Is CAA a perivascular brain clearance disease? A discussion of the evidence to date and outlook for future studies.

The brain's network of perivascular channels for clearance of excess fluids and waste plays a critical role in the pathogenesis of several neurodegenerative diseases including cerebral amyloid angiopathy (CAA). CAA is the main cause of hemorrhagic stroke in the elderly, the most common vascular comorbidity in Alzheimer's disease and also implicated in adverse events related to anti-amyloid immunotherapy. Remarkably, the mechanisms governing perivascular clearance of soluble amyloid ß-a key culprit in CAA-from the brain to draining lymphatics and systemic circulation remains poorly understood. This knowledge gap is critically important to bridge for understanding the pathophysiology of CAA and accelerate development of targeted therapeutics. The authors of this review recently converged their diverse expertise in the field of perivascular physiology to specifically address this problem within the framework of a Leducq Foundation Transatlantic Network of Excellence on Brain Clearance. This review discusses the overarching goal of the consortium and explores the evidence supporting or refuting the role of impaired perivascular clearance in the pathophysiology of CAA with a focus on translating observations from rodents to humans. We also discuss the anatomical features of perivascular channels as well as the biophysical characteristics of fluid and solute transport.

Endovascular thrombectomy for acute ischaemic stroke with established large infarct: multicentre, open-label, randomised trial.

BACKGROUND: Recent evidence suggests a beneficial effect of endovascular thrombectomy in acute ischaemic stroke with large infarct; however, previous trials have relied on multimodal brain imaging, whereas non-contrast CT is mostly used in clinical practice. METHODS: In a prospective multicentre, open-label, randomised trial, patients with acute ischaemic stroke due to large vessel occlusion in the anterior circulation and a large established infarct indicated by an Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) of 3-5 were randomly assigned using a central, web-based system (using a 1:1 ratio) to receive either endovascular thrombectomy with medical treatment or medical treatment (ie, standard of care) alone up to 12 h from stroke onset. The study was conducted in 40 hospitals in Europe and one site in Canada. The primary outcome was functional outcome across the entire range of the modified Rankin Scale at 90 days, assessed by investigators masked to treatment assignment. The primary analysis was done in the intention-to-treat population. Safety endpoints included mortality and rates of symptomatic intracranial haemorrhage and were analysed in the safety population, which included all patients based on the treatment they received. This trial is registered with ClinicalTrials.gov, NCT03094715. FINDINGS: From July 17, 2018, to Feb 21, 2023, 253 patients were randomly assigned, with 125 patients assigned to endovascular thrombectomy and 128 to medical treatment alone. The trial was stopped early for efficacy after the first pre-planned interim analysis. At 90 days, endovascular thrombectomy was associated with a shift in the distribution of scores on the modified Rankin Scale towards better outcome (adjusted common OR 2·58 [95% CI 1·60-4·15]; p=0·0001) and with lower mortality (hazard ratio 0·67 [95% CI 0·46-0·98]; p=0·038). Symptomatic intracranial haemorrhage occurred in seven (6%) patients with thrombectomy and in six (5%) with medical treatment alone. INTERPRETATION: Endovascular thrombectomy was associated with improved functional outcome and lower mortality in patients with acute ischaemic stroke from large vessel occlusion with established large infarct in a setting using non-contrast CT as the predominant imaging modality for patient selection. FUNDING: EU Horizon 2020.

KCNA2 IgG autoimmunity in neuropsychiatric diseases.

BACKGROUND: Autoantibodies against the potassium voltage-gated channel subfamily A member 2 (KCNA2) have been described in a few cases of neuropsychiatric disorders, but their diagnostic and pathophysiological role is currently unknown, imposing challenges to medical practice. DESIGN / METHODS: We retrospectively collected comprehensive clinical and paraclinical data of 35 patients with KCNA2 IgG autoantibodies detected in cell-based and tissue-based assays. Patients' sera and cerebrospinal fluid (CSF) were used for characterization of the antigen, clinical-serological correlations, and determination of IgG subclasses. RESULTS: KCNA2 autoantibody-positive patients (n = 35, median age at disease onset of 65 years, range of 16-83 years, 74 % male) mostly presented with cognitive impairment and/or epileptic seizures but also ataxia, gait disorder and personality changes. Serum autoantibodies belonged to IgG3 and IgG1 subclasses and titers ranged from 1:32 to 1:10,000. KCNA2 IgG was found in the CSF of 8/21 (38 %) patients and in the serum of 4/96 (4.2 %) healthy blood donors. KCNA2 autoantibodies bound to characteristic anatomical areas in the cerebellum and hippocampus of mammalian brain and juxtaparanodal regions of peripheral nerves but reacted exclusively with intracellular epitopes. A subset of four KCNA2 autoantibody-positive patients responded markedly to immunotherapy alongside with conversion to seronegativity, in particular those presenting an autoimmune encephalitis phenotype and receiving early immunotherapy. An available brain biopsy showed strong immune cell invasion. KCNA2 autoantibodies occurred in less than 10 % in association with an underlying tumor. CONCLUSION: Our data suggest that KCNA2 autoimmunity is clinically heterogeneous. Future studies should determine whether KCNA2 autoantibodies are directly pathogenic or develop secondarily. Early immunotherapy should be considered, in particular if autoantibodies occur in CSF or if clinical or diagnostic findings suggest ongoing inflammation. Suspicious clinical phenotypes include autoimmune encephalitis, atypical dementia, new-onset epilepsy and unexplained epileptic seizures.

Stenting with dual-layer CGuard stent in acute sub-occlusive carotid artery stenosis and in tandem occlusions: a monocentric study.

PURPOSE: Double-layer design carotid stents have been cast in a negative light since several investigations reported high rates of in-stent occlusions, at least in the acute setting of tandem occlusions. CGuard is a new generation double-layered stent that was designed to prevent periinterventional embolic events. The aim of this study was to analyze the safety and efficacy of the CGuard in emergent CAS and for the acute treatment of tandem occlusions in comparison with the single-layer Carotid Wallstent (CWS) system. METHODS: All patients who underwent CAS with CGuard or CWS after intracranial mechanical thrombectomy (MT) between 11/2018 and 12/2022 were identified from our local thrombectomy registry. Clinical, interventional and neuroimaging data were analyzed. Patency of the stent was assessed within 72 h. Intracranial hemorrhage and modified Rankin score (mRS) at discharge were the main endpoints. RESULTS: In total, 86 stent procedures in 86 patients were included (CWS: 44, CGuard: 42). CGuard had a lower, but not statistically significant rate (p = 0.431) of in-stent occlusions (n = 2, 4.8%) when compared to the CWS (n = 4, 9.1%). Significant in-stent stenosis was found in one case in each group. There was no statistically significant difference in functional outcome at discharge between the two groups with a median mRS for CGuard of 2 (IQR:1-5) vs. CWS 3 (IQR:2-4). CONCLUSION: In our series, the rate of in-stent occlusions after emergent CAS was lower with the dual-layer CGuard when compared to the monolayer CWS. Further data are needed to evaluate the potential benefit of the design in more detail.

Cerebral small vessel disease burden and cognitive and functional outcomes after stroke: A multicenter prospective cohort study.

INTRODUCTION: It remains unknown whether the global small vessel disease (SVD) burden predicts post-stroke outcomes. METHODS: In a prospective multicenter study of 666 ischemic and hemorrhagic stroke patients, we quantified magnetic resonance imaging (MRI)-based SVD markers (lacunes, white matter hyperintensities, microbleeds, perivascular spaces) and explored associations with 6- and 12-month cognitive (battery of 15 neuropsychological tests) and functional (modified Rankin scale) outcomes. RESULTS: A global SVD score (range 0-4) was associated with cognitive impairment; worse performance in executive function, attention, language, and visuospatial ability; and worse functional outcome across a 12-month follow-up. Although the global SVD score did not improve prediction, individual SVD markers, assessed across their severity range, improved the calibration, discrimination, and reclassification of predictive models including demographic, clinical, and other imaging factors. DISCUSSION: SVD presence and severity are associated with worse cognitive and functional outcomes 12 months after stroke. Assessing SVD severity may aid prognostication for stroke patients. HIGHLIGHTS: In a multi-center cohort, we explored associations of small vessel disease (SVD) burden with stroke outcomes. SVD burden associates with post-stroke cognitive and functional outcomes. A currently used score of SVD burden does not improve the prediction of poor outcomes. Assessing the severity of SVD lesions adds predictive value beyond known predictors. To add predictive value in assessing SVD in stroke patients, SVD burden scores should integrate lesion severity.

COVID-19 Vaccine-Associated Cerebral Venous Thrombosis in Germany.

OBJECTIVE: We aimed to estimate the incidence of cerebral sinus and venous thrombosis (CVT) within 1 month from first dose administration and the frequency of vaccine-induced immune thrombotic thrombocytopenia (VITT) as the underlying mechanism after vaccination with BNT162b2, ChAdOx1, and mRNA-1273, in Germany. METHODS: A web-based questionnaire was e-mailed to all departments of neurology. We requested a report of cases of CVT occurring within 1 month of a COVID-19 vaccination. Other cerebral events could also be reported. Incidence rates of CVT were calculated by using official statistics of 9 German states. RESULTS: A total of 45 CVT cases were reported. In addition, 9 primary ischemic strokes, 4 primary intracerebral hemorrhages, and 4 other neurological events were recorded. Of the CVT patients, 35 (77.8%) were female, and 36 (80.0%) were younger than 60 years. Fifty-three events were observed after vaccination with ChAdOx1 (85.5%), 9 after BNT162b2 (14.5%) vaccination, and none after mRNA-1273 vaccination. After 7,126,434 first vaccine doses, the incidence rate of CVT within 1 month from first dose administration was 0.55 (95% confidence interval [CI] = 0.38-0.78) per 100,000 person-months (which corresponds to a risk of CVT within the first 31 days of 0.55 per 100,000 individuals) for all vaccines and 1.52 (95% CI = 1.00-2.21) for ChAdOx1 (after 2,320,535 ChAdOx1 first doses). The adjusted incidence rate ratio was 9.68 (95% CI = 3.46-34.98) for ChAdOx1 compared to mRNA-based vaccines and 3.14 (95% CI = 1.22-10.65) for females compared to non-females. In 26 of 45 patients with CVT (57.8%), VITT was graded highly probable. INTERPRETATION: Given an incidence of 0.02 to 0.15 per 100,000 person-months for CVT in the general population, these findings point toward a higher risk for CVT after ChAdOx1 vaccination, especially for women. ANN NEUROL 2021;90:627-639.

Workflow Times and Outcome of Endovascular Therapy in Stroke Patients with Initial MRI or CT.

INTRODUCTION: Treatment of patients with acute large vessel occlusion (LVO) stroke is highly time dependent. MRI and CT are both used as primary neuroimaging modalities in these patients, which may be associated with differences in workflow times of endovascular therapy (ET), thus potentially affecting clinical outcome. We here aimed to compare workflow times and clinical outcome in a large cohort of patients initially examined by MRI or CT. METHODS: We analyzed patients who underwent ET between 2015 and 2019 and were enrolled into the prospective multicenter German Stroke Registry-Endovascular Therapy (GSR-ET). Patients who had an MRI prior to ET were compared to patients with a pretreatment CT regarding baseline data, in-hospital workflow times, and clinical outcome. RESULTS: Three hundred seventy out of 4,638 patients were examined with an initial MRI (8.0%). Compared to patients with an initial CT, MRI patients had a longer median time from hospital admission to imaging acquisition (23 vs. 14 min). All consecutive workflow times did not significantly differ between both groups after adjustment for confounders. Moreover, the clinical outcome did not differ between MRI and CT patients after adjustment for confounders. CONCLUSION: In LVO stroke patients undergoing ET, pretreatment imaging with MRI instead of CT leads to a delay of imaging acquisition after hospital admission without having a measurable impact on consecutive workflow steps and clinical outcome.

Endovascular Treatment for Acute Stroke in Cerebral Amyloid Angiopathy.

Background and Purpose: We aimed to compare outcome of endovascular thrombectomy in acute ischemic stroke in patients with and without cerebral amyloid angiopathy (CAA). Methods: We included patients with and without possible or probable CAA based on the modified Boston criteria from an observational multicenter cohort of patients with acute ischemic stroke and endovascular thrombectomy, the German Stroke Registry Endovascular Treatment trial. We analyzed baseline characteristics, procedural parameters, and functional outcome after 90 days. Results: Twenty-eight (17.3%) of 162 acute ischemic stroke patients were diagnosed with CAA based on iron-sensitive magnetic resonance imaging performed before endovascular thrombectomy. CAA patients were less likely to have a good 90-day outcome (14.3 versus 37.8%). National Institutes of Health Stroke Scale score (adjusted odds ratio, 0.88; P<0.001), successful recanalization (adjusted odds ratio 6.82; P=0.005), and CAA (adjusted odds ratio 0.28; P=0.049) were independent outcome predictors. Intravenous thrombolysis was associated with an increased rate of good outcome (36.3% versus 0%, P=0.031) in CAA. Conclusions: Endovascular thrombectomy with or without thrombolysis appears beneficial in acute ischemic stroke patients with possible or probable CAA, but is associated with a worse functional outcome. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03356392.

Antibody-mediated procoagulant platelets in SARS-CoV-2-vaccination associated immune thrombotic thrombocytopenia.

The COVID-19 pandemic has resulted in significant morbidity and mortality worldwide. To prevent severe infection, mass COVID-19 vaccination campaigns with several vaccine types are currently underway. We report pathological and immunological findings in 8 patients who developed vaccine-induced immune thrombotic thrombocytopenia (VITT) after administration of SARS-CoV-2 vaccine ChAdOx1 nCoV-19. We analyzed patient material using enzyme immune assays, flow cytometry and heparin-induced platelet aggregation assay and performed autopsies on two fatal cases. Eight patients (5 female, 3 male) with a median age of 41.5 years (range, 24 to 53) were referred to us with suspected thrombotic complications 6 to 20 days after ChAdOx1 nCoV-19 vaccination. All patients had thrombocytopenia at admission. Patients had a median platelet count of 46.5 x109/L (range, 8 to 92). Three had a fatal outcome and 5 were successfully treated. Autopsies showed arterial and venous thromboses in various organs and the occlusion of glomerular capillaries by hyaline thrombi. Sera from VITT patients contain high titer antibodies against platelet factor 4 (PF4) (OD 2.59±0.64). PF4 antibodies in VITT patients induced significant increase in procoagulant markers (P-selectin and phosphatidylserine externalization) compared to healthy volunteers and healthy vaccinated volunteers. The generation of procoagulant platelets was PF4 and heparin dependent. We demonstrate the contribution of antibody-mediated platelet activation in the pathogenesis of VITT.

The NALP3 inflammasome is involved in the innate immune response to amyloid-beta.

The fibrillar peptide amyloid-beta (A beta) has a chief function in the pathogenesis of Alzheimer's disease. Interleukin 1 beta (IL-1 beta) is a key cytokine in the inflammatory response to A beta. Insoluble materials such as crystals activate the inflammasome formed by the cytoplasmic receptor NALP3, which results in the release of IL-1 beta. Here we identify the NALP3 inflammasome as a sensor of A beta in a process involving the phagocytosis of A beta and subsequent lysosomal damage and release of cathepsin B. Furthermore, the IL-1 beta pathway was essential for the microglial synthesis of proinflammatory and neurotoxic factors, and the inflammasome, caspase-1 and IL-1 beta were critical for the recruitment of microglia to exogenous A beta in the brain. Our findings suggest that activation of the NALP3 inflammasome is important for inflammation and tissue damage in Alzheimer's disease.

PRediction of acute coronary syndrome in acute ischemic StrokE (PRAISE) - protocol of a prospective, multicenter trial with central reading and predefined endpoints.

BACKGROUND: Current guidelines recommend measurement of troponin in acute ischemic stroke (AIS) patients. In AIS patients, troponin elevation is associated with increased mortality and worse outcome. However, uncertainty remains regarding the underlying pathophysiology of troponin elevation after stroke, particularly regarding diagnostic and therapeutic consequences. Troponin elevation may be caused by coronary artery disease (CAD) and more precisely acute coronary syndrome (ACS). Both have a high prevalence in stroke patients and contribute to poor outcome. Therefore, better diagnostic algorithms are needed to identify those AIS patients likely to have ACS or other manifestations of CAD. METHODS/DESIGN: The primary goal of the "PRediction of Acute coronary syndrome in acute Ischemic StrokE" (PRAISE) study is to develop a diagnostic algorithm for prediction of ACS in AIS patients. The primary hypothesis will test whether dynamic high-sensitivity troponin levels determined by repeat measurements (i.e., "rise or fall-pattern") indicate presence of ACS when compared to stable (chronic) troponin elevation. PRAISE is a prospective, multicenter, observational trial with central reading and predefined endpoints guided by a steering committee. Clinical symptoms, troponin levels as well as findings on electrocardiogram, echocardiogram, and coronary angiogram will be recorded and assessed by central academic core laboratories. Diagnosis of ACS will be made by an endpoint adjudication committee. Severe adverse events will be evaluated by a critical event committee. Safety will be judged by a data and safety monitoring board. Follow-up will be conducted at three and twelve months and will record new vascular events (i.e., stroke and myocardial infarction) as well as death, functional and cognitive status. According to sample size calculation, 251 patients have to be included. DISCUSSION: PRAISE will prospectively determine the frequency of ACS and characterize cardiac and coronary pathologies in a large, multicenter cohort of AIS patients with troponin elevation. The findings will elucidate the origin of troponin elevation, shed light on its impact on necessary diagnostic procedures and provide data on the safety and diagnostic yield of coronary angiography early after stroke. Thereby, PRAISE will help to refine algorithms and develop guidelines for the cardiac workup in AIS. TRIAL REGISTRATION: NCT03609385 registered 1st August 2018.

Stroke target identification guided by astrocyte transcriptome analysis.

Astrocytes support normal brain function, but may also contribute to neurodegeneration when they become reactive under pathological conditions such as stroke. However, the molecular underpinnings of this context-dependent interplay between beneficial and detrimental properties in reactive astrogliosis have remained incompletely understood. Therefore, using the RiboTag technique, we immunopurified translating mRNAs specifically from astrocytes 72 hr after transient middle cerebral artery occlusion in mice (tMCAO), thereby generating a stroke-specific astroglial translatome database. We found that compared to control brains, reactive astrocytes after tMCAO show an enrichment of transcripts linked to the A2 phenotype, which has been associated with neuroprotection. However, we found that astrocytes also upregulate a large number of potentially neurotoxic genes. In total, we identified the differential expression of 1,003 genes and 38 transcription factors, of which Stat3, Sp1, and Spi1 were the most prominent. To further explore the effects of Stat3-mediated pathways on stroke pathogenesis, we subjected mice with an astrocyte-specific conditional deletion of Stat3 to tMCAO, and found that these mice have reduced stroke volume and improved motor outcome 72 hr after focal ischemia. Taken together, our study extends the emerging database of novel astrocyte-specific targets for stroke therapy, and supports the role of astrocytes as critical safeguards of brain function in health and disease.

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.

Reverse NCX Attenuates Cellular Sodium Loading in Metabolically Compromised Cortex.

In core regions of ischemic stroke, disruption of blood flow causes breakdown of ionic gradients and, ultimately, calcium overload and cell death. In the surrounding penumbra, cells may recover upon reperfusion, but recovery is hampered by additional metabolic demands imposed by peri-infarct depolarizations (PIDs). There is evidence that sodium influx drives PIDs, but no data exist on PID-related sodium accumulations in vivo. Here, we found that PIDs in mouse neocortex are associated with propagating sodium elevations in neurons and astrocytes. Similar transient sodium elevations were induced in acute tissue slices by brief chemical ischemia. Blocking NMDA-receptors dampened sodium and accompanying calcium loads of neurons in tissue slices, while inhibiting glutamate transport diminished sodium influx into astrocytes, but amplified neuronal sodium loads. In both cell types, inhibition of sodium/calcium exchange (NCX) increased sodium transients. Blocking NCX also significantly reduced calcium transients, a result confirmed in vivo. Our study provides the first quantitative data on sodium elevations in peri-infarct regions in vivo. They suggest that sodium influx drives reversal of NCX, triggering a massive secondary calcium elevation while promoting export of sodium. Reported neuroprotective effects of NCX activity in stroke models might thus be related to its dampening of ischemia-induced sodium loading.

Successful mechanical thrombectomy in stroke with thrombolysis-associated intracerebral hemorrhage-a case report.

BACKGROUND: Intravenous thrombolysis and mechanical thrombectomy are the standard of care for patients with acute ischemic stroke with large vessel occlusion. Intracerebral hemorrhage is a main complication of intravenous thrombolysis, however, no data are available on the efficacy and safety of mechanical thrombectomy in patients with thrombolysis-associated intracerebral hemorrhage. This constellation is expected to become more frequent as increasing numbers of patients are treated under the drip-and-ship paradigm. CASE REPORT: A 75-year-old male patient was admitted to an emergency department with acute onset dysarthria and left side hemiparesis due to right middle cerebral artery occlusion. Intravenous thrombolysis was initiated and the patient transferred to our center for mechanical thrombectomy. Upon arrival, cerebral imaging showed persistent right middle cerebral artery occlusion and new onset left frontal, temporal, and parietal intracerebral hemorrhage. Thrombectomy was performed and perfusion completely re-established with excellent neurological outcome. Follow-up imaging revealed probable cerebral amyloid angiopathy. CONCLUSION: Mechanical thrombectomy may be safe and effective in ischemic stroke with large vessel occlusion and thrombolysis-associatied intracerebral hemorrhage.

Coronary Angiographic Findings in Acute Ischemic Stroke Patients With Elevated Cardiac Troponin: The Troponin Elevation in Acute Ischemic Stroke (TRELAS) Study.

BACKGROUND: A relevant proportion of patients with acute ischemic stroke (AIS) have elevated levels of cardiac troponins (cTn). However, the frequency of coronary ischemia as the cause of elevated cTn is unknown. The aim of our study was to analyze coronary vessel status in AIS patients with elevated cTn compared with patients presenting with non-ST-segment-elevation acute coronary syndrome (NSTE-ACS). METHODS AND RESULTS: Among 2123 consecutive patients with AIS prospectively screened at 2 tertiary hospitals, 13.7% had cTn elevation (>50 ng/L). According to a prespecified sample size estimation, 29 patients with AIS (median age, 76 years [first-third quartiles, 70-82 years]; 52% male) underwent conventional coronary angiography and were compared with age- and sex-matched patients with NSTE-ACS. The primary end point was presence of coronary culprit lesions on coronary angiograms as analyzed by independent interventional cardiologists blinded for clinical data. Median cTn on presentation did not differ between patients with AIS or NSTE-ACS (95 versus 94 ng/L; P=0.70). Compared with patients with NSTE-ACS, patients with AIS were less likely to have coronary culprit lesions (7 of 29 versus 23 of 29; P<0.001) or any obstructive coronary artery disease (15 of 29 versus 25 of 29; P=0.02; median number of vessels with >50% stenosis, 1 [first-third quartiles, 0-2] versus 2 [first-third quartiles, 1-3]; P<0.01). CONCLUSIONS: Coronary culprit lesions are significantly less frequent in AIS patients compared with age- and sex-matched patients with NSTE-ACS despite similar baseline cTn levels. Half of all AIS patients had no angiographic evidence of coronary artery disease. Further studies are needed to clinically identify the minority of patients with AIS and angiographic evidence of a culprit lesion. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01263964.

TRPV4 channels contribute to calcium transients in astrocytes and neurons during peri-infarct depolarizations in a stroke model.

Stroke is one of the leading causes of death and long-term disability. In the penumbra, that is, the area surrounding the infarct core, peri-infarct depolarizations (PIDs) are accompanied by strong intracellular calcium elevations in astrocytes and neurons, thereby negatively affecting infarct size and clinical outcome. The dynamics of PIDs and the cellular pathways that are involved during PID formation and progression remain incompletely understood. We have previously shown that inositol triphosphate-gated calcium release from internal stores is a major component of PID-related astroglial calcium signals, but whether external calcium influx through membrane-localized channels also contributes to PIDs has remained unclear. In this study, we investigated the role of two astroglial membrane channels, transient receptor vanilloid 4 (TRPV4) channel and aquaporin-4 (AQP4). We combined in vivo multiphoton microscopy, electrophysiology as well as laser speckle contrast imaging with the middle cerebral artery occlusion stroke model. Using knockout mice and pharmacological inhibitors, we found that TRPV4 channels contribute to calcium influx into astrocytes and neurons and subsequent extracellular glutamate accumulation during PIDs. AQP4 neither influenced PID-related calcium signals nor PID-related edema of astrocyte somata. Both channels did not alter the dynamics, frequency and cerebrovascular response of PIDs in the penumbra. These data indicate that TRPV4 channels may represent a potential target to ameliorate the PID-induced calcium overload of astrocytes and neurons during acute stroke.

Differential effects of energy deprivation on intracellular sodium homeostasis in neurons and astrocytes.

The maintenance of a low intracellular sodium concentration by the Na+ /K+ -ATPase (NKA) is critical for brain function. In both neurons and glial cells, NKA activity is required to counteract changes in the sodium gradient due to opening of voltage- and ligand-gated channels and/or activation of sodium-dependent secondary active transporters. Because NKA consumes about 50% of cellular ATP, sodium homeostasis is strictly dependent on an intact cellular energy metabolism. Despite the high energetic costs of electrical signaling, neurons do not contain significant energy stores themselves, but rely on a close metabolic interaction with surrounding astrocytes. A disruption of energy supply as observed during focal ischemia causes a rapid drop in ATP in both neurons and astrocytes. There is accumulating evidence that dysregulation of intracellular sodium is an inherent consequence of a reduction in cellular ATP, triggering secondary failure of extra- and intracellular homeostasis of other ions -in particular potassium, calcium, and protons- and thereby promoting excitotoxicity. The characteristics, cellular mechanisms and direct consequences of harmful sodium influx, however, differ between neurons and astrocytes. Moreover, recent work has shown that an intact astrocyte metabolism and sodium homeostasis are critical to maintain the sodium homeostasis of surrounding neurons as well as their capacity to recover from imposed sodium influx. Understanding the mechanisms of sodium increases upon metabolic failure and the differential responses of neurons and glial cells as well as their metabolic interactions will be critical to fully unravel the events causing cellular malfunction, failure and cell death following energy depletion. © 2017 Wiley Periodicals, Inc.

Mechanical recanalization in basilar artery occlusion: the ENDOSTROKE study.

OBJECTIVE: A study was undertaken to evaluate clinical and procedural factors associated with outcome and recanalization in endovascular stroke treatment (EVT) of basilar artery (BA) occlusion. METHODS: ENDOSTROKE is an investigator-initiated multicenter registry for patients undergoing EVT. This analysis includes 148 consecutive patients with BA occlusion, with 59% having received intravenous thrombolysis prior to EVT. Recanalization (defined as Thrombolysis in Cerebral Infarction [TICI] score 2b-3) and collateral status (using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology collateral grading system) were assessed by a blinded core laboratory. Good (moderate) outcome was defined as a modified Rankin Scale score of 0 to 2 (0-3) assessed after at least 3 months (median time to follow-up = 120 days). RESULTS: Thirty-four percent had good and 42% had moderate clinical outcome; mortality was 35%. TICI 2b-3 recanalization was achieved by 79%. Age, hypertension, National Institutes of Health Stroke Scale scores, collateral status, and the use of magnetic resonance imaging prior to EVT predicted clinical outcome, the latter 3 remaining independent predictors in multivariate analysis. Independent predictors of recanalization were better collateral status and the use of a stent retriever. However, recanalization did not significantly predict clinical outcome. INTERPRETATION: Beside initial stroke severity, the collateral status predicts clinical outcome and recanalization in BA occlusion. Our data suggest that the use of a stent retriever is associated with high recanalization rates, but recanalization on its own does not predict outcome. The role of other modifiable factors, including the choice of pretreatment imaging modality and time issues, warrants further investigation.