Post-injury immunosuppression and secondary infections are caused by an AIM2 inflammasome-driven signaling cascade.

Loss of lymphocytes, particularly T cell apoptosis, is a central pathological event after severe tissue injury that is associated with increased susceptibility for life-threatening infections. The precise immunological mechanisms leading to T cell death after acute injury are largely unknown. Here, we identified a monocyte-T cell interaction driving bystander cell death of T cells in ischemic stroke and burn injury. Specifically, we found that stroke induced a FasL-expressing monocyte population, which led to extrinsic T cell apoptosis. This phenomenon was driven by AIM2 inflammasome-dependent interleukin-1ß (IL-1ß) secretion after sensing cell-free DNA. Pharmacological inhibition of this pathway improved T cell survival and reduced post-stroke bacterial infections. As such, this study describes inflammasome-dependent monocyte activation as a previously unstudied cause of T cell death after injury and challenges the current paradigms of post-injury lymphopenia.

Circadian Biology and the Neurovascular Unit.

Mammalian physiology and cellular function are subject to significant oscillations over the course of every 24-hour day. It is likely that these daily rhythms will affect function as well as mechanisms of disease in the central nervous system. In this review, we attempt to survey and synthesize emerging studies that investigate how circadian biology may influence the neurovascular unit. We examine how circadian clocks may operate in neural, glial, and vascular compartments, review how circadian mechanisms regulate cell-cell signaling, assess interactions with aging and vascular comorbidities, and finally ask whether and how circadian effects and disruptions in rhythms may influence the risk and progression of pathophysiology in cerebrovascular disease. Overcoming identified challenges and leveraging opportunities for future research might support the development of novel circadian-based treatments for stroke.

Consensus Recommendations for Standardized Data Elements, Scales, and Time Segmentations in Studies of Human Circadian/Diurnal Biology and Stroke.

Increasing evidence indicates that circadian and diurnal rhythms robustly influence stroke onset, mechanism, progression, recovery, and response to therapy in human patients. Pioneering initial investigations yielded important insights but were often single-center series, used basic imaging approaches, and used conflicting definitions of key data elements, including what constitutes daytime versus nighttime. Contemporary methodologic advances in human neurovascular investigation have the potential to substantially increase understanding, including the use of large multicenter and national data registries, detailed clinical trial data sets, analysis guided by individual patient chronotype, and multimodal computed tomographic and magnetic resonance imaging. To fully harness the power of these approaches to enhance pathophysiologic knowledge, an important foundational step is to develop standardized definitions and coding guides for data collection, permitting rapid aggregation of data acquired in different studies, and ensuring a common framework for analysis. To meet this need, the Leducq Consortium International pour la Recherche Circadienne sur l'AVC (CIRCA) convened a Consensus Statement Working Group of leading international researchers in cerebrovascular and circadian/diurnal biology. Using an iterative, mixed-methods process, the working group developed 79 data standards, including 48 common data elements (23 new and 25 modified/unmodified from existing common data elements), 14 intervals for time-anchored analyses of different granularity, and 7 formal, validated scales. This portfolio of standardized data structures is now available to assist researchers in the design, implementation, aggregation, and interpretation of clinical, imaging, and population research related to the influence of human circadian/diurnal biology upon ischemic and hemorrhagic stroke.

Circadian rhythm of ischaemic core progression in human stroke.

INTRODUCTION: Experimental stroke studies suggest an influence of the time of day of stroke onset on infarct progression. Whether this holds true after human stroke is unknown, but would have implications for the design of randomised controlled trials, especially those on neuroprotection. METHODS: We pooled data from 583 patients with anterior large-vessel occlusion stroke from three prospectively recruited cohorts. Ischaemic core and penumbra volumes were determined with CT perfusion using automated thresholds. Core growth was calculated as the ratio of core volume and onset-to-imaging time. To determine circadian rhythmicity, we applied multivariable linear and sinusoidal regression analysis adjusting for potential baseline confounders. RESULTS: Patients with symptom onset at night showed larger ischaemic core volumes on admission compared with patients with onset during the day (median, 40.2 mL vs 33.8 mL), also in adjusted analyses (p=0.008). Sinusoidal analysis indicated a peak of core volumes with onset at 11pm. Core growth was faster at night compared with day onset (adjusted p=0.01), especially for shorter onset-to-imaging times. In contrast, penumbra volumes did not change across the 24-hour cycle. DISCUSSION: These results suggest that human infarct progression varies across the 24-hour cycle with potential implications for the design and interpretation of neuroprotection trials.

Endovascular thrombectomy for basilar artery occlusion stroke: Analysis of the German Stroke Registry-Endovascular Treatment.

BACKGROUND AND PURPOSE: Acute ischemic stroke due to basilar artery occlusion (BAO) causes the most severe strokes and has a poor prognosis. Data regarding efficacy of endovascular thrombectomy in BAO are sparse. Therefore, in this study, we performed an analysis of the therapy of patients with BAO in routine clinical practice. METHODS: Patients enrolled between June 2015 and December 2019 in the German Stroke Registry-Endovascular Treatment (GSR-ET) were analyzed. Primary outcomes were successful reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] score of 2b-3), substantial neurological improvement (≥8-point National Institute of Health Stroke Scale [NIHSS] score reduction from admission to discharge or NIHSS score at discharge ≤1), and good functional outcome at 3 months (modified Rankin Scale [mRS] score of 0-2). RESULTS: Out of 6635 GSR-ET patients, 640 (9.6%) patients (age 72.2 ± 13.3, 43.3% female) experienced BAO (median [interquartile range] NIHSS score 17 [8, 27]). Successful reperfusion was achieved in 88.4%. Substantial neurological improvement at discharge was reached by 45.5%. At 3-month follow-up, good clinical outcome was observed in 31.1% of patients and the mortality rate was 39.2%. Analysis of mTICI3 versus mTICI2b groups showed considerable better outcome in those with mTICI3 (38.9% vs. 24.4%; p = 0.005). The strongest predictors of good functional outcome were intravenous thrombolysis (IVT) treatment (odds ratio [OR] 3.04, 95% confidence interval [CI] 1.76-5.23) and successful reperfusion (OR 4.92, 95% CI 1.15-21.11), while the effect of time between symptom onset and reperfusion seemed to be small. CONCLUSIONS: Acute reperfusion strategies in BAO are common in daily practice and can achieve good rates of successful reperfusion, neurological improvement and good functional outcome. Our data suggest that, in addition to IVT treatment, successful and, in particular, complete reperfusion (mTICI3) strongly predicts good outcome, while time from symptom onset seemed to have a lower impact.

Larger ischemic cores and poor collaterals among large vessel occlusions presenting in the late evening.

BACKGROUND: Components critical to cerebral perfusion have been noted to oscillate over a 24-h cycle. We previously reported that ischemic core volume has a diurnal relationship with stroke onset time when examined as dichotomized epochs (i.e. Day, Evening, Night) in a cohort of over 1,500 large vessel occlusion (LVO) patients. In this follow-up analysis, our goal was to explore if there is a sinusoidal relationship between ischemic core, collateral status (as measured by HIR), and stroke onset time. METHODS: We retrospectively examined collection of LVO patients with baseline perfusion imaging performed within 24 h of stroke onset from four international comprehensive stroke centers. Both ischemic core volume and HIR, were utilized as the primary radiographic parameters. To evaluate for differences in these parameters over a continuous 24-h cycle, we conducted a sinusoidal regression analysis after linearly regressing out the confounders age and time to imaging. RESULTS: A total of 1506 LVO cases were included, with a median ischemic core volume of 13.0 cc (IQR: 0.0-42.0) and median HIR of 0.4 (IQR: 0.2-0.6). Ischemic core volume varied by stroke onset time in the unadjusted (p = 0.001) and adjusted (p = 0.003) sinusoidal regression analysis with a peak in core volume around 7:45PM. HIR similarly varied by stroke onset time in the unadjusted (p = 0.004) and adjusted (p = 0.002) models with a peak in HIR values at around 8:18PM. CONCLUSION: The results suggest that critical factors to the development of the ischemic core vary by stroke onset time and peak around 8PM. When placed in the context of prior studies, strongly suggest a diurnal component to the development of the ischemic core.

Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability.

RATIONALE: Arterial inflammation manifested as atherosclerosis is the leading cause of mortality worldwide. Genome-wide association studies have identified a prominent role of HDAC (histone deacetylase)-9 in atherosclerosis and its clinical complications including stroke and myocardial infarction. OBJECTIVE: To determine the mechanisms linking HDAC9 to these vascular pathologies and explore its therapeutic potential for atheroprotection. METHODS AND RESULTS: We studied the effects of Hdac9 on features of plaque vulnerability using bone marrow reconstitution experiments and pharmacological targeting with a small molecule inhibitor in hyperlipidemic mice. We further used 2-photon and intravital microscopy to study endothelial activation and leukocyte-endothelial interactions. We show that hematopoietic Hdac9 deficiency reduces lesional macrophage content while increasing fibrous cap thickness thus conferring plaque stability. We demonstrate that HDAC9 binds to IKK (inhibitory kappa B kinase)-α and ß, resulting in their deacetylation and subsequent activation, which drives inflammatory responses in both macrophages and endothelial cells. Pharmacological inhibition of HDAC9 with the class IIa HDAC inhibitor TMP195 attenuates lesion formation by reducing endothelial activation and leukocyte recruitment along with limiting proinflammatory responses in macrophages. Transcriptional profiling using RNA sequencing revealed that TMP195 downregulates key inflammatory pathways consistent with inhibitory effects on IKKß. TMP195 mitigates the progression of established lesions and inhibits the infiltration of inflammatory cells. Moreover, TMP195 diminishes features of plaque vulnerability and thereby enhances plaque stability in advanced lesions. Ex vivo treatment of monocytes from patients with established atherosclerosis reduced the production of inflammatory cytokines including IL (interleukin)-1ß and IL-6. CONCLUSIONS: Our findings identify HDAC9 as a regulator of atherosclerotic plaque stability and IKK activation thus providing a mechanistic explanation for the prominence of HDAC9 as a vascular risk locus in genome-wide association studies. Its therapeutic inhibition may provide a potent lever to alleviate vascular inflammation. Graphical Abstract: A graphical abstract is available for this article.

Minor stroke in large vessel occlusion: A matched analysis of patients from the German Stroke Registry-Endovascular Treatment (GSR-ET) and patients from the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register (SITS-ISTR).

BACKGROUND AND PURPOSE: Reperfusion treatment in patients presenting with large vessel occlusion (LVO) and minor neurological deficits is still a matter of debate. We aimed to compare minor stroke patients treated with endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT) or IVT alone. METHODS: Patients enrolled in the German Stroke Registry-Endovascular Treatment (GSR-ET) and the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) between June 2015 and December 2019 were analyzed. Minor stroke was defined as National Institutes of Health Stroke Scale (NIHSS) score ≤5, and LVO as occlusion of the internal carotid, carotid-T, middle cerebral, basilar, vertebral or posterior cerebral arteries. GSR-ET and SITS-ISTR IVT-treated patients were matched in a 1:1 ratio using propensity-score (PS) matching. The primary outcome was good functional outcome at 3 months (modified Rankin Scale score 0-2). RESULTS: A total of 272 GSR-ET patients treated with EVT and IVT (age 68.6 ± 14.0 years, 43.4% female, NIHSS score 4 [interquartile range 2-5]) were compared to 272 IVT-treated SITS-ISTR patients (age 69.4 ± 13.7, 43.4% female, NIHSS score 4 [2-5]). Good functional outcome was seen in 77.0% versus 82.9% (p = 0.119), mortality in 5.9% versus 7.9% (p = 0.413), and intracranial hemorrhage in 8.8% versus 12.5% (p = 0.308) of patients in the GSR-ET versus the SITS-ISTR IVT group, respectively. In a second PS-matched analysis, 624 GSR-ET patients (IVT rate 56.7%) and 624 SITS-ISTR patients (IVT rate 100%), good outcome was more often observed in the SITS-ISTR patients (68.2% vs. 80.9%; p < 0.001), and IVT independently predicted good outcome (odds ratio 2.16, 95% confidence interval 1.43-3.28). CONCLUSIONS: Our study suggests similar effectiveness of IVT alone compared to EVT with or without IVT in minor stroke patients. There is an urgent need for randomized controlled trials on this topic.

Serum Sphingosine-1-Phosphate Levels Are Associated With Severity and Outcome in Patients With Cerebral Ischemia.

BACKGROUND AND PURPOSE: The aim of this study was to examine whether sphingosine-1-phosphate (S1P) levels in patients with acute stroke are associated with stroke severity and outcome. METHODS: In a prospective stroke cohort (MARK-STROKE), 374 patients with acute ischemic stroke or transient ischemic attack were enrolled (mean age: 67.9±13.0 years, sex: 64.7% male), and serum-S1P at admission was analyzed with tandem mass spectrometry. In addition to cross-sectional analyses, 79 adverse events (death, stroke, myocardial infarction, rehospitalization) were recorded in 270 patients during follow-up. Regression analyses were adjusted for age, sex, low-density lipoprotein cholesterol, and vascular risk factors. Results were validated in an independent stroke cohort with 219 patients with acute ischemic stroke (CIRCULAS). RESULTS: Low serum-S1P was associated with higher National Institutes of Health Stroke Scale score at admission and with anterior circulation nonlacunar infarcts determined by multivariate regression analyses. During a follow-up of 294±170 days, patients with S1P in the lowest tertile (<1.33 µmol/L) had more adverse events (Kaplan-Meier analysis, P=0.048 for trend). In adjusted Cox regression analysis, the lowest S1P tertile was associated with a worse outcome after stroke (hazard ratio, HR 0.51 [95% confidence interval 0.28-0.92]). Results were confirmed in an independent cohort, ie, low S1P levels were associated with higher National Institutes of Health Stroke Scale, larger infarct volumes and worse outcome after 90 days (ß-coefficient: -0.03, P=0.026; ß-coefficient: -0.099, P=0.009 and odds ratio 0.52 [0.28-0.96], respectively). CONCLUSIONS: Our findings imply a detrimental role of low S1P levels in acute stroke and therefore underpin the therapeutic potential of S1P-mimics.

Computed Tomography Perfusion Deficit Volumes Predict Functional Outcome in Patients With Basilar Artery Occlusion.

Background and Purpose: Basilar artery occlusion is associated with high morbidity and mortality. Optimal imaging and treatment strategy are still controversial and prognosis estimation challenging. We, therefore, aimed to determine the predictive value of computed tomography perfusion (CTP) parameters for functional outcome in patients with basilar artery occlusion in the context of endovascular treatment. Methods: Patients with basilar artery occlusion who underwent endovascular treatment were selected from a prospectively acquired cohort. Ischemic changes were assessed with the posterior-circulation Acute Stroke Prognosis Early Computed Tomography Score on noncontrast computed tomography, computed tomography angiography (CTA) source images, and CTP maps. Basilar artery on CTA score, posterior-circulation CTA score, and posterior-circulation collateral score were evaluated on CTA. Perfusion deficit volumes were quantified on CTP maps. Good functional outcome was defined as modified Rankin Scale score ≤3 at 90 days. Statistical analysis included binary logistic regressions and receiver operating characteristics analyses. Results: Among 49 patients who matched the inclusion criteria, 24 (49.0%) achieved a good outcome. In univariate analysis, age, National Institutes of Health Stroke Scale score on admission, posterior cerebral artery involvement, absence of or hypoplastic posterior communicating arteries, basilar artery on CTA score, posterior-circulation Acute Stroke Prognosis Early Computed Tomography Score, and perfusion deficit volumes on all CTP parameter maps presented significant association with functional outcome (P<0.05). In multivariate analyses, Basilar artery on CTA score, posterior-circulation Acute Stroke Prognosis Early Computed Tomography Score (odds ratio range, 1.31­2.10 [95% CI, 1.00­7.24]), and perfusion deficit volumes on all CTP maps (odds ratio range, 0.77­0.98 [95% CI, 0.63­1.00]) remained as independent outcome predictors. Cerebral blood flow deficit volume yielded the best performance for the classification of good clinical outcome with an area under the curve of 0.92 (95% CI, 0.84­0.99). Age and admission National Institutes of Health Stroke Scale had lower discriminatory power (area under the curve, <0.7). Conclusions: CTP imaging parameters contain prognostic information for functional outcome in patients with stroke due to basilar artery occlusion and may identify patients with higher risk of disability at an early stage of hospitalization.

Tandem Lesions in Anterior Circulation Stroke: Analysis of the German Stroke Registry-Endovascular Treatment.

[Figure: see text].

Circadian Biology and Stroke.

Circadian biology modulates almost all aspects of mammalian physiology, disease, and response to therapies. Emerging data suggest that circadian biology may significantly affect the mechanisms of susceptibility, injury, recovery, and the response to therapy in stroke. In this review/perspective, we survey the accumulating literature and attempt to connect molecular, cellular, and physiological pathways in circadian biology to clinical consequences in stroke. Accounting for the complex and multifactorial effects of circadian rhythm may improve translational opportunities for stroke diagnostics and therapeutics.

Circulating Metabolites Differentiate Acute Ischemic Stroke from Stroke Mimics.

OBJECTIVE: Early discrimination of patients with ischemic stroke (IS) from stroke mimics (SMs) poses a diagnostic challenge. The circulating metabolome might reflect pathophysiological events related to acute IS. Here, we investigated the utility of early metabolic changes for differentiating IS from SM. METHODS: We performed untargeted metabolomics on serum samples obtained from patients with IS (N = 508) and SM (N = 349; defined by absence of a diffusion weighted imaging [DWI] positive lesion on magnetic resonance imaging [MRI]) who presented to the hospital within 24 hours after symptom onset (median time from symptom onset to blood sampling = 3.3 hours; interquartile range [IQR] = 1.6-6.7 hours) and from neurologically normal controls (NCs; N = 112). We compared diagnostic groups in a discovery-validation approach by applying multivariable linear regression models, machine learning techniques, and propensity score matching. We further performed a targeted look-up of published metabolite sets. RESULTS: Levels of 41 metabolites were significantly associated with IS compared to NCs. The top metabolites showing the highest value in separating IS from SMs were asymmetrical and symmetrical dimethylarginine, pregnenolone sulfate, and adenosine. Together, these 4 metabolites differentiated patients with IS from SMs with an area under the curve (AUC) of 0.90 in the replication sample, which was superior to multimodal cranial computed tomography (CT; AUC = 0.80) obtained for routine diagnostics. They were further superior to previously published metabolite sets detected in our samples. All 4 metabolites returned to control levels by day 90. INTERPRETATION: A set of 4 metabolites with known biological effects relevant to stroke pathophysiology shows unprecedented utility to identify patients with IS upon hospital arrival, thus encouraging further investigation, including multicenter studies. ANN NEUROL 2020;88:736-746.

Safety and efficacy of mechanical thrombectomy in infective endocarditis: A matched case-control analysis from the German Stroke Registry-Endovascular Treatment.

BACKGROUND AND PURPOSE: Up to 30% of infective endocarditis (IE) patients have ischemic stroke as a complication. Standard treatment with mechanical thrombectomy (MT) with or without intravenous thrombolysis for large vessel occlusion (LVO) has not been evaluated formally in these patients. METHODS: Patients enrolled in the German Stroke Registry-Endovascular Treatment (GSR-ET) between June 2015 and December 2019 were analyzed. Patients with stroke due to IE and patients with cardioembolic stroke and atrial fibrillation (AF) were compared using propensity score matching. Successful reperfusion was defined as modified Thrombolysis in Cerebral Infarction score = 2b-3. Modified Rankin Scale (mRS) = 0-2 at 3 months indicated good outcome. RESULTS: Of 6635 patients, 55 patients (age = 69.0 ± 13.3 years, 43.6% female, median premorbid mRS (pmRS) = 1, interquartile range [IQR] = 0-1, National Institutes of Health Stroke Scale [NIHSS] = 15, IQR = 10-21) presented with septic embolic stroke due to IE and were compared to 104 patients (age = 66.5 ± 13.4 years, 39.4% female, pmRS = 0, IQR = 0-2, NIHSS = 16, IQR = 10-20) with cardioembolic stroke due to AF. Successful recanalization was achieved in 74.5% of endocarditis patients compared to 87.5% of controls (p = 0.039). Intracranial hemorrhage rates were comparable (30.9% vs. 21.6%, p = 0.175). Good functional outcome was 20.0% in patients with IE compared to 43.3% in matched patients (p = 0.006), with a significantly higher mortality (60.0% vs. 28.8%, p < 0.001). IE was strongly associated with poor outcome (odds ratio [OR] = 0.32, 95% confidence interval [CI] = 0.11-0.87, p = 0.03 for good outcome) and mortality (OR = 4.49, 95% CI = 1.80-10.68, p = 0.001). CONCLUSIONS: Although MT results in high successful recanalization rates with acceptable safety profile, patients with LVO stroke due to IE have poor outcome.

[Thrombectomy in clinical practice-What do we learn from registry studies?] / Thrombektomie in der klinischen Praxis ­ Was lernen wir aus Registerstudien?

BACKGROUND: In 2015, randomized controlled trials (RCT) provided high-level evidence for the efficacy of endovascular thrombectomy in selected patients with acute ischemic stroke due to large vessel occlusion of the anterior circulation. Ever since, thrombectomy is strongly recommended for these patients and has been broadly implemented in clinical practice. OBJECTIVE: To determine whether registry studies depicting real-life data provide additional information beyond RCTs. MATERIAL AND METHODS: Literature review of RCTs and registry studies related to thrombectomy. RESULTS: Data from registry studies on thrombectomy are important to 1. evaluate whether RCT results can be directly transferred into clinical practice, 2. comparatively describe the efficacy of thrombectomy in patient groups underrepresented in RCTs, such as older patients, 3. compare device performances and assess technical developments, and 4. determine how treatment processes and outcomes change over time. CONCLUSION: Beyond RCTs, registry studies are imperative for the continuous analysis and improvement of treatment processes and outcomes as well as technical devices in daily clinical practice.

Stroke Etiology Modifies the Effect of Endovascular Treatment in Acute Stroke.

Background and Purpose- Stroke etiology drives thrombus composition. We thus hypothesized that endovascular treatment shows different efficacy in cardioembolic versus noncardioembolic large-vessel occlusions (LVOs). Methods- Procedural characteristics, grade of reperfusion, and functional outcome at discharge and 90 days were compared between patients with cardioembolic versus noncardioembolic LVO from the GSR-ET (German Stroke Registry-Endovascular Treatment; n=2589). To determine associations with functional outcome, adjusted odds ratios and 95% CIs were calculated using ordinal multivariable logistic regression models adjusting for potential baseline confounder variables. Results- Endovascular treatment of cardioembolic LVO had a higher rate of successful reperfusion (85.6% versus 81.0%; P=0.002) and a higher rate of complete reperfusion after a single thrombectomy pass (45.7% versus 38.1%; P<0.001) compared with noncardioembolic LVO. Cardioembolic LVO was associated with better functional outcome at discharge (adjusted odds ratio, 1.61 [95% CI, 1.37-1.88]) and 90 days (adjusted odds ratio, 1.29 [95% CI, 1.09-1.53]). In mediation analysis, reperfusion explained 47% of the effect of etiology on functional outcome at discharge. Conclusions- These results provide evidence for higher efficacy of endovascular treatment in cardioembolic LVO compared with noncardioembolic LVO.

Genome-wide association study of cerebral small vessel disease reveals established and novel loci.

Intracerebral haemorrhage and small vessel ischaemic stroke (SVS) are the most acute manifestations of cerebral small vessel disease, with no established preventive approaches beyond hypertension management. Combined genome-wide association study (GWAS) of these two correlated diseases may improve statistical power to detect novel genetic factors for cerebral small vessel disease, elucidating underlying disease mechanisms that may form the basis for future treatments. Because intracerebral haemorrhage location is an adequate surrogate for distinct histopathological variants of cerebral small vessel disease (lobar for cerebral amyloid angiopathy and non-lobar for arteriolosclerosis), we performed GWAS of intracerebral haemorrhage by location in 1813 subjects (755 lobar and 1005 non-lobar) and 1711 stroke-free control subjects. Intracerebral haemorrhage GWAS results by location were meta-analysed with GWAS results for SVS from MEGASTROKE, using 'Multi-Trait Analysis of GWAS' (MTAG) to integrate summary data across traits and generate combined effect estimates. After combining intracerebral haemorrhage and SVS datasets, our sample size included 241 024 participants (6255 intracerebral haemorrhage or SVS cases and 233 058 control subjects). Genome-wide significant associations were observed for non-lobar intracerebral haemorrhage enhanced by SVS with rs2758605 [MTAG P-value (P) = 2.6 × 10-8] at 1q22; rs72932727 (P = 1.7 × 10-8) at 2q33; and rs9515201 (P = 5.3 × 10-10) at 13q34. In the GTEx gene expression library, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1 × 10-4 in tibial nerve), NBEAL1, FAM117B and CARF (P < 2.1 × 10-7 in arteries) and COL4A2 and COL4A1 (P < 0.01 in brain putamen), respectively. Leveraging S-PrediXcan for gene-based association testing with the predicted expression models in tissues related with nerve, artery, and non-lobar brain, we found that experiment-wide significant (P < 8.5 × 10-7) associations at three genes at 2q33 including NBEAL1, FAM117B and WDR12 and genome-wide significant associations at two genes including ICA1L at 2q33 and ZCCHC14 at 16q24. Brain cell-type specific expression profiling libraries reveal that SEMA4A, SLC25A44 and PMF1 at 1q22 and COL4A1 and COL4A2 at 13q34 were mainly expressed in endothelial cells, while the genes at 2q33 (FAM117B, CARF and NBEAL1) were expressed in various cell types including astrocytes, oligodendrocytes and neurons. Our cross-phenotype genetic study of intracerebral haemorrhage and SVS demonstrates novel genome-wide associations for non-lobar intracerebral haemorrhage at 2q33 and 13q34. Our replication of the 1q22 locus previous seen in traditional GWAS of intracerebral haemorrhage, as well as the rediscovery of 13q34, which had previously been reported in candidate gene studies with other cerebral small vessel disease-related traits strengthens the credibility of applying this novel genome-wide approach across intracerebral haemorrhage and SVS.

Clinical and Imaging Parameters Associated With Hyperacute Infarction Growth in Large Vessel Occlusion Stroke.

Background and Purpose- Large vessel occlusion stroke leads to highly variable hyperacute infarction growth. Our aim was to identify clinical and imaging parameters associated with hyperacute infarction growth in patients with an large vessel occlusion stroke of the anterior circulation. Methods- Seven hundred twenty-two consecutive patients with acute stroke were prospectively included in our monocentric stroke registry between 2009 and 2017. We selected all patients with a large vessel occlusion stroke of the anterior circulation, documented times from symptom onset, and CT perfusion on admission for our analysis (N=178). Ischemic core volume was determined with CT perfusion using automated thresholds. Hyperacute infarction growth was defined as ischemic core volume divided by times from symptom onset, assuming linear progression during times from symptom onset to imaging on admission. For collateral assessment, the regional leptomeningeal collateral score (rLMC) was used. Clinical data included the National Institutes of Health Stroke Scale score on admission and cardiovascular risk factors. Regression analysis was performed to adjust for confounders. Results- Median ischemic core volume was 34.4 mL, and median hyperacute infarction growth was 0.27 mL/min. In regression analysis including age, sex, National Institutes of Health Stroke Scale, clot burden score, diabetes mellitus, smoking, hypercholesteremia, hypertension, Alberta Stroke Program Early CT Score, and rLMC scores, only the rLMC score had a significant, independent association with hyperacute infarction growth (adjusted ß=-0.35; P<0.001). Trichotomizing patients by rLMC scores yielded 65 patients with good (rLMC >15), 67 with intermediate (rLMC 11-15) and 46 with poor collaterals (rLMC <11) with an infarction growth of 0.17 mL/min, 0.26 mL/min, and 0.41 mL/min, respectively. Conclusions- Hyperacute infarction growth strongly depends on collaterals. In primary stroke centers, hyperacute infarction growth may be extrapolated to estimate the stroke progression during transfer times to thrombectomy centers and to support decisions on which patients to transfer.

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.

RNA-Seq Identifies Circulating miR-125a-5p, miR-125b-5p, and miR-143-3p as Potential Biomarkers for Acute Ischemic Stroke.

RATIONALE: Currently, there are no blood-based biomarkers with clinical utility for acute ischemic stroke (IS). MicroRNAs show promise as disease markers because of their cell type-specific expression patterns and stability in peripheral blood. OBJECTIVE: To identify circulating microRNAs associated with acute IS, determine their temporal course up to 90 days post-stroke, and explore their utility as an early diagnostic marker. METHODS AND RESULTS: We used RNA sequencing to study expression changes of circulating microRNAs in a discovery sample of 20 patients with IS and 20 matched healthy control subjects. We further applied quantitative real-time polymerase chain reaction in independent samples for validation (40 patients with IS and 40 matched controls), replication (200 patients with IS, 100 healthy control subjects), and in 72 patients with transient ischemic attacks. Sampling of patient plasma was done immediately upon hospital arrival. We identified, validated, and replicated 3 differentially expressed microRNAs, which were upregulated in patients with IS compared with both healthy control subjects (miR-125a-5p [1.8-fold; P=1.5×10-6], miR-125b-5p [2.5-fold; P=5.6×10-6], and miR-143-3p [4.8-fold; P=7.8×10-9]) and patients with transient ischemic attack (miR-125a-5p: P=0.003; miR-125b-5p: P=0.003; miR-143-3p: P=0.005). Longitudinal analysis of expression levels up to 90 days after stroke revealed a normalization to control levels for miR-125b-5p and miR-143-3p starting at day 2 while miR-125a-5p remained elevated. Levels of all 3 microRNAs depended on platelet numbers in a platelet spike-in experiment but were unaffected by chemical hypoxia in Neuro2a cells and in experimental stroke models. In a random forest classification, miR-125a-5p, miR-125b-5p, and miR-143-3p differentiated between healthy control subjects and patients with IS with an area under the curve of 0.90 (sensitivity: 85.6%; specificity: 76.3%), which was superior to multimodal cranial computed tomography obtained for routine diagnostics (sensitivity: 72.5%) and previously reported biomarkers of acute IS (neuron-specific enolase: area under the curve=0.69; interleukin 6: area under the curve=0.82). CONCLUSIONS: A set of circulating microRNAs (miR-125a-5p, miR-125b-5p, and miR-143-3p) associates with acute IS and might have clinical utility as an early diagnostic marker.