bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract WP283: Comparative Accuracy of Transcranial Doppler, Transthoracic Echocardiography, Transesophageal Echocardiography, and Cardiac CT in Detecting Right-to-Left Shunt in Embolic Stroke of Undetermined Source
Authors: Ravi Vikas , Pirahanchi Yasaman , Jazayeri Seyed Behnam , Carrion Penagos Julian , Bowers Jeffrey , Meyer Brett , Agrawal Kunal , Modir Royya , Hemmen Thomas , Meyer Dawn , Hailey Lovella , Mortin Melissa , Bavarsad Shahripour Reza
Published: January 2025

Introduction:
Embolic Stroke of Undetermined Source (ESUS) represents about 25% of ischemic strokes, with patent foramen ovale (PFO) involved in roughly 25% of those cases. Recent studies (REDUCE, CLOSE, RESPECT) indicate that PFO closure may benefit select patients. Accurate PFO diagnosis is crucial for treatment decisions but current methods, such as transcranial Doppler (TCD) with bubble study, transthoracic echocardiography with bubble study (TTE), transesophageal echocardiography (TEE), and cardiac computed tomography (CT), vary in accuracy. This study aims to assess the diagnostic performance of TCD compared to TTE, TEE, and cardiac CT, to determine the most reliable modality for detecting PFO in patients with ESUS.

Methods:
We conducted a retrospective analysis of ESUS patients aged 18 and older referred to our vascular lab between July 2023 and September 2024. Each patient underwent at least two PFO detection methods: TCD with bubble study, TTE with bubble study, TEE, and cardiac CT. PFO presence was confirmed if identified by at least two detection methods. Patients with extracardiac shunts were excluded. Sensitivity, specificity, and overall test performance were evaluated using the Area Under the Curve (AUC) of a Receiver Operating Characteristic (ROC) curve, with higher AUC values indicating better performance. Differences in AUCs were assessed using DeLong’s test. Statistical analysis was performed using Analyse-it for Microsoft Excel (version 2.30).

Results:
Of 187 enrolled patients, 63 (33.7%) had evidence of right-to-left shunt. The mean age of the cohort was 63 ± 18 years, with 51% being male. PFO was confirmed in 36 patients. Sensitivity was highest for TCD (93.1%), followed by TTE (87.1%), TEE (86.7%), and cardiac CT (42.9%). Specificity was highest for cardiac CT (87.5%), followed by TTE (84%), TCD (59.1%), and TEE (47.1%). The AUC was highest for TTE (AUC: 0.85, 95% CI: 0.76–0.95), followed by TCD (AUC: 0.75, 95% CI: 0.64–0.87), TEE (AUC: 0.66, 95% CI: 0.50–0.81), and cardiac CT (AUC: 0.65, 95% CI: 0.42–0.88). No statistically significant differences in diagnostic performance across pairwise comparisons were found (p > 0.05).

Conclusion:
TCD with bubble study is highly sensitive for screening right-to-left shunt, while cardiac CT is highly specific for detecting PFO in ESUS patients. Further studies with larger sample sizes are needed to confirm these findings and refine diagnostic strategies.
Abstract WP284: Recurrent stroke in patients with incident cryptogenic stroke and underlying malignancy: A secondary analysis of the CASPR study
Authors: Eklund Kelsey , Siegler James , Bowman Anna , Van Coevering Russell , Chen Lucia , Penckofer Mary , Kerrigan Deborah , Aboul-Nour Hassan , Nahab Fadi , Yaghi Shadi , Khasiyev Farid , Lineback Christina , Culbertson Collin , Sharma Richa , Sathya Anvitha , Jillella Dinesh , Aziz Yasmin , Alvi Muhammad , Herpich Franziska , Shahrivari Mahan , Elangovan Cheran , Zha Alicia , Farooqui Mudassir , Rothstein Aaron , Khan Farhan , Brorson James , Brown Samantha , Abu Qdais Ahmad , Liebeskind David , Nedelcu Simona , Nguyen Thanh , Thon Jesse , Salehi Omran Setareh
Published: January 2025

Introduction:
Malignancy represents an important subgroup of embolic stroke of undetermined source (ESUS). We aim to compare infarct features, potential embolic sources, and long-term outcomes in ESUS patients with and without malignancy.

Methods:
In this pre-specified secondary analysis of the Cardiac Abnormalities in Stroke Prevention and Recurrence (CASPR) retrospective cohort study, active cancers were identified by site investigators and adjudicated as malignant if they were non-squamous or non-basal cell skin cancers. We compared the prevalence of various potential embolic sources (e.g., patent foramen ovale, left ventricular dysfunction, post-stroke atrial fibrillation) among patients with and without malignancy. The risk of recurrent stroke, major bleeding, or death was evaluated using adjusted Cox proportional hazards models, accounting for age, sex, vascular risk factors, competing potential embolic sources, and initial treatment with anticoagulation versus non-anticoagulant (e.g., antiplatelet) regimen.

Results:
Of the 2201 patients followed over a median of 564 days, 236 (10.7%) were diagnosed with cancer at the time of stroke. Patients with malignancy were older, more frequently hypertensive and did not differ with regards to prevalence of specific infarct patterns or potential cardiac embolic sources. No difference was observed in the composite outcome of recurrent stroke, major bleeding, or death (adjusted HR 1.02, 95% CI, 0.71-1.46). Age (adjusted HR per year 1.02, 95% CI, 1.01-1.03), baseline stroke severity (adjusted HR 1.03 per NIHSS point, 95% CI, 1.01-1.05), prior stroke (adjusted HR 1.68, 95% CI, 1.38-2.05), and multi-territorial infarct pattern (adjusted HR 1.67, 95% CI, 1.33-2.08) were significantly associated with this composite outcome, but anticoagulation was not. There was a nominally lower rate of major bleeding with malignancy (adjusted HR 0.45, 95% CI, 0.19-1.04), a significantly higher rate of death (adjusted HR 1.58, 95% CI, 1.09-2.30), but no significant difference in recurrent ischemic stroke (p=0.31).

Conclusions:
Patients with malignancy and ESUS had higher mortality but did not differ in recurrent stroke risk or major bleeding when compared to patients without malignancy. Anticoagulation was not independently associated with better outcomes. Further analysis of infarct topology and risk factors may better identify patients for whom anticoagulation may benefit.
Abstract WP286: MRI-derived Pressure Ratio for Stroke Risk Assessment of Symptomatic Intracranial Atherosclerotic Stenosis
Authors: YANG YIFAN , Luo Jichang , Wang Tao , Liu Delin , Gong Haozhi , Guo Shuaiwei , Yang Bin , Nogueira Raul , Ma Yan , Jiao Liqun
Published: January 2025

Background:
Hemodynamic evaluation is crucial in assessing stroke risk in patients with symptomatic intracranial atherosclerotic stenosis (sICAS). A new CFD model based on high-resolution MRI and phase-contrast MR angiography was developed to calculate translesional pressure ratio, called MRI-derived pressure ratio (MPR).

Purpose:
We plan to conduct two studies to assess the diagnostic accuracy of MPR in detecting insufficient brain perfusion and its predictive value for clinical outcomes in sICAS patients.

Methods:
In the first study, sICAS patients who underwent percutaneous transluminal angioplasty and stenting (PTAS) were prospectively screened, with an arterial spin labeling-derived relative cerebral blood flow ratio (rCBF) of < 0.9 before PTAS. MPR (the ratio of poststenotic to prestenotic pressure) was calculated and collected before and after PTAS. If postoperative rCBF returned to normal (rCBF ≥ 0.9), the preoperative MPR was considered indicative of hemodynamic impairment, while the postoperative value was no. In the second study, patients with sICAS were prospectively enrolled and followed for one year under optimal medical treatment. MPR was assessed and recorded before enrollment. The primary outcome was a composite of recurrent ischemic stroke or TIA within the same arterial territory over one year.

Results:
In the first study, involving 22 patients (median age = 53 years, 81.8% males), MPR increased from 0.51 to 0.86 after PTAS. Cut-off values of MPR<0.74 identified as indicators of hemodynamic impairment. In the second study, 209 patients (median age = 55.0 years, 63.2% males) were included. Twenty patients (9.6%) experienced ischemic stroke or TIA during the one-year follow-up. Cut-off values of MPR < 0.56 was identified to best predict recurrent stroke or TIA. Multivariate logistic regression revealed that MPR (adjusted OR = 0.096, 95% CI = 0.013-0.71) was independently associated with the primary outcome. Next, patients were divided into three groups based on two cut-off values: low-risk (MPR≥0.74), intermediate-risk (0.56≤MPR<0.74), and high-risk (MPR<0.56). The one-year risk of stroke/TIA was significantly higher in the high-risk group compared to the low-risk (22.6% vs 3.1%,
P
<0.001) and intermediate-risk groups (22.6% vs 6.0%,
P=
0.023).

Conclusions:
This study demonstrates that MPR is a reliable metric for risk stratification in sICAS patients. Future randomized trials are necessary to validate clinical decision-making guided by MPR.
Abstract WP293: The Effect of Selective Serotonin Reuptake Inhibitors on Stroke Risk in Migraine
Authors: Wood Stefanie , Parrish Michael , Titus Ryan , VerKuilen Haley , Rosamond Wayne , Sen Souvik
Published: January 2025

Introduction:
Migraine sufferers are at an increased risk of ischemic stroke which is one of the leading causes of disability worldwide. The impact of Selective Serotonin Reuptake Inhibitors (SSRI) on stroke risk remains inconclusive, and there has been no investigation yet into their effect on stroke risk among migraineurs.

Methods:
Data was provided by Atherosclerosis Risk in Communities Cohort (ARIC)’s ongoing, prospective, longitudinal community-based cohort study, where participants were given an interview ascertaining migraine history in 1993–1995, and were followed for all vascular events, including stroke. The medication list of migraine-experiencing participants was evaluated and if they were found to be taking an SSRI, were included in our exposure group while the remainder of the participants were included in the control group. We used survival analysis to evaluate the incidence of ischemic stroke in migraine-experiencing participants on SSRIs when compared to those who are not on SSRIs. Cox proportional hazards models were used to analyze the association among migraine sufferers on SSRIs, migraine sufferers not on SSRIs, and incidence of ischemic stroke.

Results:
Among the 1614 migraine-experiencing participants without prior history of stroke, 264 (16%) were on SSRIs while 1350 (84%) were not on SSRIs. Of the 264 on SSRIs, 35 (13%) of them had an incident stroke while 121 (9%) of the 1350 participants not on SSRIs, had an ischemic stroke. The mean age of the study participants was 58 years at the time of the start of the prospective follow up (visit 3) when migraine was assessed; 85% were white and 77% were women. It was found that migraine sufferers on SSRIs were more likely to have an incident stroke than those not on SSRIs (log rank p<0.001), as depicted in the Kaplan-Meier curve. Proportional hazards assumption was met. Cox regression produced a crude hazards ratio (HR) of 1.67 with a 95% confidence interval (CI) of 1.14-2.43. The HR remained significant after adjustment for age, gender and race, adjusted HR 1.72 with a 95% CI of 1.17-2.51. The HR was nonsignificant after adjustment for age, gender, race, hypertension, diabetes, hypercholesterolemia and smoking status, adjusted HR 1.33 with a 95% CI of 0.89-1.99.

Conclusion:
We report a possible association between migraine sufferers on SSRIs and risk for incident stroke. This might be explained by the presence of vascular risk factors and helps understand this association.
Abstract WP30: Detection of Somatic Mutations in Brain Arteriovenous Malformation Patients Using Non-Invasive Cell-Free DNA Screening
Authors: Wetzka Isabella , Sanchez Damian , Bhalla Shubhang , Nelson Jeffrey , McCulloch Charles , Ko Nerissa , Winkler Ethan , Kim Helen , Weinsheimer Shantel
Published: January 2025

Introduction:
Brain arteriovenous malformations (bAVMs) are vascular anomalies resulting from defective morphogenesis of blood vessels in the brain. Kirsten rat sarcoma virus (
KRAS)
somatic activating gene mutations have been identified in the majority of bAVMs using digital droplet PCR-based assays (ddPCR). Currently, bAVM somatic mutation genetic characterization requires sequencing surgically excised lesion DNA, but recent advancements have overcome some conventional biopsy limitations through sequencing cell-free DNA (cfDNA) which is directly released into the blood circulation from cell breakdown and turnover at the site of the lesion. Therefore, cfDNA released from the mutated bAVM tissue cells may be detectable in a peripheral blood sample, providing a non-invasive approach for somatic mutation screening.

Hypothesis:
We hypothesize that somatic
KRAS G12D
mutations in bAVM patients can be detected using non-invasive cfDNA screening.

Methods:
We selected six bAVM patients whose surgically-resected bAVM lesions screened positive for somatic
KRAS G12D
mutation using ddPCR and had contributed a peripheral blood sample for research within 2 months prior to surgery. For each patient, cfDNA was isolated from 1.0 mL of banked plasma using the Circulating cfDNA/RNA Isolation Kit (Qiagen). We used the ddPCR
KRAS G12D
assay (Bio-Rad) to screen cfDNA samples for presence of the mutation. Samples were screened in duplicate using 8 uL and 4 uL of cfDNA eluate and assays included both positive controls (synthetic
KRAS G12D
oligo sequence (Integrated DNA Technologies)) and negative controls (no template and water). The variant allele frequency was estimated for each sample as the (target concentration)/(target + reference concentration).

Results:
Of the six bAVM cases, five screened positive for
KRAS G12D
mutation in the cfDNA sample. The
KRAS G12D
cfDNA variant allele frequency ranged from 0.20 - 0.54% for the five positive samples.

Conclusions:
We detected somatic
KRAS G12D
mutations in bAVM patients using non-invasive cfDNA screening. While further studies are needed to validate these findings, these exciting results suggest that we may be able to perform non-invasive
KRAS
somatic mutation screening using cfDNA in a greater number of bAVM cases (e.g., not just those undergoing surgery), which may be useful to clinically stratify bAVM patients and provide targeted therapies based on specific genetic defect.
Abstract WP306: Exploring the Cardiovascular Effect and Downstream Proteomic Signature of Pharmacologic Targeting of Circulating Adiponectin Levels in a Drug-Target Mendelian Randomization Framework
Authors: Myserlis Evangelos Pavlos , Gill Dipender , Georgakis Marios , Lioutas Vasileios , Selim Magdy , Rosand Jonathan , Banerjee Chirantan , Anderson Christopher
Published: January 2025

Introduction:
Previous studies have suggested that increased body fat is associated with elevated cardiovascular disease (CVD) risk. We have previously shown that apart from common vascular risk factor modification, adipose tissue-specific factors, such as adiponectin, may mediate the relationship between body fat and vascular risk. Here, we use large-scale omics data to explore whether pharmacologic targeting of the adiponectin pathway may contribute to lowering CVD risk.

Methods:
To proxy the effect of pharmacologically perturbing the adiponectin pathway we used a drug-target mendelian randomization (MR) approach. We selected genome-wide, independent (r
2
<0.1) variants in the vicinity (300 kb) of the
ADIPOQ
gene from a GWAS of circulating adiponectin levels (n=~38,600). Using these variants, we performed MR on ischemic stroke (n=62,100)/subtypes (large artery=6,399; cardioembolic=10,804; small vessel=6,811), white matter hyperintensities (WMH) (n=42,310), and coronary artery disease (CAD) (n=181,522) using GWAS data of the respective traits. We also leveraged pQTL data from two proteomics studies (deCODE; 35,559 Icelanders; 4,719 proteins, and UK Biobank Pharma Proteomics Project; ~50,000 participants; ~3000 proteins) to perform MR at the proteome-wide level, with the aim of identifying the downstream proteomic effect of adiponectin targeting.

Results:
Fourteen genetic variants in the
ADIPOQ
locus were associated with circulating adiponectin levels. Higher genetically-proxied,
ADIPOQ
-mediated circulating adiponectin levels were associated with lower WMH (IVW β=-0.131 per μg/ml increase in adiponectin levels; 95% CI: (-0.217) - (-0.044); p=0.003) and CAD (IVW OR 0.93 per μg/ml increase in adiponectin levels; 95% CI: 0.88-0.98; p=0.006) risk, but not ischemic stroke/subtypes (all p-values > 0.05). Results were consistent in sensitivity analyses. After FDR correction per proteomic dataset (p-FDR < 0.05), higher genetically-proxied,
ADIPOQ
-mediated circulating adiponectin levels were associated with proteins involved in various pathways including the inflammatory (e.g.
CXCL17
,
CRP
), thrombogenic (e.g. factor X, plasminogen), cardiometabolic (e.g.
IGFBPL1
,
NOTCH3
), and oncologic (e.g
IL9
) pathways
(Figures 1, 2)
.

Conclusions:
Pharmacologic targeting of circulating adiponectin levels may be associated with decreased risk of CAD and covert brain damage. The extent that this effect is driven by pleiotropic mediatory proteomic pathways warrants further research.
Abstract WP314: Trends in adherence to secondary prevention guidelines after stroke
Authors: Tack Reinier , Senff Jasper , Tan Benjamin Yong Qiang , Kimball Tamara , Prapiadou Savvina , Yechoor Nirupama , Rosand Jonathan , Singh Sanjula , Anderson Christopher
Published: January 2025

Introduction:
Of all strokes, 25% are attributable to recurrent events, of which 80% can be prevented by adherence to secondary prevention guidelines. These involve managing and controlling risk factors for recurrence, such as blood pressure, body mass index (BMI), low-density lipoprotein (LDL) cholesterol, glycated hemoglobin (HbA1c), smoking, alcohol consumption and physical activity. We aimed to determine which proportion of stroke survivors adheres to standard AHA secondary prevention guidelines for risk factor management, the trends in adherence over time, and whether guideline adherence is associated with a lower risk of mortality.

Methods:
We collected cross-sectional data on stroke survivors using the National Health and Nutrition Examination Survey (NHANES) from 1999-2018 linked to death certificate records up to December 2019. We collected data on demographics and determined adherence using secondary stroke prevention guidelines per risk factor. We compared proportion of participants that adhere to guidelines to an age, sex and race matched control population, examined trends over time using a generalized linear model and used cox proportional hazards models to determine the effect of adherence to individual risk factor guidelines on post-stroke mortality. All analyses were performed using the survey weights provided by the NHANES designed to make the population representative of US demographics.

Results:
We included 2,197 stroke survivors, of whom 51% were female with a mean age of 68. For the AHA secondary prevention guidelines, stroke survivors were less likely than controls to adhere to blood pressure, BMI, smoking and physical activity guidelines, but more likely to adhere to LDL guidelines. In stroke survivors, adherence to blood pressure (+1.4% per 2-year increment) and LDL (+3.0%) guidelines improved over time, while adherence to physical activity guidelines (-1.1%) declined. Adherence to guidelines on blood pressure (HR 0.55 [95% CI 0.41-0.64]), smoking (HR 0.55 [95% CI 0.44-0.69]) and physical activity (HR 0.51 [95% CI 0.41-0.64]) was associated with a reduced risk of mortality during a median follow-up of 70 months.

Conclusion:
Many stroke survivors are unable to meet standard secondary prevention guidelines, but adherence to blood pressure and LDL guidelines is improving. Adherence to secondary prevention guidelines is associated with lower mortality among stroke survivors.
Abstract WP33: Platelet Transfusion and Antiplatelet Timing Not Associated with Decreased Rates of Ventriculostomy Hemorrhage in Aneurysmal Subarachnoid Hemorrhage
Authors: Taman Mazen , Chuck Carlin , Oldam Joseph , Feler Joshua , Torabi Radmehr , Moldovan Krisztina , Furie Karen , Wolman Dylan , Jayaraman Mahesh , Mahta Ali
Published: January 2025

Introduction:
Antiplatelet therapy (APT) is increasingly common in the treatment of aneurysmal subarachnoid hemorrhage (aSAH) with the growth of endovascular therapy, raising concerns about ventriculostomy-related hemorrhage (VRH). This study aimed to evaluate whether platelet transfusion or ventriculostomy timing relative to APT initiation reduces VRH risk.

Methods:
We conducted a retrospective review of a prospectively collected cohort of aSAH patients treated at a single academic center between 2016 and 2023. The study focused on those who underwent ventriculostomy and received APT. Patients on anticoagulation were excluded. The cohort was then split into three groups: 1) APT at ventriculostomy without platelet transfusion, 2) APT at ventriculostomy with platelet transfusion, and 3) APT initiated post-ventriculostomy. Univariate and multivariate analyses assessed the incidence of tract hemorrhage, symptomatic tract hemorrhage, and poor neurologic outcomes defined as modified Rankin scale (mRS) ≥3 at three months.

Results:
Among 404 identified aSAH cases, 129 patients were on APT during or after ventriculostomy. The mean age was 59.5 years (SD=13.9), with 38.8% male, and 74.4% white. Comparison between patients who received APT without platelet transfusion (n = 24) and those who received APT with platelet transfusion (n = 34) showed no significant association with reduced rates of VRH or symptomatic VRH on univariate (37.5% vs. 29.4%;
P
=0.52 and 4.2% vs. 5.9%;
P
=0.77, respectively) or multivariate analysis (OR 0.79, 95%CI [0.24, 2.61];
P
=0.7 and OR 1.92, 95%CI [0.14, 52.3];
P
=0.6). Similarly, when compared to those already on APT, initiating APT post-ventriculostomy did not significantly alter VRH or symptomatic VRH rates on univariate (37.5% vs. 25.4%;
P
=0.26 and 4.2% vs. 1.4%;
P
=0.42, respectively) or multivariate analysis (OR 0.74, 95%CI [0.42, 1.31];
P
=0.3 and OR 0.28, 95%CI [0.01, 7.99];
P
=0.4). No differences in neurologic outcomes were observed at 3-month follow-up in either analysis.

Conclusion:
Our study did not identify benefits conferred from platelet transfusion in VRH or outcomes regarding ventriculostomy placement in aSAH patients on APT. Additionally, the timing of APT initiation relative to ventriculostomy did not significantly affect VRH rates. With the increasing use of endovascular therapies, ventriculostomy placement under APT is increasingly common, and further research is needed to identify effective strategies for minimizing VRH risk.
Abstract WP333: Population-based Study of Stroke Recurrence in Overweight or Obese Patients: Considerations for Future Prevention Trials
Authors: Yahnke Ian , Sucharew Heidi , Broderick Joseph , Robinson David , Kleindorfer Dawn , Ferioli Simona , Mackey Jason , Woo Daniel , DeLosRiosLaRosa Felipe , Demel Stacie , Mistry Eva , Coleman Elisheva , Jasne Adam , Slavin Sabreena , Walsh Kyle , Star Michael , Stanton Robert , Ljungberg Lovisa , Kamel Hooman , Haverbusch Mary , Kissela Brett
Published: January 2025

Introduction:
Recurrent stroke accounts for approximately 1/4 of all strokes and is associated with high morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1), while originally developed to treat diabetes, have demonstrated efficacy in preventing cardiovascular events in overweight or obese (BMI>27) patients without diabetes. It is unknown whether these agents could also be useful for preventing recurrence in non-diabetic overweight or obese stroke patients. To guide potential trial planning, we sought to characterize the prevalence of overweight or obesity without diabetes among stroke patients and assess the recurrence rate in these patients at 3 years.

Methods:
Using the Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS) database from (2015), we identified adult patients with a diagnosis of acute ischemic stroke (AIS) or transient ischemic attack (TIA) and a BMI >27. Patients were separated into two groups based on whether they had a diagnosis of diabetes (either a prior history or a new diagnosis). Demographic information, premorbid mRS, stroke subtype, vascular risk factors and rate of stroke recurrence at 3 years were analyzed. We calculated Kaplan Meier estimates of 3-year recurrence in stroke patients with BMI>27 with and without diabetes. We used a log-rank test to test if there was a difference in the rate of recurrence between the two groups.

Results:
In 2015, of 3086 patients with an AIS or TIA, 3057 had BMI reported and 1644 (54%) with a BMI>27. 859 (52%) of these patients were female, 370 (23%) were Black, and 754 (46%) of these patients had a prior or new diagnosis of diabetes. Overweight or obese patients without diabetes differed from diabetics in race, baseline stroke severity, baseline disability, frequency of HTN and LVH, CAD, smoking and prior stroke. Unadjusted risk of recurrence in non-diabetic overweight or obese patients was 11% (95% CI: 8%, 15%) at 3 years, which was lower than the rate in diabetic overweight or obese of 20% (95% CI: 16%, 26%) (log-rank test p-value <0.01). Unadjusted survival free of stroke in non-diabetic overweight or obese patients was 71% (95% CI: 66%, 75%) at 3 years, which was higher than in diabetic overweight or obese patients of 59% (95% CI: 53%, 65%).

Conclusion:
Of all ischemic stroke and TIA patients, 29% have a BMI>27 without diabetes; these patients have a 3-year stroke recurrence rate of 11% and survival free of stroke of 71%. Clinical trials targeting this group are needed.
Abstract WP335: CT Perfusion for Predicting Ischemic Stroke in Patients with Symptomatic Carotid or Middle Cerebral Artery Occlusion: A Post-hoc Analysis of the CMOSS Study
Authors: Wang Tao , YANG YIFAN , Wang Haibo , Luo Jichang , Liu Delin , Renjie Yang , Gong Haozhi , Sun Xinyi , Derdeyn Colin , Ma Yan , Jiao Liqun
Published: January 2025

Objective:
We aim to test the ability of CT perfusion (CTP) for predicting ischemic stroke in patients with symptomatic chronic carotid or middle cerebral artery occlusion.

Methods:
This was a post-hoc analysis of the CMOSS trial (NCT01758614), a randomized controlled trial comparing extracranial-intracranial (EC-IC) bypass surgery to medical therapy in patients with symptomatic carotid or middle cerebral artery occlusion and hemodynamic insufficiency measured by CTP. Patients treated with medical treatment alone in the trial were included. Mean transit time (MTT) and relative cerebral blood flow (rCBF) from CTP were collected. The primary outcome was defined as ischemic stroke in the territory of the qualifying artery within 2 years after randomization.

Results:
All 165 per-protocol patients (median age = 53.7 years, 81.2% males) treated with medical treatment alone were analyzed. Sixteen patients (9.7%) suffered from ischemic stroke in the territory of the qualifying artery during two-year follow-ups. Cut-off values of MTT>6.5s (symptomatic side) and rCBF ≤0.5 were suggested to be associated with recurrent stroke. In multivariate Cox regression, MTT (adjusted hazard ratio [HR] = 3.50, 95% CI = 1.19-10.30, p = 0.02) and rCBF (adjusted HR = 7.36, 95% CI = 2.27-23.85, p =0.001) were independently associated with the primary outcome.

Conclusion:
This study demonstrated CTP-based hemodynamic evaluation had relative accuracy in predicting recurrent ischemic stroke in symptomatic patients with chronic carotid or middle cerebral artery occlusion, which can be potentially used in patient selection for stratified secondary prevention of stroke. Future studies are warranted to verify current findings.
Abstract WP341: Endothelial type I interferon signaling modulates vascular response to ischemic brain injury
Authors: Tuohy Mary Claire , Kuo Ping-Chang , Chelminski Adrian , Muharremi Eti , De Sanctis Claudia , Russo Alicia , Hillman Elizabeth , Crary John , Yen Jui-Hung Jimmy , Agalliu Dritan
Published: January 2025

Vascular normalization and restoration of blood-brain barrier (BBB) function are critical to reestablish a microenvironment that supports tissue repair and functional recovery after ischemic stroke. During development, central nervous system (CNS) angiogenesis and barriergenesis are coupled via canonical Wnt/β-catenin signaling. Following ischemic insult, brain endothelial cells (BECs) upregulate Wnt signaling on a background of acute inflammation. How distinct immune signaling pathways cooperate with developmental pathways to differentially regulate and temporally coordinate post-stroke vascular remodeling remains poorly understood. Here, we identify a unique BEC type I interferon (IFNI) signature in human and mouse ischemic stroke tissue using immunohistochemistry and RNA in situ hybridization. By leveraging two clinically relevant murine ischemic stroke models, single-cell transcriptomic technology, and Biocytin-TMR tracer leakage assays, we identify that genetic deletion of endothelial IFNI receptor (IFNAR1) exacerbates post-stroke barrier disruption and results in an expansion of BECs characterized by marker genes associated with angiogenesis and immature BBB. Conversely, acute administration of exogenous IFNI ameliorates post-stroke BBB disruption. Functional in vitro assays (trans-endothelial electrical resistance / wound healing) and western blotting reveal that BEC IFNI signaling modulates VE-Cadherin stabilization and vascular endothelial growth factor (VEGF) signaling to enhance BEC barrier properties and suppress angiogenic features, respectively. Together, our work supports that endogenous BEC IFNI signaling regulates acute BEC function after ischemic brain injury through the 1) restriction of angiogenesis onset and/or 2) augmentation of vascular maturation to promote barrier function. Moreover, these findings may have broader implications for understanding CNS vascular pathology and normalization in the setting of brain states characterized by acute (i.e. stroke, traumatic brain injury) or chronic (i.e. multiple sclerosis, neurodegeneration, aging) sterile inflammation.
Abstract WP348: Inflammatory biomarkers in the Golden Hour: findings from a Mobile Stroke Unit
Authors: Ledreux Aurelie , Violette John , Neumann Robert , Thompson John , Ornelas David , Paustian Whitney , Monte Andrew , Coughlan Christina , Dylla Layne , Jones William , Grotta James , Graner Michael , Kowalski Robert
Published: January 2025

Background:
The intervention of mobile stroke units (MSUs) on a patient experiencing an acute ischemic stroke significantly improves outcomes compared to standard of care provided by emergency medical services. It allows for more patients to be treated with intravenous thrombolysis during the Golden Hour after last known normal (LKN). While prompt thrombolysis treatment restores blood flow, its effect on the inflammatory cascade triggered by the stroke has not been examined.

Methods:
Blood samples were obtained on the MSU through a prospective cohort study. NIH Stroke Scale (NIHSS) scores were recorded on the MSU and at the hospital discharge. Nine proinflammatory plasma cytokines were measured with the MesoScale Discovery S-Plex assay from plasma samples obtained on the MSU and 24 hours later.

Results:
Seventy adults were analyzed, including 46 patients treated on the MSU between August 2021 and May 2024, and 24 controls. Twenty-six (56%) MSU patients were diagnosed with a confirmed acute ischemic stroke (AIS), 3 had an intracerebral hemorrhage and 17 (37%) were stroke mimics. Confirmed AIS patients had a median age of 65 (range 36-88) years, 58% were male, 73% white. Their initial median NIHSS score was 7 (range 1-22). Twenty-three (88%) received intravenous thrombolysis (tPA or TNK). Blood was obtained a median of 57 (range 26-355) minutes after LKN. We first compared AIS, stroke mimics and controls and found significant group differences for interleukins IL12p70, IL17, IL1β, IL2, IL4 and IL6. Pairwise differences indicated that IL12p70, IL17 and IL2 were significantly lower in AIS compared to stroke mimics. Among AIS patients, sixteen (61%) received treatment on the MSU within the Golden Hour. Patients treated during the Golden hour had median levels of IFNγ, IL17 and IL4 higher, while median levels of IL-12p70, IL-1β, IL-2, IL-6, TNFα and IL-10 levels were all lower, perhaps suggesting an effect of thrombolysis treatment timing. The NIHSS score changes between MSU and discharge were less favorable for patients treated after the Golden hour. Initial and 24-hr IL10 levels were positively correlated with time elapsed between LKN and MSU intervention.

Conclusions:
Our study found that the proinflammatory cytokines IL12p70 and IL2 are significantly reduced while IL4 and IL6 are significantly elevated in AIS patients, compared to normal controls. We observed some trends suggesting that thrombolysis within the Golden Hour influences the inflammatory response.
Abstract WP349: Multicenter Stroke Preclinical Assessment Network analysis of cardiovascular risk factor subgroups treated with the poly(ADP-ribose) polymerase inhibitor veliparib
Authors: Koehler Raymond , Bedirian Karni , Chen Mu-Hsun , Shi Yanrong , Cao Suyi , Avery Brooklyn , Karuppagounder Senthilkumar , Dawson Valina , Dawson Ted , Diniz Marcio , Lamb Jessica , Nagarkatti Karisma , Lyden Patrick
Published: January 2025

The first Stroke Preclinical Assessment Network (SPAN 1) tested 6 therapeutic interventions initiated at the time of reperfusion in models of focal ischemic stroke, including models of cardiovascular risk factors. To improve preclinical testing rigor and reproducibility, the testing was conducted as a large, randomized controlled trial across 6 sites with a coordinating center that concealed treatments and blinded neurobehavior video assessments. The trial had an adaptive design with preset levels of efficacy and futility interrogated after each of 4 stages relative to placebo (P). The primary outcome was turning preference on the corner test at 30 days. Secondary outcomes included corner test turns at 7 days, foot-faults on a grid walk test at 7 and 30 days, and MRI lesion volume at 2 and atrophy at 30 days. Based on the primary outcome data pooled from young mice, aging mice, high-fat diet obese mice and spontaneously hypertensive rats (SHRs), the poly(ADP-ribose) polymerase (PARP) inhibitor, veliparib (V), was considered futile after the second stage (V=271; P=171). Here, we performed a secondary analysis of the veliparib data on individual subgroup models, secondary outcomes, and effects of sex. Veliparib (10 mg/kg) injected IV at reperfusion failed to show a benefit on the corner test or grid walk test at 7 or 30 days of recovery or a reduction in lesion volume in young mice (V=114; P=56), obese mice (V=38; P=34), or SHRs (V=39; P=41). However, in aging mice (17-18-months-old; V=39; P=40), veliparib significantly improved performance on the corner test (
P
= 0.009) and grid walk test (
P
= 0.002) at 7 days; the benefit was independent of sex. However, mortality in the aging mice was greater than in the other subgroup models at all sites, and significance in the corner test was lost at 30 days (
P
= 0.10) associated with the decreased sample size. Aging mice were especially susceptible to respiratory arrest during anesthesia while conducting MRI scans. Lesion volume at 2 days was small in the veliparib (2-3% of hemisphere) and placebo (4%) groups, suggesting that the benefit of veliparib on neurobehavior might be due to its known anti-inflammatory effects rather than by decreasing infarct volume. Because ischemic stroke predominantly occurs in the aging population, further research into the neurobehavior benefit of PARP inhibitors in aged animal models of stroke is warranted in protocols that omit post-ischemic anesthesia so as to improve survival.
Abstract WP364: Translational Relevance and Versatility of the Thromboembolic Stroke Model in Mice: Implications for Pharmacological and Safety Evaluations
Authors: Letourneur Annelise , LEBRUN Florent , Lebas Héloïse , Violle Nicolas , Vivien Denis
Published: January 2025

Introduction:
In 2007, Orset et al. proposed an innovative thromboembolic stroke model in mice where murine thrombin is injected into the M2 segment of the middle cerebral artery (MCA) to induce arterial thrombosis. It emerged as a sensitive but versatile and translationally tool for evaluating pharmacological efficacy and safety of innovative drugs. After 7 years of use in our hands, we aggregate the data from a large panel of studies.

Hypothesis:
The Thromboembolic stroke model accurately mimics clinical stroke scenarios, providing a reliable platform for assessing drug efficacy and safety.

Methods:
We evaluated pharmacological efficacy of Alteplase and Tenecteplase in the thrombin stroke model and determined Alteplase therapeutic window. We compared the effects of Alteplase in thrombin-model with FeCl3-induced thrombosis model. The studies included various mouse strains (OF1 and C57BL/6), assessing the impact of diabetes and hypertension and sex-dependent responses on treatment outcomes. Safety aspects included drug interaction with reference drugs and hemorrhagic transformation (HT) rate and severity evaluation.

Results:
Both Alteplase and Tenecteplase significantly improve MCA recanalization and reduced lesion volume in the thrombin model as measured by MRI, with efficacy diminishing after 20 minutes, and no visible effects by 90 min post-stroke. Male and female mice exhibited similar response to treatment in healthy and comorbid animals. However, Alteplase showed efficacy only in OF1 mice. The FeCl3 model showed no response to Alteplase, highlighting its utility in mimicking patient subgroups with fibrinolysis resistant profiles. In the presence of comorbidities, lesion volume and HT were increased and Alteplase was ineffective. The combination of other drugs with Alteplase demonstrated additional benefits in reducing lesion volume, demonstrating that the model allows for superiority study, but also highlighted potential safety concerns.

Conclusions:
The thrombin stroke model in mice is a robust system for the translational evaluation of therapeutic agents, providing key insights into both efficacy and safety of tested drugs. Its ability to simulate several clinical scenarios, including patient comorbidities and drug interactions, positions it as a relevant model for stroke preclinical studies.
Abstract WP369: Peripheral CD200R Signaling: A Critical Regulator of Post-Stroke Inflammation
Authors: Misrani Afzal , Ngwa Conelius , Manyam Kanaka Valli , Xu Yan , McCullough Louise , Liu Fudong
Published: January 2025

Background:
Immune responses are fundamental to ischemic stroke pathology. Controlling pro-inflammatory responses helps reduce brain ischemic injury and has translational significance. The interaction between CD200R, an inhibitory receptor on immune cells, and the CD200 ligand suppresses pro-inflammatory pathways. The accumulating data have suggested that CD200R is minimally expressed on adult microglia after stroke, suggesting an inhibitory role of the CD200-CD200R axis in mobilization of peripheral immune cells.

Hypothesis:
CD200-CD200R signaling in peripheral leukocytes is more essential than the central (brain) signaling to post-stroke inflammation and outcomes.

Methods:
CD200R global knockout (KO), GFP, and C57BL/6 wild-type (WT) male and female (16-20 months) were used to generate 3 types of bone marrow chimeric (BMC) mice: GFP-to- KO (central signaling), KO-to-GFP (peripheral), and GFP-to-WT (control). All chimeras underwent a 60-minute transient middle cerebral artery occlusion (MCAO). Three days after stroke, neuroinflammation was evaluated by flow cytometry (FC; for leukocyte infiltration), and brain/plasma ELISA (cytokines). Stroke outcomes, including infarct volume and neurobehavioral deficits, were also assessed.

Results:
We have validated the three BMC models by FC (Fig. 1). FC analysis further revealed significantly more infiltration of immune cells into ischemic brains of KO-to-GFP vs. control mice; whereas no difference was seen in GFP-to-KO vs. control group. Brain and plasma ELISA data indicated significantly higher levels of pro-inflammatory cytokines (TNF-α, IL-1β) in the KO-to-GFP vs. control mice. Additionally, KO-to-GFP mice demonstrated larger infarct sizes, more severe neurological deficit scores (NDS), and greater motor impairments in the open field test (OFT) and grip strength assessment.

Conclusions:
Peripheral CD200R signaling (but not the central signaling) impacts on post-stroke inflammation and outcomes. Our data highlight a potential therapeutic target for mitigating stroke injury by modulating peripheral CD200-CD200R axis.
Abstract WP377: Long-term post-stroke cognitive dysfunction in aged subjects is associated with increased synapse pruning by reactive astrocytes
Authors: Shabani nabikandi Zahra , Pan Peipei , Li Qifeng , wang zhanqiang , huo kang , Su Hua
Published: January 2025

Background and Purpose:
Aged patients experience more cognitive dysfunction than young patients after stroke. Brain astrocytes and microglia causes excessive removal of synapses at the early stage of stroke. Inhibition of their phagocytosis improved neurobehavioral outcomes. Long-term post-stroke cognitive dysfunction in aged subjects may be associated with increased synapse pruning by astrocytes, as increased reactive astrocytes are present in and around the atrophic region.

Hypothesis:
Excessive synapse pruning by reactive astrocytes contributes to the long-lasting post-stroke memory dysfunction in aged mice.

Methods:
pMCAO was induced in young (2-month-old) and aged (15-18-month-old) mice. Memory performance was tested weekly for 8 weeks by Y-maze, and at 8 weeks post-stroke by novel objective recognition (NOR) tests. Brains were collected 8 weeks after pMCAO. Gene expressions were analyzed by RNAseq and western blot. Atrophic volume, CD68
+
cells, GFAP
+
cells, and synaptophysin (SYP) were analyzed histologically.

Results:
In Y-maze test, aged stroke mice made fewer spontaneous alternations from 3 to 8 weeks after pMCAO than young stroke and sham operated aged mice. In NOR test, aged stroke mice spent shorter time on the novel objects than young stroke and sham aged mice. RNAseq data showed up-regulation of inflammation, and down-regulation of axon growth and synaptic transmission pathways in the aged ipsilateral than young ipsilateral cortex and aged contralateral cortex. Glutamatergic and cholinergic synapses were decreased in aged ipsilateral cortex and hippocampus. GABAergic presynapse protein was increased in the aged ipsilateral hippocampus compared to the young mice. All support reduced activity in the cortex and hippocampus of aged stroke mice. Aged mice showed larger atrophic volumes, more CD68
+
and GFAP
+
cells in the peri-atrophic and hippocampi regions than young mice. About 10-fold more GFAP
+
cells were detected in aged peri-atrophic and ipsilateral hippocampi regions than CD68
+
cells; 57% GFAP
+
and 37% CD68
+
cells were SYP
+
in the ipsilateral hippocampi, 53% GFAP
+
and 39% CD68
+
cells were SYP
+
in the peri atrophic region of aged stroke brain, indicating that reactive astrocytes contributed more than microglia on synapse pruning in aged mice.

Conclusions:
Reactive astrocytes contribute more than microglia to synapse pruning at the chronic stage of stroke, which is involved in long-lasting post-stroke memory dysfunction in the aged mice.
Abstract WP393: Inception and Rupture of Intracranial Aneurysms with Daughter Sacs: A Comprehensive Hemodynamics Analysis
Authors: Bramlage Luke , Yi Hang , Yang Zifeng , Ludwig Bryan
Published: January 2025

Background and Purpose:
Intracranial aneurysms (IAs) with daughter sacs (DSs) have an increased risk for rupture yet the hemodynamic factors contributing to DS pathophysiology are still under-investigated. This study aimed to investigate hemodynamic factors in DS generation and rupture using anatomic and ablated IA models under various DS scenarios.

Methods:
113 computational models of 43 patients with at least one IA containing a DS were built based on 3D rotational angiographical images using benchmarked model reconstruction procedures. Of these 43 patients, there were 19 ruptured (RIAs) and 26 unruptured IAs (UIAs). Ablated models representing the aneurysm before the DS formation were rebuilt by virtually ablating the blebs from the anatomic models.
In-vitro
validated computational fluid dynamics simulations were conducted for both anatomic IA and ablated IA models under physiologically pulsatile flow conditions. Wall shear stress (WSS) associated parameters were used to analyze the hemodynamic factor on the DS pathophysiology statistically.

Results and Discussion:
There was a statistically significant difference seen between RIAs and UIAs in hemodynamic performances at the entire aneurysmal sac region (P<0.01). Specifically, there was a significant difference in maximum instantaneous WSS (MIWSS), maximum instantaneous WSS gradient (MIWSSG), maximum time-averaged WSS (MTAWSS), and maximum time-averaged WSS (MTAWSSG) observed between RIAs and UIAs arising from the internal carotid artery, anterior cerebral artery, and middle cerebral artery. The difference in maximum oscillatory shear index (OSI) between RIAs and UIAs was not consistent at these aneurysmal locations. In addition, on the local DS bleb region, the hemodynamic comparisons between UIAs and RIAs were not consistent with the comparisons on the entire aneurysmal sac region. Future studies include the introduction of new parameters (i.e., instantaneous/time-averaged surface-averaged WSS, WSSG, and OSI) to investigate specific hemodynamic factors associated with DS and IA rupture. Hemodynamics between anatomic and ablated IA models will also be compared to determine its contributions on DS bleb inception. In conclusion, these findings are significant as they do suggest possible factors contributing to IA rupture. Continued research in this area will help develop a diagnostic tool to analyze IA rupture risk better than current available methods.