Blood-Based Frailty Index in Patients with Acute Ischemic Stroke Undergoing Endovascular Treatment.

INTRODUCTION: Frailty is a syndrome depicting the vulnerability of multiple physiological systems to stressors. Frailty measures, such as Hospital Frailty Risk Score (HFRS), can be used to identify frailty and predict outcomes more reliably. Our aim was to analyze a blood-based frailty index (FI-B) at admission for prediction outcomes of patients with acute ischemic stroke (AIS) undergoing endovascular treatment (EVT). METHODS: We conducted a retrospective study of consecutive AIS patients undergoing EVT in a single tertiary center during a period of 5 years. A set of eighteen blood parameters at admission were collected and nine of these were utilized to calculate FI-B. We analyzed the relationship between FI-B and HFRS. We examined the baseline characteristics of the study population based on FI-B-tertiles. Multivariable regression models were employed to ascertain the association between FI-B and in-hospital mortality, 3-month mortality and 3-month functional outcome. RESULTS: The final study population comprised 489 patients, with a median age of 75.6 years, 49.5% of patients were male. The FI-B exhibited a weak positive correlation with HFRS (rho = 0.113, p = 0.016). Patients in higher FI-B-tertiles were older and more frequently presented with pre-stroke functional dependence and comorbidities. Moreover, an increasing FI-B was independently associated with increased likelihood of in-hospital mortality (adjusted odds ratio [aOR] = 1.29, 95% confidence interval [95% CI] = 1.14-1.47), 3-month mortality (aOR = 1.26, 95% CI = 1.11-1.43), and of increasing 3-month functional disability measured by utility-weighted modified Rankin Scale (common aOR = 0.84, 95% CI = 0.76-0.93). CONCLUSION: A frailty index based on blood values at admission was able to identify frailty in AIS patients undergoing EVT and was an independent predictor of short- and medium-term outcome after stroke.

Non-hemorrhagic imaging markers of cerebral amyloid angiopathy in memory clinic patients.

INTRODUCTION: The Boston criteria v2.0 for cerebral amyloid angiopathy (CAA) incorporated non-hemorrhagic imaging markers. Their prevalence and significance in patients with cognitive impairment remain uncertain. METHODS: We studied 622 memory clinic patients with available magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers. Two raters assessed non-hemorrhagic markers, and we explored their association with clinical characteristics through multivariate analyses. RESULTS: Most patients had mild cognitive impairment; median age was 71 years and 50% were female. Using the v2.0 criteria, possible or probable CAA increased from 75 to 383 patients. Sixty-eight percent of the sample had non-hemorrhagic CAA markers, which were independently associated with age (odds ratio [OR] = 1.04, 95% confidence interval [CI] = 1.01-1.07), female sex (OR = 1.68, 95% CI = 1.11-2.54), and hemorrhagic CAA markers (OR = 2.11, 95% CI = 1.02-4.35). DISCUSSION: Two-thirds of patients from a memory clinic cohort had non-hemorrhagic CAA markers, increasing the number of patients meeting the v2.0 CAA criteria. Longitudinal approaches should explore the implications of these markers, particularly the hemorrhagic risk in this population. HIGHLIGHTS: The updated Boston criteria for cerebral amyloid angiopathy (CAA) now include non-hemorrhagic markers. The prevalence of non-hemorrhagic CAA markers in memory clinic patients is unknown. Two-thirds of patients in our memory clinic presented non-hemorrhagic CAA markers. The presence of these markers was associated with age, female sex, and hemorrhagic CAA markers. The hemorrhagic risk of patients presenting these type of markers remains unclear.

Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial.

BACKGROUND: Whether thrombectomy alone is equally as effective as intravenous alteplase plus thrombectomy remains controversial. We aimed to determine whether thrombectomy alone would be non-inferior to intravenous alteplase plus thrombectomy in patients presenting with acute ischaemic stroke. METHODS: In this multicentre, randomised, open-label, blinded-outcome trial in Europe and Canada, we recruited patients with stroke due to large vessel occlusion confirmed with CT or magnetic resonance angiography admitted to endovascular centres. Patients were randomly assigned (1:1) via a centralised web server using a deterministic minimisation method to receive stent-retriever thrombectomy alone or intravenous alteplase plus stent-retriever thrombectomy. In both groups, thrombectomy was initiated as fast as possible with any commercially available Solitaire stent-retriever revascularisation device (Medtronic, Irvine, CA, USA). In the combined treatment group, intravenous alteplase (0·9 mg/kg bodyweight, maximum dose 90 mg per patient) was administered as early as possible after randomisation for 60 min with 10% of the calculated dose given as an initial bolus. Personnel assessing the primary outcome were masked to group allocation; patients and treating physicians were not. The primary binary outcome was a score of 2 or less on the modified Rankin scale at 90 days. We assessed the non-inferiority of thrombectomy alone versus intravenous alteplase plus thrombectomy in all randomly assigned and consenting patients using the one-sided lower 95% confidence limit of the Mantel-Haenszel risk difference, with a prespecified non-inferiority margin of 12%. The main safety endpoint was symptomatic intracranial haemorrhage assessed in all randomly assigned and consenting participants. This trial is registered with ClinicalTrials.gov, NCT03192332, and is closed to new participants. FINDINGS: Between Nov 29, 2017, and May 7, 2021, 5215 patients were screened and 423 were randomly assigned, of whom 408 (201 thrombectomy alone, 207 intravenous alteplase plus thrombectomy) were included in the primary efficacy analysis. A modified Rankin scale score of 0-2 at 90 days was reached by 114 (57%) of 201 patients assigned to thrombectomy alone and 135 (65%) of 207 patients assigned to intravenous alteplase plus thrombectomy (adjusted risk difference -7·3%, 95% CI -16·6 to 2·1, lower limit of one-sided 95% CI -15·1%, crossing the non-inferiority margin of -12%). Symptomatic intracranial haemorrhage occurred in five (2%) of 201 patients undergoing thrombectomy alone and seven (3%) of 202 patients receiving intravenous alteplase plus thrombectomy (risk difference -1·0%, 95% CI -4·8 to 2·7). Successful reperfusion was less common in patients assigned to thrombectomy alone (182 [91%] of 201 vs 199 [96%] of 207, risk difference -5·1%, 95% CI -10·2 to 0·0, p=0·047). INTERPRETATION: Thrombectomy alone was not shown to be non-inferior to intravenous alteplase plus thrombectomy and resulted in decreased reperfusion rates. These results do not support omitting intravenous alteplase before thrombectomy in eligible patients. FUNDING: Medtronic and University Hospital Bern.

Point-of-Care Ultrasound to Detect Acute Large Vessel Occlusions in Stroke Patients: A Proof-of-Concept Study.

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.

Factors associated with the laterality of Cardio-Embolic stroke.

OBJECTIVE: Understanding the lateralization factors, including the anatomic and hemodynamic mechanisms, is essential for diagnosing cardio-embolic stroke. This study aims to investigate the elements, for the first time together, that could affect the laterality of stroke. METHODS: We performed a monocentric retrospective case-control study based on prospective registries of acute ischemic stroke patients in the comprehensive stroke center of the RWTH University hospital of Aachen for three years (June 2018-June 2021). We enrolled 222 patients with cardioembolic stroke (136 left stroke and 86 right stroke) admitted for first-ever acute ischemic stroke with unilateral large vessel occlusion of the anterior circulation. The peak systolic velocity (PSV) asymmetry of middle cerebral artery (MCA) was assessed by doppler as well as internal carotid artery (ICA) angle, aortic arch (AA) branching pattern and anatomy were assessed by CT-Angiography. RESULTS: We found that the increasing left ICA angle (p = 0.047), presence of bovine type AA anatomy (p = 0.041) as well as slow PSV of the right MCA with a value of >15% than left (p = 0.005) were the predictors for left stroke lateralization, while the latter was an independent predictor for the left stroke (OR=3.341 [1.415-7.887]). Inter-Rater Reliability ranged from moderate to perfect agreement. CONCLUSION: The predictors for left stroke lateralization include the higher values of left ICA angle, presence of the bovine type AA and the slow right MCA PSV.

Classification of patients with embolic stroke of undetermined source into cardioembolic and non-cardioembolic profile subgroups.

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 CHA2 DS2 -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.

Seeing the good in the bad: actual clinical outcome of thrombectomy stroke patients with formally unfavorable outcome.

PURPOSE: Clinical outcome of stroke patients is usually classified into favorable (modified Rankin scale (mRS) 0-2) and unfavorable (mRS 3-5) outcome according to the modified Rankin scale. We took a closer look at the clinical course of thrombectomy stroke patients with formal unfavorable outcome and assessed whether we could achieve our treatment goals and/or neurological improvement in these patients. METHODS: We studied 107 patients with occlusions in the terminal carotid artery or the M1 segment of the middle cerebral artery, in whom complete recanalization (eTICI 3) could be achieved, and who had an mRS of 3-5 at 90 days. We analyzed whether an individual treatment goal (i.e., preventing aphasia) and neurological improvement (NIHSS) could be achieved. In addition, we examined whether there was clinical improvement on the mRS. RESULTS: The treatment goal was achieved in 52% (53/103) and neurological improvement in 65% (67/103). mRS 90 days post-stroke was better than mRS upon admission in 36% (38/107) and better than or equal to mRS upon admission in 80% (86/107). Of the 93 patients with known pre-stroke mRS, 18% (17/93) already had an mRS ≥ 3, with 15 of these 17 patients having a worse mRS on admission than before. Of these 17 patients, 18% regained baseline, and 24% improved from admission. CONCLUSION: Dichotomizing the mRS into favorable and unfavorable outcome does not do justice to the full spectrum of stroke. Patients with formal unfavorable outcome after mRS can improve neurologically, achieve treatment goals, and even regain their admission or pre-stroke mRS.

Imaging patterns of cerebral ischemia in hypereosinophilic syndrome: case report and systematic review.

INTRODUCTION: Ischemic stroke is a potential complication of hypereosinophilic syndromes (HES), and little is known about underlying pathophysiological mechanisms. We aimed to describe the imaging patterns of cerebral ischemia in patients with HES. METHODS: An individual case is reported. A systematic PubMed review of all records reporting adult patients with HES who suffered ischemic stroke and for whom neuroimaging details of ischemic lesions were available was performed. RESULTS: A 60-year-old man presented with progressive subacute gait difficulty and psychomotor slowing as well as an absolute eosinophilia (2.2 × 109/L) at admission. Brain magnetic resonance tomography revealed multiple acute and subacute internal and external border zone infarcts. Cardiac diagnostic suggested the presence of endomyocarditis. After extensive diagnostic workup, idiopathic HES was diagnosed. The systematic review yielded 183 studies, of which 40 fulfilled the inclusion criteria: a total of 64 patients (31.3% female), with mean age 51.1 years and a median absolute eosinophile count at diagnosis of 10.2 × 109/L were included in the analyses. A border zone pattern of cerebral ischemic lesions was reported in 41 patients (64.1%). Isolated peripheral infarcts were reported in 7 patients (10.9%). Sixteen patients had multiple acute infarcts with no border zone distribution (25.0%). An intracardiac thrombus was reported in 15/60 patients (25%), and findings suggestive of endomyocarditis or endomyocardial fibrosis were found in 31/60 patients (51.7%). CONCLUSIONS: Border zone distribution of cerebral ischemia without hemodynamic compromise is the most frequent imaging pattern in patients with HES, occurring in 2/3 of patients who develop ischemic stroke.

Increased Rates of Hemorrhages after Endovascular Stroke Treatment with Emergency Carotid Artery Stenting and Dual Antiplatelet Therapy.

BACKGROUND: While endovascular stroke treatment (EST) of large vessel occlusions in acute ischemic stroke (AIS) is proven to be safe and effective, there are subgroups of patients with increased rates of hemorrhages. Our goal was to identify risk factors for intracerebral hemorrhage and to assess whether acute carotid artery stenting (CAS) was associated with increased bleeding rates. METHODS: We performed a retrospective analysis of our monocentric prospective stroke registry in the period from May 2010 to May 2018 and compared AIS patients receiving EST with (n = 73) versus without acute CAS (n = 548). Patients with intracranial stents, intra-arterial thrombolysis, or dissection of the carotid artery were excluded. RESULTS: Parenchymal hemorrhage rates (PH2 according to the ECASS classification) and symptomatic hemorrhage (sICH) rates were increased in EST patients receiving CAS with odds being 6.3 (PH2) and 6.5 (sICH) times higher (PH2 17.8 vs. 3.3%, p < 0.001 and sICH: 16.4 vs. 2.9%, p < 0.001). Additional systemic thrombolysis with rtPA (IVRTPA) was no risk factor for cerebral hemorrhage (p = 0.213). CONCLUSION: AIS patients receiving EST with acute CAS and consecutive tirofiban or dual antiplatelet therapy suffered from an increased risk of relevant secondary intracranial bleeding. After adjusting for confounders, tirofiban and dual antiplatelet therapy were associated with higher bleeding rates.

Frailty is an outcome predictor in patients with acute ischemic stroke receiving endovascular treatment.

INTRODUCTION: Frailty is a disorder of multiple physiological systems impairing the capacity of the organism to cope with insult or stress. It is associated with poor outcomes after acute illness. Our aim was to study the impact of frailty on the functional outcome of patients with acute ischemic stroke (AIS) submitted to endovascular stroke treatment (EST). METHODS: We performed a retrospective study of patients with AIS of the anterior circulation submitted to EST between 2012 and 2017, based on a prospectively collected local registry of consecutive patients. The Hospital Frailty Risk Score (HFRS) at discharge was calculated for each patient. We compared groups of patients with and without favourable 3-month outcome after index AIS (modified Rankin Scale 0-2 and 3-6, respectively). A multivariable logistic regression model was used to identify variables independently associated with favourable 3-month outcome. Diagnostic test statistics were used to compare HFRS with other prognostic scores for AIS. RESULTS: We included 489 patients with median age 75.6 years (interquartile range [IQR] = 65.3-82.3) and median NIHSS 15 (IQR = 11-19). About 29.7% presented a high frailty risk (HFRS >15 points). Patients with favourable 3-month outcome presented lower HFRS and lower prevalence of high frailty risk. High frailty risk was independently associated with decreased likelihood of favourable 3-month outcome (adjusted odds ratio = 0.48, 95% confidence interval = 0.26-0.89). Diagnostic performances of HFRS and other prognostic scores (THRIVE and PRE scores, SPAN-100 index) for outcome at 3-months were similar. DISCUSSION: Frailty is an independent predictor of outcome in AIS patients submitted to EST.

Persistence and regredience of intraspinal fluid collection determine symptom control in intracranial hypotension syndrome.

BACKGROUND AND PURPOSE: An intraspinal fluid collection (ISFC) can be observed on spinal MRI in cases of intracranial hypotension syndrome (IHS). The goal of this study was to analyze the possible persistence of ISFC after therapy and its correlation to clinical disease activity and secondary complications. MATERIALS AND METHODS: Twenty patients in our database of 57 patients, who were treated for IHS between 2009 and 2015, fulfilled the inclusion criteria of (a) diagnosed and treated IHS as well as (b) an ISFC in MRI imaging. Ten of these participated in our study. We performed follow-up visits, which included a history, a clinical examination, and a spinal MRI. RESULTS: A MRI-confirmed ISFC was seen in six patients, five of which had symptoms attributable to chronic IHS. There were two cases of superficial siderosis. One patient had a persisting ISFC and was free of symptoms. Four patients did not have an ISFC and were free of symptoms (Fisher's exact test; p < 0.048). CONCLUSION: There is statistically significant correlation between the persistence of an ISFC after IHS treatment and ongoing clinical symptoms. Resolved symptoms seem to correlate with absorbed extradural ISFC and hypothetically closed leakage site. ISFC as confirmed by MRI proofs to be a reliable follow-up marker for disease activity in chronic IHS that is possibly even superior to clinical examination.

Red Cell Distribution Width is Associated with 30-day Mortality in Patients with Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Red cell distribution width (RDW) has been associated with mortality and outcome in a wide variety of non-neurological and neurological diseases, namely in myocardial infarction and acute ischemic stroke, and the reason for this is not completely understood. We aimed to investigate RDW as a potential prognostic marker in patients with intracerebral hemorrhage (ICH). METHODS: This is a retrospective study of consecutive patients with acute non-traumatic ICH admitted to a single center during a 4-year period. We reviewed individual clinical records to collect demographic and baseline information, including RDW at admission, 3-month functional status, and incidence of death during follow-up. Baseline computed tomography imaging was reviewed to classify the location of ICH, and to measure ICH volume and perihematomal edema volume. Patients were divided according to quartile distribution of RDW (RDW-Q1-4). RESULTS: The final study population consisted of 358 patients, median age 71 years (interquartile range [IQR] 60-80), 55% were male, and median Glasgow Coma Scale was 14 (IQR 10-15), with a mean follow-up of 17.6 months. Patients with higher RDW values were older (p = 0.003), more frequently presented with an active malignancy (p = 0.005), atrial fibrillation (p < 0.001), intraventricular hemorrhage (p = 0.048), and were anticoagulated (p < 0.001). Three-month functional independence was similar throughout RDW quartiles. RDW-Q4 was independently associated with increased 30-day mortality (adjusted odds ratio = 3.36, 95%CI = 1.48-7.62, p = 0.004), but not independently associated with increased mortality after 30 days (adjusted hazards ratio = 0.71, 95%CI = 0.29-1.73, p = 0.448). CONCLUSIONS: RDW is a robust and independent predictor of 30-day mortality in non-traumatic ICH patients, and further studies to understand this association are warranted.

Gaze Deviation and Paresis Score (GPS) Sufficiently Predicts Emergent Large Vessel Occluding Strokes.

OBJECTIVES: The prognosis of patients with acute ischemic stroke (AIS) essentially depends on both prompt diagnosis and appropriate treatment. Endovascular stroke therapy (EST) proved to be highly efficient in the treatment of emergent large vessel occluding (ELVO) strokes in the anterior circulation. To achieve a timely diagnosis, a robust combination of few and simple signs to identify ELVOs in AIS patients applicable by paramedics in the prehospital triage is worthwhile. MATERIALS AND METHODS: This retrospective single-center study included 904 AIS patients (324 ELVO, 580 non-ELVO) admitted between 2010 and 2015 in a tertiary stroke center. We re-evaluated two symptoms based on NIHSS items, gaze deviation and hemiparesis of the limbs ("Gaze deviation and Paresis Score, GPS") for the pre-hospital prediction of ELVO. RESULTS: A positive GPS AIS in patients predicted ELVO with a sensitivity of 0.89, specificity = 0.97, positive predictive value (PPV) = 0.95, negative predictive value (NPV) = 0.94 and diagnostic odds ratio (DOR) = 34.25 (CI: 20.75-56.53). The positive Likelihood-ratio (LR+) was 29.67, the negative Likelihood ratio (LR-) 0.11. NIHSS of patients with positive GPS (gaze palsy NIHSS ≥ 0, Motor arm NIHSS ≥2 and Motor leg NIHSS ≥2) was markedly higher compared to negative GPS patients (p < 0.001). CONCLUSIONS: The GPS proved to be similarly accurate in detecting ELVO in the anterior circulation of AIS patients and even more specific than other published clinical scores. Its simplicity and clarity might enable non-neurological medical staff to identify ELVO AIS patients with high certainty in a preclinical setting.

StrokeWatch: An Instrument for Objective Standardized Real-Time Measurement of Door-to-Needle Times in Acute Ischemic Stroke Treatment.

OBJECTIVES: Monitoring critical time intervals in acute ischemic stroke treatment delivers metrics for quality of performance - the door-to-needle time being well-established. To resolve the conflict of self-reporting bias a "StrokeWatch" was designed - an instrument for objective standardized real-time measurement of procedural times. MATERIALS AND METHODS: An observational, monocentric analysis of patients receiving intravenous thrombolysis for acute ischemic stroke between January 2018 and September 2019 was performed based on an ongoing investigator-initiated, prospective, and blinded endpoint registry. Patient data and treatment intervals before and after introduction of "StrokeWatch" were compared. RESULTS: "StrokeWatch" was designed as a mobile board equipped with three digital stopwatches tracking door-to-needle, door-to-groin, and door-to-recanalization intervals as well as a form for standardized documentation. 118 patients before introduction of "StrokeWatch" (subgroup A) and 53 patients after introduction of "StrokeWatch" (subgroup B) were compared. There were no significant differences in baseline characteristics, procedural times, or clinical outcome. A non-significant increase in patients with door-to-needle intervals of 60 min or faster (93.2 vs 98.1%, p = 0.243) and good functional outcome (mRS d90 ≤ 2, 47.5 vs 58.5%, p = 0.218) as well as a significant increase in reports of delayed arrival of intra-hospital patient transport service (0.8 vs 13.2%, p = 0.001) were observed in subgroup B. CONCLUSIONS: The implementation of StrokeWatch for objective standardized real-time measurement of door-to-needle times is feasible in a real-life setting without negative impact on procedural times or outcome. It helped to reassure a high-quality treatment standard and reveal factors associated with procedural delays.

Increased Post-Hypoxic Oxidative Stress and Activation of the PERK Branch of the UPR in Trap1-Deficient Drosophila melanogaster Is Abrogated by Metformin.

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.

True First-Pass Effect.

Background and Purpose- It has been hypothesized that in stroke patients, complete reperfusion (modified Thrombolysis in Cerebral Infarction; mTICI 3) after a single thrombectomy pass is a predictor for favorable outcome (modified Rankin Scale score, 0-2), but a true first-pass effect defined as improved clinical outcome after complete reperfusion with one versus multiple passes has not yet been specifically addressed in the literature. Methods- We compared clinical outcome of 164 consecutive patients with occlusions in the anterior circulation and known symptom onset, in whom we achieved complete reperfusion (mTICI 3), depending on whether complete reperfusion was achieved after a single thrombectomy pass (n=62) or multiple thrombectomy passes (n=102). To adjust for confounding factors such as prolonged time spans between symptom onset and reperfusion, additional administration of intra-arterial thrombolysis, and clot localization, we also compared clinical outcome of our first-pass group with a matched cohort (n=54) and a superselective subgroup of first-pass patients (only M1 occlusions, no additional intra-arterial thrombolysis; n=46) with its matched cohort (n=24). Results- Multivariable analysis of our cohort of 164 nonmatched patients revealed that there was a significant association between first-pass complete reperfusion and favorable clinical outcome (P=0.013). This was confirmed in our case-control analyses (P=0.010 and P=0.042). In our matched cohorts, favorable clinical outcome was seen almost twice as often if complete reperfusion was achieved after one pass (62% and 67% versus 36% and 37%), and odds for favorable outcome were 2.4 to 3.2× higher (CIs, 1.1-4.8 and 1.0-9.9). Conclusions- First-pass complete reperfusion is an independent factor for favorable outcome and should be aimed for in mechanical thrombectomy.

Functional Outcome Following Stroke Thrombectomy in Clinical Practice.

Background and Purpose- Endovascular treatment for large vessel occlusion in ischemic stroke has proven to be effective in large clinical trials. We aimed to provide real-world estimates of endovascular treatment reperfusion rates and functional outcome on a countrywide scale. Methods- Two thousand seven hundred ninety-four patients with large vessel occlusion were included into an investigator-initiated, industry-independent, prospective registry in 25 sites in Germany between June 2015 and April 2018. The primary outcome was the score on the modified Rankin Scale ranging from zero (no symptoms) to 6 (death) at 3 months. Secondary analyses included the prediction of a good outcome (modified Rankin Scale, 0-2). Dichotomized analyses of predictors were performed using logistic regression adjusted for potential confounders. Results- Median age was 75 years (interquartile range, 64-82); median National Institutes of Health Stroke Scale score was 15 (interquartile range, 10-19). Vessel occlusion was in the anterior circulation in 2265 patients (88%) and in the posterior circulation in 303 patients (12%). Intravenous alteplase before endovascular treatment was given in 1457 patients (56%). Successful reperfusion was achieved in 2143 subjects (83%). At 3 months, 854 patients (37%) showed a good outcome; mortality was 29%. There was no difference between anterior and posterior circulation occlusions (P=0.27). Significant predictors for a good outcome were younger age (odds ratio [OR], 1.06; 95% CI, 1.05-1.07), no interhospital transfer (OR, 1.39; 95% CI, 1.03-1.88), lower stroke severity (OR, 1.10; 95% CI, 1.08-1.13), smaller infarct size (OR, 1.26; 95% CI, 1.15-1.39), alteplase use (OR, 1.49; 95% CI, 1.08-2.06), and reperfusion success (OR, 1.69; 95% CI, 1.45-1.96). Conclusions- High rates of favorable outcome can be achieved on a countrywide scale by endovascular treatment. Mortality appears to be greater in the daily routine than otherwise reported by authors of large randomized trials. There were no outcome differences between the anterior and posterior circulation. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03356392.

EPO and TMBIM3/GRINA Promote the Activation of the Adaptive Arm and Counteract the Terminal Arm of the Unfolded Protein Response after Murine Transient Cerebral Ischemia.

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.

Faim2 contributes to neuroprotection by erythropoietin in transient brain ischemia.

Delayed cell death in the penumbra region of acute ischemic stroke occurs through apoptotic mechanisms, making it amenable to therapeutic interventions. Fas/CD95 mediates apoptotic cell death in response to external stimuli. In mature neurons, Fas/CD95 signaling is modulated by Fas-apoptotic inhibitory molecule 2 (Faim2), which reduces cell death in animal models of stroke, meningitis, and Parkinson disease. Erythropoietin (EPO) has been studied as a therapeutic strategy in ischemic stroke. Erythropoietin stimulates the phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway, which regulates Faim2 expression. Therefore, up-regulation of Faim2 may contribute to neuroprotection by EPO. Male Faim2-deficient mice (Faim2-/- ) and wild-type littermates (WT) were subjected to 30 min of middle cerebral artery occlusion (MCAo) followed by 72 h of reperfusion. EPO was applied before (30 min) and after (24 and 48 h) MCAo. In WT mice application of EPO at a low dose (5000 U/kg) significantly reduced stroke volume, whereas treatment with high dose (90 000 U/kg) did not. In Faim2-/- animals administration of low-dose EPO did not result in a significant reduction in stroke volume. Faim2 expression as measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) increased after low-dose EPO but not with high dose. An extensive phenotyping including analysis of cerebral vessel architecture did not reveal confounding differences between the genotypes. In human post-mortem brain Faim2 displayed a differential expression in areas of penumbral ischemia. Faim2 up-regulation may contribute to the neuroprotective effects of low-dose erythropoietin in transient brain ischemia. The dose-dependency may explain mixed effects of erythropoietin observed in clinical stroke trials.

Modern Interdisciplinary and Interhospital Acute Stroke Therapy-What Patients Think About It and What They Really Understand.

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.