bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract WP101: Involvement of the Contralesional Angiotensin Type 2 Receptor in Compound 21 Mediated Functional Recovery After Stroke
Authors: Fouda Abdelrahman Y , Ishrat Tauheed , Ahmed Heba , Pillai Bindu , Artham Sandeep , Ergul Adviye , Fagan Susan
Published: July 2021

Introduction:
We have recently shown that the angiotensin type 2 receptor (AT2R) agonist, compound 21 (C21), provides sustained functional recovery after ischemic stroke. This was associated with upregulation of the AT2R and the neurotrophin, brain derived neurotrophic factor (BDNF), in the contralesional brain hemisphere. Here, we aimed to study the contribution of this hemisphere in C21 mediated functional recovery after stroke through localized knockdown of the AT2R.

Methods:
male wistar rats (34) received two intrastriatal injections of short hairpin RNA (shRNA) lentiviral particles against AT2R, or non-targeting control vector (NTC) into the left brain hemisphere to achieve localized AT2R knockdown. After 14 days, rats were subjected to 90 minutes right middle cerebral artery occlusion (MCAO) and received either C21 (0.03 mg/kg) or saline at reperfusion (IV) then daily (IP) for 7 days. Rats were blindly assessed for behavioral outcome up to 10 days as well as molecular analysis. Results (table): PCR and Western blotting confirmed successful knockdown of the AT2R in the left (contralesional) hemisphere by about 50%. All groups showed worsened outcome on days 1 to 3 then recovered on days 7 to 10. The C21/NTC group showed better behavioral outcome compared to other groups at days 7 and 10, while the saline/shRNA group was associated with the least recovery. Using Western blotting, C21/NTC group showed higher BDNF and lower proBDNF (pro-form) levels in the ischemic and contralesional hemispheres respectively. Expression of the pro-apoptotic P75NTR receptor of proBDNF was decreased with C21 treatment irrespective of AT2R knockdown.

Conclusion:
Contralesional AT2R could be involved in C21 mediated functional recovery after stroke.
Abstract WP104: Neuron- microglia Crosstalk Mediated by Soluble Fas Ligand after Ischemic Stroke
Authors: Meng Hailan , Li Xiaoxi , Ye Dan , Weng Leihua , Chen Yanting , Xu Yun
Published: July 2021

Objectives:
Accumulating data indicate that soluble Fas Ligand (sFasL) is involved in inflammatory cascades after cerebral ischemia. However, the potential role of sFasL in modulating the neuron-microglia crosstalk is barely understood. We hypothesized that sFasL triggers neuronal death and M1-microglia polarization after ischemic injury.

Methods:
Middle cerebral artery occlusion (MCAO) was induced in both FasL mutant gld mice and wild-type C57BL/6J mice. Microglial polarization was determined by immunohistochemical staining and real-time polymerase chain reaction. Expression of sFasL was detected by western blot. The expression of sFasL in the medium after OGD was detected by ELISA assay. Activity of sFasL was blocked by using its neutralizing antibody. Neuronal survival and apoptosis were quantified.

Results:
Expression of sFasL at protein level in the ischemic cortex was increased by 451.67% in wild-type stroke mice over the sham-operated brain. The gld mice demonstrated attenuated neuronal death and M1-microglial phenotype markers (iNOS and CD86) compared to wild-type mice after MCAO. Protein expression of sFasL was increased both in the neuronal and microglial culture medium after OGD. In addition, conditioned medium obtained from ischemic neuron drove microglial polarization toward the M1 phenotype producing more pro-inflammatory cytokines (IL-1β, TNF-α and MCP-1). Meanwhile, conditioned medium from ischemic microglia exacerbated neuronal death dramatically. sFasL neutralizing antibody, however, significantly decreased these changes. Furthermore, phosphorylated JAK2/STAT3(Y705 and S727) was increased in microglia after neuronal-conditioned medium treatment, which was decreased following inhibition of sFasL activity.

Conclusions:
The gld mice demonstrated attenuated ischemic brain damage. sFasL is involved in modulating the crosstalk between these two cells in a contact-independent way. Microglia-released sFasL exacerbated neuronal death while neuron-released sFasL induced M1-microglia polarization after ischemic stroke. Neutralization of sFasL, thereby, may protect against ischemic brain damage and provide novel views on post-stroke neuroimmune regulation.
Abstract WP108: Co-transplantation of NPCs and EPCs Synergistically Promotes Brain Recovery After Ischemia-reperfusion Injury in Mice
Authors: Wang Jinju , Ma Xiaotang , Chen Shuzhen , Xiao Xiang , Bihl Ji , Zhao Bin , Chen Yanfang
Published: July 2021

Introduction:
The promising of neuron progenitor cells (NPCs) or endothelial progenitor cells (EPCs) for treating ischemic stroke has been recognized. In this study, we determined the therapeutic effects of NPC and EPC co-transplantation and the underlying mechanisms in a mouse model of ischemia-reperfusion (I-R) stroke.

Methods:
NPCs and EPCs were generated from human inducible pluripotent stem cells. C57BL/6 adult mice were subjected to middle cerebral artery occlusion (MCAO; 90 min) followed by reperfusion (30 min), and treated with (n=10/group): 1) PBS; 2) EPCs; 3) NPCs; 4) EPCs+NPCs (1:1 ratio); 5) EPCs+NPCs (1:1 ratio)+LY294002 (1μM). Cells (3x105/2μl PBS) were injected into ipsilateral striatum at 2 sites (1μl/site). Bromodeoxyuridine (BrdU, 65 mg/g/day, i.p.) was injected to label the new generated cells. Mice were sacrificed at days 2 and 10. Motor function (Rotarod test and neurologic deficit score), infarct volume, cerebral microvascular density (cMVD), neurogenesis and angiogenesis, and gene expressions of the PI3K/Akt pathway were evaluated.

Results:
Co-transplantation of EPCs and NPCs exhibited synergistic effects on improving motor function, increasing cMVD in the peri-infarct area, and decreasing infarct volume at days 2 and 10 (refer to table). Moreover, neurogenesis (Brdu+NeuN+) and angiogenesis (Brdu+CD31+) in the peri-infarct area were largely enhanced in the co-transplantation group at day 10 (refer to table). In addition, the protein ratio of p-Akt/Akt was increased in the brain in the co-transplantation group (p<0.05). These effects were significantly reduced by LY294002 administration.

Conclusion:
Co-transplantation of NPCs and EPCs synergistically increases cMVD, promotes angiogenesis and neurogenesis, and improves functional outcome in I-R injured mice. Activation of the PI3K/Akt signal pathway contributes to the synergistic effects of NPCs and EPCs.
Abstract WP111: Activation of α7 Nicotinic Acetylcholine Receptor Improves Blood-Brain Barrier Integrity in Mice with Ischemic Stroke and Bone Fracture
Authors: Zou Dingquan , Han Zhenyi , Zhan Lei , Zhu Wan , Kang Shuai , Bao Chen , Sadighi Alireza , Li Zhao , Nelson Jeffrey , Zhang Rui , Su Hua
Published: July 2021

Background & Purpose:
Stroke is an important risk factor and one of the most devastating complications for bone fracture. We showed previously that bone fracture at the acute stage of ischemic stroke worsens, and activation of α7 nicotinic acetylcholine receptor (α7 nAchR) improves stroke recovery through attenuation of inflammation. We hypothesized that activation of α7 nAchR also improves blood-brain barrier integrity.

Methods:
Permanent distal middle cerebral artery occlusion (pMCAO) was performed on C57BL/6J mice followed by tibia fracture 1 day later. Mice were treated intra-peritoneally with 0.8 mg/kg PHA 568487 (PHA, α7 nAchR-specific agonist), 6 mg/kg methyllycaconitine (MLA, α7 nAchR antagonist), or saline 1 and 2 days after pMCAO. Brain water content was assessed by measuring the wet and dry weight 3 days after pMCAO. The expression of monoamine oxidase B (MAO-B) in astrocytes and tight junction proteins was quantified in the peri-infarct region using immunostained brain sections (N=6).

Results:
Tibia fracture increased water content in the ischemic stroke brain (p<0.001) and MAO-B positive astrocytes (p<0.001), and decreased tight junction protein expression. Compared to saline treatment, PHA reduced and MLA increased water content and the MAO-B positive astrocytes in the brain of pMCAO and pMCAO-plus-tibia-fracture mice (p<0.05). PHA also increased and MLA decreased tight junction protein expression.

Conclusions:
In addition to inhibiting inflammation, activation of α7 nAchR also reduces astrocyte oxidative stress and improves blood-brain barrier integrity. Thus, the α7 nAchR-specific agonist can be developed into a new therapy for improving recovery patients with stroke or stroke plus bone fracture.
Abstract WP116: Patterns of Vascular Calcification in Young Patients With Intracranial Stenosis
Authors: Strohm Tamara , Katzan Irene , Uchino Ken
Published: July 2021

Introduction:
Intravascular calcification is thought to be a marker of atherosclerosis in patients with stenosis and vascular risk factors. Little is known about the utility of quantifying intracranial calcification to help determine mechanism of stenosis. The objective of our study was to compare presence and patterns of intracranial calcification in patients with intracranial stenosis due to atherosclerosis and other etiologies.

Methods:
Retrospective cohort study of 89 patients
<
50 years with diagnosis of intracranial stenosis who had undergone CT angiogram from 2008-2013; 44 had presumed atherosclerosis as etiology (
>
3 vascular risk factors with no other identified cause). CTAs were reviewed for presence and location of intracranial calcification.

Results:
Of patients with atherosclerotic stenosis, 28 (64%) had intravascular calcification compared to 16 (36%) of those with stenosis of other etiologies (P=0.0039). There was no significant difference in pattern or location of stenosis between groups. One-third had calcification outside the region of stenosis in both groups. Distal internal carotid artery and distal vertebral artery were the most common sites of intracranial calcification (Table).

Conclusion:
Intracranial calcification is more commonly seen in patients
<
50 years old with stenosis secondary to atherosclerosis, but the pattern and location was similar between groups. More research is needed to determine the utility of using the presence of vascular calcification to help determine mechanism of intracranial stenosis in the young.
Abstract WP156: Assessment and Provision of Rehabilitation Among Acute Ischemic Stroke Patients Hospitalized in China: Findings From the China National Stroke Registry II
Authors: Li ZiXiao , Prvu Bettger Janet , Xian Ying , Liu Liping , Zhao Xingquan , Li Hao , Wang Chunxue , Li Linzi , Wang Chunjuan , Meng Xia , Wang Anxin , Pan Yuesong , Peterson Eric D , Wang Yilong , Wang Yongjun
Published: July 2021

Background:
Stroke rehabilitation improves functional recovery among stroke patients. However, little is known about clinical practice in China regarding the assessment and provision of rehabilitation among patients with acute ischemic stroke (AIS).

Aims:
We examined the frequency and determinants of an assessment for rehabilitation among AIS patients from the China National Stroke Registry II.

Methods:
Data for 19,294 AIS patients admitted to 219 hospitals from June 2012 to January 2013 were analyzed. The multivariable logistic regression model with the generalized estimating equation method accounting for in-hospital clustering was used to identify patient and hospitals factors associated with having a rehabilitation assessment during the acute hospitalization.

Results:
Among 19,294 AIS patients, 11,451 (59.4%) were assessed for rehabilitation. Rehabilitation assessment rates varied considerably among centers: median 64.8% (interquartile range: 41.4%-83.3%). Factors associated with increased likelihood of a rehabilitation assessment in the multivariable model (p<0.05) included disability prior to this stroke, increasing NIHSS on admission, receiving dysphagia screening, deep venous thrombosis prophylaxis, and carotid vessel imaging, longer length of stay, and increasing hospital beds (per 100 units). In contrast, patients with a history of atrial fibrillation, and increasing annual stroke discharges (per 100 patients) were less likely to receive rehabilitation assessment during the acute stroke hospitalization.

Conclusions:
Up to a third of patients in China do not receive rehabilitation assessment follow an AIS. Thus, there appears to be opportunities to improve adherence to recommended care for stroke survivors in China.
Abstract WP195: Patients Beginning Community Based Outpatient Stroke Rehabilitation Program More Than 6 Months Post Stroke Achieve Equally Excellent Outcomes as Sub-Acute Patients
Authors: Breen Joan , Andrusin Jeanne , Ferlito Tom
Published: July 2021

Background:
Despite the availability of community based outpatient rehabilitation programs in the U.S., few use standardized measure sets and assessments, and outcomes studies are sparse. There is especially a knowledge gap regarding outcomes of participating chronic stroke patients (rehabilitation begins more than 6 months post stroke).

Methods:
Prospective observational study of stroke patients treated between 12/2011-1/2015 in an interdisciplinary outpatient rehabilitation program that addresses health literacy, risk factors, physical, psychosocial, cognitive, communicative and vocational issues. Patients were classified as chronic if admitted to the program >6 months and sub-acute if admitted <6 months post stroke.

Results:
Among 96 consecutive patients, 71 were sub-acute (72% ischemic, 28% hemorrhages) and 25 chronic (68% ischemic, 32% hemorrhages) who were admitted to the program an average 18.5 months post stroke (range 6-121 months). Chronic vs subacute stroke patients were 64% vs 59% male, with no difference in age (mean 66, range 27-90 years vs 65, range 18-90 years), but with greater stroke severity (chronic mean NIHSS score 8.32, range 2-15 vs subacute NIHSS of 5.2, range 0-16). On admission, chronic vs subacute patients were 44% vs 34% aphasic and 96% vs 86% needed assistance with activities of daily living (chronic with modified Rankin Scale [mRS] of 3=28% and 4=68% vs subacute mRS of 3=65% and 4=21%). The percent change in outcomes from baseline to program discharge for subacute and chronic stroke patients is presented in the Table.

Conclusions:
Although age, sex and stroke types were similar in both groups, chronic patients were more severely impaired than subacute patients but achieved greater improvement in activities of daily living, recovery, walking speed, balance, and risk factor knowledge. These findings demonstrate that outpatient rehabilitation programs can aid in stroke recovery independent of time since stroke onset.
Abstract WP198: Is There a "Smoker's Paradox" in Acute Reperfusion Therapies?
Authors: Bavarsad Shahripour Reza , Donnelly John P , Shiue Harn , Gadpaille Alissa , Arora Kanika , Sisson April , Lyerly Michael , Gropen Toby
Published: July 2021

Background & Purpose:
Recent studies have suggested a “smoker’s paradox,” referring to higher recanalization rates and better outcomes after IV thrombolytic therapy for ischemic stroke in smokers compared to nonsmokers. Our goal was to evaluate whether this paradox exists for both IV and endovascular therapies (ET) in our population.

Methods:
We retrospectively evaluated consecutive AIS patients (March 2014-April 2015) admitted to our comprehensive stroke center. Patients were stratified by treatment: IV tPA, ET, or neither. The primary endpoint was the modified Rankin scale (mRS) at discharge (“favorable outcome” score 0- 2) analyzed by logistic regression adjusted for demographic factors and admission NIHSS score. Successful reperfusion after ET was classified as Thrombolysis in Cerebral Infarction (TICI) scores of 2b or greater on immediate angiographic imaging.

Results:
Of 765 patients, 29 % were smokers (n= 222) including 63 % white (Table). Among smokers, 15% received tPA and 3% of patients received ET. Among nonsmokers 14% received tPA and 6% received ET. There was no difference in favorable outcome between smokers and nonsmokers in patients treated with tPA (60.6% vs. 52.6%; P= 0.43) or ET (26% vs. 40.0%; P= 0.325). There was no difference between smokers and nonsmokers in re-canalization after ET (70.6 % vs. 70.0%; P= 0.62). In patients without tPA or ET treatment, favorable outcome was more frequent in smokers compared to nonsmokers (66.5% vs. 47.8 %; P< 0.001). In a regression model adjusted for admission NIHSS, age, gender, and race, the prevalence of good outcome in smokers was 18% more than nonsmokers. (PR 1.177; 95% CI: 1.021 - 1.409).

Conclusions:
Our study did not support presence of the “Smoker’s Paradox” in AIS patients who receive IV or ET therapy. A rigorous adjustment for risk factors is likely to eliminate the paradoxical finding of more frequent favorable outcome in smokers who have not received tPA or ET.
Abstract WP23: Clot Burden and Collateral Flow on Multiphase CT: Predictor of Outcomes After Recanalization Therapy in Acute Middle Cerebral Artery Infarction
Authors: Hwang Jaechun , Lee Mi Ji , Park Hae Ree , Bang Oh Young , Kim Gyeong-moon , Chung Chin-sang , Lee Kwang Ho
Published: July 2021

Introduction and Hypothesis:
We evaluated the ability of mixed grading system based on thrombus burden and collateral status assessed by multiphase computed tomography (MPCT) as a predictor of outcome after recanalization therapy.

Methods:
Eighty-six consecutive patients who underwent MPCT for acute M1 middle cerebral artery occlusion within 6 hours of symptom onset were included. Collateral status to the occluded MCA territory was classified as follows: grade 1, no collaterals; grade 2, slow collaterals with persistence of defect; Grade 3, slow but complete collateral; grade 4, rapid complete collateral. A grade of 1-2 was designated as poor, 3-4 as good collateral flow. Short clot segment was defined as contrast filling defect length on MPCT < 1 centimeter. We divided patients into 3 groups based on collateral status and clot segment length: good collateral with short clot segment (N=29), good collateral with long clot segment (N=34), poor collateral (N=23).

Results:
Clinical characteristics were not different between 3 groups. Good functional outcome (3 months modified Rankin scale scores ≤ 2) and major neurologic improvement (1 day NIHSS score improved to 0 or 1 point or > 8 points decrease from baseline) were more frequent for short clot segment group and good collateral group than poor collateral group. In logistic regression, after adjusting other variables, good collateral and short clot segment were independent predictors for good functional outcome compared poor collateral (good collateral: OR 12.117, p=0.013; short clot segment with good collateral: OR 44.418, p=0.003). Similarly, the major neurologic improvement was significantly related with good collateral and short segment group. (good collateral: OR 8.903, p=0.41; short clot segment with good collateral: OR 40.430, p=0.006)

Conclusions:
Short clot segment and good collateral flow assessed with MPCT were useful additional markers predicting clinical outcomes after recanalization therapy.
Abstract WP241: Direct Doctor-to-Doctor Telecommunication Between a Stroke Center and Local Hospitals: a Tool to Enhance Clinical Outcome of Intraarterial Thrombectomy for Acute Ischemic Stroke Patients First Visit Local Hospitals
Authors: Jeong Hye Seon , Kwon Hyon-Jo , Koh Hyeon Song , Yu Hee Sun , Yun Na Young , Kim Hyung Ki , Oh Sang-Geun , Kwag Hyun Jeong , Han Ho Sung , Kim Eun Hee , Song Hee-Jung , Kim Jei
Published: July 2021

Background:
We have executed a direct doctor-to-doctor telecommunication system (D2D-Call) to perform intraarterial thrombectomy (IAT) for acute ischemic stroke patients, who first visited at local hospitals. We evaluated whether the D2D-Call was effective to perform successful IAT for acute stroke patients visited first at the local hospitals.

Methods:
We analyzed clinical data of 201 consecutive patients (male:female=126:75, mean age±SD, 68.4±12.5 years), who underwent IAT to recanalize occluded intracranial vessels from January, 2011 to May, 2015. The patients were classified by the arrival manners at our center; 1) Direct-Arrival at our center (n=140), 2) transfer after D2D-Call (n=38), and 3) transfer with No-D2D-Call (n=23) from local hospitals. Differences of the time intervals from arrival at our center to IAT start (Arrival-to-Puncture) and from symptom onset to recanalization (Onset-to-Recanalization) were analyzed between the three groups. The recanalization rates and clinical outcome of the three groups were also compared between them.

Results:
D2D-Call group showed shorter Arrival-to-Puncture time than the other groups (Direct-Arrival, 107.1±28.1; D2D-Call, 49.6±18.3; No-D2D-Call group, 109.8±28.3 minutes, p<0.001). On Onset-to-Recanalization time analysis, D2D-Call group was late 44 minutes yet, but, faster 90 minutes than No-D2D-Call group (Direct-Arrival, 263.9±120.1; D2D-Call, 307.1±70.7; No-D2D-Call group, 393.6±74.9 minutes, p<0.001). Overall recanalization rate of D2D-Call group (76%) was lower than Direct-arrival (84%), but, higher than Non-D2D-call group (65%, p=0.075). Good clinical outcome (defined as 0-3 of modified Rankin Scale) of D2D-Call group (66%) was similar with Direct-Arrival (68%) at 3 months after IAT, but, significantly higher than Non-D2D-Call group (39%) (p=0.030).

Conclusion:
Direct communication between doctors of a stroke center and local hospitals could reduce overall onset-to-recanalization time of IAT by shortening of staying in emergency room, and, ultimately could achieve better clinical outcome after IAT for acute ischemic stroke patients visited first at local hospitals.
Abstract WP25: A Novel Adaptive Trial Design Increases the Power of Endovascular Stroke Studies
Authors: Lansberg Maarten , Bhat Ninad , Broderick Joseph P , Palesch Yuko Y , Lavori Philip W , Lai Tze L , Yeatts Sharon D , Albers Gregory W
Published: July 2021

Introduction:
It is difficult to choose trial enrollment criteria that will yield a robust treatment effect. To address this problem, we developed a novel trial design that restricts enrollment criteria to the patient subgroup most likely to show benefit, if an interim analysis indicates futility in the overall sample. Future recruitment, and the population in which the primary hypothesis is tested, is limited to the selected subgroup.

Hypothesis:
A design with adaptive subgroup selection increases the power of endovascular stroke studies.

Methods:
We ran simulations to compare the power of the adaptive design with that of a traditional design. Trial parameters were: type I error 0.025, type II error 0.1, analysis after 450, 675 and 900 patients (interim and final analyses in IMS III). Outcome data were based on 90 day mRS scores observed in IMS III among patients with a vessel occlusion on baseline CTA (n=289). Subgroups were defined a priori according to vessel occlusion (ICA ± distal occlusion vs M1 vs M2-4), onset-to-randomization time (early vs late), and treatment allocation (IA+IV vs IV alone). The treatment effect in the overall cohort was a mean mRS improvement of 0.15 (2.41 for IV+IA vs 2.56 for IV alone; SD 1.45). The subgroup treatment effects were: early ICA = 0.54, late ICA = 0.60, early M1 = 0.33, late M1 = 0.07, early M2-4 = -0.66, and late M2-4 = -0.35.

Results:
The traditional design showed a treatment benefit in 31% of simulations. The adaptive design showed benefit in 91%, failed to show benefit after enrollment of the maximum sample in 1%, and stopped early for futility in 8% of simulations. The adaptive trial stopped early for benefit in 84% of simulations. Due to early stopping, the mean number of patients randomized is 590±140 with the adaptive design vs 900 with a traditional design. Of the adaptive trial simulations that showed benefit, 91% occur after subgroup selection. The subgroup selected most often (31% of all simulations) includes early and late ICA patients.

Conclusions:
A trial with adaptive subgroup selection can efficiently test the effect of endovascular stroke treatment. Simulations suggest that with this design, IMS III would have 91% power and would typically stop early after interim analysis shows benefit in a patient subgroup.
Abstract WP257: Metabolic Profiling in the Plasma of Rats in Response to Aging and Ischemic Stroke by Nuclear Magnetic Resonance Spectroscopy
Authors: Bhute Vijesh J , Wesley Umadevi V , Hatcher James F , Dempsey Robert J , Palecek Sean P
Published: July 2021

Introduction:
Metabolic dysfunction is a common hallmark of aging, and it influences the neurodegenerative diseases including stroke incidence and outcome. Several metabolomics-based studies have revealed metabolite biomarkers in stroke patients and yet metabolic changes as a result of aging and focal ischemia/reperfusion (I/R) time are not completely elucidated. In this study, we examined the dysregulation of metabolites in the plasma as a function of age and cerebral ischemic injury.

Methods:
We compared the metabolic pattern in young (3 months) and older rats (12 months) before, and 2 days after I/R injury. Stroke was induced by middle cerebral artery occlusion. For time course study, plasma samples from younger animals were collected at day 1, 2, 3, 7, 14 and 21 of I/R (n=3). We used Nuclear Magnetic Resonance spectroscopy and compared the metabolite peaks using spectral binning and targeted profiling. The data was analyzed using one way analysis of variance, principal component analysis (PCA) and hierarchical clustering. Pathway enrichment and topological analysis tools were used to identify the age and stroke responsive metabolic pathways.

Results:
PCA revealed global differences in plasma of naïve young and old rats, with old rats showing significantly lower glucose levels, and higher formate levels. Also, older animals showed reduced levels of acetate and formate and very high levels of 3-hydroxybutyrate 2 days after I/R. Younger rats showed significant differences starting from day 3 onwards with lower glucose concentration and increased 3-hydroxybutyrate, creatine, formate and glycine concentrations, which remained at a higher level on day 7 of I/R. Interestingly, the metabolic profile of plasma at day 21 of I/R showed similar pattern as that of control naïve animals. Pathway topology analysis revealed enrichment of citric acid cycle and glycine, serine and threonine metabolic pathways in older animals as early as 2 days after I/R. However, younger animals showed a delayed metabolic response after day 3 of I/R.

Conclusions:
We have demonstrated that the metabolic profile of plasma is altered as a function of age, ischemic stroke and time of reperfusion. These results suggests an important role for imbalance in metabolites in stroke pathogenesis.
Abstract WP268: Leukemia Inhibitory Factor Upregulates Superoxide Dismutase 3 in Neurons via Activation of Myeloid Zinc Finger-1
Authors: Davis Stephanie M , Collier Lisa A , Fazal Jawad A , Leonardo Christopher C , Ajmo Craig T , Pennypacker Keith R
Published: July 2021

Objective:
To determine whether leukemia inhibitory factor (LIF) upregulates superoxide dismutase 3 (SOD3), a neuroprotective antioxidant enzyme, through the transcription factor myeloid zinc finger-1 (MZF-1).

Hypothesis:
MZF-1 facilitates LIF-mediated neuroprotection by increasing transcription of the SOD3 gene in neurons.

Methods:
After middle cerebral artery occlusion or sham surgery, male Sprague-Dawley rats were injected with PBS or LIF (125 μg/kg) (n=4 per group). Rats were euthanized 72 h after injury and western blotting was used to measure MZF-1 protein expression in brain tissue. For in vitro studies, rat neurons were transfected with scrambled or MZF-1 siRNA (n=3 per group). Neurons were treated with PBS or 200 ng/mL LIF prior to 24 h in vitro ischemia induced by oxygen glucose deprivation. Lactate dehydrogenase (LDH) release was measured to assess neuronal death. MZF-1 levels were quantified in cultured neurons with immunocytochemistry. SOD3 and MZF-1 mRNA levels were measured with real-time PCR.

Results:
LIF (0.938 OD units ± 0.170), but not PBS (0.562 OD units ± 0.223), significantly increased MZF-1 protein expression in ipsilateral tissue 72 h after stroke compared to sham surgery (0.411 OD units ± 0.039, p<0.05). LIF treatment prior to 24 h in vitro ischemia significantly increased the percentage of MZF-1-positive neurons (52.17 % ± 0.93) compared to PBS 44.84 % ± 1.11, p<0.01). PCR results confirmed the increase in MZF-1 mRNA (1.89 fold change ± 0.33) in LIF-treated neurons compared to PBS-treated neurons (1.00 fold change ± 0.23, p<0.05). Moreover, LIF increased SOD3 mRNA after 24 h ischemia (1.35 fold change ± 0.03) compared to PBS (1.00 fold change ± 0.13, p<0.05). LIF decreased LDH release (363,967 ± 68,557 neuronal units) compared to PBS (559,856 ± 60,555 neuronal units, p<0.05) among neurons transfected with scrambled siRNA. However, MZF-1 siRNA attenuated the neuroprotective effect of LIF (690,633 neuronal units ± 19,167; p<0.05).

Conclusions:
MZF-1 plays a fundamental role in a novel neuroprotective pathway by enhancing SOD3 expression and provides insight regarding protection by antioxidant enzymes during stroke.
Abstract WP274: Inhibition of Na+/H+ Exchanger Isoform 1 and/or Voltage Gated Proton Channel Improves Outcomes in an Embolic Stroke Model
Authors: Li Weiguo , Ward Rebecca , Sun Jingping , Guo Xinyue , Ergul Adviye , O'Connor Paul
Published: July 2021

While Na+/H+ exchanger isoform 1 inhibitor (NHEi) has been reported to be neuro- and cardio-protective in experimental stroke and myocardial infarction, respectively, clinical use of NHEi for cardioprotection has stalled due to increased cerebrovascular events. NHEi has been demonstrated to increase Hv1 activity and we recently showed that NHEi activates NADPH oxidase and results in amplified superoxide formation in a voltage gated proton channel Hv1-dependent manner. In the CNS, Hv1 is localized primarily to microglia and deletion of Hv1 is neuroprotective after permanent and transient middle cerebral artery occlusion (MCAO). In the current study, we hypothesized that beneficial effect of NHEi after MCAO will be greater in a rat model lacking Hv1 due to loss of a potentially deleterious increase in Hv1 activation and NADPH oxidase activity. The wild type (WT) and Hv1 knockout (KO) rats (n=4-6) were treated with vehicle or NHEi (KR-32568, 2 mg/kg, i.v.) at 30 min after embolic MCAO. The neurological deficiency, infarct size, HT index, and edema ratio were assessed 3 days after surgery (Table). Compare to WT rats, KO rats had smaller infarct, less edema, and better neurological outcomes as previously found in the suture model. NHEi decreased infarct size and edema in both strains. While there was no significant difference in HT between WT and KO rats, the HT was less in WT rats with NHEi. Functional outcomes were significantly improved with NHEi in WT group, while the KO groups had a trend for a better outcomes with NHEi. These data indicate that NHE inhibition in the acute stroke period is similarly effective in both WT and Hv1 KO animals in providing neurovascular protection. Our data do not support the hypothesis that a deleterious increase in Hv1 dependent NADPH oxidase activity limits the beneficial actions of NHEi in embolic stroke. Further studies are needed to explore the underlying mechanism of the interaction between NHEi and the Hv1 channel in ischemic stroke.
Abstract WP278: Effects of Prasugrel on Cerebral Infarction and Neurological Deficits in a Non-human Primate Model of Thrombotic Stroke
Authors: Tomizawa Atsuyuki , Ohno Kousaku , Jakubowski Joseph A , Mizuno Makoto , Sugidachi Atsuhiro
Published: July 2021

Introduction:
Several clinical trials have demonstrated the benefits of thienopyridine monotherapy in ischemic stroke patients. Non-human primate models of ischemic stroke have been used for various antithrombotic agents; however, to our knowledge, there is no data on the effects of P2Y
12
antagonists in a primate thrombotic middle cerebral artery occlusion (MCAO) model. Accordingly, it remains unclear what level of inhibition of platelet aggregation (IPA) by thienopyridine antiplatelet drugs is required for optimal treatment of ischemic stroke.

Hypothesis:
We assessed the hypothesis that prasugrel, the third-generation thienopyridine antiplatelet drug, would be effective in a non-human primate model of thrombotic stroke.

Methods:
Prasugrel hydrochloride was administered orally once daily for 3 d to cynomolgus monkeys. Ex vivo platelet aggregation induced by 5 μM ADP in platelet-rich plasma was determined before the 1st dose and 4, 5, 8 and 24 h after the final dose (N=4 per group). Thrombotic MCAO was induced photochemically by employing rose bengal 4 h after the final dose (N=8 per group). Cerebral infarct volume and neurological deficit score were determined 24 h after the MCAO.

Results:
Prasugrel showed significant and stable antiplatelet effects. The IPA on Day 3 ranged from 31.4% ± 8.0% to 36.4% ± 5.5% at 0.3 mg/kg/d and from 43.8% ± 6.6% to 49.8% ± 5.6% at 1 mg/kg/d. In the thrombotic MCAO model, prasugrel increased MCA patency in a dose-dependent manner. Prasugrel significantly reduced ischemic infarction to 755.1 ± 293.3 mm
3
(
P
<0.01) at 0.3 mg/kg/d and 333.2 ± 187.7 mm
3
(
P
<0.01) at 1 mg/kg/d compared to control (2641.8 ± 480.5 mm
3
) without increasing hemorrhagic infarction. Prasugrel also significantly reduced neurological deficit scores to 14 ± 4 (
P
<0.05) at 0.3 mg/kg/d and 6 ± 3 (
P
<0.01) at 1 mg/kg/d compared to control (33 ± 3).

Conclusions:
Prasugrel is effective in the primate model of thrombotic stroke. These data suggest that prasugrel monotherapy would be beneficial in thrombotic stroke patients. In addition, this non-human primate model of photochemically induced MCA thrombosis is a useful model for stroke research.
Abstract WP284: Regional Disparities in the Quality of Stroke Care
Authors: Seabury Seth , Bognar Katalin , Xu Yaping , Huber Caroline , Commerford S. R , Tayama Darren
Published: July 2021

Background:
Geographic variation in healthcare quality, including an urban-rural difference, is well recognized. For stroke care, we were interested in the relationship with stroke center certification and access to neurological services.

Hypothesis:
We assessed the hypothesis that the use of thrombolytic therapy (t-PA) is associated with stroke certification level and access to neurological services.

Methods:
Performance measure data in the 2015 Hospital Compare, a CMS quality reporting system, were used to document the gap in care quality among hospitals according to large, medium, small-metro, and non-metro areas and Joint Commission (JC) certification. Regression analysis was used to estimate the association between t-PA use and certification level or access to neurological services.

Results:
On average, non-metro hospitals performed worse than metro hospitals on JC-endorsed stroke quality measures; the biggest disparity was in the use of t-PA for eligible patients arriving within 2 hours (STK-4). Certified stroke centers in every geographic designation provided higher quality of care; however, a large variation was observed among non-certified hospitals (Figure). Regression analysis suggested that improvements in certification or access were associated with 45% and 21% absolute improvements, respectively, in the percent of patients receiving t-PA (Table).

Conclusion:
The large quality gap in stroke care between metro and non-metro areas can, in part, be addressed by approaches to achieve stroke center certification or to adopt decision support systems such as telemedicine.
Abstract WP288: Variations in the Reliability of ICD-9-CM Codes by Hospital Characteristics and Stroke Severity: The Paul Coverdell National Acute Stroke Program
Authors: Chang Tiffany , Lichtman Judith , Goldstein Larry , George Mary
Published: July 2021

Background:
ICD-9-CM codes recorded in administrative databases are often used to identify patients with specific clinical conditions. We determined if there are variations in the accuracy of stroke and transient ischemic attack (TIA) ICD-9-CM codes based on hospital characteristics and stroke severity.

Methods:
We used the records of patients discharged from hospitals in the Paul Coverdell National Acute Stroke Program in 2013. Diagnosis categories included ischemic stroke, TIA, subarachnoid hemorrhage, and intracerebral hemorrhage. We compared the agreement between the principal ICD-9-CM code and attending physician’s clinical diagnosis. The effects of hospital characteristics and stroke severity (National Institutes of Health Stroke Scale score, NIHSS) on percent agreement were assessed.

Results:
Among 67,442 patient records with hospital characteristic data, agreement between ICD-9-CM codes and the clinical diagnosis for ischemic stroke was higher for hospitals with stroke units, stroke teams, larger numbers of beds, and locations in metropolitan areas (P<0.05) (Table). For 55,373 records with a documented NIHSS at admission, agreement was lower for mild ischemic strokes (NIHSS 0-7) compared with more severe strokes (P<0.001); disagreements were commonly due to the patient having a carotid endarterectomy (potentially reflecting continuity of care for a stroke event) or TIA rather than a stroke.

Conclusion:
Systematic variations in the accuracy of ICD-9-CM codes by hospital characteristics and stroke severity may affect case identification in epidemiologic studies and have implications for hospital-level quality metrics.
Abstract WP296: Poststroke Dementia is Associated With Early Institutionalization
Authors: Gerli Sibolt , Curtze Sami , Melkas Susanna , Pohjasvaara Tarja , Kaste Markku , Karhunen Pekka J , Oksala Niku K , Erkinjuntti Timo
Published: July 2021

Objective:
To investigate whether poststroke dementia diagnosed after ischemic stroke is associated with earlier permanent institutionalization.

Methods:
We included 410 consecutive patients aged 55 to 85 years with ischemic stroke admitted to the Helsinki University Central Hospital (The SAM cohort) with a 21-year follow-up. Hospitalization and nursing home admissions were reviewed from national registers. Dementia was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders 3rd edition (DSM-III) criteria. Kaplan-Meier plots log-rank and binary logistic regression (odds ratio, OR) and Cox multivariable proportional hazards model were used to study the association of poststroke dementia status and time of permanent institutionalization. HR and OR with their 95% confidence intervals (CI) are reported.

Results:
Poststroke dementia was associated with more frequent (OR 2.05; CI 1.29-3.24) permanent institutionalization (Mantel-Haenszel), and earlier permanent institutionalization (5.6 versus 13.6 years; log-rank p<0.001). After adjusting for significant covariates from univariable analyses, poststroke dementia was associated with increased hazards ratio of permanent institutionalization during 21 years of follow-up (1.52; CI 1.05-2.19), see Table.

Conclusions:
Poststroke dementia at 3 month after stroke is associated with earlier permanent institutionalization compared with stroke patient without poststroke dementia.
Abstract WP301: Noninvasive Beat-to-Beat Assessment of Blood Pressure Variability, Heart Rate Variability and Baroreflex Sensitivity: Which Parameters Best Predict Clinical Outcome After Acute Ischemic Stroke?
Authors: Xiong Li , Tian Ge , Chen Xiangyan , Leung Howan , Leung Thomas , Soo Yannie , Wong Ka-Sing
Published: July 2021

Background and Objectives:
Blood pressure variability (BPV), heart rate variability (HRV) and baroreflex sensitivity (BRS) as measures of autonomic function might provide prognostic information in ischemic stroke. We aimed to study noninvasive beat-to-beat assessment of BPV, HRV and BRS in the acute phase of ischemic stroke to determine whether any of them predicted clinical outcome.

Methods & Patients:
Consecutive ischemic stroke patients within 7 days of symptom onset were enrolled. The frequency components of BPV and HRV by means of power spectral analysis [very low frequency (VLF; < 0.04 Hz); low frequency (LF; 0.04-0.15 Hz); high frequency (HF; 0.15-0.40 Hz); power spectral density (PSD; <0.40 Hz) and LF/HF ratio] were calculated from 10-minute recordings of beat-to-beat blood pressure and heart rate monitoring. The baroreflex slope and baroreflex effectiveness index (BEI) were determined using the sequence method for BRS. Clinical outcome was assessed at 3 months after stroke onset as good or poor by modified Rankin Scale (mRS) (good outcome, mRS ≤ 2).

Results:
82 patients were recruited (mean age, 64.6 ± 9.9 years; 89.3% males). Univariate analysis showed that there were significant differences in National Institutes of Health Stroke Scale (NIHSS) at recruitment, VLF diastolic BPV, VLF, HF and PSD systolic BPV, and down ramp BEI between the good and poor outcome groups (all P < 0.05). After adjusting for NIHSS, multivariate logistic regression showed that only HF systolic BPV (OR 1.320; 95% CI, 1.050-1.659; P=0.017) and down BEI (OR 0.950; 95% CI, 0.912-0.990; P=0.014) were independently correlated with poor functional outcome.

Conclusions:
Beat-to beat highly variable systolic blood pressure and impaired BRS as evaluated by decreased down BEI are associated with an unfavorable functional outcome after acute ischemic stroke. Important prognostic information can be readily obtained from a short period of noninvasive hemodynamics monitoring in the acute stroke patient.
Abstract WP309: Detection of Depressive Symptoms Among Ischemic Stroke Patients not Screened in the Acute Setting
Authors: Sharrief Anjail , Okpala Munachi , Wadhwania Rozina N , Mughal Mansoor , Vahidy Farhaan , Denny Mary C , Savitz Sean I
Published: July 2021

Introduction:
Depression screening may not be feasible for all stroke patients during their hospitalization, and depression may be missed if screening is not performed in the outpatient setting.

Hypothesis:
We sought to assess the proportion of patients with depression, and describe the severity of depressive symptoms in patients who could not be screened during hospitalization. We hypothesized that depressive symptoms can be missed in those who are not screened.

Methods:
Ischemic strokes (July 2014- July 2015) were identified from the clinic registry. In the clinic, we use Patient Health Questionnaire 9 (PHQ-9) to assess depressive symptoms for all patients. Univariate and multivariable linear regression analyses were used to evaluate associations between PHQ-9 and age, sex, race, baseline National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), and antidepressant use for patients who missed inpatient depression screening.

Results:
Among 159 ischemic stroke patients, 136 completed outpatient PHQ-9 within 90 days from stroke onset. Of these 41 (30%) were missing inpatient PHQ-9. Reasons for missing scores included aphasia or cognitive impairment (20), failed inpatient attempt (16), or unspecified reasons (5). Among the 41 patients, median time to follow-up was 40 days (IQR 33 - 50). Mean (SD) age was 63.7 (13.8) and 51.2% were female. Mean (SD) PHQ-9 score was 8.0 (6.61). The overall proportion of patients having at least mild depression was 60.1% (95 % CI 45.3, 76.5) and PHQ-9 scores were distributed as follows: none to minimal depressive symptoms, 39.0%; mild to moderate, 43.9%, moderately severe to severe, 17.1%. In the regression model, mRS at follow-up (dichotomized < 3 & ≥ 3) was associated with severity of depressive symptoms after adjusting for age, sex, and baseline NIHSS, (coefficient 4.1, 95% CI 1.38, 6.82). Other variables were not associated with severity of depressive symptoms.

Conclusions:
Patients who cannot be screened for depression during hospitalization may have depressive symptoms and should be screened as soon as feasible after discharge. Alternative methods to screen cognitively impaired patients need to be developed.
Abstract WP347: Clopidogrel Plus Aspirin in Patients With Different Types of Single Small Subcortical Infarction_Subgroup Analysis of CHANCE Trial
Authors: Wang Yilong , Yang Xiaomeng , Jing Jing , Zhao Xingquan , Liu Liping , Wang Chunxue , Wang David , Wang Anxin , Meng Xia , Wang Yongjun
Published: July 2021

Objective:
We aim to investigate the effects and safety of clopidogrel plus aspirin in patients with different types of single small subcortical infarction(SSSI) in the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial.

Methods:
In this subgroup analysis, SSSI was defined as single DWI lesion of ≤2.0 cm and SSSI with stenosis of any degree of the parent artery was regarded as a SSSI+PAD. We assessed the interaction of the treatment effects of clopidogrel plus aspirin versus aspirin alone among patients with and without PAD. Efficacy was assessed by intention to treat analysis and safety was assessed in the on-treatment population.

Results:
A total of 338 patients with SSSI were included in the final analysis,105 with SSSI+PAD and 233 SSSI-PAD. In SSSI+PAD patients, 10.9% (5/46) had recurrent stroke in the clopidogrel-aspirin group as compared to 13.6% (8/59) in the aspirin group (adjusted hazard ratio, 0.66; 95% confidence interval, 0.20-2.20; P=0.50). In SSSI-PAD patients, 8.9% (11/124) had recurrent stroke in the clopidogrel-aspirin group as compared 7.3% (8/109) in the aspirin group (adjusted hazard ratio, 1.64; 95% confidence interval, 0.61- 4.38; P=0.32). The number of bleeding events was similar between the clopidogrel-aspirin group and aspirin group regardless of SSSI+PAD or SSSI-PAD.

Conclusions:
Although dual antiplatelet therapy did not significantly reduce the risk of recurrent stroke than aspirin alone in patients with SSSI. It was potentially beneficial to the patients with SSSI+PAD. Dual antiplatelet treatment did not increase the risk of bleeding in patients with any kind of SSSI.
Abstract WP35: Outcomes of Mechanical Embolectomy in Patients Treated Beyond 8 hours From Stroke Onset: a Subanalysis of the North American SOLITAIRE Stent-retriever Acute Stroke Registry
Authors: Abou-Chebl Alex , Castonguay Alicia , Marden Franklin A , Nogueira Raul G , Novakovic Robin , Zaidat Osama O
Published: July 2021

Background and Purpose:
Endovascular therapy (EVT) with stent-retrievers is safe and effective within 6-8hours of acute ischemic stroke onset; however a large proportion of patients present beyond 8hrs. There is a paucity of data on the safety and effectiveness of EVT in this latter population.

Methods:
We reviewed demographic, clinical, procedural and clinical outcomes data from consecutive patients treated with the Solitaire™ FR device in the investigator-initiated NASA Registry. Patients were divided into early (≤8hrs) and late (>8hrs) presenting groups. Primary outcomes (90-day mRS 0-2, mortality, and symptomatic ICH) were compared.

Results:
Three hundred and fifty-four patients from 24 centers were enrolled in NASA. Sixty-three (18%) patients presented >8hrs from onset and were treated. Baseline demographic and procedural factors were comparable between the early and late groups, except for time-to-treatment (271.9±97.3min vs. 754±269.3min, p<0.0001), IV tPA utilization (52.6% vs. 11.1%, <0.0001), baseline diastolic BP (77.9±16.8mmHg vs. 83.8±20.2mmHg, p=0.03), and frequency of vertebrobasilar occlusions (7.1% vs. 19.1%, p=0.0034). Procedural aspects were similar except for time to recanalization (early 73.8±84.5min vs. late 53.6±32min, p=0.0074). Recanalization success (TICI≥2b) was comparable (early 74.4% vs. late 76.2%, p=0.76). The primary outcome measures including symptomatic ICH (11.6% vs. 4.8%, p=0.11), mortality (29.9% vs. 29.3%, p=0.93), and mRS 0-2 (44.4% vs. 34.5%, p=0.17) were similar between the early and late groups, respectively. When only anterior circulation strokes were included (N=301), the data did not change significantly and the primary endpoints of symptomatic ICH (12.1% vs. 5.9%, p=0.2), mortality (27.9% vs. 27.7%, p=0.97) and mRS 0-2 (44.6% vs. 36.2%, p=0.29) remained comparable between the early and late groups, respectively.

Conclusions:
The NASA Registry has demonstrated that clinical outcomes of patients treated >8hrs from stroke onset are favorable and comparable to the outcomes of patients treated earlier. Later treatment in these selected patients was not associated with an increased risk of symptomatic ICH. Future trials should prospectively evaluate the benefit of EVT beyond 8hrs.