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Background and purposeA subset of ischaemic stroke patients with atrial fibrillation (AF) have ischaemic stroke despite anticoagulation. We sought to determine the association between prestroke anticoagulant therapy and recurrent ischaemic events and symptomatic intracranial haemorrhage (sICH).MethodsWe included consecutive patients with acute ischaemic stroke and AF from the Initiation of Anticoagulation after Cardioembolic stroke (IAC) study from eight comprehensive stroke centres in the USA. We compared recurrent ischaemic events and delayed sICH risk using adjusted Cox regression analyses between patients who were prescribed anticoagulation (ACp) versus patients who were nai¨ve to anticoagulation therapy prior to the ischaemic stroke (anticoagulation nai¨ve).ResultsAmong 2084 patients in IAC, 1518 had prior anticoagulation status recorded and were followed for 90 days. In adjusted Cox hazard models, ACp was associated with some evidence of a higher risk higher risk of 90-day recurrent ischaemic events only in the fully adjusted model (adjusted HR 1.50, 95% CI 0.99 to 2.28, p=0.058) but not increased risk of 90-day sICH (adjusted HR 1.08, 95% CI 0.46 to 2.51, p=0.862). In addition, switching anticoagulation class was not associated with reduced risk of recurrent ischaemic events (adjusted HR 0.41, 95% CI 0.12 to 1.33, p=0.136) nor sICH (adjusted HR 1.47, 95% CI 0.29 to 7.50, p=0.641).ConclusionAF patients with ischaemic stroke despite anticoagulation may have higher recurrent ischaemic event risk compared with anticoagulation-nai¨ve patients. This suggests differing underlying pathomechanisms requiring different stroke prevention measures and identifying these mechanisms may improve secondary prevention strategies.

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Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke.

IntroductionPredictors of long-term ischaemic and haemorrhagic complications in atrial fibrillation (AF) have been studied, but there are limited data on predictors of early ischaemic and haemorrhagic complications after AF-associated ischaemic stroke. We sought to determine these predictors.MethodsThe Initiation of Anticoagulation after Cardioembolic stroke study is a multicentre retrospective study across that pooled data from consecutive patients with ischaemic stroke in the setting of AF from stroke registries across eight comprehensive stroke centres in the USA. The coprimary outcomes were recurrent ischaemic event (stroke/TIA/systemic arterial embolism) and delayed symptomatic intracranial haemorrhage (d-sICH) within 90 days. We performed univariate analyses and Cox regression analyses including important predictors on univariate analyses to determine independent predictors of early ischaemic events (stroke/TIA/systemic embolism) and d-sICH.ResultsOut of 2084 patients, 1520 patients qualified; 104 patients (6.8%) had recurrent ischaemic events and 23 patients (1.5%) had d-sICH within 90 days from the index event. In Cox regression models, factors associated with a trend for recurrent ischaemic events were prior stroke or transient ischemic attack (TIA) (HR 1.42, 95% CI 0.96 to 2.10) and ipsilateral arterial stenosis with 50%–99% narrowing (HR 1.54, 95% CI 0.98 to 2.43). Those associated with sICH were male sex (HR 2.68, 95% CI 1.06 to 6.83), history of hyperlipidaemia (HR 2.91, 95% CI 1.08 to 7.84) and early haemorrhagic transformation (HR 5.35, 95% CI 2.22 to 12.92).ConclusionIn patients with ischaemic stroke and AF, predictors of d-sICH are different than those of recurrent ischaemic events; therefore, recognising these predictors may help inform early stroke versus d-sICH prevention strategies.

BackgroundThere is limited data on predictors of symptomatic intracranial haemorrhage (sICH) in patients who underwent mechanical thrombectomy. In this study, we aim to determine those predictors with external validation.MethodsWe evaluated mechanical thrombectomy in a derivation cohort of patients at a comprehensive stroke centre over a 30-month period. Clinical and radiographic data on these patients were obtained from the prospective quality improvement database. sICH was defined using the European Cooperative Acute Stroke Study III. We compared clinical and radiographic characteristics between patients with and without sICH using χ2and t tests to identify independent predictors of sICH with p<0.1. Significant variables were then combined in a multivariate logistic regression model to derive an sICH prediction score. This score was then validated using data from the Blood Pressure After Endovascular Treatment multicentre prospective registry.ResultsWe identified 578 patients with acute ischaemic stroke who received thrombectomy, 19 had sICH (3.3%). Predictive factors of sICH were: thrombolysis in cerebral ischaemia (TICI) score, Alberta stroke program early CT score (ASPECTS), and glucose level, and from these predictors, we derived the weighted TICI-ASPECTS-glucose (TAG) score, which was associated with sICH in the derivation (OR per unit increase 1.98, 95% CI 1.48 to 2.66, p<0.001, area under curve ((AUC)=0.79) and validation (OR per unit increase 1.48, 95% CI 1.22 to 1.79, p<0.001, AUC=0.69) cohorts.ConclusionHigh TAG scores are associated with sICH in patients receiving mechanical thrombectomy. Larger studies are needed to validate this scoring system and test strategies to reduce sICH risk and make thrombectomy safer in patients with elevated TAG scores.

The inverse association between prenatal smoking and preeclampsia is puzzling, given the increased risks of prematurity and low birthweight associated with both smoking and preeclampsia. We analyzed the Norwegian Mother and Child Birth Cohort (MoBa) to determine whether the associations varied by timing of prenatal smoking.

Introduction:Stroke is the fifth leading cause of death in the US and a major cause of disability. Atrial fibrillation (AF) increases the risk of ischemic stroke fivefold. Cardioembolic stroke in patients with AF is associated with high mortality. The association of elevated cardiac troponin with mortality in patients with acute ischemic stroke has been studied previously; however, there is limited data in subgroups of ischemic stroke etiology. We sought to determine the association of troponin elevation at presentation with 90-day all-cause mortality in patients with acute ischemic stroke and AF.Methods:The Initiation of Anticoagulation after Cardioembolic Stroke (IAC) study is a multicenter cohort drawn from eight US Stroke Centers. We included consecutive patients hospitalized with acute ischemic stroke and AF between 2015-2018, who had an initial baseline cardiac troponin I (bcTnI) obtained at presentation. The primary outcome was all-cause mortality at 90 days from stroke onset. We undertook multivariable logistic regression to determine the association between elevated bcTnl (≥0.1 ng/mL) and 90-day mortality.Results:Of the 2084 patients enrolled in IAC, 1889 patients had 90-day follow-up of which 1461 patients had bcTnI available. 239 of the included patients (16.4%) had an elevated bcTnl, and death within 90-days occurred in 323 patients (22.1%). Elevated bcTnI was associated with 90-day mortality in univariable analysis (49.4% vs 24.9%; OR 1.71, 95% CI 1.17-2.50, p<0.001). This association persisted after adjusting for potential confounders: age, NIHSS, coronary artery disease, congestive heart failure and initial systolic blood pressure (OR 1.71, 95% CI 1.17-2.50, p=0.006); and in sensitivity analysis adding CrCl to the adjusted model above (OR 1.57, 95% CI 1.03-2.39, p=0.037).Conclusion:In acute ischemic stroke patients with AF, elevated bcTnI was independently associated with 90-day all-cause mortality.

Introduction:Neurologic deterioration (ND) occurs in a quarter of acute lacunar infarcts and may lead to severe disability, but underlying pathophysiology of ND remains poorly understood. We sought to identify risk factors and clinical characteristics associated with ND.Methods:This retrospective observational study included consecutive patients with acute lacunar stroke admitted to New York University Langone Health and Brown University (NYU/Brown). Lacunar stroke was defined as a subcortical infarct <1.5 cm on CT or <2 cm on diffusion-weighted imaging without significant stenosis (>50%) in the parent vessel and no cardioembolic source. We defined ND as any neurologic deterioration referable to the lacunar stroke and not related to a medical or non-cerebrovascular neurological complication. We used logistic regression analyses to determine associations between ND and luminal stenosis (<50%) vs no luminal stenosis, after adjustment for key confounders. Furthermore, we attempted to validate findings using the Columbia University (CU) stroke registry and perform a meta-analysis combining the derivation and validation groups due to expected small samples and event rates.Results:The NYU/Brown sample included 205 patients, of whom 41 (20%) had ND. In adjusted models, we found no definite association between luminal stenosis and ND (aOR 1.74, 95% CI 0.73-4.14). From CU, 361 total patients were included, of whom 59 (16%) had ND. In adjusted models, we found an association between luminal stenosis and ND (aOR 2.28 95% CI 1.15-4.50). Meta-analysis of both cohorts found luminal stenosis associated with ND (RR [95% CI]: 1.75 [1.23-2.49]).Conclusions:In this multi-center study, luminal stenosis (<50%) may be associated with ND following an acute lacunar infarct. Larger studies using high-resolution vascular imaging modalities such as vessel wall imaging are needed to validate our findings.

Dopamine D2 receptors are configured in interconvertible states of high (D(2 high)) or low (D(2 low)) affinity for agonists. The in vivo proportion of sites in high-affinity state remains poorly documented. Previous studies have established the D2 agonist [11C]N-propyl-norapomorphine (NPA) as a suitable positron emission tomography radiotracer for imaging D(2 high) in the living brain. To elucidate the proportion of D2 receptors configured in D(2 high) states in vivo, imaging studies were conducted in three baboons with both [11C]NPA and the D2 receptor antagonist [11C]raclopride. These studies were performed under noncarrier- and carrier-added conditions, to compare the Bmax of [11C]NPA and [11C]raclopride in the same animals. [11C]raclopride in vivo KD and Bmax were 1.59 +/- 0.28 nM (n = 3) and 27.3 +/- 3.9 nM (n = 3), respectively. The in vivo KD of [11C]NPA was 0.16 +/- 0.01 nM (n = 3), consistent with its affinity for D(2 high) reported in vitro. The maximal density of sites for [11C]NPA was 21.6 +/- 2.8 nM (n = 3), i.e., 79% of the [11C]raclopride Bmax. This result suggested that 79% of D2 receptors are configured as D(2 high) in vivo. This large proportion of D(2 high) sites might explain the vulnerability of D2 radiotracers to competition by endogenous dopamine, and is consistent with a previous report that the in vivo binding of agonist radiotracer [11C]NPA is more vulnerable to competition by endogenous dopamine than that of antagonist radiotracer [11C]raclopride.

Background and Purpose:Multiple studies have established that intravenous thrombolysis with alteplase improves outcome after acute ischemic stroke. However, assessment of thrombolysis’ efficacy in stroke patients with atrial fibrillation (AF) has yielded mixed results. We sought to determine the association of alteplase with mortality, hemorrhagic transformation (HT), infarct volume, and mortality in patients with AF and acute ischemic stroke.Methods:We retrospectively analyzed consecutive acute ischemic stroke patients with AF included in the Initiation of Anticoagulation after Cardioembolic stroke (IAC) study, which pooled data from 8 comprehensive stroke centers in the United States. 1889 (90.6%) had available 90-day follow up data and were included. For our primary analysis we used a cohort of 1367/1889 (72.4%) patients who did not undergo mechanical thrombectomy (MT). Secondary analyses were repeated in the patients that underwent MT (n=522). Binary logistic regression was used to determine whether alteplase use was independently associated with risk of HT, final infarct volume, and 90-day mortality, respectively, adjusting for potential confounders.Results:In our primary analyses we found that alteplase use was independently associated with an increased risk for HT (adjusted OR 2.14, 95% CI 1.49 - 3.07, p <0.001) but overall reduced risk of 90-day mortality (adjusted OR 0.58, 95% CI 0.39 - 0.87, p = 0.009). Among patients undergoing MT, alteplase use was associated with a trend towards a reduction in 90-day mortality (adjusted OR 0.68 95% CI 0.45 - 1.04, p = 0.077). In the subgroup of patients prescribed DOAC treatment (n = 327; 24 received alteplase), alteplase treatment was associated with a trend towards smaller infarct size (< 10 mL), (adjusted OR 0.40, 95% CI 0.15 - 1.12, p = 0.082) without a significant difference in the odds of 90-day mortality (adjusted OR 0.51, 95% CI 0.12 - 2.13, p = 0.357) or hemorrhagic transformation (adjusted OR 0.27, 95% CI 0.03 - 2.07, p = 0.206).Conclusion:Thrombolysis with intravenous alteplase was associated with reduced 90-day mortality in AF patients with acute ischemic stroke not undergoing MT. Further study is required to assess the safety and efficacy of alteplase in AF patients undergoing MT and those on DOACs.

Background:Emergent treatment with intravenous thrombolysis and mechanical thrombectomy improved outcomes in patients with acute ischemic stroke. We aim to identify differences in acute stroke treatment trends between strokes occurring in the anterior versus posterior circulation.Methods:The IAC (Initiation of Anticoagulation after Cardioembolic stroke) study represents pooled data registry of 8 comprehensive stroke centers across the United States and included patients with cardioembolic stroke in the setting of AFib. In a post hoc analysis, we identified and separated patients into posterior circulation stroke (PCS) and anterior circulation stroke (ACS) groups based on imaging. Patients without infarct locations or those with multi-circulation infarcts were excluded. We compared baseline characteristics, stroke severity and the treatment trends with alteplase (tPA) and mechanical thrombectomy (MT) in PCS vs ACS using Fisher exact test, t-test and non-parametric tests. We then performed multivariable logistic regression adjusted for baseline differences to determine the associations between PCS and tPA or MT.Results:Of the 2084 patients in IAC cohort, 1589 met inclusion criteria for this study, in which 294 (22.7%) had PCS. Mean age was 76.8 years, 29.3% received tPA and 26.9% had MT. When compared to ACS, patients with PCS were more likely to be men (55.4% vs 45.6%, p=0.003), have diabetes (42.8% vs 29.8, p< 0.001) and lower median NIHSS score on admission (4 vs 8, p<0.001). Patients with PCS were less likely to receive tPA (16.3% vs 32.3%, p<0.001) or MT (10.9% vs 30.6%, p<0.001). Other variables were not significantly different. When adjusted for baseline differences, patients with PCS remained less likely to be treated with tPA (adjusted OR 0.49, 95%CI 0.35-0.70, p<0.001) or MT (adjusted OR 0.38, 95%CI 0.25-0.58, p<0.001).Conclusion:Posterior circulation strokes are half as likely to receive thrombolytic therapy and almost a third as likely to have thrombectomy, even after adjusting for baseline stroke severity scores. This is possibly due to difficulty in timely identification and diagnostic delays. There is need for better tools incorporating posterior circulation stroke signs and symptoms to allow for early detection and treatment.

Introduction:Neurologic deterioration (ND) occurs in a quarter of acute lacunar infarct patients and may lead to severe disability. The underlying pathophysiology of ND in these patients is not clearly understood. We sought to identify risk factors and clinical characteristics associated with ND.Methods:This retrospective study included consecutive patients admitted to NYU Langone Medical Center and Brown University for lacunar-type strokes from 2017-2019. Lacunar infarct was defined as subcortical infarct <1.5cm on CT or <2cm on diffusion-weighted imaging without significant stenosis (>50%) in the parent vessel and no cardioembolic source. Available non-invasive imaging (CTA or MRA) was reviewed by a neuroradiologist or vascular neurologist to determine the presence or absence of stenosis (<50%) or luminal irregularity without stenosis in the stem artery segment at the location of the perforator corresponding to the infarct. Fazekas score was determined from available MRI T2 images. We defined ND as those with any neurologic deterioration during their hospitalization referable to lacunar stroke and not related to a medical or non-cerebrovascular neurological complication. We compared clinical and radiographic characteristics of those with and without ND.Results:Among 242 lacunar stroke patients (mean age 68.9±12.2 years, 43.8% women, 61.2% white, 12.8% black, and 13.2% Hispanic), we identified 46 (19%) with ND. There were no demographic differences between those with and without ND. Those with ND were more likely to have systemic atherosclerotic disease (34.8% vs 19.9%, p=0.049) and higher low-density lipoprotein (111 vs 100 mg/dL, p=0.034). Those with ND had less white matter disease on MRI (lower Fazekas score) and were less likely to have chronic lacunes than those without ND. We did not find any association between radiographic subclinical perforator atherosclerotic disease and ND (odds ratio [95% confidence interval]: 1.83 [0.81-4.14], p=0.147).Conclusions:In this multi-ethnic population, patients with neurologic deterioration following an acute lacunar stroke were more likely to have markers of atherosclerotic disease and less likely to have imaging findings suggestive of chronic small vessel disease.

Background:Perforator disease caused by parent artery atheromatous disease is one of the mechanisms implicated in the pathogenesis of lacunar infarcts, but there is limited data on its prevalence. We sought to determine the prevalence of parent vessel atheromatous disease in patients with lacunar infarcts.Methods:This is a retrospective study of consecutive patients with lacunar strokes admitted to NYU Langone Medical Center and Brown University from 2017-2019. Lacunar infarct was defined as subcortical infarct <1.5cm on CT or <2cm on diffusion-weighted imaging without significant stenosis (>50%) in the parent vessel and no cardioembolic source. Non-invasive imaging (CTA or MRA) was reviewed by a neuroradiologist or a vascular neurologist to determine the presence or absence of stenosis (< 50%) or luminal irregularity without stenosis in the stem artery segment at the location of the perforator corresponding to the infarct. Patients were divided into two groups: luminal irregularity/stenosis vs. none. We compared clinical and radiographic characteristics and rates of neurological deterioration between the two groups.Results:Among 208 patients with lacunar infarcts (mean age 68.9±11.9 years, 40.9% women, 61.1% White, 13.9% Black, and 12.5% Hispanic), 42 (20.2%) had luminal stenosis and 90 (43.3%) had luminal irregularity without stenosis. Baseline characteristics and prevalence of risk factors were similar between the two groups. Patients with luminal irregularity/stenosis had longer median infarct diameter (10.6 mm vs 8.7 mm, p=0.007). Other imaging variables such as the presence of prior lacunar infarcts and white matter disease burden assessed by Fazekas Score were not significantly different between the two groups. The rate of any neurological deterioration after admission was similar between the two groups (22.7% vs. 15.8%, p=0.283).Conclusion:In this multi-ethnic population, nearly two-thirds of patients with a lacunar infarct were found to have luminal irregularity or stenosis in the parent artery corresponding to the infarct, implying a potential atherosclerotic mechanism. Future studies are needed using advanced imaging of the stem artery to define plaque characteristics which may help determine the underlying mechanism.

Objective:We aim to investigate infarct patterns and 90-day recurrence in patients with symptomatic intracranial atherosclerotic disease.Background:Large artery atherosclerosis subtype carries a high risk of early recurrent stroke despite medical management. Predictors of recurrence remain poorly understood. We hypothesized that border-zone infarcts are associated with a higher risk of recurrence.Design/Methods:We included consecutive patients admitted to NYU Langone Health (Manhattan and Brooklyn campuses) over 32-months with a diagnosis of acute ischemic stroke secondary to symptomatic intracranial or tandem atherosclerosis. Patients with purely extracranial stenosis were excluded. The primary predictor was infarct pattern (border-zone vs. non-border-zone infarction), defined in accordance to previous studies. We used univariate and multivariable cox-regression models to determine associations between infarct pattern and recurrent cerebrovascular events (RCVE) at 90-days.Results:Ninety-nine patients met the inclusion criteria; 95 were intracranial and 4 were tandem lesions. The mean age was 70 years, 58.6% were men, 15.1% Black and 16.1% Asian. The median symptom onset to arrival time was 1 day, nearly 74.7% of patients were treated with dual antiplatelet therapy and 99% were treated with high intensity statin. Within 90 days of follow up, 19.2% (19/99) had RCVE. In univariate analyses, the only factor associated with RCVE was border-zone infarct pattern when compared to non-border-zone infarct pattern (30.2% vs. 10.7%, p=0.02). In cox regression models, after adjusting for age and sex, border-zone infarct pattern was associated with increased risk of RCVE (adjusted HR 3.21 95% CI 1.21-8.51, p=0.019). Sensitivity analyses excluding patients with tandem lesions (n = 4) did not meaningfully change our findings (adjusted HR 3.04 95% CI 1.11-8.31, p=0.031).Conclusions:In real world post-SAMMPRIS medically treated patients with ICAD, infarct pattern was predictive of 90-day RCVE. Border-zone infarcts are likely a surrogate marker of impaired distal blood flow, highlighting the importance of targeting stroke mechanisms and developing alternative treatment strategies for this high-risk cohort.