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Background and Purpose: A primary admission of patients with suspected acute ischemic stroke and large vessel occlusion (LVO) to centers capable of providing endovascular stroke therapy (EVT) may induce shorter time to treatment and better functional outcomes. One of the limitations in this strategy is the need for accurately identifying LVO patients in the prehospital setting. We aimed to study the feasibility and diagnostic performance of point-of-care ultrasound (POCUS) for the detection of LVO in patients with acute stroke., Methods: We conducted a proof-of-concept study and selected 15 acute ischemic stroke patients with angiographically confirmed LVO and 15 patients without LVO. Duplex ultrasonography (DUS) of the common carotid arteries was performed, and flow profiles compatible with LVO were scored independently by one experienced and one junior neurologist., Results: Among the 15 patients with LVO, 6 patients presented with an occlusion of the carotid-T and 9 patients presented with an M1 occlusion. Interobserver agreement between the junior and the experienced neurologist was excellent (kappa = 0.813, p < 0.001). Flow profiles of the CAA allowed the detection of LVO with a sensitivity of 73%, a positive predictive value of 92 and 100%, and a c-statistics of 0.83 (95%CI = 0.65-0.94) and 0.87 (95%CI = 0.69-0.94) (experienced neurologist and junior neurologist, respectively). In comparison with clinical stroke scales, DUS was associated with better trade-off between sensitivity and specificity., Conclusion: POCUS in acute stroke setting is feasible, it may serve as a complementary tool for the detection of LVO and is potentially applicable in the prehospital phase.

Epicardial adipose tissue is involved in the pathophysiology of atrial fibrillation (AF). This study aimed to analyze its relevance as a stroke etiology marker. A retrospective study of acute ischemic stroke patients with large vessel occlusion was conducted, periatrial epicardial adipose tissue thickness (pEATT) on admission computed tomography angiography was measured. One hundred and twenty-one patients with AF-related stroke and 94 patients with noncardioembolic stroke were included. Patients with AF-related stroke had increased pEATT. CT-measured left-sided pEATT was an independent predictor of AF-related stroke (adjusted odds ratio per 1 mm increase = 1.27, 95% CI = 1.05-1.53, p = 0.012). pEATT is an independent marker of AF-related stroke., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Purpose: It is currently thought that embolic stroke of undetermined source (ESUS) has diverse underlying hidden etiologies, of which cardioembolism is one of the most important. The subgroup of patients with this etiology could theoretically benefit from oral anticoagulation, but it remains unclear if these patients can be correctly identified from other ESUS subgroups and which markers should be used. We aimed to determine whether a machine-learning (ML) model could discriminate between ESUS patients with cardioembolic and those with non-cardioembolic profiles using baseline demographic and laboratory variables., Methods: Based on a prospective registry of consecutive ischemic stroke patients submitted to acute revascularization therapies, an ML model was trained using the age, sex and 11 selected baseline laboratory parameters of patients with known stroke etiology, with the aim of correctly identifying patients with cardioembolic and non-cardioembolic etiologies. The resulting model was used to classify ESUS patients into those with cardioembolic and those with non-cardioembolic profiles., Results: The ML model was able to distinguish patients with known stroke etiology into cardioembolic or non-cardioembolic profile groups with excellent accuracy (area under the curve = 0.82). When applied to ESUS patients, the model classified 40.3% as having cardioembolic profiles. ESUS patients with cardioembolic profiles were older, more frequently female, more frequently had hypertension, less frequently were active smokers, had higher CHA 2 DS 2 -VASc (Congestive heart failure or left ventricular systolic dysfunction, Hypertension, Age ≥ 75 [doubled], Diabetes, Stroke/transient ischemic attack [doubled], Vascular disease, Age 65-74, and Sex category) scores, and had more premature atrial complexes per hour., Conclusions: An ML model based on baseline demographic and laboratory variables was able to classify ESUS patients into cardioembolic or non-cardioembolic profile groups and predicted that 40% of the ESUS patients had a cardioembolic profile., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Inflammasomes are known to contribute to brain damage after acute ischemic stroke (AIS). TAK1 is predominantly expressed in microglial cells and can regulate the NLRP3 inflammasome, but its impact on other inflammasomes including NLRC4 and AIM2 after AIS remains elusive. EPO has been shown to reduce NLRP3 protein levels in different disease models. Whether EPO-mediated neuroprotection after AIS is conveyed via an EPO/TAK1/inflammasome axis in microglia remains to be clarified. Subjecting mice deficient for TAK1 in microglia/macrophages (Mi/MΦ) to AIS revealed a significant reduction in infarct sizes and neurological impairments compared to the corresponding controls. Post-ischemic increased activation of TAK1, NLRP3, NLRC4, and AIM2 inflammasomes including their associated downstream cascades were markedly reduced upon deletion of Mi/MΦ TAK1. EPO administration improved clinical outcomes and dampened stroke-induced activation of TAK1 and inflammasome cascades, which was not evident after the deletion of Mi/MΦ TAK1. Pharmacological inhibition of NLRP3 in microglial BV-2 cells did not influence post-OGD IL-1β levels, but increased NLRC4 and AIM2 protein levels, suggesting compensatory activities among inflammasomes. Overall, we provide evidence that Mi/MΦ TAK1 regulates the expression and activation of the NLRP3, NLRC4, AIM2 inflammasomes. Furthermore, EPO mitigated stroke-induced activation of TAK1 and inflammasomes, indicating that EPO conveyed neuroprotection might be mediated via an EPO/TAK1/inflammasome axis., (© 2021. The Author(s).)

Transforming growth factor-β-activated kinase 1 (TAK1) is upregulated after cerebral ischemia and contributes to an aggravation of brain injury. TAK1 acts as a key regulator of NF-ΚB and the MAP kinases JNK and p38 and modulates post-ischemic neuroinflammation and apoptosis. Microglia are the main TAK1-expressing immunocompetent cells of the brain. However, little is known about the function and regulation of microglial TAK1 after cerebral ischemia. Tamoxifen-dependent conditional depletion of TAK1 in microglial cells was induced in Cx3cr1 creER -Tak1 fl/fl mice. The cre ER -negative Tak1 fl/fl mice and vehicle-treated (corn oil) mice served as control groups. A transient intraluminal middle cerebral artery occlusion of 30 min followed by 6 h and 72 h of reperfusion was performed in male mice. Oxygen-glucose-deprivation (OGD) was performed with primary cortical glial cell cultures to examine the effect of microglial-specific and general (5Z-7-Oxozeaenol) TAK1 inhibition after different reperfusion times (1 h, 6 h, and 72 h). Cx3cr1 creER -Tak1 fl/fl mice showed reduced infarct sizes and improved neurological outcomes compared to the control group. The mRNA and protein levels of pro-inflammatory Il1b/IL-1β and Tnf/TNF-α in the peri-infarct zones of microglial-specific TAK1-depleted mice were significantly reduced. Furthermore, TAK1 depletion in vitro led to reduced cell death rates after OGD. Moreover, hypoxia-mediated activation of TAK1 and its downstream signalling proteins, JNK and p38, were dampened by microglial TAK1 depletion. In contrast, 5Z-7-Oxozeaenol-induced pharmacological inhibition of TAK1 completely diminished MAPK-signalling including the kinases JNK and p38 in all cells. Microglial TAK1 depletion abrogates post-ischemic neuroinflammation and apoptosis in the acute phase, hence might be considered as a potential target in the treatment of cerebral hypoxia. KEY MESSAGES: TAK1 is activated after cerebral ischemia and induces MAP kinases p38 and JNK. Activated TAK1 increases apoptosis rate and the level pro-inflammatory cytokines IL-1β and TNF-α. Microglial cells seem to be the main source of TAK1-mediated post-ischemic neuroinflammation. Microglial-specific TAK1-depletion mediates sustainable neuroprotective effects, which might be superior to global TAK1 inhibition.

Background: Access to reperfusion therapies in patients with large vessel occluding acute ischemic stroke demands process reorganization and optimization. Neurovascular networks are being built up to provide 24/7 endovascular stroke therapy service. In times of an increasingly complex stroke rescue chain little is known about patients' and their relatives' treatment awareness., Methods: All patients, who received any kind of acute reperfusion treatment between January and August 2017 in the university hospital Aachen, and their proxies, were included in the survey. Patients were either primarily or secondarily transferred., Results: For all questions regarding stroke treatment patients and their caregivers provided concurring answers. 40% of both patients and caregivers did not understand the treatment that was performed. Finally, patients who perceived on their own that stroke detection was delayed had significantly longer onset to door times than patients who did not have this impression., Conclusions: This study showed that patients' and proxies' answers correlated significantly. In case of patients' unavailability extrapolation of treatment satisfaction from answers by proxies might be permitted. High percentages of patients and caregivers do not understand relevant information, possibly due to limits of communication in an emergency setting or deficits in communication during the hospital stay. More emphasis should be laid on providing further information during the hospital stay., (Copyright © 2018. Published by Elsevier Inc.)

Hypoxia is known to impair mitochondrial and endoplasmic reticulum (ER) homeostasis. Post-hypoxic perturbations of the ER proteostasis result in the accumulation of misfolded/unfolded proteins leading to the activation of the Unfolded Protein Response (UPR). Mitochondrial chaperone TNF receptor-associated protein 1 (TRAP1) is reported to preserve mitochondrial membrane potential and to impede reactive oxygen species (ROS) production thereby protecting cells from ER stress as well as oxidative stress. The first-line antidiabetic drug Metformin has been attributed a neuroprotective role after hypoxia. Interestingly, Metformin has been reported to rescue mitochondrial deficits in fibroblasts derived from a patient carrying a homozygous TRAP1 loss-of-function mutation. We sought to investigate a putative link between Metformin, TRAP1, and the UPR after hypoxia. We assessed post-hypoxic/reperfusion longevity, mortality, negative geotaxis, ROS production, metabolic activity, gene expression of antioxidant proteins, and activation of the UPR in Trap1-deficient flies. Following hypoxia, Trap1 deficiency caused higher mortality and greater impairments in negative geotaxis compared to controls. Similarly, post-hypoxic production of ROS and UPR activation was significantly higher in Trap1-deficient compared to control flies. Metformin counteracted the deleterious effects of hypoxia in Trap1-deficient flies but had no protective effect in wild-type flies. We provide evidence that TRAP1 is crucially involved in the post-hypoxic regulation of mitochondrial/ER stress and the activation of the UPR. Metformin appears to rescue Trap1-deficiency after hypoxia mitigating ROS production and downregulating the pro-apoptotic PERK (protein kinase R-like ER kinase) arm of the UPR. [ABSTRACT FROM AUTHOR]

Acute ischemic stroke (AIS) is a devastating neurological condition with a lack of neuroprotective therapeutic options, despite the reperfusion modalities thrombolysis and thrombectomy. Post-ischemic brain damage is aggravated by an excessive inflammatory cascade involving the activation and regulation of the pro-inflammatory cytokines IL-1β and IL-18 by inflammasomes. However, the role of AIM2 and NLRC4 inflammasomes and the influence of the neuroprotective steroids 17β-estradiol (E2) and progesterone (P) on their regulation after ischemic stroke have not yet been conclusively elucidated. To address the latter, we subjected a total of 65 rats to 1 h of transient Middle Cerebral Artery occlusion (tMCAO) followed by a reperfusion period of 72 h. Moreover, we evaluated the expression and regulation of AIM2 and NLRC4 in glial single-cell cultures (astroglia and microglia) after oxygen–glucose deprivation (OGD). The administration of E2 and P decreased both infarct sizes and neurological impairments after cerebral ischemia in rats. We detected a time-dependent elevation of gene and protein levels (Western Blot/immunohistochemistry) of the AIM2 and NLRC4 inflammasomes in the post-ischemic brains. E2 or P selectively mitigated the stroke-induced increase of AIM2 and NLRC4. While both inflammasomes seemed to be exclusively abundant in neurons under physiological and ischemic conditions in vivo, single-cell cultures of cortical astrocytes and microglia equally expressed both inflammasomes. In line with the in vivo data, E and P selectively reduced AIM2 and NLRC4 in primary cortical astrocytes and microglial cells after OGD. In conclusion, the post-ischemic elevation of AIM2 and NLRC4 and their down-regulation by E2 and P may shed more light on the anti-inflammatory effects of both gonadal hormones after stroke. [ABSTRACT FROM AUTHOR]

Ischemic stroke is known to cause the accumulation of misfolded proteins and loss of calcium homeostasis leading to impairment of endoplasmic reticulum (ER) function. The unfolded protein response (UPR) is an ER-located and cytoprotective pathway that aims to resolve ER stress. Transmembrane BAX inhibitor-1 motif-containing (TMBIM) protein family member TMBIM3/GRINA is highly expressed in the brain and mostly located at the ER membrane suppressing ER calcium release by inositol-1,4,5-trisphosphate receptors. GRINA confers neuroprotection and is regulated by erythropoietin (EPO) after murine cerebral ischemia. However, the role of GRINA and the impact of EPO treatment on the post-ischemic UPR have not been elucidated yet. We subjected GRINA-deficient (Grina−/−) and wildtype mice to transient (30 min) middle cerebral artery occlusion (tMCAo) followed by 6 h or 72 h of reperfusion. We administered EPO or saline 0, 24 and 48 h after tMCAo/sham surgery. Oxygen–glucose deprivation (OGD) and pharmacological stimulation of the UPR using Tunicamycin and Thapsigargin were carried out in primary murine cortical mixed cell cultures. Treatment with the PERK-inhibitor GSK-2606414, IRE1a-RNase-inhibitor STF-083010 and EPO was performed 1 h prior to either 1 h, 2 h or 3 h of OGD. We found earlier and larger infarct demarcations in Grina−/− mice compared to wildtype mice, which was accompanied by a worse neurological outcome and an abolishment of EPO-mediated neuroprotection after ischemic stroke. In addition, GRINA-deficiency increased apoptosis and the activation of the corresponding PERK arm of the UPR after stroke. EPO enhanced the post-ischemic activation of pro-survival IRE1a and counteracted the pro-apoptotic PERK branch of the UPR. Both EPO and the PERK-inhibitor GSK-2606414 reduced cell death and regulated Grina mRNA levels after OGD. In conclusion, GRINA plays a crucial role in post-ischemic UPR and the use of both GSK-2606414 and EPO might lead to neuroprotection. [ABSTRACT FROM AUTHOR]

Transmembrane BAX Inhibitor-1 Motif-containing (TMBIM) family members exert inhibitory activities in apoptosis and necroptosis. FAIM2 (TMBIM-2) is neuroprotective against murine focal ischemia and is regulated by erythropoietin (EPO). Similar to FAIM2, GRINA (TMBIM-3) is predominantly expressed in the brain. The role of GRINA in transient brain ischemia, its potential synergistic effects with FAIM2 and its regulation by EPO treatment were assessed. We performed transient (30 min) middle cerebral artery occlusion (tMCAo) followed by 72 h of reperfusion in GRINA-deficient (GRINA−/−), FAIM2-deficient (FAIM2−/−), double-deficient (GRINA−/-FAIM2−/−) and wildtype littermates (WT) mice. We administered EPO or saline 0, 24 and 48 h after tMCAo. We subjected primary murine cortical neurons (pMCN) of all mouse strains to oxygen–glucose deprivation (OGD) after GRINA and/or FAIM2 gene transfection. Compared to wildtype controls GRINA deficiency led to a similar increase in infarct volumes as FAIM2 deficiency (p <.01). We observed the highest neurological deficits and largest infarct sizes in double-deficient mice. EPO administration upregulated GRINA and FAIM2 mRNA levels in wildtype littermates. EPO decreased infarct sizes and abrogated neurological impairments in wildtype controls. GRINA and/or FAIM2 deficient mice showed increased expression levels of cleaved-caspase 3 and of pro-apoptotic BAX mRNA. Further, caspase 8 was upregulated in FAIM2−/− and caspase 9 in GRINA−/− mice. Overexpression of GRINA and FAIM2 in wildtype and in double deficient pMCN decreased cell death rate after OGD. GRINA and FAIM2 are highly expressed in the brain and convey EPO-mediated neuroprotection after ischemic stroke involving different caspases. Unlabelled Image • TMBIM family members FAIM2 (TMBIM2) and GRINA (TMBIM3) are highly expressed in the murine brain. • FAIM2 and GRINA seem to have synergistic or partly compensatory effects after stroke. • FAIM2 seems to be involved in the extrinsic (via caspase 8) and GRINA in the intrinsic (via caspase 9) apoptotic pathway. • EPO decreased infarct sizes, abrogated neurological deficits and up-regulated FAIM2 and GRINA mRNA after ischemic stroke. • TMBIM family members FAIM2 and GRINA are involved in EPO-mediated neuroprotection after stroke. [ABSTRACT FROM AUTHOR]