microglia, which were different from M1-like or M2-like depolarization. SPP1+ microglia interacted with oligodendrocytes and contributed to the demyelination of nerve tracts. Cyclin B1 regulated the proliferation of SPP1+ microglia. Cucurbitacin E, a cyclin B1 inhibitor, reduced the proliferation of SPP1+ microglia around the injured myelin sheath and alleviated the demyelination. Moreover, cucurbitacin E treatment decreased the ischemic infarction volume and neurological deficits after pontine infarction. SPP1+ microglia contributed to axonal demyelination in the pontine infarction, and inhibition of SPP1+ microglia provided neuroprotection for pontine infarction.

Impacts of stress hyperglycemia ratio on early neurological deterioration and functional outcome after endovascular treatment in patients with acute ischemic stroke.

Background and Purpose: Hyperglycemia has been associated with unfavorable outcome of acute ischemic stroke, but this association has not been verified in patients with endovascular thrombectomy treatment. This study aimed to assess the impact of stress hyperglycemia ratio on early neurological deterioration and favorable outcome after thrombectomy in patients with acute ischemic stroke. Methods: Stroke patients with endovascular thrombectomy in two comprehensive centers were enrolled. Early neurological deterioration was defined as ≥4 points increase of National Institutes of Health Stroke Scale (NIHSS) at 24 hours after endovascular procedure. Favorable outcome was defined as modified Rankin Scale (mRS) score of 0-2 at 90 days of stroke onset. Multivariate regression analysis was used to identify the predictors for early neurological deterioration and favorable outcome. Results: Among the 559 enrolled, 74 (13.2%) patients developed early neurological deterioration. The predictors for early neurological deterioration were high stress hyperglycemia ratio at baseline (OR =5.77; 95% CI, 1.878-17.742; P =0.002), symptomatic intracranial hemorrhage (OR =4.90; 95% CI, 2.439-9.835; P <0.001) and high NIHSS score after 24 hours (OR =1.11; 95% CI, 1.071-1.151; P <0.001). The predictors for favorable outcome were stress hyperglycemia ratio (OR =0.196, 95% CI, 0.077-0.502; P =0.001), age (OR =0.942, 95% CI, 0.909-0.977; P =0.001), NIHSS score 24 hours after onset (OR =0.757, 95% CI =0.693-0.827; P <0.001), groin puncture to recanalization time (OR =0.987, 95% CI, 0.975-0.998; P =0.025), poor collateral status before treatment (ASITN/SIR grade 0-3, OR =62.017, 95% CI, 25.920-148.382; P <0.001), successful recanalization (mTICI 2b or 3, OR =7.415, 95% CI, 1.942-28.313; P =0.001). Conclusion: High stress hyperglycemia ratio may be related to early neurological deterioration and decreased likelihood of favourable outcomes after endovascular thrombectomy in patients with acute ischemic stroke.

Synaptotagmin-3 interactions with GluA2 mediate brain damage and impair functional recovery in stroke.

Synaptotagmin III (Syt3) is a Ca2+-dependent membrane-traffic protein that is highly concentrated in synaptic plasma membranes and affects synaptic plasticity by regulating post-synaptic receptor endocytosis. Here, we show that Syt3 is upregulated in the penumbra after ischemia/reperfusion (I/R) injury. Knockdown of Syt3 protects against I/R injury, promotes recovery of motor function, and inhibits cognitive decline. Overexpression of Syt3 exerts the opposite effects. Mechanistically, I/R injury augments Syt3-GluA2 interactions, decreases GluA2 surface expression, and promotes the formation of Ca2+-permeable AMPA receptors (CP-AMPARs). Using a CP-AMPAR antagonist or dissociating the Syt3-GluA2 complex via TAT-GluA2-3Y peptide promotes recovery from neurological impairments and improves cognitive function. Furthermore, Syt3 knockout mice are resistant to cerebral ischemia because they show high-level expression of surface GluA2 and low-level expression of CP-AMPARs after I/R. Our results indicate that Syt3-GluA2 interactions, which regulate the formation of CP-AMPARs, may be a therapeutic target for ischemic insults.

Astrocyte-Derived Neuronal Transdifferentiation as a Therapy for Ischemic Stroke: Advances and Challenges.

After the onset of ischemic stroke, ischemia-hypoxic cascades cause irreversible neuronal death. Neurons are the fundamental structures of the central nervous system, and mature neurons do not renew or multiply after death. Functional and structural recovery from neurological deficits caused by ischemic attack is a huge task. Hence, there remains a need to replace the lost neurons relying on endogenous neurogenesis or exogenous stem cell-based neuronal differentiation. However, the stem cell source difficulty and the risk of immune rejection of the allogeneic stem cells might hinder the wide clinical application of the above therapy. With the advancement of transdifferentiation induction technology, it has been demonstrated that astrocytes can be converted to neurons through ectopic expression or the knockdown of specific components. The progress and problems of astrocyte transdifferentiation will be discussed in this article.

The prevalence and clinical significance of intracranial vertebral artery terminated in posterior inferior cerebellar artery: A multicenter hospital-based study in China.

Objective: Intracranial vertebral artery terminated in the posterior inferior cerebellar artery (PICA-VA) is the most popular variant of the posterior inferior cerebellar artery, while its prevalence and clinical significance remained unclear. In the present study, we aimed to investigate the prevalence and clinical significance of PICA-VA. Methods: This was a multicenter hospital-based cross-sectional study. Patients were enrolled for cerebral MRI and MRA within 1 week of stroke onset. Clinical characteristics were recorded. PICA-VA is termed as a vertebral artery that does not communicate with the basilar artery but terminates in an ipsilateral PICA. We observed the prevalence of PICA-VA and identified a relationship between PICA-VA and vertebrobasilar stroke. Results: From 1 August 2015 to 31 May 2017, a total of 2,528 patients were enrolled in the present study. Among them, 95 patients (3.76%, 95/2,528) had the variation of PICA-VA, 51 of which (53.7%) were located on the right side. The prevalence of vertebrobasilar stroke was considerably higher in patients with PICA-VA than those without (40.2%, 37/92 vs. 17.1%, 417/2,436, p < 0.01). PICA-VA was an independent risk for vertebrobasilar stroke after being adjusted for a history of intracranial hemorrhage, diabetes, body mass index, and triglyceride. Conclusion: The present study showed that 3.76% of patients with acute stroke had PICA-VA, which independently increased the risk of acute vertebrobasilar stroke.