Cerebral Artery Occlusion Research Articles

Inadvertent Detachment of Stent Retrievers: Report of 2 Cases.

Mechanical thrombectomy using a stent retriever is a widely-used technique for recanalizing occluded cerebral arteries in acute ischemic stroke. Although rare, inadvertent stent detachment has primarily been reported with earlier stent retriever designs. We present 2 cases of inadvertent stent detachment with the pRESET stent. In the first case, an elderly patient presented with right middle cerebral artery occlusion and experienced stent detachment during the second retrieval. Despite this, successful recanalization was achieved through balloon angioplasty. In the second case, an elderly patient experienced stent detachment after the third retrieval, and recanalization of the M1 segment was unsuccessful due to the inability to pass the microcatheter. The first patient had a modified Rankin scale (mRS) score of 3, while the second had a poor prognosis with an mRS score of 5. These cases highlight that inadvertent stent detachment can impact outcomes, and balloon angioplasty may serve as a useful salvage therapy.

8291 Graves’ Disease and Moyamoya Syndrome: A Complex Case of Thyroid Dysfunction and Neurovascular Abnormalities

Abstract Disclosure: A. Jamil: None. Q.V. Luong: None. A. Llorens Bonilla: None. A. Siddiqui: None. Background: Moyamoya disease is a cerebrovascular disease characterized by progressive stenosis and occlusion of cerebral arteries, particularly the internal carotid arteries, proximal anterior and middle cerebral arteries associated with a net-like collateral vessel formation. Moyamoya disease in association with certain systemic conditions (e.g. Graves’ disease, sickle cell anemia, neurofibromatosis type 1, and Down Syndrome) has been referred to as moyamoya syndrome. Graves’ disease is an autoimmune disease in which the development of thyroid-stimulating hormone (TSH) receptor autoantibodies leads to overproduction of thyroid hormones. Although the pathophysiology is unclear, Graves’ disease can adversely impact the clinical course of moyamoya syndrome.Clinical Case: A 26-year-old woman diagnosed with Graves’ disease at the age of 20 years who was in remission presented to the ED with right upper extremity weakness and headache. A stroke work-up was performed, and an initial CT head without contrast showed an acute infarct in the left temporal area. Extensive workup for hypercoagulability and cardiac causes were negative. MRI brain showed multiple infarcts of the left cerebral hemisphere with ivy sign, which are prominent linear or punctate high intensity areas in the subarachnoid space reflecting the development of collaterals that occurs in moyamoya disease. TSH at the time was noted to be <0.01 uIU/mL (range: 0.30-4.20 uIU/mL), indicating a thyrotoxic state. She was discharged on methimazole and antiplatelet therapies. However, the patient continued to have hypertension and headaches which did not resolve with the return to euthyroidism. At age 29, she again developed acute right upper and lower extremity weakness, and consequently presented to the ED. Imaging studies showed multiple punctate infarcts in her bilateral frontal lobes and bilateral ICA stenosis consistent with moyamoya disease. However, her biochemical studies showed euthyroidism. Ultimately, she underwent right frontotemporal craniotomy and direct parietal superficial temporal artery to middle cerebral artery bypass by neurosurgery to decrease her future stroke risk for her moyamoya syndrome, and her Graves’ disease remains in remission.Conclusions: The coexistence of Graves’ disease in moyamoya syndrome may suggest a pathophysiologic connection. It has been suggested that hemodynamic changes in cerebrovascular flow due to thyrotoxicosis might contribute to ischemic neurologic deficits. Surgical intervention for revascularization procedures should be attempted after optimal control of thyrotoxicosis, as this may help to prevent further ischemic events in the future and improve patient outcomes. Presentation: 6/1/2024

Impact of double stent retriever configuration on first-pass effect in stroke: a multicenter study

BackgroundEfficient recanalization of occluded cerebral arteries is crucial in the treatment of acute ischemic stroke. Double stent retrievers have shown the potential to enhance the rates of recanalization on the...

A phenome-wide association and factorial Mendelian randomization study on the repurposing of uric acid-lowering drugs for cardiovascular outcomes

Uric acid has been linked to various disease outcomes. However, it remains unclear whether uric acid-lowering therapy could be repurposed as a treatment for conditions other than gout. We first performed both observational phenome-wide association study (Obs-PheWAS) and polygenic risk score PheWAS (PRS-PheWAS) to identify associations of uric acid levels with a wide range of disease outcomes. Then, trajectory analysis was conducted to explore temporal progression patterns of the observed disease outcomes. Finally, we investigated whether uric acid-lowering drugs could be repurposed using a factorial Mendelian randomization (MR) study design. A total of 41 overlapping phenotypes associated with uric acid levels were identified by both Obs- and PRS- PheWASs, primarily cardiometabolic diseases. The trajectory analysis illustrated how elevated uric acid levels contribute to cardiometabolic diseases, and finally death. Meanwhile, we found that uric acid-lowering drugs exerted a protective role in reducing the risk of coronary atherosclerosis (OR = 0.96, 95%CI: 0.93, 1.00, P = 0.049), congestive heart failure (OR = 0.64, 95%CI: 0.42, 0.99, P = 0.043), occlusion of cerebral arteries (OR = 0.93, 95%CI: 0.87, 1.00, P = 0.044) and peripheral vascular disease (OR = 0.60, 95%CI: 0.38, 0.94, P = 0.025). Furthermore, the combination of uric acid-lowering therapy (e.g. xanthine oxidase inhibitors) with antihypertensive treatment (e.g. calcium channel blockers) exerted additive effects and was associated with a 6%, 8%, 8%, 10% reduction in risk of coronary atherosclerosis, heart failure, occlusion of cerebral arteries and peripheral vascular disease, respectively. Our findings support a role of elevated uric acid levels in advancing cardiovascular dysfunction and identify potential repurposing opportunities for uric acid-lowering drugs in cardiovascular treatment.

Overexpression of olfactory receptor 78 ameliorates brain injury in cerebral ischaemia-reperfusion rats by activating Prkaca-mediated cAMP/PKA-MAPK pathway.

Ischemic stroke is one of the main causes of disability and death. However, recanalization of occluded cerebral arteries is effective only within a very narrow time window. Therefore, it is particularly important to find neuroprotective biological targets for cerebral artery recanalization. Here, gene expression profiles of datasets GSE160500 and GSE97537 were downloaded from the GEO database, which were related to ischemic stroke in rats. Olfactory receptor 78 (Olfr78) was screened, and which highly associated with Calcium signalling pathway and MAPK pathway. Interacting protein of Olfr78, Prkaca, was predicted by STRING, and their interaction was validated by Co-IP analysis. Then, a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) and a neuronal cell model stimulated by oxygen-glucose deprivation/reoxygenation (OGD/R) were constructed, and the results showed that expression of Olfr78 and Prkaca was downregulated in MCAO rats and OGD/R-stimulated neurons. Overexpression of Olfr78 or Prkaca inhibited the secretion of inflammatory factors, Ca2+ overload, and OGD/R-induced neuronal apoptosis. Moreover, Overexpression of Prkaca increased protein levels of cAMP, PKA and phosphorylated p38 in OGD/R-stimulated neurons, while SB203580, a p38 inhibitor, treatment inhibited activation of the cAMP/PKA-MAPK pathway and counteracted the effect of Olfr78 overexpression on improvement of neuronal functions. Meanwhile, overexpression of Olfr78 or Prkaca markedly inhibited neuronal apoptosis and improved brain injury in MCAO/R rats. In conclusion, overexpression of Olfr78 inhibited Ca2+ overload and reduced neuronal apoptosis in MCAO/R rats by promoting Prkaca-mediated activation of the cAMP/PKA-MAPK pathway, thereby improving brain injury in cerebral ischaemia-reperfusion.

Alcohol consumption may be a risk factor for cerebrovascular stenosis in acute ischemic stroke and transient ischemic attack

BackgroundAtherosclerosis are well established risk factors for ischemic stroke, however the association between alcohol consumption and atherosclerosis is controversial. This study aims to explore the potential correlation between alcohol consumption and cerebral stenosis in patients with acute ischemic stroke and transient ischemic attack (TIA).MethodsNine hundreds and eighty-eight patients with first acute ischemic stroke attack or TIA were recruited retrospectively. Alcohol consumption was classified into five consumption categories (non-drinkers, occasional drinkers, < 140 g per week [mild drinkers], 140–279 g per week [moderate drinkers], ≥ 280 g per week [heavy drinkers]). Computed tomography angiography (CTA) and digital subtraction angiography (DSA) were utilized to assess the carotid and cerebral artery in all patients. Five-step scale for degree of stenosis was applied: normal (0, 0 points), mild (< 50%, 1 point), moderate (50–69%, 2 points), severe (70–99%, 3 points), and occlusion (100%, 4 points).ResultsThe carotid and cerebral artery stenosis scores were positively correlated with moderate alcohol consumption (B = 1.695, P < 0.001). Compared with nondrinkers, moderate alcohol consumption had significant increasing risk of moderate carotid and cerebral artery stenosis (OR = 4.28, 95% CI: 1.47–12.49, P = 0.008) and severe stenosis (OR = 4.24, 95% CI: 1.55–11.64, P = 0.005) and occlusion (OR = 3.87, 95% CI: 1.65–9.06, P = 0.002). Compared with nondrinkers, heavy alcohol consumption patients had significant higher risk of carotid and cerebral artery occlusion (OR = 2.71, 95% CI: 1.36–5.41, P = 0.005).ConclusionsHigher alcohol consumption may associate with higher risk and more severity of carotid and cerebrovascular stenosis.

The case for neuregulin-1 as a clinical treatment for stroke.

Ischemic stroke is the leading cause of serious long-term disability and the 5th leading cause of death in the United States. Revascularization of the occluded cerebral artery, either by thrombolysis or endovascular thrombectomy, is the only effective, clinically-approved stroke therapy. Several potentially neuroprotective agents, including glutamate antagonists, anti-inflammatory compounds and free radical scavenging agents were shown to be effective neuroprotectants in preclinical animal models of brain ischemia. However, these compounds did not demonstrate efficacy in clinical trials with human patients following stroke. Proposed reasons for the translational failure include an insufficient understanding on the cellular and molecular pathophysiology of ischemic stroke, lack of alignment between preclinical and clinical studies and inappropriate design of clinical trials based on the preclinical findings. Therefore, novel neuroprotective treatments must be developed based on a clearer understanding of the complex spatiotemporal mechanisms of ischemic stroke and with proper clinical trial design based on the preclinical findings from specific animal models of stroke. We and others have demonstrated the clinical potential for neuregulin-1 (NRG-1) in preclinical stroke studies. NRG-1 significantly reduced ischemia-induced neuronal death, neuroinflammation and oxidative stress in rodent stroke models with a therapeutic window of >13 h. Clinically, NRG-1 was shown to be safe in human patients and improved cardiac function in multisite phase II studies for heart failure. This review summarizes previous stroke clinical candidates and provides evidence that NRG-1 represents a novel, safe, neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke.

Abstract WP30: Therapeutic Hypothermia With Thin Liquid Convection is Safe and Feasible in Acute Stroke Patients: The Helping Stroke Patients With ThermoSuit Cooling (SISCO) Pilot Study

Introduction: Animal studies have shown that therapeutic hypothermia of 32-34°C (TH) leads to a drop in infarct size after cerebral artery occlusion. Data suggests that early, rapid TH must be achieved to maximize neuroprotection from ischemic injury. There have been two RCTs of TH in stroke patients, both of which cooled slowly and failed to show the benefit of TH. Objective: The present study assessed the safety and feasibility of the ThermoSuit System (TSS) to induce rapid TH in acute ischemic stroke patients enrolled in the SISCO pivotal phase I trial. The TSS circulates cold water directly over the patient’s skin to achieve TH and has previously demonstrated significantly faster cooling than other methods. Methods: Eligible stroke patients were enrolled with an NIHSS &gt; 5, less than 8 hours from LKW, or who met the extended window thrombectomy criteria. Patients were sedated and intubated according to protocols. Cooling was initiated by circulating ice-cold water (0-8°C) through the TSS. The patients were cooled until the core temperature reached 34-33°C, and the suit was removed. Temperature was maintained at 32°C to 34°C for 24 hours following the cooling induction using a conventional cooling blanket. Criteria for study success were defined as 1) at least 50% of the patients achieving 32-34°C within 1 hour; 2) NIHSS and mRS scores at 90 days post-stroke were not statistically worse than historical controls; 3) no significant increase in adverse event rates in cooled subjects vs. historical controls. RESULTS 14 subjects were enrolled, and 13 were cooled. 2 patients were excluded due to treatment delays and 1 due to missing outcome data, leaving 10 patients available for complete analysis. The average NIHSS on admission was 18, and the average patient age was 65. 7 patients had an LVO in the anterior circulation and 3 had posterior circulation strokes. All study success criteria were met. The median cooling time to 34°C was 40 minutes. The rates of unacceptable outcomes at 90 days (mRS &gt;3) were 45% in 1314 published historical controls but only 10% in cooled subjects. Conclusion: The TSS is a safe and effective tool for rapid TH in ischemic stroke patients. Further studies are warranted to assess whether this cooling method is neuroprotective for these patients.

Interferon Beta Modulation of Brain Endothelial Cell Activation in Ischemic Stroke

Background and Hypothesis:Every year, more than 690,000 people in the United States suffer an ischemic stroke. Many survivors are left with long-term disability. While the initial insult to the brain is caused by hypoxia resulting from cerebral artery occlusion, a secondary insult is caused by peripheral immune cell infiltration across the blood brain barrier (BBB) and subsequent cytotoxic insult. Previous studies have demonstrated that interferon beta (IFNβ) limits peripheral immune cell infiltration across the BBB and reduces brain infarction volume. We hypothesize that during ischemic stroke IFNβ suppresses brain endothelial cells (bECs) activation to reduce their expression of adhesion molecules as one of the mechanisms by which it decreases peripheral immune cell infiltration across the BBB.&#x0D; Experimental Design:In this project, bEnd.3 cells, a cell line of bECs, were activated by TNF-α, a pro-inflammatory cytokine. Tissue plasminogen activator (tPA), an FDA-approved thrombolytic for ischemic stroke, was included in the study. bEnd.3 cells were treated with IFNβ at 1.5 hours prior TNF-α or TNF-α + tPA stimulation to evaluate its modulation of adhesion cell expression. The adhesion molecule expression was determined by flow cytometry. Results were further confirmed by in vivo studies in which stroke animals were subjected to tPA treatment in the presence or absence of IFNβ.&#x0D; Results:Our results showed that TNF-α induced ICAM-1, VCAM-1, E-selectin, and P-selectin expression. Importantly, we found IFNβ suppressed the expression of aforementioned adhesion molecules in bEnd.3 cells treated with TNF-α or TNF-α+tPA. Our in vivo results demonstrated that IFNβ treatment reduced ICAM-1 and E-selectin, but not VCAM-1 or P-selectin expression in the ischemic brain.&#x0D; Conclusion and Potential Impact:Our study demonstrates that IFNβ modulates bEC expression of adhesion molecules in vitro and in vivo of ischemic stroke, suggesting IFNβ, an FDA-approved drug for Multiple Sclerosis, shows potential to improve ischemic stroke outcomes.

The History of Endovascular Stroke Treatment: From Local Intraarterial Fibrinolysis to Stent Retriever Thrombectomy.

Background Acute thromboembolic occlusions of large intracranial arteries are associated with high rates of permanent disability and mortality. Intravenous thrombolysis (IVT) in these patients resulted in an inadequate rate of recanalization and has had limited clinical success. Various endovascular procedures have been attempted to remove intracranial thrombi and reopen occluded vessels. These technical innovations led to the publication of initial case reports, but the methods ultimately did not endure. Endovascular treatment of acute cerebral ischemia was performed only rarely and in selected centers as part of individualized curative attempts. The Solitaire stent was originally developed to treat intracranial aneurysms through stent-assisted coil occlusion. The suggestion that this stent could also be used for intracranial thrombectomy was made as early as 2003 and was clinically confirmed in 2008. Releasing a Solitaire stent into an embolically occluded large cerebral artery, with an incubation time of approximately 3 minutes and slow retraction of the stent, has led to unprecedented success rates of thrombus removal and (sub)total recanalization in more than 90 % of patients. Methods This review article aimed to describe the steps in the development of endovascular stroke therapy, beginning with intra-arterial thrombolysis and early technical innovations leading to the eventual success of stent retriever thrombectomy. Conclusion The potential for mechanical recanalization of acutely occluded large cerebral arteries could not be fully exploited until the advent of stent retriever thrombectomy. The entire concept of stroke treatment fundamentally changed after complete and rapid recanalization first became possible. Randomized controlled trials have shown superiority of stent retriever thrombectomy over IVT. An unparalleled boom in endovascular stroke therapy followed. Key Points:

Diagnostic accuracy of large and medium vessel occlusions in acute stroke imaging by neurology residents and stroke fellows: A comparison of CT angiography alone and CT angiography with CT perfusion.

Neurology senior residents and stroke fellows are first to clinically assess and interpret imaging studies of patients presenting to the emergency department with acute stroke. The aim of this study was to compare the diagnostic accuracy of brain CT angiography (CTA) with and without CT perfusion (CTP) between neurology senior residents and stroke fellows. In this neuroimaging study, nine practitioners (four senior neurology residents (SNRs) and five stroke fellows (SFs)) clinically assessed and interpreted the imaging data of 50 cases (15 normal images, 21 large vessel occlusions (LVOs) and 14 medium vessel occlusions (MeVOs) in two sessions, 1 week apart in comparison to final diagnosis of experienced neuroradiologist and experienced stroke neurologist consensus. Interrater agreement of CTA alone and CTA with CTP was quantified using kappa statistics, sensitivity, specificity and overall accuracy. Overall, arterial occlusions were correctly identified in 221/315 (70.1%) with CTA alone and in 266/315 (84.4%) with CTA and CTP (p < 0.001). The sensitivity of overall arterial occlusions detection with CTA alone was 94.2% (95% CI: 90.8%-96.6%) while with addition of CTP was 98% (95% CI: 95.6%-99.3%), The specificity of CTA alone was 74.7% (95% CI: 67.2%-81.3%) which increased with CTP to 84.4% (95% CI: 77.7%-89.8%). The likelihood of correct identification with CTA alone was 156/189 (82.54%) for LVOs and 65/126 (51.59%) for MeVOs. This increased to 169/189 (89.42%; p = 0.054) for LVOs and 97/126 (76.98%; p < 0.001) for MeVOs when the CTA images with CTP were viewed. There was good overall interrater agreement between readers when using CTA alone (k 0.71, 95% CI, 0.62-0.80) and almost perfect (k 0.85, 95% CI, 0.76-0.94) when CTP was added to the image for interpretation. CTA and CTP had a significantly lower median interquartile range (IQR) interpretation time than CTA alone (114 [IQR, 103-120] s vs 156 [IQR, 133-160] s, p < 0.001). In cerebral arterial occlusions, the rate of LVO and MeVOs detections increases when adding CTP to CTA. The accuracy and time for diagnosing arterial occlusion can be significantly improved if CTP is added to CTA. As MeVOs are commonly missed by front-line neurology senior residents or stroke fellows, cases with significant deficits and no apparent arterial occlusions need to be reviewed with neuroradiological expertise.

Three-dimensional vessel wall imaging with 1.5-T MRI to visualize invisible occluded cerebral artery.

Endovascular thrombectomy (EVT) is performed for acute ischemic stroke (AIS) caused by large vessel occlusion; therefore, preoperative visualization of the occluded invisible vessel course reduces complications and ensures success. Three-dimensional (3D) proton density-weighted (PDW) vessel wall imaging (VWI) using variable refocusing flip angle pulse-turbo spin-echo sequences (VRFA-TSE) with 3.0-T magnetic resonance imaging (MRI) can provide this information. To assess the effectiveness of 3D PDW-VWI using 1.5-T MRI without VRFA function. Five consecutive patients with AIS caused by large vessel occlusion underwent EVT in our institute. VWI with 1.5-T MRI using 3D PDW-fast spin echo (FSE) technique was added to conventional brain imaging. PDW-FSE was successfully performed in all cases. 3D PDW-FSE was useful to visualize both the anterior and posterior circulations by clearly revealing invisible vessels but could not demonstrate the length and size of the clot in all five cases. 3D PDW-FSE with 1.5-T MRI without VRFA could clearly depict the course of the invisible occluded artery and might support favorable outcomes after EVT in patients with AIS.

Effects of comprehensive care measures based on the HAPA model on self-care, neurotransmitters and clinical outcomes in cerebral infarction patients.

Cerebral infarction is induced by cerebral artery occlusion, resulting in ischemia, hypoxia, necrosis of brain cells in the corresponding blood supply area, and then dysfunction. Health action process approach (HAPA) model emphasizes the proposal and practice of health behavior as a whole and uses self-monitoring and encouraging ultimately developed health behavior. The present study explores the effects of comprehensive nursing measures of HAPA model on neurotransmitters, self-care ability and clinical outcomes of cerebral infarction patients. One hundred and ten patients with cerebral infarction diagnosed and treated in our hospital from July 2020 to February 2022 were included as the subjects. The subjects were randomly grouped as the control (55 patients) and the study group (55 patients) and received conventional nursing measures and additional comprehensive nursing measures of HAPA model, respectively. The patients were tested for changes in self-care ability, nerve damage [myelin basic protein (MBP), S100B, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE)] and neurotransmitter indexes [acid-soluble protein (Asp), neuropeptide Y (NPY), substance P (SP), glutamate (Glu)], respectively. The patients were considered as the good prognosis group (47 cases) and poor prognosis group (63 cases) according to the prognosis after comprehensive care. The logistic regression model was used to analyze the risk factors affecting the poor prognosis of patients with cerebral infarction. After nursing, China Stroke Scale (CSS) score, the Fugl Meyer Rating Scale (FMA) score and Barthel index were significantly higher in both groups than before nursing, and all indexes were significantly higher in the study group than in the control group (p< 0.05). The length of hospital stay was significantly shorter in the study group than in the control group (p< 0.05). Compared with before nursing, the health knowledge, self-care skills, self-responsibility and self-concept of two groups were strongly increased after nursing, and the study group had much higher indexes than the control group (p< 0.05). After nursing, the levels of MBP, S100B, GFAP, NSE, Asp, NPY, SP and Glu in both groups were largely decreased, and more significant decrease was found in the study group (p< 0.05). Age, body mass index (BMI), hypertension history, coronary heart disease history and National Institutes of Health Stroke Score (NIHSS) score after treatment were significantly different between the good and poor prognosis groups (p< 0.05). The prognosis of patients in the study group was 52.73%, which was significantly higher than 32.73% in the control group (p< 0.05). Age, hypertension history, and post-treatment NIHSS score were independent risk factors related to poor prognosis by logistic multiple regression analysis (p< 0.05). Comprehensive care measures of HAPA model may be used with advantage to improve the self-care ability, reduce the degree of neurological damage, and improve neurological function in cerebral infarction patients. Age, hypertension history, and NIHSS score after treatment were all risk factors related to poor prognosis.

MALAT1 knockdown alleviates the pyroptosis of microglias in diabetic cerebral ischemia via regulating STAT1 mediated NLRP3 transcription

BackgroundDysregulated long non-coding RNAs participate in the development of diabetic cerebral ischemia. This study aimed to investigate the underlying mechanism of lncRNA MALAT1 in diabetic cerebral ischemia.MethodMiddle cerebral artery occlusion (MCAO) was performed to establish diabetic cerebral I/R in vivo. TTC and neurological deficits assessment were performed to assess cerebral ischemic injury. LDH was conducted to detect cytotoxicity. RT-qPCR and western blotting assays were applied to determine mRNA and protein expression. Flow cytometry was performed to detect the pyroptosis of BV2 cells. Immunofluorescence and FISH were conducted for subcellular localization of MALAT1 and STAT1. ELISA was performed to determine cytokine release. Dual luciferase reporter, RIP, and ChIP assays were used to validate the interaction between STAT1 and MALAT1/NLRP3. Diabetes aggravated cerebral injury in vivo and in vitro. Diabetic cerebral ischemia induced inflammatory response and inflammation-induced cell pyroptosis.ResultMALAT1 was overexpressed in diabetic cerebral ischemia models in vivo and in vitro. However, knockdown of MALAT1 suppressed inflammatory response and the pyroptosis of BV2 cells. Moreover, MALAT1 interacted with STAT1 to transcriptionally activate NLRP3. Knockdown of STAT1 significantly reversed the effects of MALAT1. Furthermore, STAT1 promotes the MALAT1 transcription. MALAT1 interacts with STAT1 to promote the pyroptosis of microglias induced by diabetic cerebral ischemia through activating NLRP3 transcription.ConclusionThus, knockdown of MALAT1 may be a potential promising therapy target for diabetic cerebral ischemia.

Human umbilical cord-derived mesenchymal stem cell transplantation supplemented with curcumin improves the outcomes of ischemic stroke via AKT/GSK-3β/β-TrCP/Nrf2 axis

BackgroundHuman umbilical cord-derived mesenchymal stem cell (hUC-MSC) engraftment is a promising therapy for acute ischemic stroke (AIS). However, the harsh ischemic microenvironment limits the therapeutic efficacy of hUC-MSC therapy. Curcumin is an anti-inflammatory agent that could improve inflammatory microenvironment. However, whether it enhances the neuroprotective efficacy of hUC-MSC transplantation is still unknown. In the present study, we investigated the therapeutic efficacy and the possible mechanism of combined curcumin and hUC-MSC treatment in AIS.MethodsMiddle cerebral artery occlusion (MCAO) mice and oxygen glucose deprivation (OGD) microglia were administrated hUC-MSCs with or without curcumin. Neurological deficits assessment, brain water content and TTC were used to assess the therapeutic effects of combined treatment. To elucidate the mechanism, MCAO mice and OGD microglia were treated with AKT inhibitor MK2206, GSK3β activator sodium nitroprusside (SNP), GSK3β inhibitor TDZD-8 and Nrf2 gene knockout were used. Immunofluorescence, flow cytometric analysis, WB and RT-PCR were used to evaluate the microglia polarization and the expression of typical oxidative mediators, inflammatory cytokines and the AKT/GSK-3β/β-TrCP/Nrf2 pathway protein.ResultsCompared with the solo hUC-MSC-grafted or curcumin groups, combined curcumin-hUC-MSC therapy significantly improved the functional performance outcomes, diminished the infarct volumes and the cerebral edema. The combined treatment promoted anti-inflammatory microglia polarization via Nrf2 pathway and decreased the expression of ROS, oxidative mediators and pro-inflammatory cytokines, while elevating the expression of the anti-inflammatory cytokines. Nrf2 knockout abolished the antioxidant stress and anti-inflammation effects mediated with combined treatment. Moreover, the combined treatment enhanced the phosphorylation of AKT and GSK3β, inhibited the β-TrCP nucleus translocation, accompanied with Nrf2 activation in the nucleus. AKT inhibitor MK2206 activated GSK3β and β-TrCP and suppressed Nrf2 phosphorylation in nucleus, whereas MK2206 with the GSK3β inhibitor TDZD-8 reversed these phenomena. Furthermore, combined treatment followed by GSK3β inhibition with TDZD-8 restricted β-TrCP nucleus accumulation, which facilitated Nrf2 expression.ConclusionsWe have demonstrated that combined curcumin-hUC-MSC therapy exerts anti-inflammation and antioxidant stress efficacy mediated by anti-inflammatory microglia polarization via AKT/GSK-3β/β-TrCP/Nrf2 axis and an improved neurological function after AIS.

Health Conditions Associated with Alzheimer's Disease and Vascular Dementia.

We examined medical records to determine health conditions associated with dementia at varied intervals prior to dementia diagnosis in participants from the Baltimore Longitudinal Study of Aging (BLSA). Data were available for 347 Alzheimer's disease (AD), 76 vascular dementia (VaD), and 811 control participants without dementia. Logistic regressions were performed associating International Classification of Diseases, 9th Revision (ICD-9) health codes with dementia status across all time points, at 5 and 1 year(s) prior to dementia diagnosis, and at the year of diagnosis, controlling for age, sex, and follow-up length of the medical record. In AD, the earliest and most consistent associations across all time points included depression, erectile dysfunction, gait abnormalities, hearing loss, and nervous and musculoskeletal symptoms. Cardiomegaly, urinary incontinence, non-epithelial skin cancer, and pneumonia were not significant until 1 year before dementia diagnosis. In VaD, the earliest and most consistent associations across all time points included abnormal electrocardiogram (EKG), cardiac dysrhythmias, cerebrovascular disease, non-epithelial skin cancer, depression, and hearing loss. Atrial fibrillation, occlusion of cerebral arteries, essential tremor, and abnormal reflexes were not significant until 1 year before dementia diagnosis. These findings suggest that some health conditions are associated with future dementia beginning at least 5 years before dementia diagnosis and are consistently seen over time, while others only reach significance closer to the date of diagnosis. These results also show that there are both shared and distinctive health conditions associated with AD and VaD. These results reinforce the need for medical intervention and treatment to lessen the impact of health comorbidities in the aging population. ANN NEUROL 2023;93:805-818.

Complete Sudden Recanalization: There Is Hope Beyond the First Pass Effect

Background In the endovascular treatment of stroke, achieving complete recanalization in a minimum number of attempts is the main procedural objective. We aimed to explore the effect of the per pass recanalization pattern in patients with final complete recanalization. Methods We analyzed all patients admitted in our center from 2014 to 2022 with a terminal internal carotid artery or M1‐middle cerebral artery occlusion who received endovascular treatment and achieved complete recanalization (expanded thrombolysis in cerebral infarction 2c–3) in our center. Complete sudden recanalization (cSR) was considered when expanded thrombolysis in cerebral infarction improved from 0–1 to 2c–3 in a single pass as opposed to complete progressive recanalization when partial recanalization (2a or 2b) was observed after interim passes. Results Among the 400 included patients with final complete recanalization, 301 (75%) showed a cSR pattern. There were no differences in baseline demographic characteristics between patients with cSR and complete progressive recanalization, including intravenous tissue plasminogen activator treatment (42.2% versus 44.4%; P =0.69). The rate of terminal carotid artery occlusion (28.6% versus 44.4%; P =0.003), median number of passes (1 [interquartile range 1—2] versus 2 [2–3]; P &lt;0.001), and time from puncture to recanalization (27 [interquartile range 18–43] versus 46 [34–66] minutes; P &lt;0.001) were lower in cSR group. At 90 days cSR was an independent predictor of good functional outcome (57.8% versus 44.4%, adjusted odds ratio 1.72 [CI 95% 1.03–2.88]; P =0.038). The rate of favorable outcome did not decrease with additional passes as long as cSR was observed (cSR after pass 1: 57.6%, after pass 2: 55.6%, after &gt;2 passes: 63.6%; P =0.825). Conclusion Among stroke patients with a large vessel occlusion, the cSR pattern predicted favorable outcome independently of the number of thrombectomy passes.

Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases

BackgroundDysregulated activation of the inflammasome is involved in various human diseases including acute cerebral ischemia, multiple sclerosis and sepsis. Though many inflammasome inhibitors targeting NOD-like receptor protein 3 (NLRP3) have been designed and developed, none of the inhibitors are clinically available. Growing evidence suggests that targeting apoptosis-associated speck-like protein containing a CARD (ASC), the oligomerization of which is the key event for the assembly of inflammasome, may be another promising therapeutic strategy. Lonidamine (LND), a small-molecule inhibitor of glycolysis used as an antineoplastic drug, has been evidenced to have anti-inflammation effects. However, its anti-inflammatory mechanism is still largely unknown.MethodsMiddle cerebral artery occlusion (MCAO), experimental autoimmune encephalomyelitis (EAE) and LPS-induced sepsis mice models were constructed to investigate the therapeutic and anti-inflammasome effects of LND. The inhibition of inflammasome activation and ASC oligomerization by LND was evaluated using western blot (WB), immunofluorescence (IF), quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) in murine bone marrow-derived macrophages (BMDMs). Direct binding of LND with ASC was assessed using molecular mock docking, surface plasmon resonance (SPR), and drug affinity responsive target stability (DARTS).ResultsHere, we find that LND strongly attenuates the inflammatory injury in experimental models of inflammasome-associated diseases including autoimmune disease-multiple sclerosis (MS), ischemic stroke and sepsis. Moreover, LND blocks diverse types of inflammasome activation independent of its known targets including hexokinase 2 (HK2). We further reveal that LND directly binds to the inflammasome ligand ASC and inhibits its oligomerization.ConclusionsTaken together, our results identify LND as a broad-spectrum inflammasome inhibitor by directly targeting ASC, providing a novel candidate drug for the treatment of inflammasome-driven diseases in clinic.

Transient receptor potential ion channels and cerebral stroke.

The databases Pubmed, and the National Library of Medicine were searched for literature. All papers on celebral stroke and transient receptor potential ion channels were considered. Stroke is the second leading cause of death and disability, with an increasing incidence in developing countries. About 75 per cent of strokes are caused by occlusion of cerebral arteries, and substantial advances have been made in elucidating mechanisms how stroke affects the brain. Transient receptor potential (TRP) ion channels are calcium-permeable channels highly expressed in brain that drives Ca2+ entry into multiple cellular compartments. TRPC1/3/4/6, TRPV1/2/4, and TRPM2/4/7 channels have been implicated in stroke pathophysiology. Although the precise mechanism of transient receptor potential ion channels in cerebral stroke is still unclear, it has the potential to be a therapeutic target for patients with stroke if developed appropriately. Hence, more research is needed to prove its efficacy in this context.

Delivery of self-replicating messenger RNA into the brain for the treatment of ischemic stroke.

Ischemic stroke is caused by the occlusion of cerebral arteries. In the ischemic stroke, ischemia-reperfusion injury increases the damage in the brain after reperfusion. In the previous study, heme oxygenase-1 (HO1) mRNA was delivered into the ischemic brain, showing that HO1-mRNA had higher therapeutic effect and less side-effect than HO1-plasmid (pHO1). However, mRNA is degraded faster than plasmid DNA reducing the duration of gene expression. In this study, self-replicating mRNA (Rep-mRNA) was developed using a replicon system from Venezuelan Equine Encephalitis virus to compensate this disadvantage of mRNA delivery. Deoxycholic acid-conjugated polyethylenimine (DA-PEI) was used as a carrier of the mRNAs. The Rep-mRNA/DA-PEI complex had a size of around 90nm and a zeta-potential of 33mV. In the in vitro transfection assays, gene expression by the HO1-Rep-mRNA/DA-PEI complex persisted at least 14days, while that by the HO1-mRNA/DA-PEI complex approached basal level at 3days after transfection. Therapeutic effects of the HO1-Rep-mRNA/DA-PEI complexes were evaluated in the ischemic stroke animal model. The complexes were injected into the brain stereotaxically. HO1 expression by the HO1-Rep-mRNA/DA-PEI complex persisted at least 7days after injection, but the pHO1/DA-PEI or HO1-mRNA/DA-PEI complex showed basal level of HO1-expression at 7days after injection. Due to higher and longer expression of HO1, the apoptosis level and infarct size were decreased by the HO1-Rep-mRNA/DA-PEI complexes, compared with the pHO1/DA-PEI and HO1-mRNA/DA-PEI complex. These results suggest that HO1-Rep-mRNA/DA-PEI complex may have a potential as a long-lasting therapeutic system for the treatment of ischemic stroke.