bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract TP305: Primary Language Has No Affect on Onset to Emergency Arrival Time or Door to Needle Time for Intravenous Thrombolysis
Authors: Anderson Noriko , Janarious Afra , Stradling Dana , Flanagan Lisa , Yu Wengui
Published: January 2019

Objective:
To determine if primary language affects acute ischemic stroke evaluation and door-to-needle time for intravenous (IV) tissue plasminogen activator (tPA).

Methods:
This is a retrospective study of acute ischemic stroke patients at our center from January 2013 to December 2016. Charts were reviewed to identify preferred language. Data were collected from the Get With the Guidelines Database, including last known well (LKW)-to-door time, door-to-imaging time and door-to-needle time. Patients were divided into English and non-English speaking groups. The non-English speaking group was further divided into Spanish, Vietnamese, and Other groups. Mann Whitney test was used to assess differences between the English and Non-English groups for LKW-to-door time and door-to-imaging time. A chi-squared test was used for pairwise comparisons of English, Non-English, Spanish, Vietnamese, and Other language groups to assess whether language affects likelihood of receiving tPA.

Results:
The study included 1,118 ischemic stroke patients; 188 received IV tPA. Among them 758 were English speaking and 360 non-English speaking patients (196 Spanish, 101 Vietnamese and 63 other language speaking minorities). Between the non-English and English speaking groups there was no significant difference in the average last known well-to-door time (275 minutes vs. 224 minutes p=0.29), door-to-imaging time (23 minutes vs. 22 minutes, p=0.47) and door-to-needle time (51 minutes vs. 55 minutes, p=0.37). In subgroup analyses primary language was not found to have a significant effect on LKW-to-door time for language groups when compared to English. Also, there is no a significant difference for non-English groups when compared to English who present to the hospital within 24 hours of symptom onset.

Conclusions:
Primary language had no significant effect on door-to-needle time for IV tPA or LKW-to-door time. Yet, about one fourth of all patients arrived greater than 24 hours of symptom onset which excludes them from receiving treatment. Increasing targeted community stroke education is essential to help improve recognition of stroke symptoms and timely presentation to stroke centers.
Abstract TP308: Predictive model for Stroke Mimics during Code Stroke Evaluation
Authors: Hathidara Mausaminben , Santucci Joshua , Dupree James , Hollabaugh Kimberly , Ray Bappaditya , Sidorov Evgeny
Published: January 2019

Introduction:
A common approach at differentiating acute ischemic stroke (AIS) from stroke mimics (SM) is medical history and clinical presentation. However, combination of certain clinical symptoms and signs are more associated with SM than with AIS. Identifying these clinical features during “Code Stroke “would help clinicians to raise high suspicion to identify SM and thus prevent futile IV thrombolysis.

Hypothesis:
A predictive model will identify a combination of signs and symptoms associated with SM.

Methods:
A retrospective cohort over a 4-year period was used to construct a predictive model with recursive partitioning.

Results:
During the study period, out of 1467 “Code Stroke” activations, 508 patients were eligible for IV thrombolysis. After initial analysis of 43 “Code Stroke” clinical features, we identified 11 signs and symptoms that were significantly different in AIS and SM patients: age, systolic blood pressure, atrial fibrillation (AF), being on antithrombotic at presentation, similar admissions in the past, seizure at onset, headache at presentation, encephalopathy, focal neurological symptoms, NIHSS and old stroke on head CT. Using a predictive model analysis, headache at presentation, absence of focal symptoms, and seizure at onset significantly predicted of SM. A high predictive value of 92%, (CI: 88-95%) for SM included: i) headache at presentation, ii) no headache without focal symptoms, iii) no headache with at least one focal symptom and seizure at onset. While a low SM predictive value of 29% (CI: 23-35%) included no headache at presentation with at least one focal symptom and no seizure at onset.

Conclusion:
Our study found that among other symptoms, headache, absence of focal symptoms, and seizure at onset have strongest association with SM during “Code Stroke”. Study results further need to be validated in prospective cohort.
Abstract TP31: Endovascular Thrombectomy for Patients With Acute Stroke With Low Aspect Score
Authors: Tetsuya Ioku , Keisuke Imai , Masashi Hamanaka , Masahiro Itsukage , Kazuma Tsuto , Atsushi Yamamoto , toshi Sai , Masanori Cho , Kanako Menjo , Hidekazu Yamazaki
Published: January 2019

Background:
It is generally believed that patientswith acute stroke with ASPECT score (ASPECTS) ≥6 benefit from endovascular thrombectomy.OBJECTIVE:The purpose of the study was to examine the benefit of endovascular thrombectomy for stroke patients with low ASPECTS.

Materials and Methods:
Among 425 consecutive stroke patients treated with endovascular recanalization for occlusion of the anterior circulation at our hospital from March 2007 to June 2018, those with ASPECTS≤6 were included in the study. These patients were classified into three groups based on ASPECTS of 6 (APS6), 5 (APS5), and ≤4 (APS4). Preprocedural factors, procedures, and angiographic and clinical outcomes were compared among the three groups.

Results:
A total of 125 patients were included in the analysis, with 48, 39, and 38 in the APS6, APS5, and APS4 groups, respectively. Median age (75, 77, and 80 years), median DWI-ASPECTS (5, 3, and 3), sparing of pyramidal tract (33, 20, and 8), median baseline NIHSS (21, 23, and 23), occluded site (ICA-MCA: 16-32, 16-23, and 19-19), median onset to door time (128, 204, and 220 min), median door to puncture time (98, 74, and 74 min), intravenous rt-PA (8, 6, and 5), median door to recanalization time (94, 76, and 90 min), median onset to recanalization time (326, 350, and 399 min), complete recanalization (TICI 2b/3: 38, 30, and 24), and median onset to recanalization time (326, 350, and 399 min) did not differ significantly among the three groups. However, the APS4 group had a lower favorable outcome rate (mRS 0-2 at 3 months: 25%, 21%, and 7.8%) and a higher cerebral herniation rate (6.3%, 5.1%, and 18%).

Conclusions:
Caution is required regarding the indication for endovascular thrombectomy in stroke patients with ASPECTS≤4 because these patients may have a lower favorable outcome rate and a higher rate of cerebral herniation.
Abstract TP311: Improving Acute Stroke Management Through Multidisciplinary Case Simulation
Authors: Lima Jussie C , Hosley Catherine , Abbott Lincoln , Griswold Mathew , Price Cynthia , Ruby David , Nowicki Thomas , Beland Dawn , Hoffman Emily , Mack Kelsey , Nouh Amre
Published: January 2019

Background:
Acute stroke management in the ED is complex requiring a team-based approach, particularly as the therapeutic window for ischemic strokes has been extended to 24 hours from symptom onset.

Objectives:
To train and educate neurology, emergency medicine (EM) residents and nursing staff on acute stroke management in the ED using a case simulation based approach.

Methodology:
We designed five case studies (4 standardized patients and 1 high-fidelity mannequin) exhibiting signs and symptoms of acute stroke. Two anterior circulation large vessel occlusions (one eligible for IV thrombolytic and one eligible for mechanical thrombectomy in the extended time window), one basilar thrombosis requiring intervention, one hypertensive hemorrhage and one stroke mimic were included. A total of 17 PGY 1 EM, 7 PGY 2 neurology, 1 stroke fellow, 5 ED nurses, 3 ED and 2 Neurology faculty members divided into 5 teams rotating through all cases. All residents completed didactic education, a 7 item survey (rated 1-5) and a 10 item quiz on acute stroke management pre- and post-simulation. Each group was allotted 15 minutes to assess the patient, interpret results and advice management followed by a10 minute focused debriefing and feedback session. Objective improvements were assessed using paired T-test analysis of pre and post testing.

Results:
Pre vs. post simulation self-assessment survey of: I. Knowledge, understanding and management of acute stroke (2.83 +/- 0.82 vs. 3.63 +/- 0.6, p < 0.0001); II. Use of IV-tPA (3.13 +/- 0.85 vs. 4.17 +/- 0.70, p < 0.0001); III. Mechanical thrombectomy (3.00 +/- 0.83 vs. 4.13 +/- 0.74, p < 0.0001); IV. Blood pressure management (3.21 +/- 0.83 vs. 4.12 +/- 0.76, p < 0.0001); V. Team member responsibilities (2.73 +/- 0.98 vs. 4.08 +/- 0.83, p < 0.0001) and VI .Asking for help (3.71 +/- 1.04 vs. 4.58 +/- 0.58, p = 0.0003) improved. The role of neurology in stroke management from the ED perspective remained unchanged (3.75 +/- 0.99 vs. 4.13 +/- 0.74, p = 0.1191), however all quiz results improved (7.33 +/- 1.83 vs. 8.58 +/- 1.35, p = 0.0048).

Conclusion:
Case based simulation was successful in training and educating neurology and EM residents and ED nursing staff on acute stroke management, improving medical knowledge, communication and effective teamwork.
Abstract TP312: Direct Visits to Comprehensive Stroke Centers Reduce Time Delays for Thrombolytic Therapy in Acute Ischemic Stroke
Authors: Kim Chang Hun , Kang Jongsoo , Kim Soo-Kyoung , Choi Nack-Cheon
Published: January 2019

Background and Purpose
The benefits of thrombolytic therapy for the treatment of acute ischemic stroke are time-dependent. However, many hospitals are not capable of performing endovascular thrombectomy, so patients are often transferred to comprehensive stroke centers, resulting in a delay of treatment. We evaluated the differences in time to thrombolytic therapy between directly admitted patients and referred patients.

Methods:
Between July 2014 and February 2018, 382 patients (mean age: 69.0±11.4 years; men: 52.5%) who received thrombolytic therapies within specified therapeutic time windows were included in this study. We identified stroke patients who received intravenous tissue plasminogen activator within 4.5 hours and/or endovascular thrombectomy within 6 hours of symptom onset. We divided the patients into two groups - those who presented to our center directly, and those who were referred from outside hospitals. Baseline characteristics and time variables were compared between the two groups, and we also evaluated the factors associated with favorable outcomes at 3 months.

Results:
A total of 108 (28.2%) patients were referred from other hospitals, whereas 275 (71.8%) patients presented to our hospital directly. Direct visit patients received thrombolytic therapies faster than the referred group, according to the onset-to-needle time (126 vs. 163 minutes, p < 0.001) and onset-to-puncture time (194 versus 226 minutes, p < 0.001). Younger age (odds ratio (OR) 0.94; 95% confidence interval (CI) 0.92-0.97; p<0.001), lower National Institutes of Health Stroke Scale (NIHSS) score (OR 0.86; 95% CI 0.82-0.90; p<0.001), and direct presentation to the stroke center (OR 1.75; 95% CI 1.02-3.03; p=0.044) were independently associated with favorable outcomes at 3 months.

Conclusions:
Bypassing local hospitals to present directly to the comprehensive stroke center reduced time delays for thrombolytic therapies and improved favorable outcomes in patients with acute ischemic stroke.
Abstract TP314: EEG Has High Precision for Diagnosing Stroke Hours After Onset
Authors: Erani Fareshte , Zolotova Nadezhda , Vanderschelden Benjamin , Wu Jennifer C , Wodeyar Anirudh , Sarian Hagop , Chakravarthy Bharath , Hoonpongsimanont Wirachin , Yu Wengui , Srinivasan Ramesh , Shahbaba Babak , Cramer Steven C
Published: January 2019

Background:
Improvements are needed in prehospital diagnosis of stroke. The electroencephalogram (EEG) changes immediately after brain ischemia, and advances in EEG technology enable rapid acquisition in the acute care setting. We hypothesized that EEG data increase the accuracy with which patients are correctly classified as having acute stroke or not, and so performed a study in the Emergency Department (ED) as an initial step towards evaluating prehospital utility of EEG.

Methods:
Patients with suspected stroke in a comprehensive stroke center ED underwent a 3 min EEG using a wireless, dry-electrode system; data were analyzed offline. A model was developed to classify patients as stroke/TIA vs non-stroke using a training set of 60 randomly selected patients. The model was then tested in an independent validation cohort of 40 new patients. EEG variables were selected using Lasso regression. Four models were examined, the first three using logistic regression: [1] clinical data only; [2] EEG data only; [3] combined clinical and EEG data; [4] a deep learning neural network model using clinical and EEG data.

Results:
Of the 100 ED patients (mean age 64.5 ± 15.7), 63 were ultimately discharged with a diagnosis of stroke (43 ischemic, 7 hemorrhagic) or TIA (13). Median time from last known well (LKW) to EEG was 9.4 hours; from ED arrival to EEG, 3.7 hours. Median time to prepare/place EEG leads then initiate recording was 9 min, shortened during the study (p<0.0001), and was as brief as 36 seconds. To classify patients as stroke/TIA vs non-stroke: [1] The clinical data (including LKW and Rapid Arterial Occlusion Evaluation score) model had AUC=62.3. [2] The EEG data (Lasso selected 4 frontocentral leads, in higher frequencies) model had AUC=78.2. [3] The clinical+EEG data model had AUC=80.3. [4] The deep learning neural network model yielded AUC=87.8.

Conclusions:
The data support the feasibility of using a dry lead EEG system to rapidly acquire EEG in the acute stroke ED setting and suggest utility to improve prehospital stroke diagnosis once acquisition and analysis approaches are appropriately streamlined. EEG captures a signal that is diagnostically useful, independent from clinical measures, and improves the precision with which acute stroke can be diagnosed.
Abstract TP315: A Novel Mechanism for Hemorrhagic Transformation of Ischemic Strokes
Authors: Zheng Yi , Lieschke Franziska , Foerch Christian , Wang Xiaoying , Van Leyen Klaus
Published: January 2019

Introduction:
Ischemic strokes are frequently accompanied by subsequent hemorrhage, particularly in patient subpopulations treated with anticoagulants or platelet inhibitors. In an AHA-funded study, we are investigating how symptomatic hemorrhagic transformation (HT) occurs subsequent to experimental ischemic stroke in mice.

Hypothesis:
In various settings where HT contributes to stroke pathology, increased vascular 12/15-lipoxygenase (12/15-LOX) is central to a vascular injury program that causes HT.

Methods:
Mice were pretreated with warfarin for 24h, or with aspirin plus clopidogrel (ASA/CPG) for 72h, in both cases added to the drinking water. Control mice in both cases received regular drinking water. The filament model was used to induce MCAO in C57Bl6J mice for the times indicated. tPA was infused i.v. at the time of reperfusion, and the 12/15-LOX inhibitor ML351 or vehicle were injected i.p. Shortwave infrared (SWIR) imaging of i.v. injected fluorescent quantum dot nanoparticles was used in some mice to detect early HT in vivo, and used to determine the appropriate time point for sacrifice. Immunohistochemistry of brain sections was used to further analyze the hemorrhage and surrounding areas.

Results:
Pretreatment with either warfarin or with aspirin plus clopidogrel led to increased 12/15-LOX predominantly in the vasculature of mice subjected to experimental stroke. SWIR imaging of brain sections taken at the early stages of hemorrhage showed 12/15-LOX specifically increased near sites of hemorrhage. ASA/CPG pretreatment combined with tPA at the time of reperfusion led to increased HT, which was significantly reduced when the 12/15-LOX inhibitor ML351 was administered.

Conclusions:
12/15-LOX is increased in the vasculature under conditions that favor HT, suggesting it may have a causal role. Inhibition of 12/15-LOX may be considered as a strategy to limit HT of ischemic strokes.
Abstract TP317: Chemokine Production by Microglia Mediates Blood-Derived Monocytes Trafficking in Neuroinflammation
Authors: Huang Meiying , Kim Jong Youl , Park Joohyun , Barua Sumit , Lee Jong Eun
Published: January 2019

Introduction:
After ischemic stroke, microglia and recruited macrophages play major roles in neuroinflammation. We explored how these cells affect counterpart’s polarization and infiltration and revealed some chemokines and receptors can be important modulators of the interaction.

Methods:
BV2 (microglia cell line) were treated with lipopolysaccharides (LPS) or interleukin-4, and the supernatant was collected as M1 or M2 conditioned media of BV2. The supernatant of PMA differentiated THP-1 (monocyte cell line) followed by LPS treatment or interleukin-13 & IL-4co-treatment were collected as M1 or M2 conditioned media of THP-1. After BV2 or THP-1 cultured in conditioned media, the activation and polarization were assessed by ICC and confocal microscopy for CD11b, CD86 and CD206. Transwell inserts of 3 and 8 μm pore membrane were used for THP-1 infiltration and BV2 migration assay. M1/M2 conditioned media of BV2 and THP-1 and the brain tissue of ischemic mouse model were assessed by proteome profiler array (PPA) to find target cytokine and chemokine. THP-1 pretreated with antagonists of CCR2, CCR4, CXCR4 and CCR5 were used for infiltration assay, the expression of chemokine receptor in THP-1 were confirmed by western blotting.

Results:
Both THP-1 and BV2 expressed CD206 when cultured in M2 conditioned media of BV2 or THP-1. M2 conditioned media of BV2 increased the infiltratory ability of THP-1 while M1 conditioned media of THP-1 enhanced BV2 migration. After ischemic stroke, chemokines were significantly expressed at 3 days than at 7 days in the PPA and several chemokines such as CCL2, CCL3, CCL4 and CCL5 were match to the conditioned media of BV2 while their receptor CCR4, CCR5 shows high expression in THP-1. Antagonists of CCR2, CCR4 and CCR5 significantly reduced the infiltration ability of THP-1 to BV2 M2 conditioned media.

Conclusion:
CCL2, CCL3, CCL4, CCL5 and their receptors CCR4, CCR5 can be strong candidates of target proteins in new therapeutic strategies to acute brain inflammation by modulating the functions of microglia and monocytes.
“This research was supported by the Brain Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Science, ICT & Future Planning(NRF-2016M3C7A1905098)“
Abstract TP318: Ethyl Pyruvate Treatment Increases Post-ischemic Levels of Selected Metabolites Detected by Labelled Cerebral Microdialysis
Authors: Nygaard Kevin H , Havelund Jesper , Nielsen Troels H , Færgeman Niels J , Nordström Carl-Henrik , Poulsen Frantz R , Gramsbergen Jan Bert , Forsse Axel
Published: January 2019

Introduction:
Metabolic perturbations associated with mitochondrial function are common after transient cerebral ischemia and are detectable using cerebral microdialysis (CMD). Several putative neuroprotective treatments including ethyl pyruvate (EP) target mitochondrial energy metabolism, but continuous real-time effects have not been described. Using
13
C-succinate labelled CMD with Liquid Chromatography - Mass Spectrometry (LC-MS) we hypothesized that effects of EP treatment on mitochondrial function after transient ischemia could be monitored in vivo.

Methods:
Adult Sprague Dawley rats (n=11) were subjected to transient ischemia by stereotaxic microinjection of vasoconstricting endothelin-1 (ET-1) and monitored for 5 hours after reperfusion with trace amount labelled
13
C-succinate CMD during intravenous treatment with EP (40 mg/kg) or vehicle (Ringer’s solution). Using mixed effect linear regression, values of labelled and endogenous energy metabolites after reperfusion were compared to baseline.

Results:
ET-1 induced vasoconstriction resulted in transient depression of glucose and elevation of lactate. After reperfusion labelled malate and endogenous xanthine displayed significantly higher concentrations in the EP-group compared to the placebo-group: (mean±SEM) 39.5±14.9%, p<0.01 and 93.9±28.3%, p<0.001 respectively. Endogenous glucose-6-phosphate, pyruvate, succinate, fumarate, malate and isocitrate showed larger variance and no significant difference. Neither did labelled pyruvate, lactate fumarate or isocitrate.

Conclusions:
EP treatment potentiates mitochondrial de novo synthesis of malate after transient cerebral ischemia. Differences compared to other Krebs’ cycle intermediates may be explained by a pronounced labelling ratio difference influenced by proximity to labelling source in the metabolic pathway. Increased amounts of endogenous xanthine may be explained by ROS scavenging effects of EP maintaining a beneficial NAD
+
/NADH ratio required for efficient purine metabolism. Labelled CMD combined with LC-MS enables detailed temporal monitoring of energy metabolites aiding evaluation of putative neuroprotective treatments in vivo.
Abstract TP319: Vasoinhibins Overexpression in the Central Nervous System Leads to an Increased Damage After an Ischaemic Insult, While Endogenous Prolactin is Neuroprotective
Authors: Castillo Ximena , Tovar y Romo Luis B , Clapp Carmen , Martínez de la Escalera Gonzalo
Published: January 2019

Cerebral hyperaemia and autoregulation are fundamental players in the maintenance of central nervous system (CNS) homeostasis, and these mechanisms takes place at the neurovascular unit composed mainly by neurons, astrocytes and endothelial cells. Prolactin/Vasoinhibin (PRL/Vi) axis is an endocrine system that regulates blood vessel growth, inflammatory and immune processes by a tight regulation of the counteractive effects of PRL and Vi, the latter being endogenously generated by proteolytic cleavage of PRL. In the nervous system, we have shown Vi-mediated inhibition of neurite outgrow from dorsal root ganglion neurons stimulated by NGF. In the present work, we aimed to identify if PRL/Vi axis may play a role in the functional regulation of the neurovascular unit through direct actions on neurons, glial and/or endothelial cells in the pathological context of transient cerebral ischaemia. An immunohistochemistry approach was used to visualize transduction of adeno-associated viruses (AAV) type 2 overexpressing PRL, Vi or green fluorescent protein (GFP) administered intracerebroventricularly. Ischaemia was modeled
in vivo
by transient middle cerebral artery occlusion (tMCAO) in wild-type mice. PRL receptor knockout mice were subjected to tMCAO without AAV administration. Our results show that AAV2 are transduced mainly in the choroid plexus and the hippocampus, and that mice overexpressing AAV2-PRL showed no difference in the lesion volume after 40 min tMCAO, in comparison with mice transduced with AAV2-GFP (22.9mm
3
+/- 4.44 SEM
Vs
22.5mm
3
+/- 3.56 SEM). Mice overexpressing AAV2-Vi (43.7mm
3
+/- 8 SEM) or lacking PRL receptors (75.1mm
3
+/- 18.84SEM) developed bigger lesion sizes compared to mice transduced with AAV2-GFP (22.5mm
3
+/- 3.56 SEM). Therefore, we conclude that signaling from endogenous PRL is neuroprotective; and that Vi exerts an antagonistic effect in the CNS as thoroughly described previously in the vascular endothelium and other systems.
Abstract TP321: Role of PGE
2
EP1 Receptor Antagonist on Stroke Outcomes in Alzheimer Disease Mouse Models
Authors: Mendes Fulvio R , Leclerc Jenna L , Liu Lei , Kamat Pradip , Hernandez Damian , Naziripour Arash , Ahmad Abdullah S , Dore Sylvain
Published: January 2019

Background:
AD is the most common memory disorder and its prevalence is expected to triple by the year 2050. Neuroinflammation is recognized as an important player in the pathogenesis of AD. One of the most recognized pathways in mediating the neuroinflammation is of prostaglandin E
2
(PGE
2
) EP1 receptor pathway. Role of PGE
2
EP1 receptor in AD mouse models following stroke has not been studied. In this study, we examined the efficacy of a selective EP1 antagonist, ONO-8713, on lesion volumes and behavioral indexes in AD mouse models after stroke.

Methods:
Two cohorts of transgenic, APP/PS1 and 3xTg, and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion (pdMCAO) and sham surgeries. EP1 antagonist ONO-8713 or vehicle was then administered to analyze its effect on anatomical and functional outcomes.

Results:
The functional outcomes were significantly deteriorated in the APP/PS1 and the 3xTg mice after stroke. Interestingly, the ONO-8713-treated groups of WT mice performed significantly (p<0.001) better in open field test than the respective groups of 3xTg mice. For the passive avoidance test, APP/PS1+ONO-8713 mice exhibited significant (p<0.05) difference in retention as compared with the vehicle group; whereas, there was a significant difference in acquisition between WT+ONO-8713 and 3xTg+ONO-8713 (p<0.05). There was a significantly lower tissue injury in APP/PS1+Veh mice when compared to the APP/PS1+ONO-8713 mice (p<0.02). Percent tissue injury was significantly higher in APP/PS1+ONO-8713 mice when compared to WT+ONO-8713 mice (p<0.05). Similarly, in the 3xTg cohort, percent tissue injury and percent tissue loss were significantly higher in 3xTg+ONO-8713 mice than in WT+ONO-8713 mice (p<0.02).

Conclusion:
The EP1 receptor antagonist ONO-8713 shows some beneficial effects on functional and anatomical outcomes after stroke in APP/PS1 and 3xTg mice models of AD; though, the effects were not significant in all outcomes investigated. Further studies are needed to understand the role and optimal timing of EP1 receptor blockade in the context of AD etiopathology.

Funding support:
Grants from the São Paulo Research Foundation, FAPESP (FRM), NIH, and the Ed and Ethel Moore Alzheimer's Disease Research Program (SD).
Abstract TP323: Novel Combinatory Therapy With LAU-0901 Plus NPD1 for Experimental Ischemic Stroke
Authors: Belayev Ludmila , Khoutorova Larissa , Mukherjee Pranab K , Obenaus Andre , Bazan Nicolas G
Published: January 2019

Objective:
Acute ischemic stroke triggers complex neurovascular, neuroinflammatory, and synaptic alterations. Our study tested the prediction that blocking platelet-activating factor-receptors (PAF-Rs)-induced pro-inflammatory signaling plus administering a docosanoid after middle cerebral artery occlusion (MCAo) would lead to sustained neurological recovery. Thus we used two small molecules: a) LAU-0901, an antagonist of the PAF-R that blocks pro-inflammatory signaling and that has shown promising efficacy in a stroke model; and b) a bioactive derivative of docosahexaenoic acid (DHA), the docosanoid Neuroprotectin D1 (NPD1), which activates cell-survival pathways and possesses potent anti-inflammatory and neuroprotective activity in the brain.

Methods:
Sprague-Dawley rats were anesthetized with isoflurane/nitrous oxide and received 2h MCAo by intraluminal suture. Neurological status was evaluated on days 1, 3 and 7; a grading scale of 0-12 was employed. Animals were treated with LAU-0901 (i.p. 30mg/kg, 2h after onset of stroke), NPD1 (i.v. 333mg/kg, 3h after onset of stroke) and vehicles (cyclodextrin and saline). There were four groups: LAU-0901+ NPD1; LAU-0901+saline; Cyclodextrin+ NPD1; and cyclodextrin+saline. On day 7,
ex vivo
MRI of the brains was conducted using 11.7 T MRI.

Results:
LAU-0901 and NPD1 treatments alone improved behavioral scores compared to vehicle groups by 16-44%. The neuroprotective effect was enhanced using the LAU-0901+NPD1, which resulted in improved behavioral scores up to 54% on day 7. Total lesion volumes, which were computed using T2WI, were significantly reduced by 62% with LAU-0901+NPD1 treatment compared to vehicle-treated groups.

Conclusion:
We are currently exploring the detailed molecular mechanisms involved in the combination treatment of the PAF-R antagonist, LAU-0901, plus NPD1. The synergistic neuroprotection observed here for the post-ischemic brain provide the basis to explore therapeutic translational avenues for ischemic stroke.
Abstract TP328: Platelet Hyperactivity Leads to Increased Microthrombi After Subarachnoid Hemorrhage in Mice
Authors: McBride Devin W , Matsumura Kanako , Kumar T. Peeyush , Guddanti Tejesh , Capone Stephen , Blackburn Spiros L
Published: January 2019

Rationale:
Microthrombosis has been suggested as a major factor contributing to delayed neurological deterioration in patients after subarachnoid hemorrhage (SAH). Autopsy studies in humans show microthrombi throughout the brain in SAH patients. However, experimental studies on the role of platelets in microthrombosis after SAH have not investigated. Our hypothesis is that hyper active platelets will increase the microthrombi count, causing more deficits, and that preventing platelet activation will attenuate microthrombi following SAH in mice, improving outcome.

Methods:
SAH was induced in 4 month old male wild-type and LIGHT-/- mice via endovascular perforation. LIGHT-/- mice have hyperactive platelets. Mice were randomly assigned into (n=8/group/strain): Sham, SAH + saline, and SAH + tirofiban (GP IIb/IIIa antagonist, 0.25 mg/kg, IV). Neurobehavior was performed on days 1-3, 5, and 7 post-SAH using a composite neuroscore. One cohort of animals was sacrificed 2 days post-SAH, and the other at 7 days post-SAH. Microthrombi count was performed using serial sections of brains stained for fibrinogen, blood vessels (DiI), and platelets. Neurobehavioral testing performed and all data was analyzed by a blinded investigator.

Results:
Mice subjected to SAH have significantly more microthrombi and performed significantly worse in neurobehavior tests compared to Sham animals on days 2 and 7. Wild-type mice receiving tirofiban have fewer microthrombi and improved behavior. Platelet hyperactive (LIGHT-/-) mice are expected to have greater microthrombi count and preventing platelet aggregation is expected to reduce microthrombi count.

Conclusions:
The expected conclusions are that preventing platelet aggregation after SAH attenuates the formation of microthrombi, thereby reducing functional deficits. This work is expected to highlight platelets as a therapeutic target for preventing delayed neurological deterioration in SAH patients.
Abstract TP330: Selective Brain Hypothermia Augmenting Neuroprotective Effects of Decompressive Craniectomy for Permanent Middle Cerebral Artery Infarction in a Rat Model
Authors: Park Jaechan , Han Youngmin
Published: January 2019

Objective:
This study attempted to evaluate the combined effects of a decompressive craniectomy and prolonged selective brain hypothermia on large hemispheric infarction in a rat model.

Methods:
Permanent middle cerebral artery (MCA) infarction using an endovascular occlusion technique was created in the rats assigned to 4 groups. Normothermia was maintained without a craniectomy in group A (n = 20) as the controls, prolonged (> 44 hours), selective brain hypothermic treatment was performed on group B (n = 20), a craniectomy was performed on group C (n = 18), and prolonged, selective brain hypothermic treatment using a cooling coil implanted in the craniectomy site was combined with a craniectomy for group D (n = 18).

Results:
When compared with the controls, group B and C exhibited a significantly reduced infarct volume. Furthermore, group D showed a further reduction in the infarct volume (P < 0.01) and improved neurological score (P < 0.05) when compared with group C. This was associated with an increased neuronal cell count and reduced hyperactive microgia and hypertrophic astrocytes in the cortical penumbra (P < 0.01). Moreover, a higher preservation of normal-appearing axonal bundles and the blood brain barrier (BBB) was observed in the core infarct region at the caudoputamen.

Conclusions:
A decompressive craniectomy reduced the infarct volume and improved the neurological outcomes in a rat model of MCA infarction. Furthermore, when combined with prolonged selective brain hypothermia, significant additional benefits were observed for the neurological outcomes, infarct volume, and degree of neuroinflammation.
Abstract TP331: Association Between Serum Trimethylamine N-oxide (TMAO) Levels and Infarction Volume in Mice Ischemic Stroke Model
Authors: Ha Jimin , Kwon Il , Ji Da-jeong , Choi Hyun-jung , Heo Ji Hoe , Lee Sang-Guk , Nam Hyo Suk
Published: January 2019

Background:
The brain and gut are made up of a network of many neurons and are bidirectional through the vagus nerve. These two nervous systems adjust to each other when food is needed, stressed, and intestinal bacteria are out of balance. Trimethlamine N-oxide (TMAO) is produced by gut microbiota. Gut microbiota derived TMAO are known to be associated with poor outcome in various vascular diseases including coronary artery disease and peripheral artery obstructive disease. Therefore, increased TMAO may be also associated stroke outcome. We sought the association between TMAO level and infarction size in mice ischemic stroke model.

Method:
Five-week-old male C57BL / 6J mice are fed with Control, 1.2% choline and 0.12% TMAO for 6 weeks. At the 11th week, the transient middle cerebral artery occlusion model (MCAO) was performed. All assessments was blindly conducted. TMAO was measured with mass spectrometry. Infarction size was measured with 2,3,5-Triphenyltetrazolium staining at 1 day after MCAO. Neurological score was assessed with Longa score, Gracia's, and mNHSS.

Results:
During the 6 weeks of feeding, weighing was performed to confirm the diet feeding. Interestingly, the weight of TMAO group mice was generally high. The concentration of TMAO level also varied from group to group. TMAO and choline fed group had significant increase in the level of circulating TMAO compared to control diet fed group (P<0.0002). Therefore, it was found that the level of TMAO in the blood was elevated through dietary treatment with these different diets. We also evaluated infarction volume. Compared with the control group, the infarct volume was decreased in the group with higher TMAO level than the control group (control 18.9±7.4 vs. higher TMAO group 13.6±5.9, p=0.032).

Conclusion:
We found that the infarction volume was associated with TMAO level. Increased TMAO may be beneficial in acute ischemic stroke.
Abstract TP332: Hypoxia-Inducible Factor 1-Alpha (HIF1α)-Mediated Phosphoenolpyruvate (PEP) Carboxykinase-1 (PCK1) Upregulation & Metabolic Injury in Stroke
Authors: Cosky Eric E , Guan Longfei , Shen Jiamei , Geng Xiaokun , Ding Yuchuan
Published: January 2019

Introduction:
In acute ischemic stroke (AIS), neurons upregulate glycolysis in an attempt to meet their energy demands, which causes lactic acidosis and reactive oxygen species (ROS) formation. These metabolic changes injure brain tissue by decreasing pH and disrupting local redox balance. There is emerging evidence that gluconeogenesis occurs in the brain. In AIS, the energy-requiring gluconeogenic pathway may be incomplete due to lack of ATP. In hepatocytes, HIF1α upregulates gluconeogenesis at the PCK1 promoter, which catalyzes oxaloacetate (OAA) decarboxylation to CO
2
and PEP. In AIS, HIF1α may act similarly, but its precise molecular mechanism in neuronal gluconeogenesis is unknown. It is hypothesized that gluconeogenesis is stunted through HIF1α upregulation of PCK1 in ischemia, which contributes to increased acidotic & oxidative injury and neuron damage.

Methods:
Four cell culture groups (SH-SY5Y neurons) were cultivated: (1) control, (2) control cells transfected with HIF1α shRNA, (3) cells with oxygen-glucose deprivation (OGD) for 2 h and reoxygenation for 24 h, and (4) OGD cells transfected with HIF1α knockdown shRNA. The amount of lactate and ROS were assayed. Cell damage was determined by the WST-1 viability assay and apoptotic protein expression. The mRNA and protein levels were measured through qRT-PCR and Western blotting.

Results:
Cell viability decreased amidst increased lactate and ROS levels after OGD, and there was decreased Bcl2 (anti-apoptotic) and increased Bax (pro-apoptotic) protein expression. HIF1α and PCK1 mRNA and protein levels increased after OGD along with decreased glucose and OAA. The lactate and ROS were reduced (p<0.05) and glucose and OAA were elevated (p<0.05) with HIF1α shRNA treatment. Cell viability was enhanced by HIF1α shRNA after OGD, as expression of Bax decreased and Bcl2 increased. HIF1α shRNA decreased HIF1α and PCK1 mRNA and protein levels.

Conclusion:
Decreased acidotic, apoptotic, and oxidative damage by HIF1α knockdown aligned with enhanced cell survival through decreased PCK1 and decreased gluconeogenic activity. HIF1α-upregulated PCK1 stunted gluconeogenesis, leading to neuronal damage through lactate and ROS toxicity.
Abstract TP335: Intracerebral Hemorrhage Deteriorates the Mortality and Slows Functional Recovery in a Mouse Model of Alzheimer's Disease
Authors: Hayashi Kenyu , Hasegawa Yu , Takemoto Yushin , Mukasa Akitake , Kim-Mitsuyama Shokei
Published: January 2019

Background:
Alzheimer’s disease (AD) is the main form of dementia and sometimes coexists with stroke including intracerebral hemorrhage (ICH), especially in elder patients. However, the detailed relationships between them are undetermined. In this study, we investigated how ICH affected the prognosis and the pathology in AD model mice.

Material and Method:
We employed seventeen-and-eighteen-month-old male 5XFAD (5X), an AD model mouse, and littermate mice (LT). The mice were injected collagenase type VII (ICH) or saline (vehicle) into left striatum. In experiment I, to address the acute effect of ICH in AD, LT-ICH (n=10) and 5X-ICH (n=10) mice were evaluated hemorrhagic volume and brain edema at 72 hours after ICH induction. In experiment II, to examine the chronic effect of ICH in AD, mice were divided into the following 4 groups; 1) LT-vehicle, 2) LT-ICH, 3) 5X-vehicle, 4) 5X-ICH and then assessed blood pressure (BP), mortality rate, neurological finding, and cognitive function. Their brains were removed, and performed immunohistochemistry to confirm the effect of ICH on inflammatory responses and accumulation of amyloid β (Aβ) protein in AD pathology.

Results:
In experiment 1, there were no significant differences of hemorrhagic volume and brain edema between the mice. In experiment 2, the 5X-ICH mice showed significantly higher mortality rate and slower recovery of motor function. Oxidative stress detected by gp91 and microphage expression was significantly increased in 5X-ICH compared with 5X-vehicle. On the other hand, BP, cognitive function, and accumulated Aβ proteins were not affected by ICH in 5XFAD.

Conclusions:
ICH deteriorated the mortality and slowed functional recovery in AD model mice, which might be associated with enhancement of oxidative stress under accumulated Aβ proteins.
Abstract TP338: Knowledge of Stroke Core Symptoms Are Important for Help-seeking Behavior and Receiving Reperfusion Therapy
Authors: Iversen Ane B , Thomsen Rikke B , Blauenfeldt Rolf , Andersen Grethe
Published: January 2019

Introduction:
We investigated the association between pre-stroke core symptom knowledge and recognition of core symptoms at stroke onset, with prehospital delay and receiving reperfusion therapies. Core symptoms are defined as facial palsy, palsy of extremities and aphasia/dysarthria.

Methods:
A cross-sectional study of consecutive patients with acute stroke and TIA admitted at two stroke centres in the Central Denmark Region, between January 28
th
2018 and May 10
th
2018. Structured interviews of patients and bystanders (separately), combined with clinical information from the Danish stroke registry were obtained. Eligible patient were > 18 years, independent in daily activities (mRS<3) with stroke onset-to-interview ≤7 days.

Results:
We included 469 of 1210 stroke/TIA patients in the period with a median (IQR) age of 71 (61-80). Median (IQR) admission-to-interview time was 1 (1-1) day. Pre-stroke knowledge of ≥ 1 core symptom was 46 % for patients and 71 % for bystanders. Knowledge of ≥ 2 core symptoms was 22 % and 52 % respectively.
Pre-stroke knowledge
in patients was not significantly associated to EMS contact, onset-to admission < 3 hours or reperfusions therapy, but in bystanders pre-stroke knowledge of ≥ 2 core symptoms was associated with increased EMS contact OR (95% CI) 2,35 (1,24-4.45) and receiving reperfusion therapy 1,94 (1,04-3.61).
Help-seeking
based on ≥ 1 observed core symptom at onset by bystanders and ≥ 2 core symptoms experienced by patients were significantly associated with a direct EMS contact, onset-to admission < 3 hours and receiving reperfusions therapy.

Conclusions:
Pre-stroke knowledge and help-seeking based on observed core symptoms at onset is essential reducing prehospital delay and increasing reperfusion rates. The pivotal role of bystanders “to act” should be a target for future stroke awareness campaigns.
Abstract TP339: Off Hours Presentation is Not Associated With Poor Functional Outcomes or Faster Recanalization Times in Stroke Patients Receiving Mechanical Thrombectomy in a Large Volume Comprehensive Stroke Center
Authors: Al Kasab Sami , Samaniego Edgar , Kimmel Eric , Holcombe Andrea , Lopez-Cardenas Gloria , Hernandez Helin , Dandapat Sudeepta , Asi Khaled , Derdeyn Colin , Ortega-Gutierrez Santiago
Published: January 2019

Background:
Faster revascularization times are associated with better functional outcome in patients undergoing thrombectomy. We aim to evaluate the impact of time of day presentation on thrombectomy metrics and its association with long-term functional outcome in an IR equipped OR setting.

Methods:
We retrospective reviewed all stroke patients who received mechanical thrombectomy between December 2012 and December 2017 at our CSC from our prospectively collected database. Work hours were defined by official OR work hours (Monday-Friday 7 AM and 5PM) and after hours as between 5 PM and 7 AM during weekdays and weekends as well as official hospital holidays. Collected data included baseline demographics, admission NIHSS, receipt of tPA, and location of occlusion. Primary outcomes were delta NIHSS between admission and discharge and 90-day modified Rankin Scale (mRS). Secondary outcomes included door to groin time and revascularization rate (TICI2b and 3). Multivariable logistic and Wilcoxon Rank test were performed to compare groups.

Results:
A total of 78 (38%) patients underwent mechanical thrombectomy during work hours and 125 (62%) during after-hours. There were more females in the after-hours group (55% vs 40%, P=0.046). There was no difference in mean age (66.8 vs 68.1, P=0.457), race (93% whites in both group) and median admission NIHSS (17 in both groups). Median door to groin time was 85 minutes during work hours vs. 94 minutes during after-hours (P=0.93). There was no difference in revascularization rate (70% vs 76%, P=0.67), delta NIHSS (2.9 vs 5.7, P=0.173) or long-term functional outcome (43% vs 53%, P=0.121) between after-hours vs work hours respectively.

Conclusion:
Studies suggest that after hours delay could impact functional outcomes on stroke patients undergoing thrombectomy. In-house 24/7 Anesthesia and IR tech services might improve metrics and mitigate this effect.
Abstract TP34: Malignant CT Perfusion Profile is Associated With Increased Sensitivity to Blood Pressure Reductions During Endovascular Stroke Therapy
Authors: Strander Sumita , Wang Anson , Kodali Sreeja , Silverman Andrew , Agarwal Tijil , Stretz Christoph , Zheng-Lin Binbin , Lopez Cardenas Gloria V , Sansing Lauren H , Schindler Joseph L , Matouk Charles , Hebert Ryan , Sheth Kevin N , Ortega Gutierrez Santiago , Petersen Nils H
Published: January 2019

Background:
After large-vessel occlusion (LVO), blood flow to the ischemic penumbra largely depends on collateral perfusion. Blood pressure (BP) reductions during endovascular therapy (EVT) have been associated with increased infarct size and unfavorable functional outcome. We hypothesized that patients with poor collateral circulation assessed using CT perfusion imaging are at increased risk for infarct progression associated with intraprocedural BP reductions.

Methods:
We prospectively enrolled 90 patients with LVO stroke who underwent perfusion imaging and EVT at two comprehensive stroke centers. Volumes of arterial tissue delay >10 seconds (ATD10) were estimated with RAPID software; a malignant profile was defined as ADT10 >100 ml. BP reduction was defined as the difference between baseline mean arterial pressure (MAP) at the start of EVT and the lowest MAP during the procedure. Sustained relative hypotension was calculated as the area between baseline MAP and continuous measurements of intraprocedural MAP.

Results:
Sixty-seven patients (mean age 67 ± 15, 38 F, mean NIHSS 16) who were successfully revascularized (TICI 2B/3) were included in analysis. Mean baseline MAP was 119 ± 23 mmHg and median BP reduction was 28 (IQR 20 - 53). These values did not differ significantly among those with malignant (n=19) and non-malignant (n=48) collateral profiles, yet average infarct volume on follow-up was significantly greater among patients with poor collaterals (65 mL vs 32 ml) after adjusting for age and admission NIHSS (p=0.029). A significant interaction was found between the malignant collateral profile and intraprocedural BP reduction (p=0.02, Figure 1A&B).

Conclusions:
Patients with malignant collateral profiles are more sensitive to BP reductions during EVT, leading them to develop significantly larger infarcts. These results emphasize the importance of intraprocedural blood pressure management for this at-risk group.
Abstract TP345: Early Mobilization Following Recombinant Tissue Plasminogen Activator Administration and/or Mechanical Thrombectomy Reduces Length of Stay
Authors: O'Connor Kevin , Frazure Allison , Campbell Margie , Polly Megan , Reckner Katie , Lee Jessica D
Published: January 2019

Background:
Nearly 800,000 strokes occur each year in the United States and are a leading cause of disability. They result in an annual financial burden of roughly $34 billion, which includes hospitalization and rehabilitation thereafter. Despite this cost, data regarding appropriate timing of mobilization follow administration of intravenous recombinant tissue plasminogen activator (rt-PA) is lacking. As value-based payment models drive systems to reduce length of stay (LOS) and cost of care, early mobilization following rt-PA provides a means to achieve those ends in addition to potentially improving outcomes.

Methods:
We conducted a retrospective case-control study including all acute ischemic stroke (AIS) patients admitted to a tertiary academic hospital stroke service from November 2017 to July 2018 who received IV rt-PA locally or by drip and ship, and/or underwent mechanical thrombectomy. The control group includes AIS patients from November 2017 to April 1, 2018. Per protocol, controls (Group 1) were maintained on bedrest for 24 hours after receiving IV rt-PA. Beginning April 2, 2018, a total of 88 (Group 2) patients were managed with early mobility protocols stratifying patients for early mobilization based on NIHSS score, presence of severe aphasia, whether they underwent thrombectomy, and their clinical stability.

Results:
Among Group 1 (n=109), the mean time from rt-PA bolus to PT/OT assessment was 38 hours 55 minutes, and the average LOS was six days. With delays removed (PT/OT unable to assess due to intubation/sedation), mean time from bolus to assessment was 33 hours 25 minutes (n=101) and average LOS was five days. Following implementation of early mobility protocols in Group 2 (n=81 treated with IV rt-PA), patients had a mean time from bolus to PT/OT assessment of 22 hours 29 minutes, with an average LOS of 4.42 days. With delays removed, mean time from bolus to assessment was 18 hours 10 minutes, with an average LOS of 3.66 days. No adverse events were seen related to early mobilization in Group 2.

Conclusions:
These data suggest that early mobilization following IV thrombolysis is safe and results in decreased time to PT/OT evaluation with subsequent reduction in length of stay. Further study is needed to evaluate for potential impacts on outcome.