bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 128: Amelioration of Ischemic Stroke Damage Through Inhibition of Interleukin-6 Signaling With Tocilizumab Requires Sex Specific Dosing
Authors: Hudobenko Jacob , Chauhan Anjali , McCullough Louise
Published: January 2019

Introduction:
Interleukin 6 (IL-6) is a proinflammatory cytokine. Higher plasma IL-6 levels in stroke patients are correlated with increased stroke severity and poor prognosis. Our work has shown that tocilizumab, an FDA approved drug that blocks the IL-6 receptor (IL-6R) significantly reduced acute and long-term brain infarct and atrophy in aged male mice after stroke. At the same dose, tocilizumab had no significant effect on stroke outcome in aged females.

Methods:
We utilized aged (18-20 month) C57BL/6J male (N= 27) and female (N= 30) mice to examine neuroprotection and behavioral deficits with treatment. Mice were randomly assigned into 4 groups of either stroke or sham and drug or IgG control treatment. Stroke was induced by 1 hour of transient right middle cerebral artery occlusion followed by reperfusion for 35 days. Four hours after the onset of ischemia mice were given an intraperitoneal injection of either tocilizumab (20mg/1kg) or an IgG control. Tests were conducted to evaluate motor, sensory and cognitive deficits. Another aged female cohort (N= 15) was used to assess tocilizumab efficacy at reducing infarct 3 days post stroke with a higher dose (100mg/1kg).

Results:
Soluble IL-6R expression, while equivalent at baseline, is significantly higher after stroke in aged female mice compared to males (P= 0.0070). Tocilizumab treatment reduced brain atrophy (P= 0.0120), mortality (P= 0.0239) and behavioral deficits in aged males on multiple behavior tests (P< 0.05). Females did not show similar benefits at the same dose (20mg/1kg). A higher dose of tocilizumab (100mg/1kg) reduced brain infarct acutely in aged females 3 days post stroke (P= 0.0005). This affect at only the higher dose in females is likely related to the higher level of soluble IL-6R seen post stroke compared to males. Testing in human stroke patient plasma revealed that women, as in mice, had significantly higher soluble IL-6R level compared to men after stroke (P= 0.0047).

Conclusion:
These results support our hypothesis that inhibition of the IL-6 receptor can be a novel therapeutic approach for stroke treatment. The neuroprotective dose of tocilizumab is different in males and females, which helps to emphasize the importance of determining dosage efficacy in a sex-specific manner.
Abstract 158: Optogenetic Theta-band Activation of Pyramidal Neurons Elicits Peri-infarct Spreading Depolarizations in the ET-1 Rat Model of Focal Cortical Ischemia
Authors: Bazzigaluppi Paolo , Dorr Adrienne , Mester James , Koletar Margaret , Carlen Peter , Stefanovic Bojana
Published: January 2019

Peri-infarct spreading depolarization (PIDs) frequently occur post ischemic stroke in animals and humans, propagating from the infarct core into the penumbra, and have been associated with worsened neurological outcome in patients. The etiology of PIDs is not well understood, complicating the development of targeted treatments. To examine the cellular origins of PIDs, we hypothesized that synchronous, frequency-specific, activation of specific neuronal subpopulation is necessary for PID occurrence. We transfected adult male Sprague Dawley rats with ChR2 either under the CamKII (AAV5.CAMKII.ArchT.GFP.WPRE.SV40) or CAG (AAV5.CAG.hChR2(H134R)-mCherry.WPRE.SV40) promoters into the somatosensory cortex to induce opsin transfection in pyramidal neurons or interneurons, respectively. Two weeks later, we assessed neuronal activity changes induced by focal cortical ischemia by inserting two electrodes ~2 mm apart in rostro-caudal direction. We then used a glass micropipette to inject 800 pmol of ET-1 into the primary somatosensory cortex in correspondence of rostral electrode, so as to examine the activity at the ‘core’ of the ischemic insult as well as from the peri-infarct zone, which coincided with the transfected area. We recorded baseline (pre-ischemic) local field potentials (LFPs) before injecting ET-1. Following ET-1 injection, we observed an average of five CSDs, with a mean amplitude of 57 mV and a mean duration of 1.2min, propagating from the infarct core to the peri-infarct tissue. In all subjects, the CSDs subsided within the first hour after the ischemic insult. In the second hour following stroke, we stimulated peri-infarct pyramidal neurons or interneurons at different frequency bands (theta, alpha, beta, low gamma, high gamma, and DC). Only theta band stimulation of the pyramidal neurons reliably triggered PIDs. Stimulating pyramidal neurons at higher frequencies or interneurons at any frequency did not elicit PIDs. Activation of peri-infarct zone pyramidal neurons in the theta band elicits cortical PIDs. The identification of a neuronal-specific and frequency-specific trigger for PIDs provides a roadmap for development of PID-targeted treatments in the acute stage of stroke.
Abstract 160: Better Collaterals Are Independently Associated With Post-thrombolysis Recanalization Before Thrombectomy
Authors: Baron Jean Claude , seners pierre , Roca Pauline , Legrand Laurence , Turc Guillaume , Mas Jean-Louis , Oppenheim Catherine ,   Predict-Recanal Collaboration
Published: January 2019

Introduction:
In acute stroke with large-vessel occlusion (LVO), the goal of intravenous thrombolysis (IVT) is to achieve early recanalization (ER). Over and above occlusion site and thrombus length, better collaterals might also facilitate ER, for instance by improving delivery of the thrombolytic agent to both ends of the thrombus. In this proof-of-concept study, we tested the hypothesis that good collaterals independently predict post-IVT recanalization before thrombectomy.

Methods:
Patients from the registries of 6 French stroke centres with the following criteria were included: (1) acute stroke with LVO treated with IVT and referred for thrombectomy between May 2015 and March 2017; (2) pre-IVT brain MRI, including diffusion weighted imaging, T2*, MR-angiography and dynamic susceptibility-contrast perfusion-weighted imaging (PWI); and (3) ER evaluated ≤3hrs from IVT start on either first angiographic run or non-invasive imaging. A collateral flow map derived from PWI source data was automatically generated, replicating Kim et al’s previously validated method (Ann. Neurol., 2014). Thrombus length was measured on T2*-based susceptibility vessel sign.

Results:
Of 224 eligible patients, 37 (16%) experienced ER. ER occurred in 10/83 (12%), 17/116 (15%) and 10/25 (40%) patients with poor/moderate, good and excellent collaterals, respectively. In multivariable analysis, better collaterals were independently associated with ER (
P
=0.029), together with shorter thrombus (
P
<0.001) and more distal occlusion site (
P
=0.010).

Conclusions:
In our sample of stroke patients imaged with PWI before IVT and intended for thrombectomy, better collaterals were independently associated with post-IVT recanalization, supporting our hypothesis. These findings strengthen the idea that advanced imaging may play a key role for personalized medicine in the thrombectomy era by identifying LVO patients most likely to benefit from IVT.
Abstract 162: Viscerotoxic Brain Infarcts: The Results of Heart-Brain Interactions Study
Authors: Chang Ken , Brown James , Beers Andrew , Kalpathy-Cramer Jayashree , Ay Hakan
Published: January 2019

Introduction:
Acute brain infarcts can provoke functional and morphologic changes in internal organs in the absence of primary visceral causes. We tested the hypothesis that infarcts in certain regions of the brain were much more likely to be associated with internal organ injury (IOI) than other regions using a method that was free from the bias of a-priori hypothesis as to any specific location.

Methods:
We generated neuroanatomic maps of brain infarcts for plasma troponin T elevation (structural cardiac marker), QTc prolongation on ECG (electrophysiological cardiac marker), pneumonia and urinary tract infection (marker for altered immune/pulmonary/urinary physiology), acute stress hyperglycemia (hepatic marker of glycogenolysis) in 1208 consecutive patients who were prospectively recruited into the NIH-funded HBI study. We utilized Threshold-Free Cluster Enhancement to examine the relationship between infarct location and IOI. We generated voxel-wise p-value maps using a permutation-based approach and identified clusters of contiguous voxels associated with IOI with a p-value <0.05.

Results:
We identified significant clusters of voxels for each form of IOI. The clusters for troponin elevation and QTc prolongation encompassed similar regions in the right insular cortex. The cluster for acute stress hyperglycemia involved the left insula. We found two large clusters for post-stroke infection, one for pneumonia in the left and one for urinary tract infection in the right hemisphere, both encompassing the insular cortex. The relationship between infarct location and IOI persisted after adjusting for infarct volume, vascular risk factors, and stroke etiology.

Conclusion:
Our results uncover the neuroanatomical substrate of post-stroke IOI. Localizing discrete regions of brain infarcts associated with IOI could be used to bootstrap towards new markers for better differentiation between neurogenic and non-neurogenic mechanisms of post-stroke IOI.
Abstract 163: Thrombus Length is a Powerful Independent Predictor of Post-Thrombolysis Early Recanalization in Minor Stroke With Large Vessel Occlusion
Authors: Baron Jean Claude , Seners Pierre , Delepierre Julie , Turc Guillaume , Mas Jean-Louis , Oppenheim Catherine ,   Predict-Recanal Collaboration
Published: January 2019

Introduction:
Whether bridging therapy (
i.e
. intravenous thrombolysis [IVT] followed by mechanical thrombectomy) is associated with better outcome as compared to IVT alone in minor yet disabling stroke (NIHSS<6) with large vessel occlusion (LVO) is unknown. Identifying strong predictors of lack of post-IVT early recanalization, a surrogate marker of poor outcome, may help to select the best candidates for additional thrombectomy and to optimally design randomized trials.

Methods:
From a large multicentre French registry of LVO patients referred for thrombectomy immediately following IVT start between May 2015 and March 2017 (n=1107), we extracted 97 minor stroke patients with both i) LVO on pre-IVT vascular imaging; and ii) recanalization evaluated on first angiographic run or non-invasive imaging ≤3hrs from IVT start. Thrombus length was measured using the Susceptibility Vessel Sign (SVS) on T2*-imaging.

Results:
Mean age was 65 years, and occlusion site was intracranial carotid, M1 and M2 in 4%, 46%, and 50% of patients, respectively. Treatment was as per the mothership and drip-and-ship paradigm in 41% and 59%, respectively. On pre-IVT MRI (performed in 98% of patients), median length of SVS (visible in 90%) was 9.2mm (IQR: 7.4-13.3). In univariable analysis including standard clinical variables, DWI ASPECTS, occlusion site and SVS length, lack of recanalization (present in 66% of patients) was associated with larger DWI lesion and longer SVS. In multivariable analysis, only the latter was independently associated with no recanalization (OR= 1.53 per 1-mm increase, 95%CI [1.21-1.92],
P
<0.001). The c-statistic of SVS length for no-recanalization prediction on the ROC was high (0.82, 95%CI 0.73-0.92), and the optimal cutoff (Youden index) was 9mm. The sensitivity and specificity of this cutoff for no-recanalization were 67.8% (95%CI 55.9-79.7) and 84.6% (95%CI

70.7-98.5), respectively.

Conclusions:
Early recanalization was frequent in this cohort of IVT-treated minor stroke patients with LVO. Thrombus length on T2* MRI was the sole - and very strong - independent predictor of no-recanalization. These findings may help design optimal randomized trials aiming to test bridging therapy
vs.
IVT alone in this population.
Abstract 166: DTN-TIMES: Telemedicine versus Comprehensive Stroke Center IV-tPA Time Metric Study—Southern California Kaiser Permanente and University of Texas Houston Telestroke Network Experience
Authors: Wu Tzu-ching , Trevino Alyssa , Ankrom Christy , Valdovinos Cristina , Sanghn Navdeep
Published: January 2019

Objective:
To compare DTN times (door to IV-tPA bolus) for patients that received IV-tPA via two large academic TS Networks to patients that received IV-tPA at the respective CSC hubs.

Methods:
We retrospectively identified patients that received IV-tPA at TS spokes in the TS networks (UT Health Telestroke Network (UTH) and Kaiser Permanente Southern California Telestroke Network (KP)), and patients that were thrombolysed at the respective CSC hubs from 1/16 to 12/17. Baseline clinical data, demographics and IV-tPA related time metrics were abstracted. In-house thrombolysis patients were excluded.

Results:
A total of 2329 patients (CSC = 436, TS = 1891) were administered IV-tPA during this time period. There was no difference in the DTN times between patients thrombolysed at a CSC hub versus a TS site. Patients were treated faster overall in the KP system, but UTH patients had significantly higher stroke severity on arrival. The percentage of patients treated ≤ 60 minutes and ≤ 45 minutes did not differ between TS and CSC, however more patients were thrombolysed in ≤ 30 minutes at a CSC hub.

Conclusion:
This is the first study that has shown that DTN times are comparable between TS sites vs CSC hubs. It demonstrates that with continuous training, education and feedback provided to spoke sites, equivalent IV-tPA time metrics can be achieved at TS spokes. Areas of improvement include treatment of patients in ≤ 30 minutes. We found that less patients in the TS group were able to achieve treatment in ≤ 30 minutes, which may be an inherent logistical disadvantage of TS over onsite stroke teams.
Abstract 170: Paramedic-Suspected Stroke Increased after Implementing a Community-Engaged Stroke Preparedness Intervention in Chicago
Authors: Richards Christopher T , Song Sarah Y , Kwon Soyang , Wymore Erin , Kandula Namratha R , Brown Jen F , Eisenstein Amy , Mason Maryann , Beckstrom Heather , Jones Peggy , Washington Knitasha V , Aggarwal Neelum T , Prabhakaran Shyam
Published: January 2019

Introduction:
Emergency medical services (EMS) utilization for acute stroke is associated with improved stroke care and outcomes. We evaluated whether a community-engaged stroke preparedness intervention would increase EMS use for suspected stroke.

Methods:
The Community Engagement for Early Recognition and Immediate Action in Stroke (CEERIAS) study was conducted in a South Side Chicago neighborhood with proximity to a primary stroke center. In early 2016, CEERIAS implemented a community-engaged stroke preparedness intervention delivered by trained laypersons from the target community who taught peers about the importance of calling 9-1-1 for acute stroke. Paramedic impressions of all EMS calls were obtained from the municipal EMS provider agency serving the study neighborhood. Using ArcGIS 10.5.1 and ArcGIS Pro 2.1.2 (Esri Inc., Redlands, CA), EMS run locations were geolocated, and Getis-Ord Gi* analysis was used to identify hot spots for EMS-suspected stroke. Statistical hot and cold spots are defined as areas where there is <1% chance of case clusters occurring by chance.

Results:
A total of 274,773 EMS runs were successfully geolocated in the 13.5 month pre-CEERIAS intervention period, and 267,061 in the 12.5 month post-CEERIAS intervention period. The study hospital’s neighborhood changed from a cold spot to a hot spot for EMS-suspected stroke (Figure). In the hot spot region adjacent to the study hospital, EMS use for suspected stroke increased 2.2-fold (p<0.001) post-CEERIAS compared to pre-CEERIAS. Overall EMS utilization and EMS utilization for stroke were similar pre- and post-CEERIAS elsewhere in the city.

Conclusions:
A community-engaged stroke preparedness intervention was associated with an increase in EMS use for suspected stroke in targeted neighborhoods of Chicago. Further studies should investigate the effect on stroke outcomes and dissemination strategies to broaden the impact of this intervention.
Abstract 172: Trends in Telestroke Care Delivery: A 15-Year Experience
Authors: Sharma Richa , Zachrison Kori S , Estrada Juan , Viswanathan Anand , Schwamm Lee H
Published: January 2019

Introduction:
Telestroke provides vascular neurology expertise to hospitals without onsite neurologists, but little is known about the temporal trends in use and timeliness of consults by spokes. We describe a telestroke network of 2 comprehensive stroke center (CSC) hubs and associated spokes.

Methods:
Telestroke consults were analyzed from 2003 to 2018. Trends in volume of consult requests and IV-tPA use were determined by generalized estimating equations, trends in treatment times by Kendall’s τβ nonparametric test, and associations between treatment metrics and utilization of telestroke by linear regressions.

Results:
The 2 hubs served 43 spokes and performed 12,808 telestroke consults of which 16% received tPA and 10% were judged eligible for thrombectomy. Spokes were in the network an average of 7.87 years, 1.82 spokes joined per year, and 1.03 exited per year. There was an overall increase in consults annually (p for temporal trend <0.0001) and patients treated with IV-tPA (p < 0.0001). Over the study period, time from last seen well to ED arrival time (KT coefficient 0.88, p <0.0001) and last seen well to consult request time (KT coefficient 0.28, p <0.0001) increased, however in hospital performance improved with decreasing times from ED arrival to IV-tPA (KT -0.13, p <0.0001), time of request to callback (KT -0.05, p <0.0001), and consult to IV-tPA administration (KT -0.09, p <0.0001) . The number of consults requested by a spoke and the number treated with IV-tPA at each spoke were positively associated (p=0.0002).

Discussion:
Telestroke was well-accepted by the spokes and utilization increased over time, with a net increase in spokes served per year. Higher consult utilization was associated with increased treatment with IV-tPA. ED time metrics have improved significantly. Being active in a telestroke network is associated with more stroke treatment which the spokes are delivering in a timely manner. Replication of these findings in other networks is warranted.
Abstract 177: Thrombectomy Results in Reduced Hospital Stay, More Time at Home, and More Favorable Living Situations for Patients in the DEFUSE 3 Trial
Authors: Tate William J , Polding Laura C , Kemp Stephanie , Mlynash Michael , Heit Jeremy J , Marks Michael P , Albers Gregory W , Lansberg Maarten G
Published: January 2019

Background:
The high burden of disease associated with stroke results in a tremendous cost to the healthcare system and a reduced quality of life for patients. The DEFUSE 3 trial found that endovascular thrombectomy in the 6-16 hour time-window results in a significant improvement in functional outcomes as measured by the modified Rankin Scale. The aim of this study was to determine the effect of this intervention on length of hospital stay, time spent at home during the first 3 months after stroke, and living situation after stroke.

Methods:
In DEFUSE 3, 182 patients were randomized to medical or endovascular therapy. Duration of hospital stay and time at home in the first 90 days following stroke onset was analyzed between the two groups using a Wilcoxon rank-sum test. Patient living situation was assessed at time of discharge, 30 days, and 90 days and categorized on an ordinal 4-point scale: as home, acute rehab unit, skilled nursing facility, or hospice / death. Differences between groups were analyzed using a Cochran-Armitage trend test.

Results:
Median length of hospital stay was 9 (IQR, 6 - 15) days in the medical group vs. 7 (IQR, 4 - 9) days in the endovascular group (p < 0.001). Median time spent at home during the first 90 days following stroke was 0 (IQR, 0 - 54) days in the medical group vs. 55 (IQR, 0 - 83) days in the endovascular group (p < 0.001). The endovascular group had more favorable living locations at time of discharge (p < 0.001), 30 days (p < 0.001), and 90 days (p < 0.001) after stroke onset (see figure).

Discussion:
Endovascular thrombectomy resulted in shorter length of hospital stay, longer time spent at home in the first 90 days, and more desirable living situations at the time of discharge, 30 days, and 90 days after stroke. These results provide additional evidence for the effectiveness of endovascular therapy in the delayed time-window as these factors are associated with improved quality of life for stroke patients and reduced costs to the healthcare system.
Abstract 186: Regional Variation in Carotid Revascularization Procedures and Outcomes Among Elderly Medicare Beneficiaries
Authors: Lichtman Judith H , Leifheit Erica C , Wang Yun , Claus Elizabeth B , Goldstein Larry B
Published: January 2019

Background:
Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are the most frequently performed revascularization procedures to prevent stroke. Little is known about national geographic patterns and outcomes for the two procedures. We evaluated geographic variation in the performance of CEA and CAS and 30-day post-procedure outcomes (ischemic stroke or death, all-cause mortality, all-cause readmission).

Methods:
Fee-for-service Medicare beneficiaries aged ≥65 years who underwent CEA or CAS from 2012-2014 were identified using ICD-9 procedure codes. Spatial mixed models with a Poisson link function and adjustment for demographics were used to calculate and map county-specific risk-standardized rates of carotid revascularization. We used mixed models and Cox regression to assess the relationship between region and 30-day outcomes, adjusting for demographics, symptomatic status, and comorbidities.

Results:
Between 2012 and 2014, 112,995 patients had a CEA (mean age 75.6y; 41.6% women) and 34,075 had CAS (mean age 75.2y; 45.7% women). The county-level risk-standardized rates per 100,000 beneficiary-years ranged from 51-248 for CEA and from 0-317 for CAS. Although the highest CEA rates were in the Midwest and South, there were pockets of high CAS rates across the country. There was no correlation between county-level rates of CEA and CAS (weighted Pearson’s r=0.011; p=0.525). In analyses stratified by age, there was no difference in the regional patterns of carotid revascularization for those aged 65-69y vs ≥70y. Compared with the Northeast, the South had worse outcomes after CEA but better outcomes after CAS, and the Midwest had better outcomes after CAS.

Conclusion:
There were differences in regional patterns of the performance of CEA and CAS and post-procedure outcomes among elderly Medicare beneficiaries. Factors contributing to geographic disparities in performance and differences in outcomes across regions require further study.
Abstract 189: Influenza-like Illness and Risk of Stroke in New York State
Authors: Alvord Trevor , Kulick Erin , Cannine Michelle , Elkind Mitchell , Boehme Amelia K
Published: January 2019

Background and Purpose:
Influenza may be associated with stroke risk. We hypothesized that risk of ischemic stroke is increased after influenza-like illness (ILI), and that these effects are even greater for those in an urban environment, of Black race, and male sex.

Methods:
A case-crossover analysis of the 2012-2014 inpatient and outpatient New York Statewide Planning and Research Cooperative System (SPARCS) was used to estimate the odds of hospitalization for ischemic stroke after hospitalization for ILI. Each patient’s case window (the time period preceding stroke) was compared to their control windows (constructed using the same dates from the previous two years) in conditional logistic regression models used to estimate odds ratios and 95% confidence intervals (OR, 95% CI). We varied the case windows from 15 to 365 days. Analyses were stratified by urban and rural status based on residential zip code, sex, and race.

Results:
A total of 30,912 patients were identified as having an ischemic stroke in 2014 and included in the study (49% male, 20% Black, 84% urban, mean age 71.9 [SD 14.7] years). ILI in the 15 days before a stroke was associated with an overall increase in odds of stroke (OR=1.39, 95% CI 1.09-1.77), and this association remained over time (Table). There was no significant interaction between ILI and urbanicity (p=0.29), sex (p=0.81), or race (p=0.85).

Conclusion:
ILI was associated with stroke risk, but there was no evidence of race, sex or location differences in the relationship between ILI and stroke.
Abstract 20: Cross-Phenotype Meta-Analysis of Intracerebral Hemorrhageand Small Vessel Ischemic Stroke Identifies Two Novel Genetic Loci at 2q33 and 13q34
Authors: Chung Jaeyoon , Marini Sandro , Traylor Matthew , Malik Rainer , Langefeld Carl D , Woo Daniel , Rosand Jonathan , Anderson Christopher D
Published: January 2019

Background:
Intracerebral hemorrhage (ICH) and small vessel ischemic stroke (SVS) are the most severe manifestation of cerebral small vessel disease (CSVD) with no established preventive approaches beyond hypertension management. Cross-phenotype analysis of these two correlated diseases will improve statistical power to detect novel genetic factors for CSVD, elucidating underlying disease mechanisms that may form the basis for future treatments.

Methods:
We performed genome-wide association studies (GWAS) for ICH by location in 1,813 ICH patients (797 lobar and 1,005 nonlobar) and 1,711 stroke-free controls after imputation using Haplotype Reference Consortium reference panels. Each ICH GWAS by location was meta-analyzed with GWAS summary statistics for SVS from MEGASTROKE (
Malik et al. 2018
), using “Multi-Trait Analysis of GWAS” (MTAG;
Turley et al. 2018
) to integrate GWAS summary data across traits and generate combined trait-specific effect estimates.

Results:
By combining GWAS datasets using MTAG, our functional sample size increased to 241,024 participants (6,255 ICH or SVS cases and 234,769 controls). Genome-wide significant (P < 5x10
-8
) associations were observed for the nonlobar ICH model enhanced by SVS with 1) rs2758605 (MTAG P-value [P] = 2.6x10
-11
) at 1q22; 2) rs72932727 (P = 1.7x10
-8
) at 2q33; and 3) rs9515201 (P = 5.3x10
-10
) at 13q34. The MTAG association strengths of these loci were at least one order of magnitude more significant than those from their individual GWAS. According to the GTEx database, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for
PMF1
(P = 1x10
-4
in nerve),
NBEAL1
,
ICA1L
, and
CARF
(P < 7.7x10
-7
in artery tibial) and
COL4A2
and
COL4A1
(P < 0.008 in thyroid), respectively.

Conclusion:
Our cross-phenotype study of ICH and SVS reveals two novel CSVD loci, including 2q33 and 13q34. The 2q33 locus was recently identified in a GWAS of white matter hyperintensity burden (
Jian et al. 2018
). We also identified the same
PMF1
association as previously seen in ICH (
Woo et al. 2014
), supporting the validity of this novel multi-trait approach. We have begun to replicate these associations and to identify functional causal variants in independent whole genome sequencing studies of ICH.
Abstract 3: Effect of BP Goal on Outcome post Mechanical Thrombectomy: Multicenter Study
Authors: Anadani Mohammad , Orabi Yser , Alawieh Ali , Goyal Nitin , Pandhi Abhi , Mitchell Hunter , Alexandrov Andrei , Maier Ilko L , Psychogios Marios-Nikos , Liman Jan , Inamullah Ovais , Swisher Christa , Rahman Shareena , Keyrouz Salah , Giles James A , Allen Michelle , Wolfe Stacey Q , Kan Peter , Nascimento Fábio A , Turkk Aquilla S , Spiotta Alejandro M
Published: January 2019

Introduction:
Current AHA/ASA guidelines recommend keeping blood pressure (BP) <180/105 after successful recanalization with MT. However, due to a concern of reperfusion injury, different BP goals are utilized across various endovascular centers. In this study, we compared functional and hemorrhagic outcomes between different BP goals.

Methods:
This was a multicenter international retrospective study that included 7 comprehensive stroke centers. Inclusion criteria were anterior circulation large vessel occlusion (LVO) that was treated with MT, and successful recanalization at the conclusion of the procedure. Patients were divided into three groups based on systolic BP (SBP) goals in the first 24 hours post MT. Group 1) included patients with SBP goal ≤140 mm Hg or ≤120 mm Hg; group 2 included patients with SBP goal ≤160 mm Hg; group 3) included patients with SBP goal ≤220 mm Hg or ≤180 mm Hg. Successful recanalization was defined as TICI 2b-3. Outcome measures included symptomatic intracerebral hemorrhage (sICH), 90-day modified Rankin Scale (mRS), and 90-day mortality.

Results:
A total of 985 patients were included in the study. More patients in group 3 were white and had Afib than groups 1-2. Likewise, more patients in group 3 received IV tPA. Complete recanalization (TICI 2c-3) was achieved in 88.2%, 53.6%, and 73.2% in groups 1,2,3 respectively (p <0.001). With respect to outcome, mRS 0-2 was achieved in 50%, 52, and 38% of patients (p=0.001) in groups 1,2,3 respectively. Similarly, sICH occurred in 2.8%, 7.1%, and 5.2% (p=0.04) in the respective groups. In multivariate analysis, moderate and intensive BP goals (groups 1-2) were associated with mRS 0-2 but not with sICH or mortality. In subgroup analysis that included only patients who achieved BP goal, group 1 but not 2 or 3 were associated with functional outcome.

Conclusion:
Blood pressure goals ≤140 and ≤160 were associated with favorable functional outcome.
Abstract 32: “Rendezvous System” for Broadening a Mobile Stroke Unit Catchment Area
Authors: Kerro Ali , Kus Teresa , Cai Chunyan , Jacob Asha , Gutierrez Nicole , Bowry Ritvij , Grotta James , Parker Stephanie
Published: January 2019

Purpose:
Mobile Stroke Units (MSU) deliver acute stroke treatment on-scene in coordination with Emergency Medical Services (EMS) prior to transport to a stroke center. One criticism is the limited range of a single MSU. The Houston MSU is the only one in the U.S. using a rendezvous system with EMS to expand its range.

Methods:
In addition to direct 911 dispatch of our MSU directly to the scene for tPA eligible patients within our “catchment” area (8 miles), we asked more distant EMS units to notify the MSU and also monitored EMS radio communication to identify eligible patients. For these “distant” patients, the MSU meets the EMS unit enroute to the stroke center and treats the patient at that intermediate location (usually a parking lot). The distribution of the distance from MSU base station to site of stroke and time from alert to tPA bolus were compared between patients treated on scene and by rendezvous using Wilcoxon rank sum test.

Results:
From August 18, 2014 to July 20, 2018, 290 acute ischemic stroke patients were treated with tPA on our MSU. Of these, 140 (48.3%) were treated on scene by direct 911 dispatch, with a median of 7 miles (IQR 5 miles) from MSU base station. 150 (51.7%) patients were treated by rendezvous. They had their strokes a median of 13 miles from base (IQR 6 miles) (p<0.0001). Time (min) from 911 alert to tPA bolus was 37.6±9.7 with on-scene, and 37.7±12.7 with rendezvous (p=0.89).

Conclusion:
A “rendezvous system” significantly expands the range of operations for a MSU in an urban area, doubling the number of patients treated, without incurring delay. This approach might be even more useful in rural areas.
Abstract 38: Racial Differences in Intracerebral Hemorrhage Risk: The REasons for Geographic and Racial Differences in Stroke Study (REGARDS)
Authors: Zakai Neil A , Koh Insu , Howard Virginia , Dittus Kim , Flaherty Matthew , Kleindorfer Dawn , Kissela Brett , Plante Timothy , Howard George , Cushman Mary
Published: January 2019

Introduction:
Intracerebral Hemorrhage (ICH) risk is higher in blacks vs whites in the U.S. especially at younger ages. We used the REGARDS study to determine what prospectively assessed factors may underlie black-white differences in ICH risk.

Methods:
REGARDS recruited black and white individuals aged 45+ in the U.S. to explain regional and racial differences in stroke risk. Cox models with an age*race interaction term estimated the age-dependent hazard ratio (HR) of black versus white individuals for ICH. The 95% confidence interval (CI) of the percent attenuation of the age-dependent hazard ratio (HR) from the baseline to the final model was calculated using bootstrapping.

Results:
Among 29,694 REGARDS participants (55% women; 41% black), 160 ICH events occurred over 254,440 person-years of follow-up (median 9.5 years). The point estimate for the black-white HR for ICH decreased with increasing age, being 4.8, 2.7, and 1.5 at ages 45y, 55y, and 65y (Table, Baseline Model). In a final model, the point estimate for ages 45, 55, and 65 decreased to 3.9, 2.3, and 1.4, corresponding to a 24% (95% CI 11%. 100%), 24% (95% CI 16%, 100%), and 20% (95% CI 14%, 100%) decrease in the HR at ages 45y, 55y, and 65y. No increased ICH risk was seen in blacks over 65y. When added individually to the baseline model, none of the risk factors except diet (modeled as 6 principle components of dietary patterns) attenuated the association of black race with ICH risk.

Conclusions:
A quarter of the association of race with ICH may be explained by the risk factors studied here. Diet, particularly salt intake, may play a large role in black-white differences of ICH risk. While the absolute number of ICH events limits our analysis, prospective assessment of risk factors is a huge strength. Future primary and secondary ICH prevention efforts, particularly in younger blacks, should assess efficacy of dietary interventions.
Abstract 48: Digital Brain Maps of 1018 Acute Supratentorial Large Artery Atherosclerotic Infarction
Authors: Kim Dong-Eog , Park Jong-Ho , Schellingerhout Dawid , Ryu Wi-Sun , Bae Hee-Joon ,   CRCS-5 Investigators
Published: January 2019

Background:
Current territorial maps are difficult to interpret because of highly variable territorial boundaries noted, thus complicating the assessment of stroke mechanism .

Objective:
To offer further knowledge on the variable anatomy of cerebral artery territory by providing terriorial maps of the anterior, middle, and posterior cerebral arteries (ACA, MCA, and PCA, respectively).

Methods and Results:
Digital maps of supratentorial infarcts were generated using diffusion-weighted MRIs of 1160 acute (<1w) stroke patients (67.0±13.3 years old, 53.7% male) recruited consecutively from 11 academic stroke centers in Korea. All had supratentorial infarction due to significant stenosis or occlusion of one of the three large supratentorial arteries, but with patent intracranial/extracranial carotid arteries. The three vascular territories were mapped individually by affected vessel, generating three datasets for which infarct frequency is defined for each voxel in the dataset. By mapping these three vascular territories collectively, we generated datasets showing the certainty index (CI) to reflect the likelihood of a voxel being a member of a specific vascular territory, calculated as either ACA, MCA, or PCA infarct frequency / total infarct frequency in that voxel. We defined border-zone maps using relative frequencies or CI differences. The volume of the MCA territory (54.1% of the supratentorial parenchymal brain volume) was about 3-fold bigger than the volumes of the ACA (13.3%) and PCA territories (13.8%). Quantitative studies using the maps showed that the medial frontal gyrus, superior frontal gyrus, and anterior cingulate were involved mostly in ACA infarcts, whereas the middle frontal gyrus and caudate were involved mostly by MCA infarcts. The PCA infarct territory was smaller and narrower than traditionally shown. Infarct territories in posterior upper brain regions were complex with a z-axis dependent order of involvement. The width of overlapping border-zones was relatively narrow in the anterior boundary of the MCA territory compared with its posterior boundary.

Conclusion:
The new topographic brain atlas can be used in clinical care and research to objectively define the supratentorial arterial territories and their borders.
Abstract 51: Aging and Metabolic Stress Are Associated With Disrupted White Matter Integrity in Children and Young Adults With Sickle Cell Disease
Authors: Guilliams Kristin P , Fields Melanie E , Fellah Slim , Binkley Michael M , Ragan Dustin K , Hulbert Monica L , Blinder Morey , Vo Katie , Chen Yasheng , Shimony Joshua S , McKinstry Robert C , An Hongyu , Lee Jin-Moo , Ford Andria L
Published: January 2019

Introduction:
Silent cerebral infarcts (SCIs) in sickle cell disease (SCD) begin in early childhood and increase with age, affecting 50% by age 30. SCIs often occur in the watershed area, where cerebral blood flow (CBF) is low, and oxygen extraction fraction (OEF) is high. Diffusion tensor imaging (DTI) measures white matter integrity; lower fractional anisotropy (FA) and higher mean diffusivity (MD) may precede the appearance of SCIs. We hypothesized that age and oxygen metabolic stress, defined by elevated watershed OEF, are associated with disruption of white matter integrity as measured by FA and MD.

Methods:
Children and young adults with and without SCD were recruited for brain MRI (T1, FLAIR, pseudocontinuous arterial spin label (CBF), asymmetric spin echo (OEF) and DTI). We averaged CBF maps of non-SCD participants and created a watershed region of interest (ROI), defined as CBF <30% of mean gray matter CBF, which was applied to individual maps. All SCIs were outlined and excluded. We evaluated age and SCD as predictors of FA and MD. Within the watershed ROI, we evaluated OEF and age as predictors of FA and MD.

Results:
Fifty SCD and 53 control participants, age 6-39 years, underwent MRI. Within all normal appearing white matter, FA decreased (p<0.001) and MD increased (p<0.001) with advancing age. MD, but not FA, changed at a faster rate with advancing age in SCD compared to controls (p=0.02). Within the watershed region, OEF significantly predicted FA (p=0.002) and MD (p <0.001), after adjusting for age.

Conclusion:
Disruption of white matter integrity worsens with early life aging, particularly in SCD. Oxygen metabolic stress within the watershed region, a region at high risk for SCIs, is associated with lower FA and higher MD, suggesting OEF may provide an early tissue marker of ischemic vulnerability in SCD, prior to developing SCIs.
Abstract 56: Diabetic Stroke Promotes a Sexual Dimorphic Expansion of Circulating and Cerebrovascular Th17 Cells in Female Rats
Authors: Jackson Ladonya , Lee Weiguo , Abdul Yasir , Guankuo Dong , Fagan Susan C , Ergul Adviye
Published: January 2019

Diabetes increases the risk & severity of hemorrhagic transformation (HT) after ischemic stroke, worsening the functional outcomes & recovery. Women experience more severe strokes and suffer from a higher rate of stroke & diabetic-related complications including cognitive impairment. Yet, experimental data on sex differences in cerebrovascular complications of stroke & diabetes is limited. We recently showed that diabetes negates neurovascular protection even in young females & amplifies HT. We hypothesized that 1) circulating &/or cerebrovascular Th17 is elevated in high fat diet (HFD)-induced diabetic females rats that develop greater HT & 2) that ischemic stroke further promotes the expansion of Th17 cells.

Methods:
Diabetes was induced in male & Female WWistar rats by a HFD and& low dose streptozotocin combination. At 12-14 weeks of age control and& diabetic rats were subjected to 1 hr middle cerebral artery occlusion (MCAO) or ShamSham surgery. Cell suspensions prepared from freshly harvested blood, brain & small intestine specimens were analyzed by flow cytometry using antibodies against cell surface markers (CD3, CD4, γδTCR) & intracellular markers (IL4, IL10, IL17, IFNγ & FOXP3) of T cells.

Results
(Table): HFD differentially increased circulating & cerebral Th17 cells in females, but not males. Non-diabetic females also had significantly more circulating & cerebral inflammatory cells than males, which was further expanded by diabetes. Stroke increased cerebral Th17 cells in the presence & absence of HFD-induced diabetes in both sexes. However, stroke in the absence of diabetes differentially increased circulating Th17 cells only in males, yet in females only after compounded with diabetes.

Conclusion:
Expansion of Th17 cells may contribute to the sexual dimorphic differences that exists in stroke & diabetes-related complications. Whether this contributes to cerebrovascular & cognitive dysfunction in females remain to be determined.
Abstract 58: Neuronal Activation of Ras-Related C3 Botulinum Toxin Substrate 1 (Rac1) Improves Post-Stroke Recovery and Axonal Plasticity in Mice
Authors: Bu Fan , Munshi Yashasvee , Furr Weldon J , Min Jia-wei , Patrizz Anthony , Qi Li , McCullough Louise D , Li Jun
Published: January 2019

Axonal plasticity is critical for functional recovery after stroke. Our previous study suggested that Rac1, a small GTPase, contributes to post-stroke axonal regeneration. However, the specific cellular and molecular mechanisms mediating its effects remain unknown. The two major factors controlling axonal plasticity in the injured brain are the neuronal intrinsic property for outgrowth and astrocytic inhibition of axonal growth. We investigated the selective roles of neuronal and astrocytic Rac1 in post-stroke recovery and axonal regeneration. Stroke was induced by middle cerebral artery occlusion for 60 minutes in 7 to 8 week old male mice. Brain injection of lentivirus encoding Rac1 with neuronal (NSE) or astrocytic (GFAP) promotors was performed 7 days after stroke in wild type mice to overexpress neuronal or astrocytic Rac1. Tamoxifen administration was started 7 days after stroke in Thy1-cre/Rac1 floxed mice to induce genetic deletion of neuronal Rac1. Delayed overexpression of neuronal Rac1 promoted sensorimotor recovery assessed using a single pellet reaching test (% success rate) from 21 to 28 days after stroke (Day 28: GFP control 51.25±4.41 vs. NSE-Rac1 66.67±2.36, n=8-9, p<0.05). Memory and cognitive function was improved after stroke as assessed by the novel object recognition test (Day 28: GFP control 1.43±0.34 vs. NSE-Rac1 2.25±0.23, n=8, p<0.05). Consistently, delayed neuronal Rac1 deletion worsened recovery assessed by pellet reaching test (WT 60±4.08 vs. KO 42.5±2.5, n=4, p<0.05), an adhesive removal test (seconds) (WT 22.67±3.71 vs. KO 70.92±15.56, n=4, p<0.05), and novel object recognition test (WT 1.59±0.17 vs. KO 1.08±0.09, n=4, p<0.05) 28 days after stroke. Interestingly, astrocytic Rac1 overexpression did not affect functional recovery (not shown). Finally, overexpression of neuronal Rac1 increased axonal density (neurofilament-L staining) in the peri-infarct zone 28 days after stroke (GFP control 1.00±0.09 vs. NSE-Rac1 2.86±0.41, n=4, p<0.05), with no effect on brain cavity size. In conclusion, neuronal Rac1 signaling enhances axonal plasticity and improves post-stroke functional recovery. Neuronal specific targeting of Rac1 may have therapeutic potential for reducing long-term disability after stroke.
Abstract 59: Relation of Plasma B-amyloid, Tau and Clusterin and Cerebral Microbleeds: Framingham Heart Study
Authors: Romero Jose R , Demissie Serkalem , Beiser Alexa , DeCarli Charles , Levy Daniel , Seshadri Sudha
Published: January 2019

Introduction:
Plasma β-amyloid (Aβ), Tau and Clusterin have been considered biomarkers of vascular and dementia pathology, and as candidate biomarkers to identify persons at high risk of dementia. Cerebral microbleeds (CMBs) are subclinical MRI markers representing the most common forms of cerebral small vessel disease: hypertensive for deep CMB and cerebral amyloid angiopathy for lobar CMB. CMB are associated with higher risk of stroke and dementia, predating clinical diagnosis by several years. We studied the association of circulating Aβ, Tau and Clusterin levels with CMB to elucidate their role as biomarkers for the angiopathies represented by CMB, and further understand the early pathophysiology of cerebrovascular disease predating diagnosis of clinical dementia and stroke.

Methods:
We included dementia and stroke-free Framingham Heart Study participants (mean age 57years, 54% women) with available brain MRI T2*gradient-echo sequences and Aβ (N=1711), Tau (N=3680) and Clusterin (N=3129) measurements. We used multivariable logistic regression analyses to relate circulating biomarker levels to CMB presence overall and stratified by brain topography (OR per SD increase in biomarker level). Models were adjusted for age, sex, time between biomarker measurement and MRI, APOE-e4 genotype, hypertension, statin and antiplatelet use, and C-reactive protein levels.

Results:
CMB were observed in 208 (5.7%) participants (any lobar 174 (4.7%), any deep (56, 1.5%). After multivariable adjustment we observed a borderline association of Aβ-40 with any CMB (OR (95%CI) 1.21(0.99, 1.46) p-value=0.058), a strong association with lobar CMB (OR (95%CI) 1.37 (1.10, 1.71) p-value=0.005), and no significant association with deep CMB. Tau levels were associated with any CMB (OR (95%CI) 1.22 (1.06, 1.40) p-value=0.006), lobar CMB (OR (95%CI) 1.17 (1.01, 1.36) p-value=0.036), and no significant association with deep CMB. No significant association of CMB with clusterin or Aβ-42 levels was found.

Conclusions:
Our results suggest that Plasma Aβ-40 and Tau may serve as biomarkers of cerebral amyloid angiopathy (represented by lobar CMB) and support the role of CMB as markers of neuronal injury.
Abstract 9: Electronic Cigarette Use is Associated With a Higher Risk of Stroke
Authors: Ndunda Paul M , Muutu Tabitha M
Published: January 2019

Introduction:
In 2016, 3.2% of US adults and 11.3% of high school students reported using electronic cigarettes (e-cigarettes) in the preceding 30 days. Its use among young people increased by 900% between 2011 and 2015. Stroke occurs in 795,000 people and causes 133,000 deaths annually in the US. The association between e-cigarette use and stroke is unknown. The purpose of this study was to determine the association between e-cigarette use and stroke.

Methods:
The study is an analysis of the 2016 Behavioral Risk Factor Surveillance System (BRFSS) an annual chronic disease and behavioral risk factor survey conducted by the CDC. The sample included 66,795 respondents that reported ever regularly using e-cigarettes. The control group was the 343,856 respondents that reported never using e-cigarettes. Odds ratios were calculated using logistic regression analysis. Among the covariates tested, age, sex, smoking status, diabetes, exercise and Body Mass Index (BMI) categories showed significant effects on the model and were adjusted for in the outcomes.

Results:
Overall 21% of BRFSS respondents reported ever using e-cigarettes, with 48.5% of them being female (P <0.0001). Compared with non-users, e-cigarette users had a lower mean age (44 vs 57 years [P <0.0001]), lower mean BMI (27.7 vs 28.1 [P <0.0001]) and a lower rate of diabetes (9.8% vs 12.1% [P <0.0001]). They however had higher rates of cigarette smoking (78.7% vs 37.4% [P <0.0001]). Compared with non-users, e-cigarette users had higher adjusted odds of stroke (OR 1.71 [1.64 - 1.8]), myocardial infarction (OR 1.59 [1.53 - 1.66]), angina or coronary heart disease (OR 1.4 [1.35 - 1.46]).

Conclusion:
E-cigarette use is associated with higher odds of stroke, myocardial infarction and angina/coronary heart disease.