bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract WMP82: Exosomes Derived From Cerebral Endothelial Cells of Young Adult Rats Reduced Cognitive Deficits in Aged Diabetic Rats
Authors: Zhang Li , Chopp Michael , Li Chao , Jiang Quan , Ding Guang Liang , Zhang Yanlu , Xiong Ye , Wei Min , Zhang Zheng Gang
Published: June 2021

Introduction:
Diabetes mellitus (DM) is associated with cognitive decline and dementia in the elderly. The glymphatic system mediates clearance of the interstitial solutes in the brain by exchange of cerebrospinal and interstitial fluid (CSF and ISF). We recently demonstrated that DM in aged rat induces impairment of the glymphatic system and cognitive decline. Exosomes, membrane vesicles, mediate intercellular communication by transferring their cargo into recipient cells. The present study investigated whether cerebral endothelial exosomes (CEE) ameliorate glymphatic system impairment and improve cognitive function in aged DM rats.

Methods and Results:
DM was induced in male Wistar rats (13 months, n=48) by injection of nicotinamide and streptozotocin. Two months after DM, rats were treated with CEE (1x10
11
exosomes/rat, IV) twice a week for 4 weeks. Age matched DM and non-DM rats were used as controls. CEE were harvested from the cultured cerebral endothelial cells of health young adult rats. Exchanges of CSF and ISF were measured by intracisternal injection of fluorescent tracer, Texas Red-dextran (TR, 3kD). Confocal microscopic analysis of brain slices revealed a progressive slowdown of ISF clearance in the hippocampi, assessed by retention of TR starting at 2.5 fold at 2M (13±5 vs 5±3% of area) and increasing to 4 fold at 4M (21±4 vs 5±2%) of DM. Paravascular amyloid β (Aβ) accumulation was only detected at 4M of DM. The CEE treatment significantly (p<0.05) reduced TR retention (10±4%) at 4M of DM and also decreased Aβ accumulation (2±1 vs 6±2/mm
2
) and parenchymal fibrin deposition (9±5 vs 23±5/mm
2
) compared to untreated DM rats. Moreover, the CEE treatment significantly improved hippocampal related learning and memory measured by the Morris Water Maze and odor-based novelty recognition for olfactory memory, without altering the glucose level. In vitro, cerebral endothelial cells isolated from 2M DM rats exhibited substantial dysfunction as measured by capillary-like tube formation and cell migration, whereas incubation with the CEE substantially reversed endothelial dysfunction.

Conclusions:
The CEE treatment reduces DM-induced glymphatic and cerebral endothelial dysfunctions, leading to improvement of cognitive function in aged DM rats.
Abstract WMP84: Intranasal Trans-olfactory Delivery of the Angiotensin Type 2 Receptor Agonist Compound 21 is Neuroprotective in Ischemic Stroke
Authors: Bennion Douglas M , Isenberg Jacob D , Dang Alex N , Jones Chad H , Graham Justin T , Steckelings Ulrike M , Sumners Colin
Published: June 2021

Background:
Compound 21 (C21), a selective small-molecule angiotensin type 2 receptor (AT2R) agonist, has been proven in multiple preclinical studies to reduce infarct size and ameliorate neurological deficits, when administered after ischemic stroke via intracerebroventricular or intraperitoneal routes. However, C21 poorly penetrates the blood brain barrier (BBB). In this study, we used the novel and non-invasive approach of intranasal trans-olfactory (INTO) application, in order to bypass the BBB and deliver C21 directly into the brain. The therapeutic efficacy of INTO application of C21 was assessed in a model of transient middle cerebral artery occlusion (MCAO).

Methods:
(i) Male SD rats (12 weeks old) underwent ischemic stroke by endothelin-1-induced MCAO. They were randomly divided into two treatment groups, either receiving 0.9% saline or C21 (1.5 ug/kg) at 1.5, 4, 24 and 48 h post-stroke, using a rat intranasal catheter device (Impel Neuropharma, Seattle, WA) for INTO application. All rats underwent blinded neurological assessments at 4, 24 and 72 h after stroke, and immediately after the 72 h tests, were euthanized and cerebral infarct volumes were assessed by TTC staining. (ii) Male SD rats (12 weeks old) underwent implantation of a telemetry transducer (DSI, St. Paul, MN) into the abdominal aorta for measurement of blood pressure, heart rate and locomotor activity after INTO C21 (1.5 ug/kg) vs. 0.9% saline at baseline and post-ischemic stroke.

Results:
(i) Post-stroke INTO delivery of C21 (1.5 ug/kg) elicited a significant lowering of % cerebral infarct volume (25.4 ± 4.7; n=9) compared with saline-treated rats (48.4 ± 4.4; n=21) [p<0.05; two-way Mann-Whitney test]. The C21 (1.5 ug/kg)-treated rats also displayed highly significant improvements in Garcia and Bederson neurological scores (p<0.01; two-way Mann-Whitney test]. (ii) INTO delivery of C21 (1.5 ug/kg) either in naïve rats (n=7), or in rats post-stroke (n=4), did not significantly alter baseline blood pressure, heart rate and locomotor activity.

Conclusions:
Our results demonstrate, that INTO delivery of C21 exerts protective effects after ischemic stroke. These studies suggest INTO administration as potential future route of application of C21 to stroke patients.
Abstract WMP85: Target Stroke Implementation: Best Practice Strategies Cut Thrombolysis Time to <30 minutes in a 1,550 Bed Academic Urban County Hospital
Authors: Marulanda-Londoño Erika T , Bhatt Nirav , Atachaneeyasakul Kunakorn , Malik Amer M , Asdaghi Negar , Akram Nida , Zhang Tony J , D’Amour Daniel , Hesse Kathy , Sacco Ralph L , Romano Jose G
Published: June 2021

Introduction:
Thrombolytic window for acute ischemic stroke is brief and crucial. The AHA/ASA Target: Stroke Best Practice Strategies (TSBPS) aim to help hospitals improve thrombolysis door-to-needle (DTN) time. We assessed long-term efficacy of TSBPS to reduce DTN in a tertiary care hospital.

Methods:
We initiated a quality improvement program across one regional academic medical center (1,550 beds, 900 annual stroke admissions) that serves a multi-ethnic population by establishing a multidisciplinary DTN committee to assess causes of delayed DTN and implement focused TSBPS. Strategies included stroke team pre-admission notification, direct transfer to CT scanner, storing and administering IV rt-PA at CT scanner, and immediate stakeholder feedback. Door-to-CT, DTN, CT to IV rt-PA and door-to-groin (DTG) times were analyzed prospectively in consecutive IV rt-PA treated patients over 27 months pre-implementation and 13 months post-implementation.

Results:
A total of 148 patients were included in the pre-implementation and 126 patients in the post-implementation group. The two groups had similar demographics, comorbidities, anticoagulation status, pre-thrombolysis hypertension treatment, stroke severity (median NIHSS 11 (6-18) vs. 11 (5-17), p= 0.483), arrival by EMS (96% vs. 97%, p=0.708), and arrival after hours. Post implementation, reductions in treatment times were observed for median DTN (IQR) 59 (52-80) to 28.5 (20-41) min (p<0.001), door-to-CT time 17 (14-21) to 16 (12-19) min (p=0.016), CT-to-IV rt-PA time 43 (31-59) to 13 (6-23) min (p<0.001), and DTG time 164 (136-188) min (n=37) to 86 (63-103) min (n=51) (p<0.001). Overall monthly IV r-tPA administration increased post-implementation (5.5 vs. 9.8, p<0.001). Rate of symptomatic intracranial hemorrhage (2.7% vs. 3.2%, p=0.817) and treatment of stroke mimics (9% vs. 13%, p=0.311) were similar pre- and post-implementation.

Conclusions:
In this study, delay in IV rt-PA administration was predominantly related to prolonged CT to IVrt-PA time. DTN committee implementation is a simple, low-cost intervention, that significantly reduced DTN and DTG with persistent effect and no increase in symptomatic intracranial hemorrhage or stroke mimic treatment rate.
Abstract WMP86: Reasons for Slower Door-to-Needle Times and Their Impact on Timing of Treatment and Outcomes: Findings From Get With The Guidelines-Stroke
Authors: Kamal Noreen , Sheng Shubin , Hill Michael D , Xian Ying , Schwamm Lee H , Bhatt Deepak L , Fonarow Gregg C , Matsouaka Roland , Saver Jeffrey L , Reeves Mathew J , Smith Eric E
Published: June 2021

Background:
Despite quality improvement programs such as the American Heart Association/American Stroke Association Target_Stroke initiative, a substantial portion of acute ischemic stroke patients are still treated with alteplase later than 60 minutes, for unclear reasons. This study aims to describe the documented reasons for delays as well as the associations between reasons for delays and patient outcomes.

Methods:
We analyzed 55,296 patients who received intravenous alteplase in 1,422 hospitals participating in Get With The Guidelines-Stroke from October 2012 to April 2015, excluding transferred patients and inpatient strokes. We assessed eligibility, medical, and hospital reasons for delays in door-to-needle time (DTN). Multivariable models were used to evaluate associations between reasons for delays, time lost, and hospital discharge outcomes, controlling for patient and hospital characteristics.

Results:
There were 27,778 (50.2%) patients treated within 60 minutes, 10,086 (18.2%) treated in more than 60 minutes without documented delays, and 17,432 (31.5%) treated in more than 60 minutes with one or more documented reasons for delay. The longest DTN times were associated with inability to determine eligibility, delay in diagnosis, further diagnostic evaluation for hypoglycemia or seizure, management of emergent medical conditions and initial patient refusal (Table). One or more reason for delays was associated with in-hospital mortality (OR 1.2; 95CI 1.1-1.3), symptomatic intracranial hemorrhage (OR 1.2; 95CI 1.1-1.3), and lower odds of independent ambulation at discharge (OR 0.92; 95CI 0.9-1.0).

Conclusions:
Hospital and eligibility delays such as delay in diagnosis and inability to determine eligibility are common and are associated with longer DTN and poorer outcomes. Improved stroke recognition and management of acute comorbidities may help to reduce DTN times and improve outcomes.
Abstract WMP89: Stroke Code De-escalation: Safety and Outcomes
Authors: Jarnot Jessica , Streib Christopher , Heyer Angela , Reichert Amy , Anderson David , Reshi Rwoof , Lakshminarayan Kamakshi , Ezzeddine Mustapha
Published: June 2021

Introduction:
“Stroke codes” (SCs) facilitate the timely treatment of acute ischemic stroke (AIS) with IV tPA or intra-arterial thrombectomy (IAT), but are inherently resource-intensive and can expose patients to unnecessary and potentially harmful interventions. While all healthcare providers are encouraged to activate SCs, this might lead to low SC-to-treatment-ratios (SCTR). We examined the impact of de-escalation of stroke codes (DSCs) on SCTR.

Methods:
DSCs were initiated in our institution in January 2015. All DSCs were reviewed for the patient’s eligibility for IV tPA or IAT, and reason for de-escalation. We reviewed all stroke codes 12 months before and after the initiation of this process and compared the SCTR by chi-squared testing.

Results:
In 2014, prior to DSCs, 253 SCs resulted in 22 AIS interventions (22 IV tPA) for a SCTR of 8.7%. In 2015, 348 SCs were activated with 64 subsequent DSCs (18.4%) and 45 AIS interventions (38 IV tPA, 7 IAT, 7 both), for a SCTR of 15.8%. The improvement in SCTR after introducing DSCs was statistically significant (p=0.012). When restricting the analysis to IV tPA interventions alone, there remained a trend (p=0.068) towards improvement in SCTR. Retrospective chart review did not reveal any DSC cases that resulted in missed opportunity for IV TPA or IAT treatment. No DSCs were due to an acute ICH. Justifications for de-escalations are summarized in figure 1.

Conclusions:
The introduction of DSCs resulted in a statistically significant absolute improvement in SCTR of 7.1%. Importantly, DSCs did not result in any eligible AIS patient forgoing IV tPA or IAT, nor missed ICH. More research is needed to increase the yield of stroke codes, refine the criteria for both activating and de-escalating them, and quantify the resource and cost implications of such de-escalations.
Abstract WMP92: Quality of Care and Outcomes for Acute Ischemic Stroke Patients Admitted During the International Stroke Conference
Authors: Messe Steven R , Mullen Michael T , Cox Marguerrite , Fonarow Gregg , Smith Eric E , Saver Jeffrey L , Reeves Mathew J , Bhatt Deepak L , Matsouaka Roland , Schwamm Lee H
Published: June 2021

Introduction:
Patients who present to the hospital during off-hours receive sub-optimal care and experience worse outcomes, often attributed to reduced staffing. It is unknown whether stroke patients receive less guideline-adherent care and experience worse outcomes when medical providers attend scientific meetings. The AHA International Stroke Conference (ISC) is the premier US conference for cerebrovascular disease and is well attended by stroke clinicians.

Methods:
The national Get With The Guidelines - Stroke (GWTG-Stroke) dataset was analyzed from 2009-2015 to identify acute ischemic stroke (AIS) patients admitted during: 1) the week of ISC, and 2) the 2 weeks before and 2 weeks after ISC. We compared adherence to GWTG-Stroke quality measures and outcomes for AIS patients admitted during these two time periods using univariable and multivariable analysis, including both patient and hospital level variables.

Results:
Overall, 69,738 AIS patients were included, mean age 72, 52% female, and 29% non-white. There was no difference between the average weekly number of AIS cases admitted during ISC weeks versus non-ISC weeks (1,984 vs 1,997, p= 0.95). Patient and hospital characteristics were also similar between ISC vs. non-ISC time periods. No significant differences were noted in 14 quality of care metrics and 5 clinical outcomes between AIS patients treated during ISC vs. non-ISC weeks (Table). After adjusting for potential confounders, among patients who presented within 2 hours of onset there was no difference in the likelihood of receiving IV tPA within 3 hours (adjusted odds ratio 0.89, 95% confidence interval [CI] 0.77 - 1.03, p=0.13), nor in the likelihood of receiving IV tPA within 60 minutes of arrival (adjusted odds ratio 0.92, 95% CI 0.83 - 1.02, p=0.13).

Conclusions:
The treatment and outcome of patients who present with AIS to a GWTG-Stroke participating hospital are not degraded during the week of the International Stroke Conference.
Abstract WMP93: Efficacy of a Comprehensive Stroke Clinic Model on Reducing Readmissions after Ischemic Stroke
Authors: Glaser Anna , Kotzen Lisa , Weissman Holly , Singer Lauren , Grysiewicz Rebbeca
Published: June 2021

Background:
Stroke is a leading cause of hospital admissions among the elderly, and reducing readmission rates has become a primary goal of healthcare reform. Hospitals are now being held financially responsible for 30 day readmission rates exceeding their expected rate [1]. Our aim was to determine if patients seen in the comprehensive stroke discharge clinic had reduced 30 day readmissions compared to standard hospital follow up after ischemic stroke.

Methods:
Patients with a discharge diagnosis of ischemic stroke receive a phone call from the neurology office staff within 3 business days of hospital discharge to schedule an appointment with a mid-level provider in the comprehensive stroke discharge clinic within 1-3 weeks. Eligibility for the clinic includes patients ≥ 18 years of age that are either discharged to home directly or discharged to home from inpatient rehabilitation. We performed a retrospective stroke database search of patients meeting this criteria from May 2015 to June 2016. Patients were excluded from the search if they had an inpatient stroke event.

Results:
Of the 526 patients reviewed, 116 patients (22.1%) were seen in the comprehensive stroke discharge clinic. The average age of patients seen in clinic was 67 years and the average age of patients in the non-clinic group was 69 years. Approximately 12% of patients in each group received acute reperfusion therapy. There was only one 30 day related readmission in the clinic group, and fourteen 30 day related readmissions in the non-clinic group (0.86% versus 3.41%; 95% CI 0.12-4.99%). There were eight 30 day all cause readmissions in the clinic group, and forty-two 30 day all cause readmissions in the non-clinic group (6.90% versus 10.24%; 95% CI -2.12-8.81%).

Conclusion:
The comprehensive stroke clinic model may reduce 30 day related readmissions for patients discharged to home. However, there were limitations to this study. The percentage of patients seen in the comprehensive stroke clinic was low. The goal is to improve the clinic follow up rate over the course of the next year. In addition, patients were excluded from the clinic if they were discharged to a skilled nursing facility, which is often associated with a higher readmission rate.
Abstract WMP94: Readmission Within 30 days After Acute Ischemic Stroke, United States 2013
Authors: Tong Xin , George Mary G , Coleman King Sallyann M , Gillespie Cathleen , Merritt Robert
Published: June 2021

Introduction:
Hospital readmissions contribute significantly to the cost of medical care and reflect the burden of disease. Limited data have been reported on national hospital readmission after acute ischemic stroke.

Methods:
Among 2013 adult hospitalizations from the National Inpatient Sample of the Healthcare Cost and Utilization Project (HCUP) Nationwide Readmissions Database (NRD), we identified acute ischemic stroke (AIS) hospitalizations using principal diagnosis ICD-9-CM codes. We provided national estimates of AIS non-elective readmission rates within 30 days.

Results:
In 2013, there were a total of 489,813 adult index AIS admissions in the United States. The readmission rate within 30 days for a new AIS as the principal diagnosis was 2.1% of index AIS admissions, and was 10.2% of all readmissions. The readmission rate for all non-elective reasons increased with age, with the lowest readmission rate (8.9%) among ages 18-44, and the highest (11.7%).among ages 85+. The readmission rate was higher among patients with public insurance (11.1%) as compared to private (7.4%) or others (7.9%). Recurrent AIS (20.2%) was the most common reason for readmission, including unspecified cerebral artery occlusion with infarction (ICD9-CM=434.91, 13.0%) and cerebral embolism with infarction (ICD9-CM=434.11, 3.1%). In addition, infections were among the most common causes (Septicemia 5.7%, UTI 2.7%, and pneumonia 2.2%) and TIA (2.4%).

Conclusions:
The findings have important implications for identifying groups and conditions at high-risk for readmission. The large number of recurrent AIS within 30 days of index AIS highlights the need for improved patient follow-up and secondary prevention treatment.
Abstract WMP95: A Transition of Care Program to Reduce Stroke Related Hospital Readmissions
Authors: Khan Heather , Hefzy Hebah M
Published: June 2021

Introduction:
Readmission to the hospital after discharge following a stroke or TIA remains a nation-wide problem. While the CMS national benchmark was approximately 12% in 2015, our hospital Medicare stroke readmission rate rose from approximately 12% at the end of 2014 to 28.6% in February 2015. Our goal was a reduction in stroke readmission rates to below the national benchmark of 12% by December 2015.

Hypothesis:
We hypothesized that implementing a transition of care program at our 200 bed community hospital would reduce hospital stroke-related readmissions.

Methods:
In March 2015, a random sample of forty stroke/TIA patients that were discharged home between December of 2014 and February of 2015 were interviewed. The patients were asked about barriers to discharge, what could have improved the discharge experience, and what problems they encountered that could have resulted in a readmission. Based on their answers, risk factors were identified using an inverse Pareto graph and a transition of care program was implemented which included the following work flow: 1) daily rounding to query patients regarding insight into stroke risk factors, environmental concerns, and social impacts to discharge in the stroke unit by the stroke coordinator (a registered nurse); 2) a discharge telephone call within two business days to high risk patients identified during rounds focusing on review of the discharge summary, re-education regarding stroke risk factors, and ensuring that follow-up appointments were in place; 3) an outpatient follow-up appointment with a board certified vascular neurologist within two weeks of discharge.

Results:
Our transition of care program resulted in an improvement of 82.5%, with a Medicare stroke re-admission rate of 5% in December 2015. As of May 2016, our year-to-date hospital stroke readmission rate is 8.1%, while the current CMS national average is 12.7%.

Conclusions:
A transition of care program is implementable in a community hospital setting, and results in reduced stroke-related hospital readmissions. Its success emphasizes the importance of identifying high risk patients and assessing individual drivers of readmission risk.
Abstract WP10: Prolonged Microcatheter-based Local Thrombolytic Infusion as a Salvage Treatment for Failed Endovascular Treatment for Cerebral Venous Thrombosis: A Multicenter Registry
Authors: Qureshi Adnan I , Grigoryan Mikayel , Guliani Gaurav K , Saleem Muhammad A , Aytac Emrah , Rodriguez Gustavo J , Suri Muhammad F
Published: June 2021

Background:
Transvenous endovascular treatment including combination pharmacological and mechanical modalities is reserved for patients with cerebral venous thrombosis (CVT) not responsive to standard anticoagulation. However, transvenous endovascular treatment may not always be successful in achieving recanalization.

Objective:
To determine the effectiveness of prolonged microcatheter based local thrombolytic infusion in treatment of patients with CVT who achieved no or suboptimal recanalization with endovascular treatment.

Methods:
Patients who underwent transvenous endovascular treatment for cerebral venous thrombosis at three hospitals were identified through local registries. The final response to treatment was assessed and prolonged microcatheter based local thrombolytic infusion was instituted in selected patients as second line treatment. Serial angiograms were performed to assess treatment response and determine the duration of infusion.

Results:
Of the 85 patients admitted with CVT, 13 patients underwent 14 transvenous endovascular treatments. Initial treatment was considered suboptimal in 10/14 procedures due to no recanalization in 6, partial recanalization in 3, and re-occlusion in 1 patient. A prolonged microcatheter-based local recombinant tissue plasminogen activator (rt-PA) infusion was used in 9 of the 10 procedures for a median duration of 16 hours (range 15-22 hours). Follow up angiography demonstrated complete recanalization in 4 procedures and improvement of the partial recanalization in 5 additional procedures. One patient died before the follow up imaging could be acquired. None of the patients developed intracranial hemorrhage associated with local thrombolytic infusion. The microcatheter position had shifted during the infusion in one procedure.

Conclusion:
Prolonged microcatheter based local thrombolytic infusion appears to effective treatment in patients who have suboptimal response to acute transvenous endovascular treatment without any additional adverse events.
Abstract WP101: Hypoxia Drives Anti-inflammatory Polarization of Microglia in Ischemic Stroke
Authors: Koellhoffer Edward C , d’Aigle John , McCullough Louise D
Published: June 2021

Background:
As the innate immune cell of the central nervous system (CNS), microglia are poised to be the first cellular responders to ischemic stroke. Microglia are capable of polarizing from a resting (M0) phenotype to a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype depending on the signals these cells receive from the microenvironment. Typically cell damage through neurological injury results in a pro-inflammatory phenotype. Paradoxically, despite the cell death that occurs following ischemic stroke that presumably polarizes microglia to a pro-inflammatory phenotype, our lab and others have shown that microglia in mice are predominantly anti-inflammatory after ischemic stroke.

Hypothesis:
To possibly explain this anomaly, we hypothesized that hypoxia itself is a stimulus of anti-inflammatory microglia M2 polarization following ischemic stroke that overrides pro-inflammatory polarizing signals from cellular damage.

Methods:
We developed a novel method of culturing primary microglia from individual male and female neonatal mice. We then exposed isolated microglia to oxygen glucose deprivation (OGD, 95% nitrogen / 5% carbon dioxide) and examined the expression of M1 and M2 genes by quantitative PCR. Media was collected at 24hr and analyzed by lactate dehydrogenase (LDH) assay and ELISA.

Results:
We found that microglia are resistant to OGD-induced cytotoxicity, with LDH assay showing only 16% cell death after 8hr of OGD (p<0.05). OGD induced a robust up-regulation of anti-inflammatory M2 genes (Interferon Regulatory Factor 4 (IRF4), 2.08±0.08-fold, p<0.05; Vascular Endothelial Growth Factor (VEGF), 1.76±0.05-fold, p<0.0001) immediately following OGD and also down-regulated expression of pro-inflammatory M1 genes (IRF5, 0.385±0.018-fold, p<0.0001; Interleukin-1β (IL1B), 0.018±0.005-fold, p<0.01; Tumor Necrosis Factor-α (TNFA), 0.345±0.024-fold, p<0.0001) in both male and female microglia (n=7). ELISA of cell culture supernatant following OGD demonstrated that microglia secrete VEGF, suggesting OGD-treated microglia have anti-inflammatory functions.

Conclusion:
Collectively, our data suggest that hypoxia drives both male and female microglia to polarize to an anti-inflammatory M2 phenotype.
Abstract WP105: Tissue Plasminogen Activator (tPA) is Essential for Functional Recovery After Stroke by Promoting Axonal Outgrowth
Authors: Ma Shubei
Published: June 2021

Objectives:
Stroke is the leading cause of long term neurological disability with limited therapeutic options. Human recombinant tissue plasminogen activator (tPA) is currently the only FDA approved drug for the thrombolytic treatment of ischemic stroke. Emerging evidence suggests that the effects of tPA in ischemic brain may extend beyond its thrombolytic activity. In this study, we investigated the role of tPA in long term stroke recovery.

Methods:
Cortical infarct was induced by distal middle cerebral artery occlusion (dMCAO) in tPA knockout (KO) and wild type (WT) mice. Sensorimotor functions were evaluated at 3-35 days after dMCAO. White matter integrity was assessed by luxol fast blue staining, immunohistochemistry for SMI-32, and diffusion tensor imaging (DTI). The neuronal tracer biotinylated dextran amine (BDA) was used to label the corticorubral tract and the corticospinal tract. For rescue experiment, tPA (2mg/kg) was delivered intranasally to tPA KO mice once a day for 14 days starting 6h after dMCAO.

Results:
Infarct volume was comparable between tPA KO and WT mice after dMCAO. Sensorimotor deficits after dMCAO were exacerbated in tPA KO mice than WT mice. tPA KO mice also showed more severe demyelination in post-stroke white matter and reduced axonal sprouting at 35 days after dMCAO compared to WT mice. DTI studies revealed deteriorated white matter integrity in tPA KO mice, as manifested by decreased fractional anisotropy. Intranasal delivery of tPA after dMCAO rescued the neurological phenotype shown by tPA KO mice.

Conclusion:
Endogenous tPA promotes white matter integrity and is essential for functional recovery after ischemic stroke. tPA may be a novel neurorestorative therapy for stroke recovery.
Abstract WP106: Attenuation of Stroke Damage by Angiotensin II Type 2 Receptor Stimulation via Peroxisome Proliferator-Activated Receptor-gamma Activation
Authors: Shan Bao-Shuai , Mogi Masaki , Iwanami Jun , Bai Hui-Yu , Kukida Masayoshi , Yamauchi Toshihiro , Higaki Akinori , Min Li-Juan , Horiuchi Masatsugu
Published: June 2021

Introduction and hypothesis:
Brain renin–angiotensin system plays a role in ischemic brain damage after stroke. It is known that stimulation of angiotensin II type 2 (AT
2
) receptor has a protective role in ischemic brain injury. We demonstrated that AT
2
receptor stimulation by compound 21 (C21), direct AT
2
receptor agonist, inhibited vascular intimal proliferation with activation of peroxisome proliferator-activated receptor-gamma (PPAR-γ). Agents with PPAR-γ agonistic effect have been demonstrated to be neuroprotective in brain ischemia. However, whether direct AT
2
receptor stimulation has a protective effect on ischemic brain injury via PPAR-γ activation is still unknown. Thus, we investigated the beneficial effect of C21 on ischemic brain damage by AT
2
receptor stimulation via PPAR-γ activation.

Methods:
Eight-week-old male C57BL/6J and human renin and human angiotensinogen double-transgenic (hRN/hANG-Tg) mice were subjected to middle cerebral artery (MCA) occlusion. Before MCA occlusion, they were administered C21 with or without GW9662, a PPAR-γ antagonist, for 2 weeks. Ischemic size, inflammation and oxidative stress were assessed 24 hours after MCA occlusion. Cerebral blood flow was measured in the core and periphery of the MCA territory before, immediately after, 1 hour and 24 hours after MCA occlusion.

Results:
Administration of C21 with or without GW9662 had no significant effect on blood pressure. Ischemic brain area at 24 hours after MCA occlusion was significantly enlarged in hRN/hANG-Tg mice, compared with C57BL/6J mice. Treatment with C21 decreased the ischemic area compared with the no-treatment group, with an increase in cerebral blood flow, both in C57BL/6J and hRN/hANG-Tg mice. Co-administration of GW9662 partially attenuated the protective effect of C21 on ischemic size, via an increment in the expression of inflammatory cytokines and superoxide production, although GW9662 treatment alone had no significant effect on ischemic size.

Conclusions:
These results suggest that direct AT
2
receptor stimulation has a beneficial effect on stroke partly due to activation of PPAR-γ.
Abstract WP111: Diffusion Tensor Imaging of Corticospinal Tract Recovery After Intra-arterial Mesenchymal Stem Cell Infusion in a Canine Stroke Model
Authors: Guada Luis , Atchaneeyasakul Kunakorn , Pattany Pradip , Saigal Gaurav , Ramdas Kevin , Watanabe Mitsuyoshi , Yavagal Dileep
Published: June 2021

Background:
Imaging biomarkers of stroke recovery are critical for translational studies. Diffusion tensor imaging (DTI) to assess white matter microstructure in the brain using fractional anisotropy (FA) to dertermine the structural integrity of the corticospinal tract (CST). Our prior data suggest a possible correlation between neurological recovery and the improvement in FA. The purpose of this study was to compare DTI analysis of the CST at 30 days after an ipsilateral intra-arterial (IA) Mesenchymal Stem Cell (MSCs) versus control, in canines with a reversible Middle Cerebral Artery occlusion (rMCAo).

Methods:
Mongrel Hounds (n=7), aged 12-36 months, were included in this study. rMCAo was induced via endovascular approach using a detachable helical ultra-coil over 35-80 min. MSCs (1-20 millions) or saline (240 cc) were infused intra-arterially 48hrs post stroke in the ipsilesional cervical internal carotid. Brain MRIs were performed at 48h post rMCAo pre-IA cell delivery, 15 & 30 days. FA values of the right and left CST were determined. DTT was also generated for a visual analysis of the CST fibers. Weekly neuro evaluations were performed using blinded canine stroke-score.

Results:
We observed a higher average change in the FA values from at 30 days post stroke in the MSCs treated group versus control (0.085 ± 0.025, n=5 versus 0.068 ± 0.058, n=2: p=0.82). A visual increase in the caliber of CST ipsilateral to stroke from IA injection to day 30 post-stroke was observed on the DTT in two of the treated canines. Figure-1 from left to right, a. FA changes, b. DTT treated group, C. DTT control.

Conclusions:
Serial DTI-DTT imaging after IA MSCs therapy in large animal stroke model appears to have a trend towards higher change in FA. These findings could support further development of DTI-DTT biomarkers to measure neurologic recovery in experimental models as well as early clinical trials of novel stroke therapies.
Abstract WP114: High-fat Diet Leads to Increased Brain Inflammation and Worse Outcomes After Stroke in Mice
Authors: Peterson Todd C , Lechtenberg Kendra , Ayyalasomayajula Ishan , Montes Iris , Buckwalter Marion
Published: June 2021

People who are obese are 64% more likely to have a stroke than those who are not. Obesity is also associated with chronic peripheral inflammation characterized by increased antigen presentation and pro-inflammatory T lymphocytes. The influence of obesity-induced peripheral inflammation on stroke outcomes has not been well studied. We hypothesized that a similar mechanism might drive detrimental inflammation after stroke in mice and lead to worse outcomes. We fed mice a 60% kCal high fat diet for six or fifteen weeks and measured the neuroinflammatory response to stroke. We verified weight changes and measured the neuroinflammatory response, infarct size, and functional outcomes following stroke (dMCAO & photothrombotic). Animals were fed a high fat diet or control diet for either 6 or 15 weeks (N = 10/group) that resulted in 36% and 78% more weight gain, respectively. Consistent with a stronger innate inflammatory response, we found increased astrogliosis (195%;
p
< 0.01) with GFAP immunostaining and microgliosis (290%;
p
< 0.0001) with CD68 in the peri-infarct area, as well as higher expression of the pro-inflammatory cytokines TNFα (
p
< 0.05) and IL-6 (
p
< 0.05). Similar to the increased adaptive immune responses in adipose tissue of the obese, we saw a significant (
p
< 0.05) increase in MHC II+ cells in the peri-infarct area as well as a 2 fold increase (
p
< 0.05) in the number of infiltrating CD3+ T-cells in the hemisphere ipsilateral to the stroke, at both 3 days and 28 days post-stroke. Animals on high fat diet had a significantly (
p
< 0.01) larger dMCAO infarct (130%) size 3 days post-stroke than animals on control diet. To determine the effect this neuroinflammatory response had on outcome mice received photothrombotic stroke over the motor cortex and were motor testing was performed prior to and 1, 3, 7, 14, and 28 days post-stroke. Mice fed a high fat diet performed significantly (
p
< 0.05) worse on both the rotating and tapered beam tasks, and also exhibited larger strokes at sacrifice. We conclude that eating a high fat diet prior to stroke increases neuroinflammation, infarct size, and functional recovery following stroke.
Abstract WP116: Combined AICAR and GW501516 Therapy Promotes Motor Recovery After Photothrombotic Stroke in Mice
Authors: Al Shoyaib Abdullah , Alamri Faisal F , Jayaraman Srinidhi , Karamyan Vardan T
Published: June 2021

In this study the combined effect of AMPK activator AICAR (500 mg/kg, SC) and PPARδ agonist GW501516 (5 mg/kg, IP) was studied on recovery of motor function in adult male mice after stroke. Vehicle or drug treatments were initiated 24 - 32 h after induction of stroke using the photothrombotic model and lasted until day 10 after stroke. In addition to pharmacological therapy, mice were allowed to voluntarily run on wheels in their home cage starting from day 7 after stroke. Motor function was assessed in grid walking and cylinder tests 3 days before and 1, 7, 14 and 21 days after stroke. On day 21 post-stroke, mouse brains were fixed by cardiac perfusion and collected for sectioning and evaluation of infarct volume in half of the experimental animals. In the second half of the experimental mice, brains were removed without fixation, the cerebral cortex involving the infarct core plus the peri-infarct region (~3mm total diameter) and the corresponding contralateral part of the cortex were excised and used for extraction and evaluation of proteins. The results of both sensorimotor tests indicated that voluntary running started 7 days post-stroke marginally facilitates motor recovery after stroke, whereas, addition of AICAR and GW501516 therapy (starting 1 day post-stroke) to running potentiates motor recovery. Interestingly, the average total distance run by mice receiving the drug therapy was less than that of the vehicle-treated group. Infarct volumes measured at day 21 post-stroke were comparable in both groups. Increased relative levels of BDNF and CpG-binding protein 2 (MECP2) were documented in the cerebral cortex of drug vs. vehicle-treated group. Our data indicate that pharmacological activation of AMPK and PPARδ following stroke enhances motor recovery offered by voluntary running, and that this effect is likely due to increased availability of BDNF and sustained activation of its downstream signaling pathways.
Abstract WP12: Impact of the Introduction of Endovascular Treatment on Acute Ischemic Stroke Therapy in a Rural Broad Region in Japan
Authors: Imahori Taichiro
Published: June 2021

Background:
Endovascular treatment (EVT) has been proven to be effective for selected patients with acute ischemic stroke (AIS). We evaluated the effect of the introduction of EVT on outcome of AIS therapy in a rural broad region in Japan, covering an area within a radius of 80km by air ambulance.

Methods:
Between January 2014 and July 2016, 210 consecutive patients with acute large vessel occlusion (189 patients in the anterior circulation and 21 in the posterior circulation) admitted to our institute were analyzed. EVT was introduced into the AIS therapy at our institute in April 2015. We compared the outcome of the patients during the period before (group 1: standard medical treatment including intravenous [IV] tPA) and after (group 2: standard medical treatment including IV tPA with or without EVT) the introduction of EVT.

Results:
In the group 1, all 87 patients (median age, 81 years; NIHSS, 20; ASPECTS, 8; onset to door, 237min; IV tPA 24%) were treated medically (Table 1). In the group 2, among 123 patients (age, 82 years; NIHSS, 20; ASPECTS, 8; onset to door, 149min; IV tPA 16%), 47 patients were treated medically, and the remaining 76 patients underwent EVT (TICI 2b or 3, 84%). Although the median transfer distance increased (23km in the group 1 vs 30km in the group 2, p=0.028), the median time from call to admission was equivalent (42min vs 43min, p=0.93) because of the increase in the proportion of the helicopter transfer (30% vs 41%, p=0.14). The rates of patients who underwent revascularization therapy with IV tPA or EVT (24% vs 66%, p<0.001) and good outcome (mRS 0 to 2) at discharge (11% vs 24%, p=0.021) increased significantly after the introduction of EVT approach.

Conclusions:
Our study showed that the introduction of EVT improved the outcome of the AIS therapy with significant increase in the number of patients receiving revascularization therapy. EVT in collaboration with air ambulance might expand the target area for revascularization therapy in a rural broad region.
Abstract WP125: Accelerated 3d Isotropic High-resolution Multi-contrast Intracranial Vessel Wall MRI For Large Artery Stroke Evaluation
Authors: Balu Niranjan , Zhou Zechen , Mossa-basha Mahmud , Yuan Chun
Published: June 2021

Introduction:
Intracranial large-artery atherosclerotic disease (ICAD) is a leading cause of death and morbidity worldwide. Vessel Wall Imaging (VWI) has potential to stratify disease beyond current angiographic methods by identifying plaque morphology and components directly. Plaque component identification requires a multi-contrast black-blood protocol. High isotropic resolution is also required due to small vessels and their complex geometry and therefore typical ICAD VWI protocols require long scan times.

Aim:
To develop a 3D 0.5 mm isotropic multi-contrast ICAD VWI with scan time of less than 30 minutes.

Methods:
Experiments were carried out on a Philips Ingenia 3T scanner with 32 channel head coil. Acceleration by K-space undersampling using CUSTOM method and compressed sensing reconstruction using STEP method [1] was used to reduce scan times. The following protocol was optimized on phantoms and volunteers: Survey scan was followed by 3D TOF, T1 weighted VISTA, PD weighted DANTE [2] VISTA, SNAP [3]. After single dose gadolinium contrast injection a post-contrast T1 weighted VISTA is obtained. Protocol parameters were optimized such that total scan time is 25 mins with all scans (except survey) being 0.5mm isotropic.

Results:
CUSTOM acceleration factors of 4X to 5X provided good image quality. Representative image quality (pre-contrast) is shown in figure 1. Total scan time for the multi-contrast protocol was 30 minutes including patient setup time. Studies on ICAD patients are ongoing with the optimized protocol.

Conclusions:
Multi-contrast 3D 0.5mm isotropic resolution MRI protocol was developed to scan ICAD patients within 30 minute scan time. Acceleration tailored for VWI allowed reducing scan times from 2 hours to less than 30 minutes thereby providing a clinically usable ICAD VWI multi-contrast protocol.

References:
[1] Zhou Z et al, MRM 2016, [2] Li L et al, MRM 2012, [3] Wang et al, MRM 2013.
Abstract WP126: Transcranial Doppler and Microemboli Detection. Relationships to Symptomatic Status and Histopathology Findings
Authors: Mitchell Carol , Wilbrand Stephanie M , Steffel Catherine N , Varghese Tomy , Meshram Nirvedh , Li Geng , Cook Thomas D , Salamat Shahriar , Dempsey Robert J
Published: June 2021

Introduction:
Microemboli, as detected by transcranial Doppler (TCD), are hypothesized to be associated with carotid plaque instability and symptomatic subject status associated with motor, sensory, visual and speech deficits of stroke and transient ischemic attack (TIA). However, the current clinical exam does not assess sequeli of small emboli and probable differences between symptomatic and asymptomatic plaques. The purpose of this study was to determine the relationship between symptomatic status, microemboli presence and histopathology findings.

Methods:
TCD examination was performed on 60 study subjects for an hour to assess the presence of microemboli, prior to undergoing clinically indicated carotid endarterectomy. Macroscopic scoring for cholesterol, thrombus, calcium and ulceration were performed with a dissecting microscope. Histopathological examination, with high power magnification on fixed plaque was scored for hemorrhage, hemosiderin, inflammation, percent cholesterol and calcium. Pearson’s chi-squared test was used to assess the frequency of microemboli between symptomatic and asymptomatic subjects. Logistic regression was used to analyze the relationship between operative and histopathology plaque findings and presence of microemboli.

Results:
The frequency of microemboli signals, as detected with TCD, was not significantly different between symptomatic and asymptomatic subject groups (p=0.88) nor was there any difference observed in the macroscopic or histopathology scoring of these plaques (p-values all > 0.05). The presence of microemboli was associated with an ulceration score (regardless of symptomatic or asymptomatic status, p=0.034), with a one level increase in ulceration rating associated with an odds ratio of 5.86 (95% [CI] 1.55, 4.34).

Conclusion:
These findings suggest that both symptomatic and asymptomatic subjects (with clinical indications for carotid endarterectomy) may have plaque with similar features of instability and ability to create emboli. Thus, identifying new ways to measure plaque instability may provide important information for optimizing treatment to prevent future stroke. It also suggests that present clinical exam does not detect the sequeli of small emboli.
Abstract WP130: Validation of Multi-parametric Ultrasonography Criteria with Catheter Angiography in Internal Carotid Artery Disease: A Prospective Multicenter Study
Authors: Barlinn Kristian , Rickmann Henning , Kitzler Hagen H , Krogias Christos , Strohm Henning , Abramyuk Andrij , Rabahi Ali , Barlinn Jessica , Siepmann Timo , Graehlert Xina , Schwanebeck Uta , Winzer Simon , Arnold Sebastian , Moennings Peter , Pallesen Lars-Peder , Bodechtel Ulf , Mudra Harald , Linn Jennifer , Reichmann Heinz , Gahn Georg , Weiss Norbert , Puetz Volker
Published: June 2021

Introduction:
Novel multi-parametric criteria for duplex ultrasonography (DUS) grading of extracranial internal carotid artery (ICA) steno-occlusive disease have been recently introduced by the German ultrasound expert panel (DEGUM). We sought to determine diagnostic accuracy of the DEGUM criteria against the gold standard catheter angiography.

Methods:
We prospectively enrolled consecutive patients who routinely underwent diagnostic or therapeutic catheter angiography of the extracranial carotid arteries at four German study sites. Internal carotid artery disease was graded according to the DEGUM multi-parametric criteria for DUS. On angiography, extracranial ICA disease was graded using the NASCET approach. Ultrasonography and endovascular raters were blinded to clinical data and any other imaging modalities. To correspond to clinically relevant NASCET groups, all stenosis measurements were stratified into ranges: normal, mild (1-49%), moderate (50-69%), severe (70-99%) and occlusion.

Results:
A total of 120 patients (median age, 69 [IQR, 16] years; 74% men; median time between DUS and angiography, 1 day [IQR, 2.5]) provided 162 DUS/angiography carotid artery pairs for final analysis. On angiography, moderate stenosis was found in 48 (30%) and severe stenosis in 63 (39%) arteries. Sensitivity of DUS for detection of moderate and severe stenosis was 35% (95%CI, 22-51%) and 81% (69-90%), with a NPV of 77% (68-84%) and 85% (75-92%), respectively. Specificity was 89% (81-94%) and 97% (94-99%), with a PPV of 57% (37-75%) and 62% (51-73%), respectively. Considering the entire spectrum of the disease (0-100%), the Bland-Altman interval limit of agreement was 51% (Figure).

Conclusions:
At laboratories experienced with ultrasound grading of the extracranial ICA, the novel DEGUM multi-parametric ultrasonography criteria do not eliminate the need for a confirmatory test for identification of clinically relevant grades of the disease.
Abstract WP132: A Genome Wide Association Study in Patients with Symptomatic Intracranial Atherostenosis
Authors: Arenillas Juan F , Carrera Caty , Cullell Natàlia , Reyes Javier , Muñoz Pedro L , Montaner Joan , Fernández-Cadenas Israel
Published: June 2021

Introduction and objective:
Intracranial atherosclerosis (ICAS) is a major cause of stroke worldwide, and its genetic background remains largely unexplored. The previous studies performed have been based on candidate-gene strategy. We aimed to perform a genome-wide association study (GWAs) to find genetic risk factors associated with symptomatic ICAS.

Methods:
We studied a cohort of 83 Caucasian patients with ischemic stroke attributed to symptomatic ICAS and 315 controls genotyped with Human Core Exome (Illumina). A score combining number and severity of intracranial stenoses was used to assess ICAS severity in each patient. Quality controls, 1000G imputation and association analysis were performed through PLINK, R, IMPUTE2 and SNPTEST software following previous recommendations. Sex, age, principal components and vascular risk factors were used as covariates.

Results:
Several loci with a genome wide significant association (P<1E-08) were found to be associated with ICAS severity score. The most robust association was found for locus in chromosome 18 (p=3.05E-14).

Conclusion:
This GWAS in symptomatic ICAS patients has revealed potential genes associated with ICAS presence and severity. These findings need to be replicated in other cohorts, ideally in patients from different ethnicities.