bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract WMP35: A Novel Microporous Covered Stent NCVC-CS1 for the Treatment of Intracranial Aneurysms: Its Functional Features and Preliminary Results of Clinical Trial
Authors: Satow Tetsu , Sakai Nobuyuki , Yamamoto Haruko , Oishi Hidenori , Ishii Akira , Nakayama Yasuhide , Takahashi Jun C
Published: January 2019

Background and Purpose:
The treatment for large and giant intracranial aneurysms remains unsatisfactory even after the introduction of flow diverters, especially in those located in posterior circulation. This study was aimed to assess the novel covered stent graft named NCVC-CS1 for the treatment of such complex aneurysms.

Materials and Methods:
NCVC-CS1 is a balloon-expandable stent covered with a thin, microporous segmented polyurethane membrane. After the confirmation of its function on navigability, aneurysm occlusion, and patency of branching vessels using animal models, an investor-initiated, first-in human clinical trial to evaluate the safety and efficacy of NCVC-CS1 was conducted. The inclusion criteria for the targeted aneurysm were unruptured, wide-necked aneurysms more than 7 mm, located in petrous/cavernous portion of ICA, intradural VA, or BA proximal to the orifice of superior cerebellar artery. The primary effectiveness endpoint was angiographic evaluation that demonstrated complete aneurysm occlusion and patency of target vessel (less than 50% stenosis) at 180 days. The primary safety endpoint was occurrence of any stroke or death related to the procedure.

Results:
A total of 10 patients were enrolled in the trial. Among them, nine aneurysms were large (more than 10mm) including one giant aneurysm (more than 25mm). Mean aneurysm size was 14.3mm. Five aneurysms (50%) were located in VA. NCVC-CS1 placement was technically successful in all cases. No coils were used. The instant cessation of inflow to the targeted aneurysm at the time of the procedure (so-called eclipse sign) was observed in nine cases (90%). Among the nine cases whose follow-up data at 180 days were obtained, five (55%) met the study’s primary effectiveness endpoint whereas the other four showed near complete occlusion without stenosis of the parent artery. As to the safety endpoint, one patient experienced a non-disabling infarction. No subsequent rupture of the aneurysm was observed during the follow-up period.

Conclusion:
NCVC-CS1 showed the safety and efficacy on its first-in-human clinical trial. This device can offer another therapeutic choice for wide-necked and large intracranial aneurysms.
Abstract WMP45: Gene Expression Levels in Acute Large Vessel Occlusion Stroke in Humans
Authors: Martha Sarah R , Collier Lisa A , Davis Stephanie M , Alhajeri Abdulnasser , Grupke Stephen , Fraser Justin F , Pennypacker Keith R
Published: January 2019

Background and Purpose:
The Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) tissue bank collects blood proximal and distal to the intracranial thrombus during the process of mechanical thrombectomy in human stroke patients. These samples provide a unique resource in evaluating acute gene expression changes at the time of ischemic stroke. The purpose of this study was to evaluate gene expression changes occurring within the thrombus and across the occlusion in the intravascular space in acute ischemic stroke patients.

Methods:
We developed the BACTRAC protocol: an IRB-approved tissue banking approach for ELVO (clinicaltrials.gov NCT03153683). We evaluated relative concentrations of gene expression in 84 inflammatory molecules in thrombi removed from adults who received thrombectomy for ischemic stroke, in static blood distal to thrombus, and in peripheral circulation.

Results:
We analyzed the first 46 subjects (age = 67 ± 14.23, 20 males) in the BACTRAC registry. Results from qPCR gene expression analyses demonstrate that 21 genes (CCL1, CCL11, CCL13, CCL17, CCL26, CCL8, CSF3, CX3CL1, CXCL1, CXCL9, IFNA2, IL13, IL17C, IL17F, IL1A, IL27, IL3, IL33, LTA, TNFSF11, and TNFSF13) had at least 25 mean fold change in the distal blood compared to the peripheral blood. Fourteen genes (AIMP1, CCL11, CCL13, CCL15, CCL16, CCL23, CCR2, CCR4, CCR8, CD40LG, CXCL10, IL10RA, IL15, and TNFSF13B) had at least 10 mean fold change in the thrombus compared to the peripheral blood. Overall, these genes are associated with chemo-attraction and cell proliferation of monocytes, neutrophils, and T cells.

Conclusions:
These findings provide a novel insight into the initial pathology of large vessel stroke in humans, particularly in regard to identifying acute gene expression changes that occur during stroke.
Abstract WMP52: Systolic Blood Pressure Variability and Incident Ischemic Stroke or All-Cause Mortality: A Secondary Analysis of the Atherosclerosis Risk in Communities Study
Authors: de Havenon Adam , Majersik Jennifer , Wong Ka-Ho , McNally Scott , Tirschwell David , Rost Natalia
Published: January 2019

Introduction:
Increased outpatient “visit-to-visit” blood pressure variability (BPV) has been linked with a higher risk of ischemic stroke, but prior studies have mostly used data from clinical trials with relatively short periods of expsoure and outcome ascertainment.

Hypothesis:
Higher BPV is associated with incident ischemic stroke and mortality in the Atherosclerosis Risk in Communities (ARIC) study.

Methods:
The study exposure was BPV during visits 1-4 (1987-1999). Patients were included if they attended all 4 visits, for a total of 12 blood pressure readings. The outcome ascertainment period was from 2000-2011. The primary outcome was stroke and the secondary outcome was all-cause mortality. Patients were excluded if they had either outcome prior to the ascertainment period.

Results:
The final cohort included 10,155 patients of whom 434 had ischemic stroke and 2,138 died. Five different statistical measures of BPV were increased in patients with stroke (Table 1) and mortality (Table 2). This association remained significant in multivariable Cox models comparing the risk of the highest to lowest tercile of BPV (Table 3).

Conclusion:
Our data reinforce prior research showing that higher “visit-to-visit” BPV is associated with future stroke or death. Additional research is needed to understand the causal mechanism and methods to reduce BPV.
Abstract WMP54: Updated Population Trends in Substance Abuse Preceding Stroke in Young Adults: 1993/1994 to 2015
Authors: De Los Rios La Rosa Felipe , Kleindorfer Dawn , Khoury Jane , Broderick Joseph P , Alwell kathleen , Moomaw Charles J , Woo Daniel , Flaherty Matthew , Khatri Pooja , Adeoye Opeolu , Mackey Jason , Martini Sharyl , Walsh Kyle , Star Michael , Demel Stacie , Jasne Adam , Slavin Sabreena , Ferioli Simona , Eilerman Jane , Kissela Brett
Published: January 2019

Objective:
To update trends on documented substance abuse among young adults (18-54 years old) with stroke within the Greater Cincinnati/Northern Kentucky Stroke Study population, to include preliminary results from 2015.

Background:
Substance abuse is associated with stroke. In our population, we previously reported increases in overall substance abuse, smoking history, and use of alcohol or drugs <24 hours prior to stroke onset. We also found increased illicit drug use in the 35 to 54 age group from 1993/94 through 2010. We now report trends after adding 2015 preliminary results.

>Design/Methods:
Using ICD-9 discharge codes 430-436, potential acute stroke events are identified among 18- to 55-year-old residents of the 5 county study region. Five one-year study periods are included (7/93-6/94, 1999, 2005, 2010, 2015). Study nurses abstract all events which then undergo physician review. We searched for trends in smoking history, illicit drug use, heavy alcohol consumption, overall substance abuse (current smoking, alcohol, and illicit drug), and urine/blood test positive for alcohol or illicit drugs at presentation.

Results:
There were 2220 stroke events (75 % ischemic). Sex and age distribution remained stable; however, percent black increased from 35% to 46% between 1993/94 and 2015, as did the proportion of ischemic strokes (74% to 77%). Current smoking and alcohol use remained stable while illicit drug use increased significantly overall and within the age subgroups of 18-34 years and 35-54 years (see table).

Conclusions:
Illicit drug use continues to increase among young adults with stroke. Even though the possibility of testing bias needs to be explored further, our reported results are likely an under estimation of true rates as there are no readily available tests for new designer drugs which have become more available since the early 2000’s. Future analysis will also focus on the relationship between our findings and the U.S. opioid epidemic.
Abstract WMP56: Risk of Atrial Fibrillation in Black versus White Medicare Beneficiaries With Implanted Cardiac Devices
Authors: Chen Monica L , Parikh Neal S , Merkler Alexander E , Kleindorfer Dawn O , Bhave Prashant D , Levitan Emily B , Soliman Elsayed Z , Kamel Hooman
Published: January 2019

Introduction:
Black individuals in the U.S. have a higher risk of ischemic stroke than whites but a lower risk of clinically apparent atrial fibrillation (AF), a strong stroke risk factor. It is unclear whether blacks truly have less AF or simply more undiagnosed AF.

Methods:
We conducted a retrospective cohort study using inpatient and outpatient claims from 2008-2015 in a nationally representative 5% sample of Medicare beneficiaries. We included patients ≥66 years old with black or white race and at least one documented
Current Procedural Terminology
code for interrogation of an implantable pacemaker, cardioverter-defibrillator, or loop recorder. The primary outcome was a composite of AF or atrial flutter (AFL). Secondary outcomes were AF, AFL, and ischemic stroke. All variables were ascertained using validated
ICD-9-CM
codes. Those diagnosed with AF, AFL, or stroke before their first recorded device interrogation were excluded. Patients were censored at their last recorded device interrogation, end of Medicare coverage, or death. Kaplan-Meier statistics and Cox proportional hazards models were used to examine the association between black race and outcomes while adjusting for age, sex, and vascular risk factors.

Results:
Among 45,615 eligible beneficiaries, the 3,192 black patients (7.0%) had more vascular risk factors than white patients. The annual incidence of AF/AFL was 12.2 (95% confidence interval [CI], 11.5-13.1) per 100 person-years among blacks and 17.8 (95% CI, 17.6-18.1) per 100 person-years among whites. After adjustment for confounders, black beneficiaries faced a lower hazard of AF/AFL than white beneficiaries (hazard ratio [HR], 0.74; 95% CI, 0.70-0.79). This reflected a lower risk of AF (HR, 0.73; 95% CI, 0.68-0.78), not AFL (HR, 1.10; 95% CI, 0.89-1.36). Despite the lower risk of AF, black patients faced a higher hazard of ischemic stroke (HR, 1.36; 95% CI, 1.22-1.53).

Conclusions and Relevance:
Among Medicare beneficiaries with implanted cardiac devices capable of detecting atrial rhythm, black patients had a lower incidence of AF despite a higher burden of vascular risk factors and a higher risk of stroke.
Abstract WMP63: New Onset Nonvalvular Paroxysmal Atrial Fibrillation After Acute Ischemic Stroke Without Atrial Cardiopathy- to or Not to Anticoagulant
Authors: Min Jiangyong , Farooq Muhammand U , Khan Muhib , Abdelhak Tamer M
Published: January 2019

Introduction:
Cardiac outcome in acute ischemic stroke (AIS) remains less well understood as do the neuroanatomic correlates of AIS associated myocardial injury. For patients with new onset paroxysmal atrial fibrillation (Afib), anticoagulant therapy is determined based on the CHA
2
DS
2
-VASc score. However, newly diagnosed short-run Afib after AIS could be neurogenic, without an increase in the risk of AIS recurrence. The present study of 68 patients with acute insular infarcts describes cardiac outcomes including newly diagnosed Afib and clinical significance.

Methods and Results:
Serial measurements of cardiac troponin I (cTnI), EKG, echocardiography (Echo) (some had transesophageal Echo) were conducted in all patients with MRI-confirmed AIS involving insular cortex. The severity of insular damage was measured with diffusion-weighted imaging. Thirty-one patients (46%) had right MCA infarcts involving insular cortex, and 37 patients had left MCA (54%) stroke with insular involvement. Patients with left MCA infarcts had higher cTnI but did not reach statistical significance. By linear regression analysis in either right or left insular AIS, there was a significant correlation between elevated cTnI and the severity of insular injury. Six patients (3 right and 3 left MCA AISs) were found to have transient cardiac dysfunction. Nine out of 68 AIS patients detected new onset transient Afib in the absence of prior heart disease, cardiac arrhythmia, or evidence of atrial myopathy. Five of them are not on anticoagulant therapy due to varied reasons. None of them experienced recurrent major cardiac events, recurrent Afib, or ischemic stroke during the 12-month follow up.

Conclusions:
Our study shows that either left or right MCA AIS involving the insular cortex may cause cardiac injury including transient Afib. We further demonstrated a correlation between the severity of insular damage and cardiac sequelae. However, there is no increased risk of recurrent ischemic stroke at 1 year in 5 patients with newly diagnosed Afib not on anticoagulant therapy. A long-term study with large number of AIS patients with newly diagnosed Afib is needed to determine if lifelong anticoagulation is required in this particular group of patients with presumed neurogenic Afib.
Abstract WMP73: Discerning How Vascular Inflammation Modulates Neuroinflammation Using Novel Vascular Brain Organ-On-A-Chip: Proof-of-Concept Study
Authors: Veldhuizen Jamieson , Truran Seth , Madine Jillian , Davies Hannah , Karamanova Nina , Nikkhah Mehdi , Migrino Raymond Q
Published: January 2019

Neuroinflammation is important in the pathophysiology of neurodegenerative diseases such as Alzheimer’s disease or vascular cognitive impairment but the role of cerebrovascular inflammation in initiating or modulating neuroinflammation is poorly defined. We aim to determine if endothelial cell inflammation, triggered by medin (a common amyloid protein that accumulates in aging vessels and induces NFκB-mediated EC inflammation) or palmitic acid (PA, the most common saturated fatty acid in Western diet) enhances astrocyte inflammatory response using a novel 3D microscale microfluidic vascular brain-organ-on-a-chip (VBOC).

Methods:
Human astrocytes on 6-well plates were exposed (20 hrs) to vehicle, medin (5 μM) or media from human umbilical vein endothelial cell (ECs) that were treated with vehicle or medin (20 hrs; n=4 each), and proinflammatory cytokine IL-8 protein was measured by ELISA. VBOCs (Fig. B) engineered to mimic physiologic diffusion conditions were fabricated and the central region (green, 500 μm width) was seeded with astrocytes and 2 outer regions (red) seeded either with (+ECs) or without ECs (No ECs). VBOCs were treated (20 hours, n=3 each) with vehicle, medin or PA (150 μM) and IL-8 protein was measured from astrocyte media.

Results:
See Fig. Astrocytes showed higher IL-8 when exposed to media from ECs treated with medin when compared to direct medin exposure (Fig. A). Astrocyte activation (GFAP staining) was more prominent in astrocytes exposed to medin in presence of ECs and IL-8 was increased only in astrocytes exposed to medin in presence of ECs (Fig. C-D).

Conclusions:
Medin-induced astrocyte inflammatory activation is enhanced by presence or action of endothelial cells. This initial prototype VBOC is a useful model to study the paracrine cross-talk between vascular and neuroinflammation which could provide mechanistic insights on the interrelationships among vascular aging, cerebrovascular and neurodegenerative diseases.
Abstract WMP77: Ischemic Preconditioning Improves Long-Term Outcomes and Preserves Blood-Brain Barrier After Ischemic Stroke via Oxidative Signaling and Nrf2 Activation
Authors: Yang Tuo , Sun Yang , Mao Leilei , Zhang Meijuan , Li Qianqian , Zhang Lili , Shi Yejie , Leak Rehana K , Chen Jun , Zhang Feng
Published: January 2019

Introduction:
Ischemic preconditioning (IPC) protects the brain against subsequent ischemic injuries. However, its protective mechanisms and long-term impact on stroke outcomes are unknown. IPC requires mild oxidative stress and may activate nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Endogenous lipid electrophiles serve as robust Nrf2 activators. This study tests long-term effects of IPC and explores the mechanisms of IPC-mediated ischemic tolerance, focusing on lipid electrophiles and Nrf2 pathway.

Methods:
Wildtype (WT) and Nrf2 knockout (KO) mice were subjected to 60-min middle cerebral artery occlusion (MCAO) 3 d after IPC (12-min MCAO). Tissue loss, blood-brain barrier (BBB) damage, and neurobehavioral outcomes were assessed up to 35 d post stroke. The molecular mechanisms were explored by primary endothelial cell (EC) cultures with plasmid transfection and molecular biological approaches.

Results:
IPC reduced sensorimotor and cognitive deficits and tissue loss up to 35 d post stroke in WT mice, while Nrf2 KO abolished IPC-mediated protection. IPC led to mild oxidative stress, lipid electrophile generation and Nrf2 pathway activation. Prominent Nrf2 activation was seen in ECs and a selected group of astrocytes in tight association with microvessels, both of which are BBB components. As expected, IPC reduced BBB leakage 48 h post stroke and increased expressions of junctional proteins Claudin-5 and VE-Cadherin. Moreover, Nrf2 directly regulated Claudin-5 and VE-Cadherin promoter activities. Finally, a novel mechanism for electrophiles to activate Nrf2 was identified-through direct inhibition of glycogen synthase kinase 3β (GSK3β) activity via GSK3β-C199 residue.

Conclusions:
IPC preserves the BBB and provides long-term neuroprotection against stroke. Mechanistically, mild oxidative stress in IPC generates a pool of electrophiles, which then activates Nrf2 pathway through direct inhibition GSK3β-dependent Nrf2 degradation.
Abstract WMP78: Hypertensive Animals Develop Increased Post-Stroke Cognitive Impairment Associated With Bilateral Enlargement of Brain Ventricles
Authors: Sayed Mohammed A , Eldahshan Wael , Ahmed Heba A , Ergul Adviye , Fagan Susan C
Published: January 2019

Introduction:
Cognitive deficits are a common occurrence in both patients and experimental models of stroke. However, there is still a gap in our understanding of the time course and mechanisms involved in the progression of cognitive dysfunction after stroke in part due to the insufficient integration of risk factors for vascular cognitive impairment such as hypertension.

Methods:
50 male rats (26 Wistar and 24 SHR), 14 weeks of age, were subjected to 1 h middle cerebral artery occlusion (MCAO) using a silicone-coated monofilament or sham surgery. Behavioral testing (Bederson, Open Field, Novel Object Recognition, Y-maze, Passive Avoidance and Morris Water Maze) was done (blinded) to examine the progression and resolution of motor and cognitive deficits, weekly for the first 6 weeks post stroke and again at 12 weeks. A brain MRI was done at week 12, animals were sacrificed and brains collected for Western blotting and immunologic staining.

Results:
Wistar animals showed a high rate of spontaneous recovery 24h after stroke. Both Wistar and SHR animals demonstrated total motor recovery by 2 weeks post stroke. Both groups showed evidence of cognitive dysfunction starting from the 4
th
week after stroke. Stroke, especially in the SHR animals, caused a bilateral enlargement of brain ventricles (by MRI) at week 12 suggesting ongoing tissue loss.

Conclusions:
Normotensive animals show more resilience to the initial insult and a higher rate of 24hr recovery. However, both Wistar and SHR animals show similar patterns in the development and resolution of motor and cognitive impairment. Hypertensive animals showed evidence of an ongoing extensive brain tissue loss up to 3 months after stroke.
Abstract WMP89: Examining the Constructs of the Patient Health Questionnaire (PHQ-8) in the Stroke Population
Authors: Dong Liming , Skolarus Lesli , Morgenstern Lewis , Lisabeth Lynda
Published: January 2019

Introduction:
Most existing screening tools used for post-stroke depression were not originally developed for stroke patients, but the same criteria for identifying depression are usually applied. For instance, the common use of the total score of the Patient Health Questionnaire (PHQ) assumes a unidimentional construct of depression, which may result in distorted performance in the presence of the complexity of stroke. This study aims to test a bifactor measurement model (a depression factor and a stroke-specific factor) using the PHQ-8 in a population-based sample of stroke patients.

Methods:
The study sample consisted of 613 first-ever stroke patients from the Brain Attack Surveillance in Corpus Christi project (2011-2015). Depressive symptoms at 90 days after stroke were assessed by the PHQ-8. A bifactor measurement model was proposed based on existing knowledge of stroke symptoms, and investigation of depressive symptoms in the study sample. The model included a general depression factor that influences all eight symptoms, and a stroke-specific factor that influences symptoms that frequently overlap between depression and stroke (Figure). The model fit was evaluated using confirmatory factor analysis, and compared with the unidimensional model.

Results:
The sample was equally distributed by sex, with a mean age of 65.7 (SD=11.0). Fifty-seven percent were Mexican Americans and 38.3% were non-Hispanic Whites. The bifactor model showed statistically significant better fit than the unidimensional model (P<0.001).

Conclusion:
Future research should explore whether a bifactor measurement model for the PHQ-8, which may result in a different scoring and classification scheme, improves the accuracy of depression screening among stroke survivors.
Abstract WMP91: Worse Outcomes After Ischemic Stroke for Dual-Eligible Medicare-Medicaid Beneficiaries
Authors: Leifheit Erica C , Wang Yun , Goldstein Larry B , Lichtman Judith H
Published: January 2019

Background:
Medicaid serves as a safety net for low-income Medicare beneficiaries with limited assets. Over 6.7 million Americans aged ≥65y rely on a combination of Medicare and Medicaid to obtain critical medical services, yet little is known about geographic patterns of dual-eligible status and whether dual eligibles have worse post-ischemic stroke outcomes than those with Medicare alone.

Methods:
We identified fee-for-service Medicare beneficiaries aged ≥65y with a primary discharge diagnosis of ischemic stroke in 2014. Those with ≥1m of Medicaid coverage were considered dual eligible. We fit spatial mixed models with county-specific random intercepts and adjustment for demographics to calculate and map the risk-standardized percentage of beneficiaries with dual eligibility and stroke hospitalization rates. Mixed models and Cox regression were used to evaluate the relationship between dual-eligible status and outcomes up to 1y, adjusting for demographic and clinical factors.

Results:
At the national level, 12.5% of beneficiaries were dual eligible. The highest rates of dual eligibility were in Maine, Alaska, and the southern half of the US (Figure), whereas the highest rates of stroke hospitalization were concentrated in the central divisions of the South and parts of the Midwest (Pearson’s r=0.469, p<0.001). Among those hospitalized for stroke, 17.5% were dual eligible (n=44,476 dual eligible: mean age 78.3y, 64% female, 36% nonwhite; n=219,426 Medicare only: mean age 78.9y, 51% female, 12% nonwhite). Dual eligibles had greater risk of readmission within 30d and were more likely to die within 6m and 1y when compared with Medicare-only beneficiaries; there was no difference for in-hospital or 30d mortality.

Conclusions:
Dual-eligible stroke patients had higher short-term readmissions and long-term mortality than other patients, even after comorbidity adjustment. A better understanding of the factors contributing to these poorer outcomes is needed.
Abstract WP102: Association of Elevated Blood Pressure Levels With Outcomes in Acute Ischemic Stroke Patients Treated With Intravenous Thrombolysis: A Systematic Review and Meta-Analysis
Authors: Malhotra Konark , Ahmed Niaz , Filippatou Angeliki , Katsanos Aristeidis H , Goyal Nitin , Tsioufis Konstantinos , Manios Efstathios , Pikilidou Maria , Schellinger Peter D , Alexandrov Anne W , Alexandrov Andrei V , Tsivgoulis Georgios
Published: January 2019

Introduction:
Although arbitrary blood pressure (BP) thresholds exist for acute ischemic stroke (AIS) patients eligible for intravenous thrombolysis (IVT), current international recommendations lack clarity on the impact of mean pre- and post-IVT BP levels on clinical outcomes.

Methods:
We identified eligible studies involving IVT-treated AIS patients that reported the association of mean systolic (SBP) or diastolic BP (DBP) levels before and after IVT with the following outcomes: three-month favorable functional outcome (FFO; mRS-scores of 0-1), three-month functional independence (FI; mRS-scores of 0-2)], three-month mortality and symptomatic intracranial hemorrhage (sICH). Unadjusted analyses of standardized mean differences (SMD) for individual outcomes and adjusted analyses of studies reporting odds ratios (ORadj) per 10mmHg BP increment were performed using the random-effects models.

Results:
We identified 26 studies comprising 56,513 patients. Higher pre- (SMD: 0.24; 95%CI: 0.04 to 0.43; p=0.02) and post-treatment (SMD: 0.50; 95%CI: 0.14 to 0.86; p=0.006) SBP levels were observed in patients with sICH. Patients with 3-month FI had lower pre- (SMD: -0.18; 95%CI: -0.34 to -0.01; p=0.04) and post-treatment (SMD: -0.19; 95%CI: -0.23 to -0.15; p<0.001) SBP. In adjusted analyses, elevated pre- (ORadj: 1.08; 95%CI: 1.01 to 1.16) and post-treatment (ORadj: 1.13; 95%CI: 1.01 to 1.25) SBP levels were associated with increased likelihood of sICH. Increasing pre- (ORadj: 0.91; 95%CI: 0.84 to 0.98) and post-treatment (ORadj: 0.70; 95%CI: 0.57 to 0.87) SBP values were also related to lower odds of 3-month FI. No association was noted between either mean pre-treatment or post-treatment SBP levels with three-month mortality. Likewise, no associations were observed with either mean pre-treatment or post-treatment DBP levels and three-month FFO, three-month FI, sICH, or three-month mortality.

Conclusions:
We found that elevated BP levels adversely impact AIS outcomes in patients receiving IVT. Future randomized-controlled clinical trials will provide definitive data regarding the potential association of BP control with improved outcomes of AIS patients treated with IVT.
Abstract WP108: What is Equipoise? Stroke Researchers and IRB Chairs Respond
Authors: Dewar Brian , Chevrier Stephanie , Fedyk Mark , Kitto Simon , Rodriguez Rosendo , Shamy Michel C
Published: January 2019

Background:
The concept of “equipoise” is often cited as a prerequisite to the conduct of ethical randomized clinical trials (RCTs). However, significant difficulties persist in determining when it exists around a specific clinical question. This issue has arisen around recent stroke RCTs such as ESCAPE and SWIFT DIRECT. We sought to capture how stroke research principal investigators (PIs) and institutional review board (IRB) chairs understand the concept of equipoise.

Methods:
We invited stroke PIs and IRB chairs to complete a telephone interview consisting of 9 semi-structured questions surrounding equipoise and the ethics of RCTs. Interviewees provided written informed consent and results remained anonymous. The study was approved by our local IRB. Interviews were recorded and transcribed. Each interview was then analyzed for relevance to the concept of equipoise, with relevant sections coded and organized into themes.

Results:
We invited 59 PIs and 84 IRB chairs, with 13 PIs and 15 IRB chairs completing the standardized interview. Respondents defined equipoise in 5 different ways, with the most common definition being uncertainty based on any of individual opinion, group opinion, evidence, lack of evidence, regional variation, or trial design. PIs sought to determine equipoise through appeals to the literature, preliminary clinical data, surveys of expert opinion, and known disagreement. IRB chairs were more dependent upon expert opinion, including that of trial PIs themselves, and were more concerned with patient protections and specifics of study design. All (100%) PIs and 77% of IRB chairs felt that the concept was helpful, though 80% of both groups also found it to be problematic.

Conclusion:
Stroke PIs and IRB chairs differ in their understanding of how equipoise is defined and operationalized, which may directly impact the design and approval of current and future stroke trials.
Abstract WP111: Who Needs Neuroprotection With Endovascular Stroke Therapy? Findings From the Trevo Retriever Registry
Authors: Liebeskind David S , Zhang Yanchang , Veznedaroglu Erol , English Joey , Baxter Blaise W , Budzik Ronald F , Bartolini Bruno M , Krajina Antonin , Malek Ali , Sarraj Amrou , Nogueira Raul G , Gupta Rishi ,   for the Trevo Retriever Registry Investigators
Published: January 2019

Background:
Combined neuroprotection with endovascular therapy may improve clinical outcomes of only a subset of individuals treated for acute ischemic stroke. The risk/benefit profile of adjunctive treatment may not warrant neuroprotection with successful reperfusion, yet many other individuals have poor outcomes despite revascularization. We hypothesized that optimal candidates for adjunctive neuroprotection may be defined by analyses of subjects with poor clinical outcome despite successful reperfusion in the Trevo Retriever Registry.

Methods:
The Trevo Retriever Registry dataset was analyzed to define the subset of cases with poor clinical outcome (day 90 mRS 4-6) after successful reperfusion (eTICI 2b50, 2b67, 2c, 3). Multivariate analyses were used to identify predictors of poor outcome using these distinct definitions of successful reperfusion. The influence of covariates, including TLSW, baseline clinical and imaging variables (e.g. ASPECTS, ASITN collateral grade), on defining such optimal neuroprotective candidates was delineated.

Results:
Successful reperfusion adjudicated by core lab, defined as eTICI ≥ 2b50 included 1,162 subjects, with eTICI ≥ 2b67 in 920, eTICI ≥ 2c in 652 and eTICI 3 in 209. Poor outcome (day 90 mRS 4-6) occurred in 316/1162 (27%) with eTICI ≥ 2b50, 243/920 (26%) with eTICI ≥ 2b67, 172/652 (26%) with eTICI ≥ 2c and 61/209 (29%) with eTICI 3. Across all subsets, multivariate analyses to predict poor outcome after successful reperfusion identified increased age (per year, OR 1.04-1.05, all p=<0.02) as a factor, adjusting for withdrawal of care. Expectedly, greater baseline NIHSS severity predicted greater day 90 disability (OR 1.07-1.08, all p<0.001). TLSW was a predictor only with eTICI ≥ 2b50 (per hour, OR 1.02, p=0.039). History of diabetes was a factor only with eTICI ≥ 2b50 and eTICI ≥ 2b67 (OR 2.05-2.19, p<0.001). Worse collateral grade (ASITN 0-1) was the most potent predictor (OR 2.27-2.71 versus ASITN 2, p=0.027-0.052; OR 3.85-4.35 versus ASITN 3-4, all p=0.003).

Conclusions:
Neuroprotection combined with endovascular therapy may optimally target stroke patients with worse collaterals, diabetes or increased age. Trial design for neuroprotection with revascularization in AIS should leverage these data.
Abstract WP121: Patient- and Aneurysm-specific Predictors of Intracranial Aneurysm Growth in a Longitudinally-followed Population
Authors: Chien Aichi , Callender Rashida , Salamon Noriko , Vinuela Fernando , Ye Yuanqing , Hildebrandt Michelle
Published: January 2019

Introduction:
Intracranial aneurysms (IA) which occur in adults are assumed to undergo growth at some point during their natural history. However, the factors which may contribute to IA growth in certain individuals are largely unresolved, with significant variation between previous studies. In this study we examine 520 IA which were longitudinally followed by 3D CT images. We examined 21 patient- and aneurysm-specific factors (including patient medical history, aneurysm size, location and multiply) with potential relevance to IA growth.

Hypothesis:
Patient- and aneurysm-specific characteristics may determine whether an IA is likely to grow.

Methods:
IA were diagnosed between 2005-2015 and were longitudinally followed with medical imaging (CTA). Univariate logistic regression with calculation of odds ratios (OR) and 95% confidence intervals (95% CI) were determined using univariate logistic regression with a growth threshold defined as an IA size increase greater than 0.6 mm.

Results:
Every 1 mm increase in initial IA size was associated with a significant 1.09-fold increase in risk of growth (95% CI: 1.04-1.15; P=0.001). Compared to patients with single IA, in patients with multiple IA, IA were 2.43-fold more likely to grow (95% CI: 1.36-4.35; P=0.003). A diagnosis of hypertension was found to associate with a borderline significant 1.76-fold increased risk of IA growth compared to patients who did not have hypertension (95% CI: 0.93-3.32; P=0.082).

Conclusions:
Previous meta-analyses have found predictors of IA growth to be extremely heterogeneous, exacerbated by the relatively small sample size of many of the included studies. In this context, our finding of IA size to be a significant predictor of growth and hypertension to be borderline significant in a relatively large set of cases contributes valuable additional data to understanding IA growth.
Abstract WP129: Development of Cerebral Aneurysm Clips to Minimize Susceptibility Artifact by Magnetic Resonance Image
Authors: Son Young-Je , Kim Jeong Eun , Cho Won Sang , Kim Kang Min , Chung Young Seob
Published: January 2019

Objective:
Surgical clipping is a major treatment modality in treating cerebral aneurysms. However, in magnetic resonance (MR) imaging, susceptibility artifact due to metal clips impedes postoperative assessments of clipped aneurysms, parent arteries, and adjacent parenchyma. Our goal was to develop an MR-compatible aneurysm clip.

Methods:
To reconcile mechanical/biologic properties with MR demands, we fabricated a prototypic clip (ZC: straight, 9-mm long), made of zirconia (body) and polyurethane (spring). Mechanical properties, closing forces, open-blade width, and artifact volumes (in vitro and in vivo) by 3T MR imaging of ZC and currently available metal clips (Yasargil [YC: curved, 8.3-mm long] and Sugita [SC: straight, 10-mm long]) were compared, using a canine venous pouch aneurysm model for in vivo study.

Results:
Respective closing force (N) values, measured at 1-mm and 8-mm distances from blade tip, were 2.09 and 3.77 in YC, 1.85 and 3.04 in SC, and 2.05 and 4.60 in ZC. Maximum open-blade widths (mm) were 6.8, 9.0, and 3.0 in YC, SC, and ZC, respectively. In vitro artifact volumes of YC and ZC were 26.0- and 1.9-fold greater than corresponding actual volumes. In vivo artifact volumes of YC, SC, and ZC were 21.4-, 29.4-, and 2.6-fold greater than actual volumes.

Conclusion:
Compared with two clips in current use, our prototypic clip showed the least susceptibility artifact, with satisfactory closing forces. However, its narrow open-blade width was a weak point. Further experimentation is needed for design refinements and durability testing before human application is feasible.
Abstract WP131: Epigallocatechin-3-gallate and cAMP Desensitize Neuronal Cells to Nogo-A by Inducing Endocytosis of Nogo-A Receptor NgR1
Authors: Gopalakrishna Rayudu , Mades Aubree , Lin Charlotte , Nguyen Julie , Yang Seolyn , Mack William J
Published: January 2019

Several axonal growth inhibitors, such as Nogo-A, block functional recovery after neuronal injuries such as stroke. Nogo-A binds to the receptor NgR1, which also serves as a common receptor for a variety of axonal growth inhibitors such as myelin-associated glycoprotein, oligodendrocyte myelin glycoprotein, and chondroitin sulfate proteoglycans. Currently various pharmacological agents are evaluated to block NgR1 as well as its downstream signaling. Some safe and inexpensive natural products that cross the blood-brain barrier such as daidzein and green tea polyphenols are well suited for axonal regeneration and functional recovery after stroke. Furthermore, understanding the mechanisms by which these natural products act will help development of drugs with greater efficacy. In our current study, we have found that epigallocatechin-3-gallate, a green tea polyphenol induced endocytosis of NgR1 in neuronal-like cells and primary cortical neurons. It also prevented both the antineuritogenic and growth-cone collapsing activities of Nogo-A. The binding of EGCG to its cell-surface high affinity receptor resulted in an elevation of intracellular cAMP. This second messenger is apparently responsible for the endocytosis of NgR1. In line with this postulation, the addition of dibutyryl-cAMP and agents that elevate intracellular cAMP such as forskolin (adenylyl cyclase activator) and rolipram (cyclic nucleotide phosphodiesterase inhibitor) caused the endocytosis of NgR1. We also observed an internalization of NgR1 by 8-pCPT-2’-
O
-methyl-cAMP, a selective activator of Epac (exchange protein directly activated by cAMP). Moreover, ESI-09, an Epac-specific inhibitor blocked both EGCG and cAMP-induced endocytosis of NgR1, suggesting a crucial role of Epac in this process. On the contrary, NgR1 internalization was not observed with N
6
-benzoyl cAMP, a selective activator of protein kinase A (PKA), which is another effector of cAMP. Furthermore, EGCG and cAMP both induced endocytosis of NgR1 in neuronal cells deficient in PKA indicating a lack of role of PKA in this process. Conceivably, endocytosis of NgR1 desensitizes neurons to various axonal growth inhibitors, which may be exploited for drug development to enhance post-stroke recovery.
Abstract WP137: Angiotensin Type 2 Receptor Stimulation With Compound 21 Prevents Delayed Cognitive Impairment in Hypertensive, Ovariectomized Female Rats After Ischemic Stroke: A Randomized, Blinded, Preclinical Study
Authors: Eldahshan Wael , Sayed Mohammed A , Ahmed Heba A , Pillai Bindu , Dong Guangkuo , Ishrat Tauheed , Ergul Adviye , Fagan Susan C
Published: January 2019

Introduction:
The angiotensin type 2 receptor (AT2R) agonist, compound 21 (C21), has been shown to be neuroprotective and neurorestorative after stroke in male rats. Here, we aim to determine the long-term impact of C21 treatment on hypertensive female rats after stroke.

Methods:
Twenty female ovariectomized spontaneously hypertensive rats (SHRs), 16 weeks of age, were subjected to 1h MCAO and randomized at 24h to receive either vehicle or IP C21 0.03 mg/kg for 5 days followed by oral C21 (0.12mg/kg/day) for 5 weeks in drinking water. Sensorimotor behavior tests (modified Bederson, 0-8, where 8 is normal) were performed at 24h and weekly, while cognitive assessments (Passive Avoidance and Novel Object Recognition) were performed at weeks 5 and 6.

Results:
(mean±SEM) All stroked animals survived and showed improved motor performance at 6 weeks, with no effect of C21. However, C21 treatment significantly improved non-spatial working memory and reference memory without an effect on anxiety level at 6 weeks post-stroke.

Conclusions:
AT2R stimulation using C21 improves sensorimotor function and prevents the development of cognitive impairment in ovariectomized female rats, even when initiated at 24 hours after stroke.
Abstract WP139: MRI Evaluation and Functional Assessment of Brain Injury Improvement After 3K3A-Activated Protein C Treatment for Murine White Matter Stroke
Authors: Wang Yaoming , Huuskonen Mikko T , Montagne Axel , Zhao Zhen , Griffin John H , Zlokovic Berislav V
Published: January 2019

Introduction:
Subcortical white matter stroke (WMS) accounts for 25% of all incidences of stroke and results in severe motor and cognitive disability. WMS stands as the second leading cause of dementia and is notably prevalent in older adults. Activated protein C (APC), a plasma serine protease with potent antithrombotic and cell-signaling activities, was engineered to reduce bleeding risk while retaining normal cell-signaling activities (anti-inflammatory, anti-apoptotic, and neuroregenerative, etc. activities). The engineered variant, 3K3A-APC, is neuroprotective in preclinical models of ischemic stroke with large infarcts involving common large arteries and gray matter. A multicenter Phase 2 randomized clinical trial enrolled 110 patients to assess the safety, pharmacokinetics, and efficacy of human recombinant 3K3A-APC in acute ischemic stroke patients following endovascular treatments (NCT02222714).

Methods:
In this new study, a murine WMS was induced by the vasoconstrictor N5-(1-iminoethyl)-L-ornithine, dihydrochloride (L-Nio) by injection into the subcortical white matter ventral to the mouse forelimb motor cortex using the Neurostar motorized ultra-precise small animal stereotaxic instrument. Mice received intravenously 0.2 mg/kg recombinant murine 3K3A-APC or saline at 4, 24, 48 and 72 h after L-Nio. Then MRI scans were performed using a 7T PET/MRI scanner (MR Solutions) and a standard quadrature coil at 1 and 7 days after the stroke.

Results:
Both MRI and histological results showed that 3K3A-APC significantly reduced the lesion volume, increased the viability of oligodendrocytes and neurons, and protected against blood brain barrier damage at 1 and 7 days after stroke. Behavioral tests showed that 3K3A-APC improved functional recovery.

Conclusions:
These results demonstrated that 3K3A-APC might be an effective treatment for white matter stroke.
Abstract WP140: The Effect of Age-related Gut Dysbiosis on Microglial Function in Cerebral Amyloid Angiopathy
Authors: Honarpisheh Pedram , Bryan Robert M , McCullough Louise D , Ganesh Bhanu P
Published: January 2019

The role of “gut-immune-brain axis” across our lifespan is well recognized as a biologic variable. As our populations age, so does the prevalence of age-related illnesses including stroke and its sequelae. We examined how manipulating the microbiome alters the natural history of cerebral amyloid angiopathy (CAA), a major cause of recurring brain hemorrhages, stroke, and cognitive decline. Microglial phenotype changes with aging and deficits in microglial phagocytosis lead to increased amyloid burden in animal models of Alzheimer’s but it is not known if this occurs in CAA.
We hypothesize that age-related dysbiosis accelerates initiation and progression of CAA and this effect is mediated by failure of microglial amyloid phagocytosis (MAP).
We have investigated the effects of dysbiosis on MAP and cognitive decline in wild-type (WT) and Tg2576 transgenic mice. Gut microbiomes were altered in pre- and post-symptomatic transgenic mice via fecal microbiota transfer (FMT) from young and aged WT mice. Cognitive decline and microglial phenotype were assessed using behavioral tests and flow cytometry. Function of microglia using
in vitro
primary and
ex vivo
sorted cultures from CAA mice were also examined. Our preliminary data shows: 1) An increased Firmicutes:Bacteroidetes ratio, indicative of an aging microbiome, occurred in young recipients given aged donor FMT; conversely, the ratio decreased in aged mice given young biome(P<0.001, n=14); 2) Microglial phagocytosis was impaired in aged WT microglia (n=7/gp, P<0.01); and 3) Motor strength in both young and aged WT mice after FMT (n=17/gp) were dependent on the
age of the donor microbiome
rather than
the age of the host
(P<0.001). Our studies demonstrate an important role for the gut microbiome in modulating CAA pathogenesis and progression in the brain. Thus, manipulation of the gut microbiota could be an effective therapy to delay the onset and/or slow the progression of disease in CAA patients.
Abstract WP142:
18
F-THK5351 PET Imaging of Wallerian Degeneration of the Pyramidal Tract in a Post-Stroke Patient: A Longitudinal Case Study
Authors: Ishibashi Kenji , Tago Tetsuro , Toyohara Jun , Ishii Kenji
Published: January 2019

Introduction:
The PET radioligand,
18
F-THK5351, was initially developed to target tau aggregation present in neurofibrillary tangles. However,
18
F-THK5351 was recently reported to bind to monoamine oxidase B (MAO-B) with a certain level of affinity. MAO-B is highly concentrated in astrocytes. MAO-B concentration increases during so-called "gliosis", which is a spectrum of changes in astrocytes that occur after brain injury. Wallerian degeneration of the pyramidal tract usually develops after a cerebral infarction including primary motor cortex. In the early stage, axonal swelling and breakdown of myelin sheath occur. In the later stage, the degenerated axons are replaced by gliosis, which is primarily the proliferation of astrocytes to form a scar. These suggest that
18
F-THK5351 concentrates in the lesion where gliosis occurs in the process of Wallerian degeneration. We now present a case showing a potential use of
18
F-THK5351 PET to identify Wallerian degeneration of the pyramidal tract after a cerebral infarction.

Methods:
A patient developed left-sided hemiplegia caused by a right middle cerebral artery infarction at the age of 39, and underwent
18
F-THK5351 PET at ages 41 and 42. Emission data were acquired for 20 min starting at 40 min after an intravenous injection of
18
F-THK5351. Images were normalized using the cerebellum as a reference region

Results:
18
F-THK5351 images at ages 41 and 42 showed intense uptake along the ipsilateral pyramidal tract from the corona radiata to the medulla (Figure 1, arrows).
18
F-THK5351 uptake slightly decreased at the age of 42.

Conclusion:
18
F-THK5351 PET can identify Wallerian degeneration of the pyramidal tract accompanied with gliosis by targeting MAO-B located. This case suggests that gliosis in the process of Wallerian degeneration of the pyramidal tract still remains even three years after the stroke.
Figure1:
MRI (A) and
18
F-THK5351 images superimposed on MRI at ages 41 (B) and 42 (C)