bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 147: Role of Nicotine in the Development of Intracranial Aneurysm Rupture
Authors: Kamio Yoshinobu , Furukawa Hajime , Yokosuka Kimihiko , Korai Masaaki , Mitsui Kazuha , Zhang Dingding , Hashimoto Tomoki
Published: June 2021

Background:
Nicotine is one of main chemicals of tobacco smoke and promotes atherosclerosis and stroke. Tobacco smoke is considered an independent risk factor for intracranial aneurysm formation, growth, and rupture. There are mainly 5 subtypes of nicotine receptors. Roles of alpha7 nicotinic acetylcholine receptor (α7nAChR) in inflammation and vascular remodeling are diverse and context-dependent. Notably, endothelial α7nAChR is considered to mediate nicotine-induced inflammation. Activation of endothelial α7nAChR by nicotine may promote aneurysm rupture by increasing the aneurysm wall inflammation. Using a mouse model of intracranial aneurysm, we examined effects of nicotine in aneurysm rupture. Moreover we investigated potential roles of α7nAChR stimulation by nicotine in the pathophysiology of intracranial aneurysms.

Methods:
Intracranial aneurysms were induced by a combination of elastase injection into the cerebrospinal fluid and deoxycorticosteron acetate-salt (DOCA-salt) hypertension in male mice. Mice were treated with (1) nicotine (5 mg/kg/day, n=25); (2) saline sc (n=22) for three weeks after aneurysm induction. To investigate the effect of α7nAChR, mice were treated with (1) saline sc + saline ip (n=11); (2) saline sc + α7nAChR antagonist (Methyllycaconitine, MLA 5mg/kg/day) ip (n=13); (3) nicotine (5 mg/kg/day, sc, 28 days) + saline ip (n=18); (4) nicotine sc + MLA ip (n=18).

Results:
Nicotine alone significantly increased aneurysmal rupture compared with saline treatment (89% vs 46%, p=0.009). While α7nAChR antagonist did not affect the incidence of aneurysm or rupture rates, the α7nAChR antagonist significantly reduced the deleterious effect of nicotine as indicated by the reduction of the rupture rates (41% vs 100%: nicotine sc + MLA ip group vs nicotine sc + saline ip group, p=0.027).

Conclusion:
Our data indicate the promotion of aneurysm rupture by nicotine may be mediated by its stimulation of alpha7nAChR.
Abstract 150: Diffusion Abnormalities and Quality of Life Outcomes After Intracerebral Hemorrhage
Authors: Kaskar Saabir , Liotta Eric , Maas Matthew , Kim Minjee , Sorond Farzaneh , Naidech Andrew , Prabhakaran Shyam
Published: June 2021

Background:
Diffusion weighted imaging (DWI) abnormalities, consistent with acute brain infarcts, occur in approximately one-quarter of patients with intracerebral hemorrhage (ICH). Prior studies have observed that DWI lesions remote from the hematoma predict long-term disability. Their impact on health-related quality of life (HRQOL) outcomes, however, has not been described. We tested the hypothesis that DWI lesions remote from the hematoma worsen HRQOL after ICH.

Methods:
From a prospective registry of consecutive patients admitted to a single center with spontaneous ICH, we identified patients in whom DWI was performed within 1 week of admission, 1 or 3 month modified Rankin (mRS) and Neuro-QOL measures for upper extremity (UE) and lower extremity(LE) motor function were obtained. We excluded patients who underwent MRI after craniotomy or angiography. Two raters independently evaluated each MRI for DWI abnormalities remote from the hematoma blinded to outcome data. We assessed whether DWI lesions independently predicted outcomes using ordinal regression for mRS and linear regression of Neuro-QOL T-scores.

Results:
Among 106 patients with ICH, 95 met inclusion criteria (mean age 61.6±14.6 years; 51.6% male; 58.9% white; median ICH score 1). DWI lesions remote from the hematoma were found in 23 (24.2%) patients. Poor outcome (mRS >2) was more common (61.9% vs. 36.1%, P=0.035) and T-scores were lower in those with versus without DWI lesions (UE: 31.7 vs. 40.5, P=0.011; LE: 32.4 vs. 41.0, P=0.021). Adjusted for ICH score and initial NIHSS score, DWI abnormality was an independent predictor of mRS (P=0.044) and UE (P=0.017) and LE T-scores (P=0.040).

Discussion:
We confirm that DWI lesions remote from the hematoma are common after spontaneous ICH and predict disability at 3 months independent of the ICH score and stroke severity. In addition, DWI lesions worsen Neuro-QOL motor function scores. Further research is needed to understand mechanisms of secondary brain ischemia after ICH and targeted approaches to prevent its occurrence.
Abstract 158: Pre-existing Cancer Exacerbates Cerebral Ischemic Stroke in Mice via Regulatory T Cell Redistribution
Authors: Wang Long , Zhou Yuxi , Yu Weifeng , Li Peiying
Published: June 2021

Background and purpose:
Accumulating epidemic evidence suggest that a considerable number of ischemic stroke patients had 1 or more cancer diagnosis before stroke attack. How the pre-existing cancer impact the cerebral ischemic injury is remarkably unknown. We tested the hypothesis that pre-existing cancer exacerbates cerebral ischemic stroke via regulatory T cell (Treg) redistribution.

Methods:
MC38 colon cancer cells or B16 melanoma cells were injected subcutaneously at the dose of 5*10
5
cells in 200μl PBS 3 weeks before distal middle cerebral artery occlusion (d-MCAO) surgery. Infarct volume was assessed at 3 days after surgery by staining the mice brain with 2,3,5-triphenyltetrazolium chloride. Sensorimotor assessments, such as body proprioception, climbing, forelimb walking, lateral turning, foot fault and adhesive removal were examined at 3, 5, 7, 14, 21 and 28 days after stroke. Neuro-inflammation was examined by measuring inflammatory cytokines with RT-PCR and immune cell infiltration using immunofluorescence and flow cytometry.

Results:
Pre-existing colon cancer and melanoma both exacerbated infarct volume growth in d-MCAO mice at 3 days after surgery. Mice with colon cancer exhibited prominently deterioration in their performance in sensorimotor functions after stroke compared with mice without cancer. Pre-existing colon cancer augmented peripheral immune cell infiltration into the ischemic brain but hindered Tregs’ recruitment into the brain. Cerebral ischemic stroke induced reduction in the number of Tregs in the peripheral blood were significantly aggravated in mice with pre-existing colon cancer. Depletion of Tregs with CD25 monoclonal antibody increased infarct volume in stroke mice but did not further exacerbate infarct growth in colon cancer stroke mice.

Conclusion:
Pre-existing cancer exacerbates ischemic brain injury and neuro-inflammation after stroke. Tregs redistribution plays an indispensable role in the cancer related deterioration of ischemic brain injury and may represent a promising target for treating stroke patients with pre-existing cancer.
Abstract 165: What Domains of Health Are Most Impacted After Ischemic Stroke?
Authors: Katzan Irene , Uchino Ken , Thompson Nicolas
Published: June 2021

Background:
Multiple domains of health are impacted in patients with ischemic stroke, which may vary by degree of disability. The objective of this study was to examine patient-reported health for 6 domains across levels of disability compared to the U.S. general population.

Methods:
Observational cohort study of 811 ischemic stroke patients (937 visits) seen in a cerebrovascular clinic 2/17/15 - 8/8/16 who completed the routinely collected PROMIS patient-reported outcome measures (PROMs): Physical Function (PF), Satisfaction with Social Roles (SatSocRol), Fatigue, Anxiety, Sleep Disturbance, and Pain Interference. PROMIS scores are standardized to the U.S. population (mean score = 50). Providers completed the NIHSS and modified Rankin (mRS). Distribution of PROMIS scores were calculated across mRS levels. Multivariable regression was performed to evaluate the association of the following factors with PROM scores: age, sex, race, mRS, and time from stroke (0-90 d, 91-365 d, >365 d).

Results:
Patients with no-minimal disability (mRS 0-1) had PROMIS scores that were similar to the general population. PROMIS scores increased at higher mRS levels, although correlation between scores and mRS level varied (Sleep ρ= 0.172 to PF ρ=0.483). Within each mRS level > 1, highest (worst) scores were in PF, SatSocRol, and Cognition domains (Graph). Female sex was associated with higher Fatigue (p=0.003), Anxiety (p<0.0001), PF (p=0.021), and Cognition (p=0.001) scores. Age was associated with higher PF (p<0.0001) and lower Anxiety (p=0.023) scores.

Conclusion:
Patients with ischemic stroke reported symptoms in multiple health domains that increase to varying degrees at higher levels of disability. PF, SatSocRol, and Cognition were most impacted at all disability levels. This information improves our understanding of stroke’s impact on patients compared to the general population and brings attention to the importance of social roles and cognition to stroke survivors.
Abstract 17: Prehospital Deterioration During Transport by Emergency Medical Services for Stroke Patients: A Population-Based Study
Authors: Gillow Sabreena J , Sucharew Heidi , Alwell Kathleen , Moonmaw Charles J , Woo Daniel , Adeoye Opeolu , Flaherty Matthew , Ferioli Simona , McMullan Jason , Mackey Jason , De Los Rios La Rosa Felipe , Martini Sharyl R , Kissela Brett M , Kleindorfer Dawn O
Published: June 2021

Introduction:
Stroke patients can experience neurological change in the prehospital setting. We sought to identify factors associated with prehospital neurologic deterioration.

Methods:
Among the Greater Cincinnati/Northern Kentucky region (pop. ~1.3 million), we screened all 15 local hospitals’ admissions from 2010 for acute stroke, and included patients with age ≥20 and complete EMS records. Glasgow Coma Scale (GCS) at hospital arrival was compared with GCS evaluated by EMS, with decrease ≥2 points considered neurologic deterioration. Data obtained included age, sex, race, medical history, antiplatelet or anticoagulant use, stroke subtype [ischemic (IS), ICH, or SAH] and IS subtype (e.g., small vessel, large vessel, cardioembolic), seizure at onset, time from symptom onset to EMS arrival, time from EMS to hospital arrival, blood pressure and serum glucose on EMS arrival, and EMS level of training. Univariate analysis was completed using Wilcoxon rank sum test for continuous measures and chi-square or Fisher’s exact test for categorical measures. Multivariate analysis was completed on variables with p ≤ 0.20 in the univariate analysis.

Results:
Of 2708 total stroke patients, 1097 (870 IS, 176 ICH, 51 SAH) had EMS records (median [IQR] age 74 [61, 83] years; 56% female; 21% black). Onset to EMS arrival was ≤4.5 hours for 508 cases (46%), and median time from EMS to hospital arrival was 26 minutes. Neurological deterioration occurred in 129 cases (12%), including 9.1% of IS and 22% of ICH/SAH. In multivariate analysis, black race, atrial fibrillation, ICH or SAH subtype, and ALS transport were associated with neurological deterioration.

Conclusion:
Atrial fibrillation may predict prehospital deterioration in stroke, and preferential transport of patients with acute worsening to centers capable of managing hemorrhagic stroke may be justifiable. Further studies are needed to identify why race is associated with deterioration and potential areas of intervention.
Abstract 179: Determinants of Cerebral Microbleeds in Acute Ischemic Stroke Patients With Non-valvular Atrial Fibrillation: SAMURAI-NVAF Study
Authors: Shiozawa Masayuki , Sato Shoichiro , Yoshimura Sohei , Fujita Kyohei , Ide Toshihiro , Yoshimoto Takeshi , Matsubara Soichiro , Arihiro Shoji , Yamagami Hiroshi , Koga Masatoshi , Toyoda Kazunori
Published: June 2021

Background and Purpose:
Cerebral microbleeds (CMBs) are now considered to be one of the neuroimaging markers of cerebral small vessel disease. It has been reported that CMBs are associated with age, hypertension, cognitive impairment, and use of antithrombotic drugs. We aimed at identifying factors associated with the presence of CMBs among acute ischemic stroke patients with non-valvular atrial fibrillation (NVAF) who participated in the multicenter Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI)-NVAF study.

Methods:
Acute ischemic stroke/transient ischemic attack (within 7 days of onset) patients with NVAF who underwent T2*-weighted images on magnetic resonance imagings at baseline were included in the analysis. Factors associated with the presence of CMBs were assessed in univariable and multivariable logistic regression models.

Results:
Of 1,099 (77.6±10.0 years, 620 male) participants, 256 (23.2%) had CMBs: single CMB in 96 (8.7%), 2-4 of CMBs in 109 (9.9%), and ≥5 CMBs in 51 (4.6%). The presence of CMBs was associated with age [per 10 years, odds ratio (OR) 1.21; 95% confidence interval (CI) 1.02-1.44], past history of stroke (OR 1.52; 95% CI 1.09-2.11), and advanced cognitive impairment (OR 1.64; 95% CI 1.02-2.61) in multivariable analysis adjusted for sex, hypertension, arterial disease, ever smoking, premorbid antithrombotic medications, and estimated glomerular filtration rate. Among 514 patients (46.8% of the participants) with the data of urinary albumin, clinical albuminuria (urinary albumin ≥300 mg/gCr) and past history of stroke were identified as independent factors associated with CMBs (OR 1.91; 95% CI 1.06-3.42 and 1.67; 1.04-2.66, respectively).

Conclusions:
Approximately one fourth of acute ischemic stroke patients with NVAF had CMBs. Past history of stroke and clinical albuminuria were identified as independent determinants of CMBs on top of established ones.

Clinical Trial Registration:
URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01581502.
Abstract 188: Safety and Efficacy of off-label Intravenous Thrombolysis in Patients With Acute Ischemic Stroke: An Observational Study From the International Safe Implementation of Treatments in Stroke (SITS) Registry
Authors: Mundiyanapurath Sibu , Hees Katharina , Ahmed Niaz , Wahlgren Nils , Uhlmann Lorenz , Kieser Meinhard , Ringleb Peter A , Hacke Werner , Nagel Simon
Published: June 2021

Introduction:
Intravenous thrombolysis is the only approved pharmacological treatment for acute ischemic stroke. Due to strict license regulations, off-label treatment is common. We aimed to analyze the safety and efficacy of off-label thrombolysis.

Methods:
Retrospective analysis of 56258 patients from the Safe Implementation of Treatments in Stroke (SITS) thrombolysis registry was performed regarding 11 off-label criteria according to the European license for alteplase. Symptomatic intracranial hemorrhage (SICH) according to SITS was defined as primary safety endpoint and SICH according to the European Cooperative Acute Stroke Study II (ECASS II) definition and the National Institute of Neurological Disorders and Stroke (NINDS) definition as secondary safety endpoints. Favorable outcome, defined as modified Rankin Scale score 3 months after stroke between 0 and 2 was the primary efficacy endpoint. Multivariable logistic regression analyses after replacing missing values using multiple imputations were performed for the efficacy and safety endpoints.

Results:
In total, 16740 (30%) patients received off-label thrombolysis. SICH according to the SITS definition occurred in 1037 (1.8%) patients. The only two off-label criteria constituting independent positive and negative predictors for SICH according to the SITS definition were elevated blood pressure (OR 1.39; p=0.012) and minor stroke (OR 0.51; p=0.002). Very severe stroke, history of stroke and diabetes, age and high glucose levels were additional independent predictors of SICH according to the ECASS II and NINDS definition. Favorable outcome was found in 24834 patients (54.5%). Independent predictors of favorable outcome comprised of minor stroke (positive predictor) and very severe stroke, history of stroke and diabetes, age and elevated blood pressure (all negative predictors). Inclusion of SICH according to the ECASS II definition in the multivariable analysis did not change the OR of these off-label criteria.

Conclusions:
Thrombolysis appears to be safe and efficient for most of the off-label criteria. Individual risk-benefit evaluation should be performed before off-label thrombolysis, especially in patients with combinations of these off-label criteria.
Abstract 190: Prediction of Intracranial Aneurysm Growth Based on Morphology
Authors: Chien Aichi , Morimoto Emiko , Yokota Hajime , Villablanca Pablo , Salamon Noriko
Published: June 2021

Introduction:
Recent studies have strongly associated intracranial aneurysm growth with increased risk of rupture. To plan more effective monitoring and intervention strategies, it would be beneficial to identify aneurysms which are likely to grow.

Hypothesis:
Morphological characteristics at initial diagnosis differ between unruptured intracranial aneurysms that will grow and those that are stable.

Methods:
A total of 58 cases of aneurysms in our medical center with follow-up imaging dates in 2015 were selected. All CTA images for the aneurysms were collected, for a total of 250 image sets. Aneurysm 3D geometry was reconstructed and morphological characteristics, including volume, surface area, and non-sphericity index (NSI) were calculated. NSI was calculated as 1 - (18π)
1/3
V
2/3
/S, where V and S represent aneurysm volume and surface area, respectively. Statistical comparisons were made using a two-tailed t-test with an assumption of unequal variance (Welch’s t-test).

Results:
Aneurysms were followed for an average of 50.5±50.9 months, with an average of 3.29±2.66 follow-up imaging dates. 9 aneurysms exhibited a size increase (>0.6mm) and the remaining 49 aneurysms did not. Based on their maximum diameter, no significant difference was found between initial aneurysm size between the growth (3.80±1.72 mm) and non-growth (4.26±2.00 mm) groups (p=0.13). Likewise, no significant differences in volume or surface area were found (p=0.33, p=0.36, respectively). However, initial NSI was found to be significantly higher in the growth (0.32±0.11) vs. the non-growth (0.23±0.08) group (p=0.049).

Conclusions:
Among aneurysms with similar size, NSI may be useful for identifying aneurysms which are more likely to grow and planning monitoring strategies accordingly. Higher initial NSI in the aneurysms which eventually grew is consistent with previous findings that higher NSI correlates with increased risk of rupture.
Abstract 191: Selective Frontal Lobe Metabolic Dysfunction After Sub-arachnoid Hemorrhage
Authors: Mangat Halinder S , Ivanidze Jana , Mao Xiangling , Shungu Dikoma , Fakhar Malik , Gupta Ajay , Stieg Philip E
Published: June 2021

Aneurysmal SAH results in high morbidity. Patients who make a good neurological recovery report significant neuropsychological impairment such as loss of motivation, interests, and concentration, all of which are commonly associated with frontal lobe dysfunction. We hypothesize that subclinical frontal lobe injury occurs in neurologically intact SAH patients and may be identified by measuring brain energy metabolism using regional N-acetyl aspartate (NAA) as an imaging marker of neuronal integrity and mitochondrial function, and CSF lactate, as a marker of anaerobic metabolism. We utilized MR Spectroscopy (MRS) to measure regional NAA in SAH patients who had suffered neither cerebral infarction nor neurological deficits. Only patients who underwent endovascular aneurysm coiling were included. Measurements were made in frontal, temporal, occipital lobes, lateral ventricles, and averaged in each hemisphere from 3 slices. Matching ROIs were placed on the most proximate CT perfusion maps to measure corresponding rCBF. MR spectra were compared to controls from our data library (7 subjects) and to rCBF. Average age was 58 years, Hunt Hess score was 2.43±1.09, modified Fisher score was 2.79±1.05. 3 patients had DCI and none had cerebral infarction. Median GCS at discharge was 15. MRS was done at 9.93±7.73 days from admission. 1 patient had no MRS data, 3 patients had no CT perfusion. SAH patients demonstrated significantly reduced NAA/RMS in frontal lobes (16.18±4.96 vs. 20.93±5.56, p=0.042) but not in temporal (16.49±4.37 vs. 19.37±4.38, p=0.09) or occipital lobes (20.62±4.50 vs. 21.05±4.23, p=0.41). CSF lactate was significantly higher in SAH patients (7.74±2.27 vs. 4.02±0.76, p=0.001). NAA/RMS did not correlate with CBF in pooled data (R
2
=0.02, p=0.40) or in frontal lobe rCBF (R
2
=0.001, p=0.92); nor with CSF lactate (R
2
=0.02, p=0.53). Total frontal lobe NAA is selectively reduced and CSF lactate is elevated in neurologically intact survivors after SAH. This preliminary data is suggestive of energy depletion and subclinical brain injury, which appears to be independent of cerebral blood flow. In addition to validating this pilot data, we will study the association with cognitive impairment in these patients.
Abstract 196: Sanguinate (PEGylated-carboxyhemoglobin-bovine) Improves Cerebral Blood Flow and Oxygen Extraction to Vulnerable Brain Regions in Patients at Risk for Delayed Cerebral Ischemia After Subarachnoid Hemorrhage
Authors: Dhar Rajat , Misra Hemant , Diringer Michael
Published: June 2021

Introduction:
Sanguinate is a dual-action oxygen transfer and carbon monoxide-releasing agent with efficacy in animal models of focal brain ischemia and established safety in health volunteers. We performed a dose-escalation study in subarachnoid hemorrhage (SAH) patients at risk for delayed cerebral ischemia (DCI) to evaluate tolerability and explore efficacy in improving cerebral blood flow (CBF) and flow-metabolism balance to vulnerable brain regions.

Methods:
12 subjects were studied over three dose tiers: 160mg/kg, 240 mg/kg, and 320 mg/kg, with close safety evaluation prior to proceeding to higher doses. After baseline
15
O-PET measurement of global and regional CBF and oxygen extraction fraction (OEF), Sanguinate was infused over two hours; PET was repeated immediately after and again at 24-hours. Vulnerable brain regions were defined as those with baseline OEF ≥ 0.5.

Results:
Sanguinate infusion resulted in a significant but transient rise in mean arterial pressure (115±15 to 127±13 mm Hg) that was not dose-dependent. No adverse physiologic or clinical effects were observed with infusion at any dose. Global CBF did not rise significantly after Sanguinate (42.6±7 to 45.9±9 ml/100g/min, p=0.18). However, in the 28% of regions classified as vulnerable, Sanguinate resulted in a significant rise in CBF (42.2±11 to 51.2±18) and reduction in OEF (0.6±0.1 to 0.5±0.11, both p<0.001). The increase in regional CBF was only seen with the two higher doses but OEF improved in all tiers. However, response was attenuated at 24-hours.

Conclusions:
We safely administered a novel oxygen transport and vasodilating agent to a cohort of patients with SAH. Sanguinate infusion appeared to improve CBF and flow-metabolism balance in vulnerable brain regions and warrants further study in those at-risk for DCI. Higher or repeat dosing may be required for sustained efficacy.
Abstract 206: High Occurrence Rate of Parent Intracranial Artery Plaque n Patients With Acute Penetrating Artery Territory Infarcts: Interim Results of the Stroke Imaging Package Study
Authors: Xu Wei-hai , Chen Huisheng , Yang Yi , Xu Jun , Zhang Meng , Lu Baoquan , Wu Shiwen , You Yong , Zhou Zhangyu , Hu Hongtao , Fang Le , Lu Zhengqi , Lou Min , Song Haiqing , Li Mingli , Huang Yining
Published: June 2021

Background:
Pathology studies suggested obstruction of the origins of penetrating arteries by parent intracranial artery plaque can cause an infarct. Using high-resolution magnetic resonance imaging(HRMRI), intracranial plaque distribution can be identified in vivo. We aimed to investigate the occurrence rate of parent intracranial artery plaque in patients with acute penetrating artery territory infarcts.

Methods:
Patients with first ever stroke within 72 hours from onset, confirmed by diffusion weighted imaging, were recruited from 16 medical centers. Conventional magnetic resonance imaging (MRI), magnetic resonance angiography, HRMRI (including 3-dimentional T1 images and 2-dimentional T2 images) and susceptibility-weighted imaging were performed. All patients received thorough evaluations to determine the cause of stroke according to TOAST classifications. A plaque was identified if there was eccentric wall thickening, whereas the thinnest part was estimated to be less than 50% of the thickest point by visual inspection. The plaques within middle cerebral artery(MCA) were further classified based on their orientation being centered on the superior, inferior, dorsal, or ventral side of the vessel. Possible culprit plaques were defined if superior and/or dorsal MCA plaques ipsilateral to the infarcts were observed. The plaques within basilar artery were further classified based on their orientation being centered on the ventral, dorsal, or lateral sides of the vessel ( ipsilateral to infarcts, or contralateral to infarcts). Possible culprit plaques were defined if dorsal plaques or the plaques ipsilateral to brain stem infarcts were observed.

Results:
Six hundred and one patients (70% male, mean age 61±16 years old, mean NIHSS 6± 5) were enrolled. Two hundred and eighty-eight(48%) patients were diagnosed with penetrating artery territory infarcts. Of them, 139 patients(48%, 85 MCAs and 54 BAs) had a plaque within the parent intracranial artery of the infarcts. Most of the parent artery plaques(119,85%) were identified as possible culprit plaques.

Conclusions:
High occurrence rate of parent intracranial artery plaques was observed in patients with acute penetrating artery territory infarcts.
Abstract 209: Association Between Medicare High Risk Criteria and Long Outcomes Following Carotid Revascularization Procedures
Authors: Hicks Caitlin W , Nejim Besma , Alshaikh Husain , Locham Satinderjit , Malas Mahmoud B
Published: June 2021

Background:
Centers of Medicare and Medicaid Services (CMS) has defined a set of high-risk criteria to help define patients who would likely benefit from CAS over CEA. The purpose of this study was to evaluate the postoperative outcomes in patients undergoing CAS vs. CEA, and whether those outcomes vary based on the CMS high-risk criteria.

Methods:
All patients undergoing CAS or CEA recorded in the Vascular Quality Initiative database (2013-2016) were included. Patients were stratified as being normal-risk (Nr) or high-risk (Hr) for undergoing CEA based on published CMS criteria. 30-day and 2-year outcomes [stroke, myocardial infarction (MI), death] were compared for CAS vs. CEA in both the Nr and Hr groups using 1:1 coarsened exact matching and multivariable Cox proportional hazards modelling.

Results:
A total of 55,765 patients (CAS=8,538; CEA=47,227) underwent carotid revascularization during the study period. A significantly higher proportion of CAS were classified as being Hr (75.1% vs. 38.5%; P<0.001). Among Nr patients, 30-day stroke (2.2% vs. 1.0%) and death (4.9% vs. 2.9%) occurred more frequently after CAS vs. CEA (P<0.001), whereas the rate of MI was similar (0.8% vs. 0.6%; P=0.17). Among the Hr patients, 30-day stroke (2.8% vs. 1.3%) and death (7.9% vs. 6.2%) also occurred more frequently after CAS vs. CEA (P<0.001), but the rate of MI was higher after CEA (0.8% vs. 1.1%, P=0.03). After matching 5,440 pairs of patients on 14 preoperative variables, the risk of 2-year stroke/death remained higher after CAS in both the Nr (HR 1.58; 1.17-2.15) and Hr (HR 1.37; 1.13-1.66) groups (Figure).

Conclusions:
In this matched cohort of patients, CAS carries a persistently higher risk of stroke/death than CEA regardless of operative risk. However, the performance difference between the two procedures dissipates in the Hr patients. Thus, CAS utilization should be considered in this group.
Abstract 216: Neuroimaging Profile and Outcomes in Vitamin K Antagonist and Direct Oral Anticoagulant Related Non-traumatic Intracerebral Hemorrhage
Authors: Tsivgoulis Georgios , Goyal Nitin , Krogias Christos , Katsanos Aristeidis H , Sharma Vijay K , Barlinn Kristian , Mikulik Robert , Giannopoulos Sotirios , Pappa Alexandra , Dardiotis Efthymios , Vadikolias Konstantinos , Kerro Ali , Tsantes Argyrios , Triantafyllou Socratis , Schroeder Cristoph , Lioutas Vasileios-Arsenios , Chang Jason , Alexandrov Anne W , Alexandrov Andrei V
Published: June 2021

Background & Purpose:
The safety and efficacy of direct oral anticoagulants (DOAC) for the prevention of thromboembolism in patients with non-valvular atrial fibrillation (NVAF) have been compared to vitamin-k antagonists (VKA) in randomized-controlled clinical trials. There are limited data regarding neuroimaging profile and outcomes in intracerebral hemorrhage (ICH) occurring during DOAC treatment. We sought to compare neuroimaging findings and outcomes in VKA- and DOAC-related ICH.

Methods:
We prospectively evaluated consecutive NVAF patients with non-traumatic, anticoagulant-related ICH that were admitted during a 1-year period in 9 stroke centers. Baseline hematoma volume was calculated by ABC/2 formula. Baseline stroke severity and 3-month functional outcome (FO) were assessed using NIHSS- and mRS-scores. The ICH severity was determined using ICH-score (severe ICH: ICH-score of 3-5).

Results:
We evaluated 91 patients with ICH due to DOAC (n=30) or VKA (n=61). The two groups did not differ in demographic, vascular risk factors, HAS-BLED & CHA2DS2-VASc scores, antithrombotic medications with the exception of higher renal failure prevalence in VKA (28% vs. 4%). DOAC group had significantly (p<0.05) lower median baseline NIHSS-score (5 vs. 12 points) and median baseline ICH volume (11 vs. 25 cm
3
). The rates of severe ICH (13% vs. 34%), perihematomal edema (44% vs.74%), midline shift (20% vs. 49%), 3-month disability (mRS-score: 3-6; 37% vs. 64%) and 3-month mortality (10% vs. 35%) were significantly (p>0.05) higher in VKA group. DOAC-related ICH was independently (p<0.05) associated with lower likelihood of severe ICH (OR=0.14;95%CI:0.03-0.75), perihematomal edema (OR=0.27;95%CI:0.09-0.81) and adverse 3-month FO (common OR= 0.27;95%CI:0.11-0.68) In multivariable logistic regression analyses adjusting for potential confounders. DOAC-related ICH was independently (p=0.028) related to reduced log-trasformed baseline ICH volume in multiple linear regression analyses adjsuting for demographics, risk factors, HAS-BLED & CHA2DS2-VASc scores, ICH location and concomittant medications.

Conclusion:
DOAC-related ICHs appear to have more favorable neuroimaging profile and functional outcome compared to VKA-related ICHs.
Abstract 218: Pericytic Laminin Regulates Blood-Brain Barrier Integrity in an Age-Dependent Manner
Authors: Yao Yao , Gautam Jyoti , Zhang Xuanming
Published: June 2021

Introduction:
Laminin, a major component of the basement membrane, plays an important role in blood brain barrier (BBB) regulation. At the neurovascular unit, astrocytes, brain endothelial cells, and pericytes synthesize and deposit different laminin isoforms into the basement membrane. Previous studies from our laboratory showed that loss of astrocytic laminin induces age-dependent and region-specific BBB breakdown and intracerebral hemorrhage, suggesting a critical role of astrocytic laminin in vascular integrity maintenance. Laminin α4 (predominantly generated by endothelial cells) has been shown to regulate vascular integrity at embryonic/neonatal stage. The role of pericytic laminin in vascular integrity, however, remains elusive.

Methods:
We investigated the function of pericyte-derived laminin in vascular integrity using laminin conditional knockout mice. Specifically, laminin floxed mice were crossed with PDGFRβ-Cre line to generate mutants (PKO) with laminin deficiency in PDGFRβ
+
cells, which include both pericytes and vascular smooth muscle cells (vSMCs). To distinguish the contribution of pericyte- and vSMC-derived laminin, we also generated a vSMC-specific condition knockout line (TKO) by crossing the laminin floxed mice with Transgelin-Cre mice. In this study, mice of both genders on a C57Bl6 background were used. At least 5-6 animals were used in biochemical and histological analyses in this study.

Results:
Pericyte-derived laminin was abrogated in all PKO mice. However, only old but not young PKO mice showed signs of BBB breakdown and reduced vessel density, suggesting age-dependent changes. Consistent with these data, further mechanistic studies revealed reduced tight junction proteins, diminished AQP4 expression, and deceased pericyte coverage in old but not young PKO mice. In addition, neither BBB disruption nor decreased vessel density was observed in TKO mice, suggesting that these vascular defects are due to loss of pericyte- rather than vSMC-derived laminin.

Conclusions:
These results strongly suggest that pericyte-derived laminin active regulates BBB integrity and vessel density in an age-dependent manner. I would like this abstract to be considered for the Stroke Basic Science Award.
Abstract 220: High Sodium Diet Increases Gut Th17 Differentiation and Induces Neurovascular and Cognitive Dysfunction Through Il-17
Authors: Faraco Giuseppe , Brea David , Wang Gang , Garcia Bonilla Lidia , Racchumi Gianfranco , Chang Haejoo , Buendia Izaskun , Koizumi Kenzo , Anrather Josef , Iadecola Costantino
Published: June 2021

High sodium diet (HSD) is a risk factor for stroke and dementia, independent of its effect on blood pressure (BP), but the mechanisms remain unclear. To investigate the cerebrovascular and cognitive impact of HSD, we fed HSD (4-8% NaCl) or normal diet (ND; 0.5% NaCl) to C57BL/6 mice for 12 weeks and assessed cerebral blood flow (CBF) in the somatosensory cortex by laser-Doppler flowmetry. HSD did not increase BP, but attenuated the CBF increase induced by neocortical application of acetylcholine (ACh)(-30.6±0.5%; p<0.05; n=8), a response mediated by endothelial nitric oxide synthase (eNOS), without affecting the response to the smooth muscle relaxant adenosine. These vascular changes were associated with a deficit in novel object exploration (-24±5%; p<0.05; n=15) and spatial learning (Barnes maze) (-31±20%; p<0.05; n=10), suggesting cognitive impairment. The ACh response suppression was associated with increased inhibitory eNOS phosphorylation in pial microvessels (≈1.6 fold increase vs ND; p<0.05; n=7). Since HSD promotes expansion of intestinal helper T lymphocytes producing the vasotoxic cytokine IL17 (Th17) (Nature, 496:518, 2013), we investigated whether IL-17 contributes to the effects of HSD. HSD increased intestinal Th17 cells (+69±20%; p<0,05; n=8), as well as IL-17 plasma levels (ND 0.9±0.2pg/ml; HSD 6.5±1.4pg/ml; p<0.05; n=5). Furthermore, genetic deletion of IL-17 or systemic administration of IL-17 blocking antibodies counteracted the vascular and cognitive effects of HSD, whereas injection of IL-17 (1μg;q.d.x7days;i.p.) reproduced them in full. In brain endothelial cell cultures, IL-17 (10ng/ml) suppressed ACh-induced NO production (-31±2%; p<0,05; n=3), by increasing Rho-kinase-dependent inhibitory eNOS phosphorylation. We conclude that HSD induces profound alterations in neurovascular regulation and cognitive function. The effect is mediated by expansion of intestinal Th17 cells and increased circulating IL-17, which, in turn, leads to inhibitory eNOS phosphorylation and reduced NO production through Rho kinase. The data suggest a neurovascular mechanism for the increased risk of stroke and dementia with HSD, and identifies IL17 as a putative therapeutic target for the deleterious effects of high salt on the brain.
Abstract 221: The P2x4 Receptor is Required for Neuroprotection via Ischemic Preconditioning
Authors: Ozaki Tomohiko , Muramatsu Rieko , Fujinaka Toshiyuki , Yoshimine Toshiki , Yamashita Toshihide
Published: June 2021

Background:
Ischemic preconditioning (IPC), a procedure consisting of transient ischemia and subsequent reperfusion, provides ischemic tolerance against prolonged ischemia in the brain. Although the blood flow changes mediated by IPC are primarily perceived by vascular endothelial cells, the role of these cells in ischemic tolerance has not fully clarified. In this research, we focused on the role of P2X4 receptor, which sense blood flow changes and is expressed on vascular endothelial cells.

Methods:
We administrated P2X4 receptor inhibitor into lateral ventricle of C57BL/6J male mice (8-10 weeks) and then conducted middle cerebral artery occlusion (MCAO). Fifteen minutes MCAO was done as IPC 48 hours before 60 minutes MCAO. To examine the necessity of P2X4 receptor expression in vascular endothelial cells, we generated a conditional knockout (CKO) mouse in which the P2X4 receptor was knocked down in VE-cadherin-positive vascular endothelial cells. To investigate molecular change by IPC, we obtained cerebrovascular endothelial cells of mice 48 hours after IPC, and real time PCR and ELISA were evaluated. To examine the molecular expression change on vascular endothelial cells by blood flow, we used in vitro culture system which generates fluid flow and real time PCR was evaluated. Inhibition of P2X4 receptor expression was conducted by P2X4 receptor siRNA transfection.

Results:
P2X4 receptor antagonist abolished neuroprotection via IPC. Moreover, the effect of IPC to P2X4 receptor CKO mice was smaller than control mice, the infarct volume of P2X4 receptor CKO was larger than control mice after 60 minutes MCAO (p<0.05, Control, n=4; CKO, n=6). IPC induced expression of osteopontin mRNA (p<0.05, n=5). Osteopontin administration attenuates the increase of infarct formation induced by P2X4 receptor inhibition (p<0.05, Control, n=5; Osteopontin, n=6). In vitro, shear stress upregulated expression of osteopontin mRNA (p<0.05, n=3). This upregulation was inhibited by P2X4 receptor siRNA (p<0.05, Control siRNA, n=6; P2X4 receptor siRNA, n=7).

Conclusion:
These results demonstrate a novel mechanism whereby vascular endothelial cells are involved in ischemic tolerance by way of the pathway about P2X4 receptor and osteopontin.
Abstract 41: Prognostic Value of Perfusion MRI in Patients with Transient Ischemic Attack or Minor Stroke
Authors: Lee Joon Hwa , Jo Hyunjin , Cha Jihoon , Seo Woo-Keun , Bang Oh Young , Chung Chin-Sang , Lee Kwang Ho , Kim Gyeong-Moon
Published: June 2021

Background and purpose:
We aimed to investigate the role of perfusion MRI parameters (TTP: time to peak, CBF: cerebral blood flow, CBV: cerebral blood volume) as a prognostic factor for the risk of stroke recurrence or cardiovascular outcome in patients with transient ischemic attack (TIA) or minor stroke.

Methods:
We retrospectively reviewed TIA or minor stroke patients who underwent our stroke MRI protocol (DWI, perfusion MRI, and MRA) in a consecutively collected stroke registry. Primary outcome was nonfatal stroke recurrence and secondary outcome was cardiovascular composite outcome. Multivariate analysis was used to examine the association of perfusion MRI parameters and angiographic findings with the risk of stroke recurrence and cardiovascular event.

Results:
Of the 326 patients who met inclusion criteria, we identified 15(4.6%) nonfatal strokes and 25(7.7%) cardiovascular composite events during the first 1 year after the index TIA or minor stroke. The presence of regional delayed perfusion on TTP maps (p=0.002) and regional hyperperfusion on CBV maps (p<0.001) were associated with recurrent stroke. In MRA images, concomitant stenosis of the intracranial arteries and/or extracranial carotid arteries was associated with cardiovascular events (p=0.009). Using multivariate cox proportional hazard analysis, presence of regional hyperperfusion on CBV remained an independent predictor of recurrent stroke (HR 10.82, 95% CI 4.19-38.67, p<0.001) and cardiovascular event (HR 6.30, 95% CI 2.67-18.25, p<0.001). The AUC of the CBV maps was also greater than other parameters for the prediction of stroke recurrence (AUC=0.701, 95% CI 0.54-0.86) and cardiovascular composite outcome (AUC=0.628, 95% CI 0.50-0.76).

Conclusions:
Increased CBV on perfusion MRI, representing the hemodynamic status of postischemic hyperperfusion, could be more useful than other perfusion parameters in predicting poor prognosis of TIA or minor stroke patients.
Abstract 48: Dysregulated Glucose Metabolism Pathway Specific Genes in Aged and Post-stroke Rat Brains: Implicating Hexokinase 3 in Glucose Regulation
Authors: Wesley Umadevi V , Bhute Vijesh J , Palecek Sean P , Dempsey Robert J
Published: June 2021

Background:
Metabolic dysregulation associated with aging impacts stroke incidence and outcome. Hyperglycemia occurs in 30% of patients with ischemic stroke, and is associated with poor stroke recovery. On the other hand, depletion of glucose within the brain prevents production of ATP, leading to energy reduction and neuronal death. Thus, balanced glucose metabolism is critical for normal brain function. However, our understanding of the regulation of genes involved in glucose metabolism and relationship to age in the post-stroke brain is elusive.

Methods:
Using transcriptomic and metabolomics approach, we examined the expression pattern of glucose metabolism pathway specific genes in the naïve and post-stroke brains of 3 month, and 12 month old rats subjected to focal cerebral ischemia by middle cerebral artery occlusion and 2 days re-perfusion. Metabolites were analyzed using Nuclear Magnetic Resonance (NMR) spectroscopy.

Results:
Our data shows substantial alterations in the glucose metabolism pathway in aged, and particularly in post stroke rat brain. Brains from 12 month old rats showed about 15 fold increase in phosphoenolpyruvate carboxykinase (PCK1), and 2 fold increase in phosphorylase kinase (PHKG1) mRNA as compared to 3 month old rats. In the post-stroke brain, mRNA levels of hexokinase 3 (HK3) was upregulated 9 fold in 3 month old rats. However, HK3 mRNA substantially increased to 26 fold in 12 month old post-stroke brain as compared to control brains. The PCK1 gene was down regulated 2-4 fold in post-stroke brain. Metabolomics studies indicated significant alterations in nucleotide metabolism and decreased antioxidants in the aged brain. Metabolic changes in post-stroke brains included depletion of ADP and AMP, and accumulation of fumarate, O-phospho-ethanolamine, glycerol, glycine, leucine, lysine and malate.

Conclusion:
Upregulation of PCK1, a key gluconeogenic enzyme may contribute to excess glucose production in aged brain, leading to increased risk of obesity and stroke. The inducible expression of HK3 in post-stroke brain suggests its adaptive role in metabolic responses to stress in the ischemic environment. Overall, HK3 by modulating glycolysis pathway, may lead to metabolic reprogramming in aged and post stroke brain.
Abstract 49: Endothelial-targeted Overexpression of Heat Shock Protein 27 Ameliorates Rapid Blood Brain Barrier Impairment and Improves Long Term Outcomes After Ischemia and Reperfusion
Authors: Shi Yejie , Jiang Xiaoyan , Zhang Lili , Pu Hongjian , Zhang Wenting , Gao Yanqin , Hu Xiaoming , Leak Rehana K , Keep Richard F , Bennett Michael V , Chen Jun
Published: June 2021

Introduction:
Blood brain barrier (BBB) damage resulting from ischemia/reperfusion (I/R) disrupts the neurovascular unit and leads to poor patient outcomes. We recently discovered that caveolin-1-independent subtle structural aberrations of brain microvascular endothelial cells (BMECs), such as abnormal actin polymerization, stress fiber formation and subsequent junctional protein (JP) disassembly, are a novel mechanism for rapid BBB breach after I/R.

Hypothesis:
Heat shock protein 27 (HSP27) reduces BBB breakdown after I/R by inhibiting actin polymerization and JP disassembly in BMECs.

Methods:
Neuron- or EC-specific HSP27-overexpressing mice were subjected to 1 h MCAO and reperfusion. BBB damage, tissue histology, and neurobehavioral performance were assessed up to 35 d after I/R. I/R-induced BBB damage was also simulated in BMEC cultures, where gene manipulations were achieved using lentiviral vectors. Cell-permeable TAT-HSP27 protein was injected
i.v.
into mice after I/R to rapidly elevate HSP27 in BMECs.

Results:
Targeted overexpression of HSP27 within ECs—but not neurons—was sufficient to reduce early (1-3 h) and late (24 h) BBB damage after I/R (p<0.01). Mechanistically, HSP27 suppressed I/R-induced actin polymerization, stress fibers, and JP disassembly in BMECs, but independent of its anti-cell death properties. Intracerebral infiltration of neutrophils and macrophages was attenuated in EC-HSP27 mice by 35% and 60%, respectively (n=6, p<0.05) at 48 h after I/R. Infarct size was reduced by 35% at 72 h, and sensorimotor functions (p<0.01, cylinder and corner tests) were improved in EC-HSP27 mice up to 21 d. Post-I/R injection of TAT-HSP27 markedly reduced BBB damage and elicited sustained (up to 35 d) protection against neurological deficits.

Conclusions:
HSP27 protects against BBB disruption after I/R by inhibiting actin polymerization and JP disassembly in BMECs. HSP27 may be a therapy for ischemic stroke in conjunction with reperfusion.
Abstract 5: Early Outcomes After Carotid Endarterectomy Compared to Carotid Artery Stenting for Carotid Stenosis in the National Surgical Quality Improvement Program Database
Authors: Alhaidar Mohammed K , Amdur Richard , Algahtani Rami , Sigounas Dimitri , Algaeed Mohanad , Leon Guerrero Christopher R
Published: June 2021

Background:
Carotid Endarterectomy (CEA) and Carotid Artery Stenting (CAS) are both viable treatment options for carotid artery stenosis. Factors including surgical risk, age, and symptomatic status are often used to help guide management decisions.

Methods:
We conducted a retrospective observational study using the National Surgical Quality Improvement Program (NSQIP) database to compare 30-day post-procedure outcomes including mortality, stroke, and myocardial infarction in patient with carotid stenosis undergoing CEA (n=54,640) versus CAS (n=488) from 2005 to 2012. Procedure type was identified by CPT codes.

Findings:
Patients undergoing CEA were more likely to be older and have symptomatic stenosis, and less likely to be white, have CHF, and have COPD. There was no significant difference between CEA and CAS in 30-day mortality (0.9% vs. 1.2%, p=0.33), stroke (1.6% vs. 1.6% p=0.93), myocardial infarction (0.9% vs. 1.6%, p=0.08), or combined outcome (3.0% vs. 4.9%, p=0.09). The interaction between symptomatic status and procedure type was not significant (p=0.29), indicating the association of symptomatic status with 30-day mortality was similar in cases receiving CEA and CAS.

Conclusion:
Early outcomes after CEA and CAS for carotid artery stenosis appear to be similar in a ‘real-world’ sample and comparable to clinical trials. Patients undergoing CAS were more likely to be younger and surgically higher risk based on baseline characteristics likely reflecting clinical practice case selection.