bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 184: The Relationship Between Carotid Plaque on Magnetic Resonance Plaque Imaging and Time From Stroke Onset
Authors: Shirakawa Manabu , Yuan Chun , Yamada Kiyofumi , Enomoto Yukiko , Kojima Takao , Wakabayashi Kazuki , Watase Hiroko , Sun Jie , Hatsukami Thomas S , Yoshimura Shinichi
Published: January 2019

Introduction:
Previous studies report that rate of recurrent stroke, as well as the risk of carotid surgery, is highest in the early stages following cerebral infarction and decreases over time, which suggests a process of plaque healing and stabilization. The purpose of this study is to identify differences in carotid plaque components according to the time from stroke onset, using carotid magnetic resonance plaque imaging (MRPI) to evaluate the dynamic phase of plaque development following an acute cerebrovascular ischemic event.Methods and

Results:
MRPI on 3T scanners was obtained in 128 patients enrolled in the Carotid Artery Stenting study (MRCAS). MRCAS is a non-randomized multicenter prospective observational study to compare the plaque characteristics evaluated by MRI and ischemic complications after CAS in Japan. Among the 128 subjects, 60 presented with TIA or stroke and 68 were asymptomatic. The 60 TIA/stroke cases were classified into four groups based on the interval from the onset of symptoms to the date of carotid MRPI (Group 1: <14 days [n=25]; Group 2: 15-30 days[n=13]; and Group 3: >31 days [n=22]). The 68 asymptomatic cases were classified as Group 4. The volume of intraplaque hemorrhage (IPH), necrotic core, calcification and loose matrix was quantified on MRPI using Radiant DICOM viewer. Further, the presence of inner Loose Matrix (iLM) was identified as a high intensity area located between the vessel lumen and necrotic core or IPH on both T2WI and proton density weighted images.Patients characteristics were not significantly different among all groups. The mean volume of loose matrix in Group 3 was significantly lower than Group 1 and Group 4 (0 mm3 vs 12.3 mm3 and 15.5 mm3; p= 0.01, 0.03, respectively). The prevalence of iLM in Group 1 was higher than in Group 3 and 4 (68% vs 18.2%, 38.3% ; p<0.01, <0.01, respectively).

Conclusions:
The prevalence of inner Loose Matrix, located at the interface between the lumen surface and the necrotic core or IPH, is significantly higher in the early stage after stoke/TIA. This study suggests that carotid plaques undergo rapid evolution, especially adjacent to the luminal surface, after an acute cerebrovascular ischemic event.
Abstract 185: Treatment of Internal Carotid Artery Near Occlusion (NEON Study): An Individual Patient Data Meta-Analysis
Authors: Meershoek Armelle , de Vries Evelien , Veen Duco , den Ruijter Hester , de Borst Gert J
Published: January 2019

Introduction:
The European Society for Vascular Surgery guideline recommends to treat patients with an internal carotid artery near occlusion (ICA NO) with best medical therapy (BMT). This recommendation is based on level III, class C evidence, published in 2003. From this time onwards, ICA NO was defined as a high-risk subgroup and these patients were excluded from randomized controlled trials. Consequently, only observational studies have been published. The aim of this individual patient data (IPD) meta-analysis was to determine the optimal treatment approach.

Methods:
A systematic search was performed in MEDLINE, EMBASE and Cochrane databases in January 2018. The primary outcome was the occurrence of any stroke or death within the first 30 days of treatment, analyzed by a multivariate mixed effect logistic regression with correction for potential confounders as age, gender, symptom status and center. The secondary outcome was the occurrence of any stroke or death beyond 30 days up till one year of treatment, analyzed by a Kaplan-Meyer survival curve.

Results:
We pooled IPD from 11 studies, 703 patients. Within 30 days, any stroke/death was reported in 8 patients (2.4%) in the CEA group, in 5 patients (2.2%) in the CAS group, and in 7 patients (4.9%) in the BMT group. This resulted in a higher 30-day stroke/death rate after BMT than after CEA (OR 5.63, 95% CI 1.3-24.45, p=0.021). No differences were found between CEA and CAS (OR 0.62, 95% CI 0.06-6.11, p=0.682). The 1-year any stroke/death free survival rate was 96.1% for CEA, 94.4% for CAS and 81.2% for BMT (see figure).

Conclusion:
BMT is not superior to CEA or CAS with respect to 30-day or 1-year stroke/death prevention in patients with internal carotid artery near occlusion. In addition, these patients do not constitute a high risk subgroup for surgery and should not be excluded from future RCTs.
Abstract 187: Odds of Stroke in the Young based on Preexisting Atherosclerotic Risk Factors
Authors: Poisson Sharon N , Hills Nancy K , Sidney Stephen , Fullerton Heather J
Published: January 2019

Background:
Recent studies suggest an increasing incidence of stroke in young populations in the last 2 decades in contrast with the declining incidence in older adults. Rising prevalence of atherosclerotic risk factors (ARF) has been proposed as an explanation for this trend. The aim of this study was to determine the odds of stroke with different ARF across the young population.

Methods:
In a case control study nested within a cohort of children (29 days-19 years) and young adults (20-49 years) enrolled in a Northern California integrated health care system between 2000-2014, cases of ischemic stroke were identified using ICD-9 codes as well as text string searches of the radiology database, and were confirmed by chart review and adjudicated by 2 MD review. Controls matched by age and dates of enrollment were randomly selected from the cohort. Charts for all cases and controls were reviewed for evidence of ARF prior to stroke diagnosis.

Results:
Strokes were identified in 141 children and 449 young adults, and 354 childhood controls and 1,014 young adult controls were randomly selected. All ARF were found at very low rates in both childhood cases and controls (figure). In the 20-29 year age group, hypertension and having more than one risk factor significantly increased the odds of stroke. In the oldest 2 groups (30-39, 40-49y), all 5 ARF significantly increased the odds of stroke, as did having more then one risk factor.

Conclusions:
ARF are very rare in children, including in those with strokes. Hypertension begins to increase the odds of stroke in the 3
rd
decade of life, but in the 4
th
and 5
th
decades, each risk factor’s impact on stroke risk is significant, with more then one risk factor increasing the odds of stroke 10-fold.
Abstract 188: Association Between Uric Acid and Stroke in the REgards Case-cohort Study
Authors: Chaudhary Ninad S , Gaffo Angelo L , Cushman Mary , Colantonio Lisandro D , Levitan Emily B , Judd Suzanne E , Singh Jasvinder , Limdi Nita A , Bridges S Louis , Howard George , Reynolds Richard J , Irvin Marguerite R
Published: January 2019

Introduction:
The association between hyperuricemia and stroke has been inconsistent especially after adjustment for cardiovascular risk factors. Previous studies were limited in the number of events and did not measure these associations in subgroups.

Methods:
We used a stratified case-cohort design within the REasons for Geographic and Racial Differences in Stroke study. Clinically adjudicated stroke events (n=903) were defined as focal neurologic deficit lasting >24 hours or non-focal neurological symptoms with brain imaging consistent with stroke. Controls (n=951) were a random stratified sample selected from baseline to ensure representation of high-risk groups. Uric acid was assayed using the baseline sample and categorized into three groups: < 6 (referent), 6-6.8, ≥ 6.8 mg/dl (hyperuricemia). Cox-proportional-hazard-models adjusted for demographic and clinical variables were fit to examine the association between uric acid levels and stroke. We repeated the analysis stratified by race, gender, and age (</≥ 65years) and finally, since uric acid is associated with hypertension, explored the count of antihypertensive treatment classes (nHTN) as a potential mediator.

Results:
Hyperuricemic individuals were more likely to be male and black. Hyperuricemia versus the referent category was significantly associated with stroke after adjustment for race, sex, age, and age*race interaction [model 1 HR(95%CI)= 1.42(1.12-1.80)], and after further adjustment for systolic and diastolic blood pressure [HR (95%CI)= 1.42(1.12-1.80)]. The associations was attenuated after full adjustment [HR (95%CI)= 1.22(0.91-1.63)]. Incremental adjustment by clinical variables suggested nHTN attenuated the association between hyperuricemia and stroke. Results were similar for hyperuricemia within subgroups defined by age, gender and race, except among men <65 years [HR (95%CI)= 2.72(1.25-5.93)]. Mediation analysis estimated that nHTN accounted for 43%(95%CI: 15 to 158%) of the relationship.

Conclusion:
We observed a significant association between hyperuricemia and stroke that was partially dependent upon hypertension severity (count of antihypertensive treatment classes). The association was strongest among males aged <65 years.
Abstract 191: Socioeconomic Disparity Independently Predicts Initial Ischemic Stroke Severity
Authors: Abdelbaky Amr , Patrich Tomas , Osborne Michael T , Tung Brian , Oberfeld Blake , Armstrong Katrina , Tawakol Ahmed , Ay Hakan
Published: January 2019

Introduction:
Lower socioeconomic status (SES) associates independently with poorer outcomes after stroke. We have previously demonstrated that the relationship between low SES and worse stroke outcomes is mediated by larger infarct size on presentation. Here, we tested the hypothesis that the relationship between SES and initial stroke severity varies across stroke subtypes.

Methods:
Consecutive patients (N=1168) presenting to Massachusetts General Hospital with acute ischemic stroke (mean age= 68, 55.1% male) underwent brain MRI within 24 hrs of admission. Infarct volume on DWI and admission NIH stroke scale (NIHSS) score were recorded. Stroke etiology was classified using the causative classification system. SES was assessed using local median household income as a proxy (by home zip code, using U.S. Census Bureau Fact Finder).

Results:
Both infarct volume and admission NIHSS score increased with decreasing SES tertiles: [NIHSS median (IQR): 5.0 (2.0, 12.0) vs. 4.0 (2.0, 11.0), vs. 3.0 (1.0, 9.0), p = 0.002], [Infarct volume median (IQR): 7.2 (1.5, 28.2) vs. 5.9 (1.5, 30.2) vs. 4.6 (1.0, 19.9), p = 0.02]. This relationship was mainly driven by LAA and CE categories (Figure). Lower SES predicted infarct volume and NIHSS score in combined group of LAA and CE after adjusting for traditional stroke risk factors and history of previous stroke (standardized β [95% CI]) NIHSS: -0.15 [-1.6, - 0.5] p < 0.001, infarct size: - 0.10 [-10.6, -1.8], p = 0.006).

Conclusions:
While disparities in post stroke care may play an important role in the relationship between lower SES and worse outcomes, we show that this association is also significantly driven by a tendency towards developing larger, more severe strokes on presentation, mainly caused by LAA and CE.
Abstract 192: Gender and Racial Disparities in Secondary Prevention of Stroke
Authors: Ndunda Paul M , Muutu Tabitha M
Published: January 2019

Introduction:
In the US, 795 000 people suffer a stroke and 133 000 die from it annually. Among the survivors, 185 000 get a recurrent stroke. There are gender and racial disparities in stroke mortality and there is need to understand the associated factors, if the AHA’s 2020 impact goal is to be achieved. The objective of this study was to assess the gender and racial differences in the use of secondary preventive measures in patients with stroke, and to identify the associated factors.

Methods:
This is an analysis of the 2015 Behavioral Risk Factor Surveillance System, a chronic disease survey conducted by the CDC. The sample included 18 269 subjects with stroke. outcomes analyzed included: exercise, diet, smoking cessation, alcohol intake, body mass index, use of blood pressure (BP) medications and the use of aspirin. Gender and racial disparities were analyzed using logistic regression analysis. Age, race, education and income were adjusted for in the outcomes.

Results:
Women comprised 58.3% of the stroke cohort. White, black and Hispanic respondents represented 75.1%, 11.5% and 4.7% respectively. The mean ages of study subjects were 66.6 and 67 years for men and women respectively. Women were more likely to continue smoking (OR 1.22 (1.13, 1.32)), less likely to meet both the AHA exercise guidelines (OR 0.87 (0.81, 0.94)) and more likely to be obese/overweight (OR 1.45 (1.35, 1.54)). They were also less likely to be on aspirin (OR 0.57 (0.40, 0.80)) and BP medications (OR 0.96 (0.85, 1.09)). Women were more likely to eat ≥1 servings of fruits (OR 1.41 (1.33, 1.50)) and vegetables (OR 1.32 (1.23, 1.40)), were more likely to have health insurance (OR 1.21 (1.04, 1.40)) and clinical provider (OR 1.76 (1.75, 1.76)). Hispanics were more likely to continue smoking compared with whites (OR 1.37 (1.15, 1.63), Blacks and Hispanics were less likely to exercise compared with whites (OR 0.66 (0.61, 0.72) and (OR 0.78 (0.68, 0.88) respectively. Blacks were less likely to eat fruits (OR 0.7 (0.64, 0.76) and vegetables (OR 0.56 (0.51, 0.61) but these effects were attenuated by adjusting for income and education.

Conclusion:
There are significant gender and racial disparities in secondary stroke preventive measures. Income and education may play an important role in the disparity.
Abstract 22: Apoptosis Signal-Regulating Kinase 1 (ASK1) is a Novel Master Molecular Switch Controlling Microglia/Macrophage Reactions That Impact Short- and Long-Term Stroke Outcomes
Authors: Shi Yejie , Zhang Wenting , Wang Rongrong , Leak Rehana K , Chen Jun
Published: January 2019

Introduction:
Recent studies suggest that the functional status of microglia/macrophages (Mi/MΦ) profoundly impacts stroke outcome. However, the molecular mechanisms regulating Mi/MΦ reactions after brain ischemia/reperfusion (I/R) are poorly understood.

Hypothesis:
Activation of ASK1, a key MAPKKK upstream of multiple inflammation-regulating pathways, critically contributes to I/R brain injury via priming Mi/MΦ towards a neurotoxic phenotype.

Methods:
We generated mice with cell-specific, tamoxifen-induced knockout of ASK1 in neurons (nKO) or Mi/MΦ (mKO). Brain injury, neuroinflammation, and various behavioral deficits were assessed after 1 h MCAO and reperfusion.

Results:
MCAO induced transient ASK1-MKK4-JNK3 activation (6-24 h) in neurons and persistent ASK1-MKK3-p38/STAT1 activation (3-5 d) in Mi/MΦ in WT, but not in ASK1 nKO or mKO mice, respectively. ASK1 nKO reduced infarct sizes by 28.5% at 2 d after MCAO (p<0.01 vs WT, n=8-10/group), but failed to prevent the release of HMGB1 from necrotic cells and Mi/MΦ activation, or exert any effect on long term (28 d) stroke outcomes. In contrast to neuronal ASK1 KO, ASK1 mKO markedly improved both short and long term sensorimotor/cognitive functions after I/R (p<0.01 vs WT, n=14-16/group). ASK1 mKO attenuated the activation of p38α and STAT1 (immunostaining), inhibited the expression of 12 proinflammatory markers in Mi/MΦ (FACS-sorting followed by qPCR; p<0.05, n=4/group), and mitigated brain inflammation (ELISA array; 19 out of 80 markers, p<0.05, n=5/group) 3 d after I/R. In consistent with the role of p38α and STAT1 as downstream mediators of ASK1 signaling in Mi/MΦ, either p38α or STAT1 mKO alleviated neuroinflammation (3 d) and improved long term (28 d) stroke outcomes (n=12/group), partially mimicking the effects of ASK1 mKO.

Conclusions:
ASK1-dependent activation of p38α and STAT1 promotes inflammation, I/R brain injury, and maladaptive behavior by priming Mi/MΦ towards a neurotoxic phenotype.
Abstract 23: Circulating Peripheral Factors Induce Age-Related Epigenetic Changes in Microglia Which Induces a Primed Phenotype
Authors: Koellhoffer Edward C , d'Aigle John , Morales-Scheihing Diego , McCullough Louise D
Published: January 2019

Background:
Microglia populate the neuroepithelium during embryonic development and reside the CNS as innate immune cells for the lifetime of the individual. However, microglia acquire a dysregulated phenotype with age and are primed to respond to neurological injury such as stroke in an exaggerated, detrimental fashion. We have previously shown that pro-inflammatory microglia are regulated epigenetically and have elevated histone H3 lysine 27 trimethylation (H3K27me3).

Hypothesis:
We hypothesized that aged microglia are epigenetically dysregulated by peripheral factors to induce a pro-inflammatory, primed phenotype.

Methods:
We used naïve 3 to 24 month-old C57Bl/6 male mice (Charles River, NIA). We also performed heterochronic parabiosis where young (2-3 month) and aged (18-20 month) male mice were surgically attached for 8 weeks and came to share a common blood supply. Isochronic young (Y ISO) and aged (A ISO) pairs served as surgical controls. A cohort of parabionts was stimulated with i.p. lipopolysaccharide (LPS) for 24hr. Brains were collected for Western blot, real-time PCR (RT-PCR), and multiplex cytokine analysis.

Results:
We found the brains of aged mice have increased levels of H3K27me3 (p<0.05). Aging increased 18 pro-inflammatory cytokines in the brain, notably IFNγ (3mo 20.5pg/mg vs. 24mo 28.7pg/mg, n=5-8, p<0.05) and GM-CSF (3mo 15.7pg/mg vs. 24mo 25.3pg/mg, p<0.005) which are both implicated in microglia priming phenotype. In brains of aged heterochronics (A HET) mice, we found a reduction in H3K27me3 and decrease in IFNγ (p<0.05) and GM-CSF (p<0.05) compared to A ISO controls. In parabionts stimulated with LPS, A HET mice had significantly less pro-inflammatory cytokines in the CNS suggesting faster neuroinflammatory recovery.

Conclusion:
We conclude that circulating peripheral factors are responsible for the epigenetic dysregulation and primed phenotype of aged microglia which may be rejuvenated by manipulation of peripheral factors.
Abstract 24: Optogenetic Stimulation of Excitatory Motor Cortex Neurons Promotes Functional Recovery After Stroke
Authors: Pendharkar Arjun V , Harvey Sean S , Chiang Terrance , Cheng Michelle Y , Steinberg Gary K
Published: January 2019

Objective:
Post-stroke brain stimulations have been shown to successfully enhance functional recovery. Previously we have demonstrated that optogenetic pan-neuronal stimulations in the ipsilesional primary motor cortex (iM1) promote functional recovery after stroke, however, the specific neuronal cell types involved (excitatory or inhibitory) remain unclear. Here we use optogenetic techniques to specifically stimulate excitatory neurons in layer V ipsilesional motor cortex and investigate the effects on functional recovery.

Methods:
C57BL/6 wild type mice were used (7-9 weeks). Mice underwent stereotaxic surgery to inject AAV1-CAMKIIa-ChR2-eYFP and implant a fiber cannula in the iM1. Six weeks later, all mice were subjected to an intraluminal middle cerebral artery suture occlusion (30 minutes). Optogenetic stimulation began at post-stroke (PD) day 5 and continued until PD14. Sensorimotor tests were used to assess behavioral recovery at PD4, 7 and 14. Mice were sacrificed at PD14 and their brains were processed for immunohistochemistry with CD68 and MAP2 for infarct analysis.

Results:
High expression of ChR2-YFP was detected in excitatory neurons of ipsilesional layer V motor cortex. Optogenetic excitatory stimulations in iM1 resulted in significant forelimb movements. Horizontal rotating beam test demonstrated that iM1-stimulated mice recovered significantly faster than non-stimulated mice in both speed and distance at PD14 after stroke. In particular, iM1-stimulated mice exhibited robust recovery in distance traveled at PD14 (p<0.01), with most mice performed similar to pre-stroke baseline. Furthermore, iM1-stimulated mice also exhibited faster regain of body weight loss after stroke. Infarct analysis using immunohistochemistry showed that there was no difference in lesion size between groups.

Conclusions:
These data highlight excitatory neurons as key cell type for brain stimulation-induced functional recovery after stroke. Current studies examine the molecular and circuit mechanisms underlying this recovery, including the role of neurotrophins in both the ipsilesional and contralesional sensory and motor cortices.
Abstract 25: Promoting Recovery After Stroke by Manipulating NMDA Receptor-Associated Signalling in the Early Post Stroke Phase
Authors: Ballarin Beatrice , Cui Hong , Teves Lucy M , Ji Zhanxin , Tymianski Michael
Published: January 2019

Introduction:
According to the World Health Organization (WHO), stroke remains a leading cause of mortality and neurological disability globally. To date, there is no effective pharmacological treatment to promote recovery from stroke. Promoting regenerative repair may improve recovery and it is known that N-methyl-D- aspartate receptors (NMDARs) play important roles in neural circuit rebuilding. Therefore, an appealing strategy to promote stroke recovery is to selectively inhibit cell death mechanisms while promoting pro-survival processes mediated by NMDARs. A promising agent for this purpose is Tat-NR2B9c (NA-1), a clinical-stage agent being tested in Phase 3 trials for acute ischemic stroke. Tat-NR2B9c promotes the activation of pro-survival signaling and is a potent neuroprotector against excitotoxicity. Here we sought to determine whether treatment with Tat-NR2B9c promotes functional recovery in rats subjected to ischemic brain damage during the subacute recovery phase.

Methods:
Stroke was induced by Pial Vessel Disruption (PVD) in Sprague Dawley rats. Permanent devascularisation was induced by removing all the pia and the attached blood vessels of the left motor cortex. Experimental groups were: PVD + Tat-NR2B9c (n = 12); PVD + Vehicle (n = 11); Sham + Tat-NR2B9c (n = 8); Sham + Vehicle (n = 8). Tat-NR2B9c was injected intravenously (IV) beginning 3 days after stroke and was administered daily for 7 days. A behavioral battery of tests followed, composed of neurological score, cylinder test, horizontal ladder and adhesive removal tests. Brains were stained with H&E and the infarct size was analyzed by ImageJ.

Results:
Repeated IV injections of Tat-NR2B9c led to a significant improvement in all motor tasks: decreased number in foot slips by 3.6-fold in horizontal ladder (P < 0.0001); improved neurological score by 4.7-fold compared to control (P < 0.0001); improved use of affected limb by 58% in cylinder test (P = 0.0006); reduced adhesive removal test time by 81% (P < 0.0001). There was no difference in infarct sizes between the groups.

Conclusion:
Treatment with Tat-NR2B9c post stroke improved functional outcome in rats subjected to PVD. Current studies are ongoing to assess the mechanism of action underlying the observed recovery.
Abstract 26: Stroke Impairs Epithelial Microfold Cells in Intestinal Peyer’s Patches
Authors: Lee Juneyoung , Lai Yun-Ju , McCullough Louise D , Venna Venugopal R
Published: January 2019

Introduction:
Peyer’s patches (PP) are lymphatic tissue in the small intestine. Tissue-resident specialized epithelial cells [microfold (M) cells] are essential for immune surveillance in the gut by sensing pathogens and eliciting immune responses by lymphocytes. Emerging evidence highlights the importance of gut microbiota as an epicenter for post-stroke infection, however the role of PP and M cells in stroke is still undefined.

Hypothesis:
Ischemic stroke influences the antigen-sampling systems in intestinal PPs.

Methods:
Young (8-10 wks) and aged (18-20 months) C57BL/6N male mice were subjected to either sham or 60-minute middle cerebral artery occlusion (MCAO) followed by reperfusion. Mice were sacrificed at day 3 after stroke. The small intestines were isolated and PP tissue was obtained. The numbers and structure of the PP and M cells were assessed using whole-mounts and confocal microscopy. Gene expression in PP was examined using real-time qPCR. Finally, immune cells in PPs were evaluated using flow cytometry.

Results:
The number of PPs was dramatically reduced at day 3 after stroke. Sham mice had 7 to 10 PPs in their small intestines, whereas stroke mice only retained 2 to 5 PPs (n=4/group,
P
<0.05). Aging also decreased the numbers of PPs both in sham (5 to 6) and stroke mice (1 to 4) (n=4/group,
P
<0.05). Whole-mount assays revealed that stroke impaired the number of UEA-1
+
WGA
-
M cells as well as the structure of the PP. Stroke induced the loss and shrinkage of villus and decreased both villus M cells and fucosylated epithelial cells in the distal ileum. Additionally, stroke abrogated the mRNA expression of Gp2 and RANKL pathway genes such as Tnfsf11 (RANK) and Tnfsf11a (RANKL) that are responsible for M cell maturation and function, respectively (1.95, 1.31 and 2.67 fold change in Gp2, Tnfsf11 and Tnfsf11a, respectively, n=4/group,
P
<0.05). However, we did not observe a significant change of immune cells in PP after stroke.

Conclusions:
The response of PP in stroke was highly epithelial M cell-specific. Although the understanding of interactions between luminal antigens including bacteria and PP is still needed, our data provides us with a new insight into how brain damage can alter antigen sampling and shape adaptive immunity in the host.
Abstract 28: Transcriptomic Profiling of Microglia in Acute and Delayed Phases Following Ischemic Stroke
Authors: Gao Tianwen , Raza Syed A , Xiao Hailian , Cheng Lihong , Yepes Manuel , Rangaraju Srikant
Published: January 2019

Background:
Neuroinflammation mediated by microglia and CNS-infiltrating macrophages (CNS-MPs) impacts neuronal survival and recovery following ischemic stroke. Transcriptomic profiling of microglia has revealed switching from homeostatic to disease-associated microglial (DAM) states in neurodegeneration but microglial profiles at acute/subacute phases post-stroke remain unclear.

Methods:
We performed transcriptomics (770 gene panel) of acutely-isolated CNS-MPs from ipsi- and contralateral hemispheres following transient (30min) middle cerebral artery occlusion (tMCAO) in adult C57BL6J mice at 24-72h post-tMCAO. Normalized data were used for differential expression analyses to identify changes distinct to the ipsilateral hemisphere as well as to delayed stages post-MCAO (>±2-fold change, p<0.05). These were contrasted with homeostatic and DAM profiles and validation quantitative RT-PCR studies were performed.

Results:
Among 533 genes included, highly abundant transcripts in our dataset were enriched (p=0.003) for abundantly expressed microglial genes, confirming microglial enrichment. 52 transcripts were differentially expressed ipsilaterally (22 upregulated, 29 downregulated) of which 17 changed 2-fold (7 upregulated: Spp1, Ccl2, Lilrb4a, Anapc15; 10 downregulated: Ppfia4, Trpm4, Reln, Ldlrad3, Camk4). Ipsilaterally, delayed differential expression was observed for 37 genes (33 upregulated including Apoe Fabp5, Il1b and Grn; 4 downregulated) suggesting an emerging DAM post-tMCAO, further corroborated by quantitative RT-PCR for DAM genes (Itgax, Timp2, Il1b, Ptgs2).

Conclusions:
Early and delayed CNS-MP transcriptomic profiles are significantly different with evidence for emergence of DAM after 72h post-ischemia. We identify microglial osteopontin (Spp1) as being highly upregulated post-MCAO and support roles for neurodegeneration-associated genes (Apoe, Grn) in delayed post-stroke neuroinflammation.
Abstract 31: Magnitude of Benefit of Prehospital Mobile Stroke Unit vs Conventional ED Thrombolysis: Final Estimate Based on PHANTOM-S Observational Registry Study
Authors: Nour May , Gornbein Jeffrey A , Kunz Alexander , Nolte Christian , Scheitz Jan F , Ebinger Martin , Audebert Heinrich , Saver Jeffrey L
Published: January 2019

Background:
Mobile stroke units (MSUs) enable faster start of IV thrombolytic therapy for acute ischemic stroke. We sought to estimate the magnitude of benefit arising from speedier lytic start upon functional outcomes at 3 months in patients with acute ischaemic who had received emergency mobile care or conventional care.

Methods:
In a prospective observational registry study in Berlin, ischemic stroke patients were treated with IV thrombolysis in a stroke emergency mobile (STEMO) vehicle or conventionally (normal ambulances and ED lytic start). Disability outcomes (modified Rankin Scale) at 3m were analyzed, adjusted for age, sex, afib, NIHSS, and intra-arterial treatment. For dichotomized mRS outcomes, benefit per thousand (BPT) and number needed to treat (NNT) were derived directly from the absolute risk difference. For disability shift across all 6 mRS levels, BPT and NNT were derived by joint outcome table multiple resampling.

Results:
Among 658 IV tPA-treated patients, 305 were treated in the MSU and 353 conventionally in ED. Of the 6 cutpoints on the mRS, 5 showed more favorable outcomes with MSU care and 1 with conventional care. The Table shows resulting BPT and NNT values. The dichotomized endpoint with the greatest group difference was disability-free (mRS 0-1) outcome, 62.7% STEMO vs 54.8% conventional, BPT 79, NNT 12.7. For the 6 possible dichotomizations of the mRS, the benefit per thousand patients ranged from -9 to 79. For benefit of improving by 1 or more mRS levels across all 6 transitions of the mRS, the BPT was 176 and NNT 5.7.

Conclusions:
This observational study, with adjustment for key prognostic features, estimates that out of every 1000 patients treated with MSU rather than conventional ED thrombolysis, 176 will have a less disabled final outcome, including 79 more who would be disability-free. Larger, formally-controlled clinical trials are needed, and under way, to confirm whether MSUs do confer these substantial clinical benefits.
Abstract 33: FAST-ED Based Pre-Hospital Stroke Triage System Improves Endovascular Treatment Times, Especially off Hours
Authors: Rynor Helen E , Starosciak Amy K , Strauss Jayme , De Los Rios La Rosa Felipe
Published: January 2019

Introduction:
Acute stroke outcomes depend on timely reperfusion. In March 2017, the Fire Officers Association of Miami-Dade (FOAMD) implemented the Field Assessment Stroke Triage for Emergency Destination (FAST-ED) scale. Those with a score ≥ 4 bypass other centers for a comprehensive stroke center (CSC) and those with a score ≥ 6 also have the interventional team activated from the field. We analyzed the impact of this initiative on volume, treatment times, outcomes, and distance traveled from scene.

Methods:
All stroke cases brought to Baptist Hospital of Miami by FOAMD during March 2016 through February 2018 were analyzed, which included a year before and after FAST-ED implementation. Treatment times were compared on vs. off hours and to those with a FAST-ED score ≥6. We used the FAST-ED score documented on the EMS run sheet and a calculated score based on the initial NIHSS.

Results:
A total of 1153 patients met criteria. Of these, 761 (67%) were coded as stroke (ischemic, hemorrhagic, or TIA), and 235 (20%) underwent reperfusion treatments. Age, sex, race/ethnicity, initial NIHSS, distance traveled, length of stay, door to needle time, and 90 day mRS were comparable between periods (Table). Scale compliance was 85%. Concordance rate of ±1 point between FOAMD and calculated score was 53%. Compared to the previous year, door to groin times (DTG) improved by 17 min (p<0.01) overall, by 25 min (26%) (p<0.001) off-hours only, and by 33 min (31%) (p<0.05) off-hours and calculated FAST-ED ≥ 6.

Discussion:
The FAST-ED initiative led to faster DTG times. The highest impact is for off-hours with field activation. Only 1 out of 3 activations led to endovascular treatment.
Abstract 35: Safety and Outcomes of Intravenous Tissue Plasminogen Activator in Acute Ischemic Stroke Patients With Recent Stroke: Findings From Get With the Guidelines-Stroke
Authors: Shah Shreyansh , Liang Li , Kosinski Andrzej , Hernandez Adrian F , Schwamm Lee H , Smith Eric E , Fonarow Gregg C , Bhatt Deepak L , Peterson Eric D , Xian Ying
Published: January 2019

Introduction:
Guidelines recommend against use of Intravenous tissue Plasminogen Activator (IV tPA) in acute ischemic stroke (IS) patients with prior IS within past 3 months. However, there are limited data on the safety of IV tPA in this population.

Methods:
Using American Heart Association Get With the Guideline-Stroke between February 2009 and December 2015 we identified 1399 acute IS patients otherwise eligible for IV tPA but with IS within prior 3 months. Of these, 293 were treated with IV tPA. We compared them with 30,655 acute IS patients treated with IV tPA but with no prior IS history. Multivariable logistic regression models were used to evaluate association between recent prior IS (within 90 days, 1-14 days, 15-30 days, 31-90 days) with symptomatic intracranial hemorrhage (sICH) and discharge outcomes after IV tPA.

Results:
Age (median 80, IQR 74-87) and stroke severity as measured by NIHSS (median 11, IQR 6-18) were similar for acute IS patients treated with IV tPA with or without recent IS. However, patients with recent IS were more likely to have higher prevalence of cardiovascular risk factors. In unadjusted analysis, patients with recent IS within prior 90 days were more likely to experience sICH and in-hospital mortality and less likely to have good functional outcomes (modified Rankin Scale score, 0-1) than those with no history of IS (Table 1). On multivariate analysis, risk for sICH and in-hospital mortality was not significantly different but good functional outcomes at discharge occurred less often among patients with history of IS within prior 90 days. In a prespecified subgroup analysis, the increased risk for sICH appeared to concentrate in those with recent IS within 14 days of the acute index IS but not in later time window.

Conclusions:
Recent IS within 90 days is associated with increased risk of worse outcomes in acute IS patients treated with tPA. In our study, the risk of sICH after tPA was highest among those with a history of prior IS within the past 14 days.
Abstract 37: Secondary Stroke Prevention With Aspirin and Clopidogrel in
CYP2C19
*17 Carriers Increases Risk of Major Non-CNS Bleeding
Authors: Simpkins Alexis N , McDonough Caitrin W , McClure Leslie A , Mitchell Braxton D , Shuldiner Alan R , Benavente Oscar R , Johnson Julie A
Published: January 2019

Combination aspirin and clopidogrel reduces risk of recurrent ischemic stroke, but was also associated with risk of non-central nervous system (CNS) major bleeding in the Platelet-Oriented Inhibition in New TIA or minor stroke clinical trial. The loss-of-function CYP2C19*2 allele potentially reduces clopidogrel efficacy, while the gain-of-function CYP2C19*17 allele may increase bleeding risk. The clinical application of these alleles is unclear. SNP genotyping of CYP2C19*2 and CYP2C19*17 are available in the Secondary Prevention of Small Subcortical Strokes clinical trial, a 2x2 factorial study in patients with lacunar infarcts where one arm tested the efficacy of secondary stroke prevention with aspirin plus clopidogrel versus aspirin alone. We hypothesized that patients carrying CYP2C19*2 would have more clopidogrel failure events (defined as a composite of ischemic stroke, transient ischemic attack, and cognitive decline), while patients carrying at least one CYP2C19*17 allele, would have more major bleeding, including sub-analysis of CNS and non-CNS major bleeding. The associations of CYP2C19*2 with treatment failure and CYP2C19*17 with major bleeding were assessed through logistic regression, adjusting for age, gender, race, and excluding CYP2C19*2/*17 carriers. The mean age of the cohort (n=522) was 62 (62% male). There were no significant differences in treatment failure events between *2 carriers and *2 non-carriers (Odds ratio (OR) [95% confidence interval (CI)] = 1.60 [0.66-3.87], p-value=0.29), adjusting for *17. Patients with a *17 allele had a significantly higher odds of a non-CNS hemorrhage (OR [95% CI] =2.50 [1.03-6.09], p-value=0.043), and a trend for significance after adjusting for *2, p-value=0.06. Only two CNS hemorrhages occurred in the total cohort; both occurred in normal CYP2C19 metabolizers. Although limited by sample size, the study suggests that CYP2C19 carrier status may contribute to non-CNS major bleeding risks seen in dual antiplatelet therapy secondary stroke prevention trials. Further studies are needed to confirm whether the presence of CYP2C19*17 or absence of *2 increases the risk of bleeding complications, which could have implications for treatment decisions in a precision medicine approach.
Abstract 39: Effect of Herpes Zoster Vaccination and Antiviral Treatment on Risk of Ischemic Stroke among Older Adults
Authors: Yang Quanhe , George Mary G , Chang Anping , Merritt Robert , Hong Yuling
Published: January 2019

Introduction:
Herpes zoster (HZ) is associated with increased risk of stroke. No study has simultaneously examined the effect of HZ vaccination and antiviral treatment following HZ on risk of acute ischemic stroke (AIS).

Methods:
We included 35,186 Medicare fee-for-service beneficiaries ≥66 years of age diagnosed with HZ and AIS from 2007-2015. We used a self-controlled case series design to examine the association between HZ and AIS, and estimated the incident rate ratio (IRR) by comparing the incidence of AIS in risk periods (periods following HZ) vs. control periods (rest periods). To minimize confounding by age, we restricted analyses to ±365 days from the HZ index date. To examine effect modification by HZ vaccination and antiviral treatment following HZ, beneficiaries were classified into four groups: (1) no vaccination and no antiviral treatment; (2) vaccination only; (3) antiviral treatment only; and (4) both vaccination and antiviral treatment. We tested for interaction to examine the changes in IRRs across the 4-groups.

Results:
Among 35,186 Medicare beneficiaries with HZ and AIS, 60.9%, 11.8%, 22.2% and 5.2% were in groups 1 to 4, respectively. IRRs at 0-14, 15-30, 31-90, and 91-180 days following HZ were 1.48 (95% CI 1.37-1.59), 1.31 (1.21-1.42), 1.18 (1.12-1.24), and 1.07 (1.03-1.13), respectively. There was no evidence of effect modification by HZ vaccination and antiviral treatment on AIS (all p-values for interaction across 4-groups IRRs >0.05 with the smallest p=0.129). The pattern of association between HZ and risk for AIS was consistent across age group (66-74yrs, 75-84yrs, and ≥85yrs), sex, and race (non-Hispanic white, non-Hispanic black, Hispanic, other).

Conclusions:
Risk of AIS increased significantly following HZ, and this increased risk didn’t appear to be modified by HZ vaccination and antiviral treatment following HZ. Primary prevention of HZ by HZ vaccination might be the most effective approach to prevent HZ-associated AIS.
Abstract 4: Endovascular Thrombectomy May Be Safe and Effective in Patients With Large Core Lesions on Either Simple CT or Perfusion Images
Authors: Sarraj Amrou , Hassan Ameer , Grotta James , Sitton Clark , Chen Peng R , Vora Nirav , Cai Chunyan , Cutter Gary , Pujara Deep , Imam Bita , Reddy Sujan , Kamal Haris , Abraham Michael , McCullough Louise , Lansberg Maarten , Savitz Sean , Gupta Rishi , Albers Gregory
Published: January 2019

Background:
Endovascular thrombectomy (EVT) efficacy and safety is not established in patients with large core. We evaluated the clinical and radiologic outcomes following EVT in acute strokes with large ischemic core lesions defined by CT ASPECTS and/or CTP.

Methods:
From a multicenter prospective cohort study of imaging selection for thrombectomy (SELECT), patients with large ischemic core on CTP (rCBF< 30%) >50 ml and/or ASPECT≤5 up to 24 hrs from last known well were identified at 9 U.S centers. All patients received a baseline CT and CTP with automated ischemic core determination by RAPID. A blinded core lab adjudicated all images. The primary outcome was 90 day mRS 0-2. Safety outcomes were sICH and mortality. Outcomes of EVT patients were compared to those who received medical management (MM) only.

Results:
Of 445 enrolled, 106 had large core on either CT or CTP: 71 ASPECTS≤5 (EVT 37, MM 34) and 75 CTP core >50 ml (EVT 40, MM 35), 40 on both CT and CTP. Median (IQR) age 66 yr, NIHSS 20 (16-23), time to puncture 224 min (range 69-832), ASPECTS 5 (4-6) and CTP core 72 ml (41-96). Baseline characteristics were similar in EVT vs. MM patients in both CT and CTP definition groups. The EVT group had better mRS 0-2 rates as compared to MM (32 % vs 14%), aOR: 2.9 (95% CI: 1.0-7.9, p=0.041) and a favorable mRS shift on ordinal analysis aOR: 2.0 (95% CI 1.0-4.1, p=0.049), smaller final infarct volume 96 (49-196) vs 175 (127-225) ml, p=0.02, and less infarct growth 44 (0.7-107.6) vs 83 (61-133) ml, p=0.03 with similar mortality 29% EVT, 42% MM, p=0.16 and sICH 13% EVT, 7% MM, p=0.3. EVT patients were more likely to achieve mRS 0-2 if treated early (0-6) vs late (>6-24 hrs) for both CTP defined (27% vs 0%) and CT defined large core (44% vs. 18%). The good outcome declined by 20% for each hr of treatment delay (Fig 1).

Conclusion:
EVT may be effective and safe for patients with a large core, especially if treated early. RCTs are needed.
Abstract 40: Risk of Recurrent Stroke by Fazekas Category and Relationship With Intensive Blood Pressure Reduction: A Secondary Analysis of the SPS-3 Trial
Authors: de Havenon Adam , Majersik Jennifer , Wong Ka-Ho , Tirschwell David , Rost Natalia
Published: January 2019

Introduction:
Prior research has shown that an increased burden of white matter hyperintensity (WMH) is an independent risk factor for ischemic stroke.

Hypothesis:
The risk of recurrent stroke in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial will increase in higher Fazekas categories, but not for patients randomized to more intensive blood pressure reduction.

Methods:
We included patients with a Fazekas score on the baseline MRI and compared rates of recurrent stroke with the chi-squared and Cox proportional hazards tests.

Results:
2,970 patients met inclusion criteria, with 236 (8.0%) recurrent strokes. The rate of stroke increased in the higher Fazekas categories (0-1=6.3%, 2=8.1%, 3=10.9%, p=0.003). This remained significant in the less intensive blood pressure reduction arm, but not in the more intensive blood pressure reduction arm (Table 1). After dichotomizing into Fazekas 0-2 versus 3, there was a significant risk of stroke for patients with less intensive blood pressure reduction and Fazekas 3 (Hazard ratio: 2.02, 95% CI: 1.40-2.92, p<0.001), but not for patients with more intensive blood pressure reduction and Fazekas 3 (Hazard ratio: 1.12, 95% CI: 0.70-1.81, p=0.633) (Figure 1).

Conclusion:
Increased WMH burden is a risk factor for recurrent stroke in patients with prior lacunar stroke. For patients with severe WMH burden (Fazekas 3), this risk is attenuated by the intensive blood pressure reduction.
Abstract 42: CAS versus CEA Treatment Differences in Long-Term Outcomes and Post-Procedural Durability: the Carotid Stenosis Trialist Collaboration (CSTC)
Authors: Brott Thomas G , Calvet David , Howard George , Gregson John , Algra Ale , Becquemin Jean-Pierre , Brown Martin M , Bulbulia Richard , Eckstein Hans-Henning , Fraedrich Gustav , Halliday Alison , Hendrikse Joroen , Jansen Olav , Roubin Gary S , Ringleb Peter A , Mas Jean-Louis , Bonati Leo H
Published: January 2019

Introduction:
A 3.4% (95% CI: 2.1% to 4.7%) higher peri-procedural stroke and death risk has been previously documented for those treated with carotid artery stenting (CAS) relative to those treated with carotid endarterectomy (CEA). However, the CAS versus CEA treatment differences in long-term outcomes and the post-procedure durability have not been described.

Methods:
Data from the 4 largest CAS-versus-CEA randomized trials for treatment of symptomatic carotid atherosclerosis (EVA-3S, SPACE, ICSS, and CREST) were pooled, and treatment differences assessed for the outcome of any stroke or death during a 120-day peri-procedural period, plus ipsilateral stroke afterward.

Results:
Long-term follow-up was analysed for 4754 patients. Median length of follow-up across the studies ranged from 2.0 to 6.9 years, with 88 peri-procedural and 55 post-procedural events among those CEA-treated, and 169 and 64 for those CAS-treated. After the peri-procedural period, the annual rates of stroke following CAS was 0.6% (95% CI: 0.5 to 0.8) and following CEA 0.6% (95% CI: 0.5 to 0.8), resulting in non-significant durability differences of less than 1% over the period extending up to 9 years (see Table). The previously-documented 3.4% higher peri-procedural event rate in the CAS group contributed to a significant 3.1% (95% CI: 1.6% to 4.7%) treatment difference at 1-year, and the aforementioned similar durability implied that this significant difference remained relatively constant over the period extending up to 9 years (see table).

Conclusions:
The post-procedure durability of CAS and CEA were similar, both with event rates below 1%. The similarity of post-procedure events rates implies that the previously-documented higher peri-procedural in the CAS group is “carried forward” with a higher risk of outcomes extending to 9-years.
Abstract 43: Characteristics of Intracranial Cerebral Aneurysms According to the Coronary Artery Calcium
Authors: Cho Bang-Hoon , Han Sang Won , Lee Kyung-yul
Published: January 2019

Introduction:
Several vascular risk factors are known to be associated with the presence of intracranial cerebral aneurysm. Coronary artery calcium (CAC) which reflects the atherosclerotic burden of coronary artery is a known predictor of cardiovascular event and stroke. We investigated the relationship between cerebral aneurysm and CAC.

Methods:
We retrospectively enrolled subjects who had both brain magnetic resonance angiography and cardiac computed tomography as part of health examinations from January 2010 to July 2017. Subjects were categorized into four groups according to the CAC score by cardiac computed tomography; none (0), low (1-99), intermediate (100-399) and high (> 400). The prevalence of cerebral aneurysm according to the CAC score groups was assessed. We also performed subgroup analysis by the sex, age and location of intracranial cerebral aneurysm.

Results:
Total 4934 subjects (age 54.1 ± 9.8 years, female 42.2%) were included for analysis. Cerebral aneurysms were detected in 258 subjects (5.23%). The prevalence of cerebral aneurysm was significantly increased as the CAC score increased (4.8%, 5.4%, 6.4% and 11.1%, respectively, p for trend = 0.004). This correlation was more prominent in women than in men over the age of 50 (7.1% vs 3.7, 8.8% vs 4.4%, 8.6% vs 6.3%, and 21.1% vs 10.0%, respectively). As to the aneurysm location, non-bifurcation aneurysm was more common than bifurcation aneurysm in high CAC score group (p=0.02). In multivariate analysis, the group of high CAC score had significantly more cerebral aneurysm than group of no CAC score (adjust odds ratio = 2.16, 95% confidence interval 1.18-3.95).

Conclusions:
CAC which reflects coronary artery atherosclerosis is also an important risk factor of intracranial cerebral aneurysm. This correlation is more prominent in female and non-bifurcation aneurysm.