bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract WP239: Apolipoprotein E4 Allele Effect on the Prevalence of Intracranial Large Artery Stenosis
Authors: Lopez-Navarro Edgar R , Khasiyev Farid , Spagnolo-Allende Antonio J , Guzman Vanessa A , Strobino Kevin , Liu Minghua , Del Brutto Oscar , Sanchez Danurys , Hilal Saima , Elkind Mitchell , Rundek Tatjana , Del Victor J , Brickman Adam , Manly Jennifer , Andrews Howard , Seshadri Sudha , Romero Jose R , Chen Christopher , Gutierrez Jose
Published: February 2024

Introduction:
Apolipoprotein E4 (ApoE4) allele is linked to increased LDL-Cholesterol, one of the main risk factors for intracranial large artery stenosis (ICAS). Evidence shows that in diabetic men, intima-media thickness is significantly higher in those with ApoE4 than those with ApoE3. While the link between ApoE4 and extracranial atherosclerosis and vascular risk factors is established, the association of these vascular factors with ICAS is unknown. This study investigates the relationship between ApoE4 carrier status and ICAS and whether vascular risk factors influence this relationship.

Methods:
We rated intracranial large arteries on MR-angiography for their degree of stenosis as 0=no stenosis, 1=<50% stenosis, 2=50-69%, 3=70% or flow gap. We added the score of each of the 11 intracranial arteries to reflect a composite measure of the severity of ICAS. We then related ApoE4 carrier status to the ICAS score using generalized linear models with a Poisson link, adjusting for demographics, vascular risk factors, and cohort. We ran pre-specified interaction models with demographics and vascular risk factors.

Results:
4099 individuals from six cohorts were included; 58% were women, the prevalence of hypertension was 76%, diabetes 31%, dyslipidemia 64%, and current smoking 13% (Table). There was no association between ApoE4 carrier and ICAS score (B= 0.08+0.06, p=0.19), but we found statistical interactions between ApoE4 carrier and male sex (p=<0.001), current smoking (p=0.05), and hypertension (p=0.003). ApoE4 carrier status was associated with higher ICAS score among hypertensive men (B=0.52±0.11, P=<0.001) and hypertensive people who smoke (B=0.58±0.20, p=0.01.

Conclusion:
ApoE4 carrier status was not associated with ICAS overall, but there were associations in subgroups defined by sex, hypertension, and smoking. Whether these interactions influence the risk of stroke and dementia should be further investigated.
Abstract WP242: Acute Ischemic Stroke With Atrial Fibrillation: Relation Between ω3/ω6 Poly Unsaturated Fatty Acids
Authors: Sato Takeo , Okumura Motohiro , Ishikawa Takahiro , Takahashi Junichiro , Tanabe Maki , ONDA ASAKO , Komatsu Teppei , Sakuta Kenichi , Sakai Kenichiro , Umehara Tadashi , Mitsumura Hidetaka , Iguchi Yasuyuki
Published: February 2024

Background & Aims:
Some poly unsaturated fatty acids (PUFA) are said to be associated with the development of atrial fibrillation (AF). Our aim is to elucidate the relation between PUFA and AF in acute ischemic stroke.

Methods:
Consecutive patients with ischemic stroke admitted between October 2012 and February 2022 were retrospectively screened. The inclusion criteria were as follows: 1) onset to door time within 7 days; and 2) availability of PUFA measurements from the day of the hospital visit or the next day. Plasma levels of PUFA, including eicosapentaenoic acid (ω3: EPA) docosahexaenoic acid (ω3: DHA), dihomo-γ-linolenic acid (ω6: DGLA), and arachidonic acids (ω6: AA), were assayed by gas chromatography. We investigated the association between each of PUFA levels and AF among the acute ischemic stroke patients.

Results:
We screened 2,122 consecutive ischemic stroke patients. Of them, 1,574 were identified (1,119 [71%] males, median age 69 years). In Poisson regression analysis with a robust variance estimator, factors associated with AF were lower DGLA level (prevalence ration (PR) 0.885, 95% CI 0.811 to 0.966,
p
= 0.006), lower AA level (PR 0.797, 95% CI 0.649 to 0.978,
p
= 0.029), and higher EPA/AA ratio (PR 1.353, 95% CI 1.036 to 1.766,
p
= 0.026). In Poisson regression analysis with a robust variance estimator for AF using PUFA quartile as indicator variables, negative linear trends were observed between the quartile of DGLA (Quartile 1: PR 1.884, Quartile 2: PR 1.530, Quartile 3: PR 1.429, Quartile 4: reference) and AA (Quartile 1: PR 1.499, Quartile 2: PR 1.199, Quartile 3: PR 1.137, Quartile 4: reference), and a positive linear trend between the quartile of EPA/AA ratio (Quartile 1: reference, Quartile 2: PR 1.544, Quartile 3: PR 1.629, Quartile 4: PR 1.781, Figure).

Conclusions:
In acute ischemic stroke, lower ω6 level and higher ω3/ω6 ratio were associated with the presence of AF. ω3/ω6 PUFA may have contrasting effects on the incidence of AF in acute ischemic stroke.
Abstract WP243: Elevated Lipoprotein(a) as a Predictor for Recurrent Ischemic Cerebrovascular Events: A Meta-Analysis of Cohort Studies
Authors: Mahadevan Arankesh , Annam Saketh , Tullimalli Immanuel R , Raj Rohan , Kaur Parvinder , Gondi Yasho , Lakkimsetti Mohit , Rajbhandari Pranaya , Valluri Jnana Pramod , Anil Peethambar Gowri , Desai Rupak
Published: February 2024

Introduction:
Elevated levels of Lipoprotein(a) [Lp(a)] have been associated with an increased risk of incidental acute ischemic stroke (AIS). Our study represents the first meta-analysis investigating the relationship between Lp(a) levels and the recurrence of AIS or transient ischemic attacks (TIA) in both adult and pediatric populations.

Methods:
We conducted a systematic search of PubMed and Google Scholar databases up to August 2023, utilizing medical subject headings and title/abstract terms. Studies reporting on Lp(a) levels predicting recurrent AIS or TIA were screened. From 85 identified studies, 8 met our inclusion criteria: 5 focusing on adults and 3 on pediatric cohorts. Binary random effects models were used to estimate pooled unadjusted and adjusted odds ratios (OR) and 95% confidence intervals (CI). Subgroup analysis was performed by country. Sensitivity analysis was done by the leave-one-out method, and the heterogeneity was assessed with I
2
statistics.

Results:
Our analysis included data from 13,549 patients. The mean age in years was 66 for adults and 7.6 for the pediatric cohort. The majority of the cohorts were male and identified as being of a white racial background. The median follow-up duration was 22.5 months. Elevated Lp(a) indicated an unadjusted OR of 1.60 (95% CI: 1.18-2.16) for recurrent AIS or TIA, with moderate heterogeneity (I
2
=56.17%, p=0.003) and the association validated by sensitivity analysis. When adjusted, the OR increased to 1.84 (95% CI: 1.20-2.84) with high heterogeneity (I
2
=82.36%, p<0.001). Country-specific sub-analysis identified the highest OR in Germany, followed by China and the USA.

Conclusion:
Elevated Lp(a) levels corresponded to a 60% unadjusted and 84% adjusted increase in the risk of recurrent AIS or TIA. This underscores the significance of Lp(a) as a valuable predictor for recurring cerebrovascular events, offering insight to inform clinical management and decision-making.
Abstract WP25: Eptifibatide in Acute Ischemic Strokes Without Large Vessel Occlusions
Authors: Bozkurt Subutay , Song Yong-Bum , Haimi Joshua , Sahito Sindhu , Nabeel Akbar Muhammad , Fanous Paul , Abualnadi Ibrahim , Amireh Abdallah , Gates Michael , Malik Marriam , Siddiqui Mariah , Briski Nicholas , Abdelmessih sarah , Akinci Yasemin , Nazanin Kiapour , Khan Hubashia , Gadallah Nancy E , tabibzadeh navid , Strauss Sara , ghori Arifa , Scarpiello Sean , Snyder Thomas
Published: February 2024

Background:
Platelet glycoprotein IIb/IIIa inhibitors are currently being researched for patients with acute ischemic stroke (AIS), however there is no consensus on which inhibitor or dose is both safe and effective. Tirofiban has recently been studied, however it was associated with an increased risk of intracranial bleeding. In this study we share our experience using eptifibatide given it has shown to be as effective as tirofiban with a better safety profile.

Methods:
In this multi-center retrospective analysis, we screened 102 patients who received an eptifibatide bolus of 135 mcg/kg followed by 0.5 mcg/kg/min infusion and 332 patients treated with usual stroke care between December 2022 and May 2023. Patients were excluded if the NIHSS on presentation but within 24 hours of last known well was less than 3 or if the patient had a large vessel occlusion (LVO). There were 7 and 31 patients included in the eptifibatide and usual care group respectively. Our primary endpoint was change in NIHSS from admission to discharge. Our safety endpoints were symptomatic ICH and any ICH.

Results:
No patients included in the study experienced a symptomatic ICH. The median time of eptifibatide infusion was 24 hours with some patients receiving the infusion for multiple days.

Conclusion:
While larger studies are needed to confirm our findings, eptifibatide may be safe and effective in the treatment of AIS without LVO.
Abstract WP251: Dietary Methionine and Homocysteine Level Interaction and Recurrent Stroke
Authors: Kabir Farah , Aldridge Chad , Worrall Bradford B
Published: February 2024

Background:
The folate one-carbon metabolism pathway (FOCM) provides vital one-carbon units for epigenetic regulation. Genetic variants in FOCM genes may affect methionine metabolism. Elevated circulating homocysteine (Hcy), a FOCM byproduct, is linked to increased stroke risk. However, the protective effects of dietary regulation of methionine and Hcy levels against recurrent stroke are uncertain.

Objective:
To investigate dietary methionine (METH) and its interaction with post-methionine load Hcy levels (POST) with recurrent stroke risk; to assess if genetically determined POST and its interaction with METH predict recurrent stroke risk.

Methods:
We utilized the Vitamin Intervention for Stroke Prevention (VISP) trial to estimate hazards ratios of METH and its interaction with POST on recurrent stroke with a Cox proportional hazards model. We also generated a POST polygenic risk score (PRS) with ridge regression using previously identified polymorphisms, located within
ALDH1L1, CPS1, GNMT, and PSPH,
as indicators of FOCM function.

Results:
The participants (n = 2,100; 64% men) had a mean (SD) age of 67 (11) years. Ancestry consisted of 82% European, 12% African, and 5.7% Other. A small portion of participants had missing POST values (7.3%). Clinical POST (HR 1.02; 95%CI 0.98, 1.06) and its interaction with METH (HR 0.99; 95% CI 0.97, 1.01) were not associated with recurrent stroke risk. Similarly, there was no significant relationship observed between PRS POST (HR 0.96; 95%CI 0.80, 1.15) and its interaction with METH (HR 1.02; 95% CI 0.94, 1.10).

Conclusion:
Dietary methionine and post-methionine load Hcy levels neither interact nor predict recurrent stroke risk. Our PRS approach showed similar negative findings. The relationship of the FOCM and recurrent stroke risk may lie in epigenetics.
Abstract WP254: Genetic Insights Into Snoring On Stroke
Authors: He Qiang , ma lu , you chao
Published: February 2024

Background:
Multiple risk factors of stroke have been identified in previous studies; however, the causal role of snoring in the onset of stroke is less investigated. To clarify the causal association of snoring on stroke and its subtypes, this study is performed.

Methods:
The single nucleotide polymorphisms in relation to snoring were retrieved from the UK biobank cohort with 408,317 participants. The data for stroke and its subtypes of European ancestry (67,162 cases and 453,702 controls) were obtained from the MEGASTROKE consortium. In single-variable Mendelian randomization (SVMR) and multivariable MR (MVMR) analyses, inverse variance weighting was used as the primary estimate, complemented with sensitivity analyses more robust to pleiotropy.

Results:
Genetically predicted snoring increased the risk of stroke (odds ratio [OR] = 2.69, 95% confidence interval [CI] = 1.19-6.08, P = 0.016) and ischemic stroke (IS) (OR = 2.82, 95% CI = 1.23-6.44, P = 0.013), but not large artery stroke (LAS) (OR = 3.02, 95% CI = 0.31-29.44, P = 0.339), cardioembolic stroke (CES) (OR = 1.51, 95% CI = 0.58-3.92, P = 0.395). We provide novel genetic evidence that snoring increases the risk of stroke and IS, but not LAS, CES, and SVS.

Conclusion:
Our findings provide novel genetic evidence that snoring increases the risk of stroke and IS, but not LAS, CES, and SVS.
Abstract WP26: Effectiveness of Tenecteplase versus Alteplase in Acute Ischemic Stroke Selected Subgroups of a Real-World-Data Set
Authors: Silva Luis , Khan Shayan , Ramezani Solmaz , Stalin Karen , Annam Saketh , Roberts Rebecca , Schneck David , Fiecas Mark , Xenopoulos-Oddsson Annette , Jagtap Pramit , Zheng Cynthia , Novy Savannah , Ikramuddin Salman , Staugaitis Abbey , Streib Christopher D
Published: February 2024

Introduction:
Tenecteplase is increasingly utilized as an alternative acute ischemic stroke (AIS) thrombolytic to Alteplase (tPA). Although many larger AIS trials have demonstrated the non-inferiority of TNK, Real World Data in many specific subgroups continue to be lacking. We studied the comparative effectiveness of AIS thrombolysis with TNK to tPA at our institution, focusing on currently understudied cohorts.

Methods:
We conducted a retrospective cohort analysis of AIS patients treated with thrombolysis within our health system. We utilized the Get With the Guidelines (GWTG) database to obtain basic demographic data. Additional variables and key outcomes (functional and radiographic) were abstracted independently by two authors from the electronic record. Disagreements were resolved by mutual consensus or a third investigator. An ordinal logistic regression model was used to assess the interventions' effectiveness, with the outcome being the modified Rankin Scale (mRS) score 90 days post-stroke. Subgroups included Age (<60, 61-80, >80), location of vessel occlusion (Large or Medium vessel), thrombolysis in the extended time window (beyond 4.5 hours), treatment via telestroke, and thrombectomy.

Results:
There were 500 consecutive AIS patients with complete outcome data. The mean age of the participants was 70.1 years, with 52.7% of patients being male. In the adjusted ordinal logistic regression analysis, the TNK group presented with 1.00 odds of a worse mRS score than the tPA group (95% CI 0.57-1.74). Subgroup regression analysis demonstrated no heterogeneity in effect size. Figure 1 is a Forest Plot demonstrating the Odds Ratio for each subgroup.

Conclusions:
It’s well-published that TNK is a comparable treatment for AIS and has demonstrated advantages. This analysis compared specific subgroups of real-world patients and showed no heterogeneity. This real-world subgroup analysis adds to the literature supporting the use of TNK for the treatment of AIS.
Abstract WP267: The Impact of Anesthetic Agents on Regional Cerebral Blood Flow During Carotid Artery Clamping in Patients With Debranching Thoracic Endovascular Aortic Repair and Carotid Endarterectomy
Authors: NAKANO YUSUKE , YOSHITANI KENJI
Published: February 2024

Background:
Carotid endarterectomy (CEA) and debranching thoracic endovascular aortic repair (debranching TEVAR) would lead to the reduction of cerebral blood flow (CBF) during carotid artery clamping. Intravenous anesthetics decrease CBF more than volatile anesthetics and may exacerbate cerebral hypoperfusion during carotid artery clamping. We have developed an innovative quantitative measure of regional cerebral blood flow (rCBF) that can be performed at the bedside using near-infrared spectroscopy (NIRS). Using this technique, we measured rCBF during CEA and TEVAR to determine the optimal anesthetic for carotid artery clamping.

Methods:
Patients undergoing debranching TEVAR and CEA were enrolled. We used NIRS and intravenous injection of Indocyanine green (ICG) to measure rCBF before carotid artery clamping, 10 minutes after clamping, and after de-clamping. The rCBF was calculated by Fick’s principle, using the maximum gradient model that combines the peak values and change in arterial blood concentration of ICG in the brain tissue. We evaluated the effects of each anesthetic (intravenous and volatile) on the rCBF of the cross-clamp side of the carotid artery.

Results:
The results of the intermediate analysis are shown below. Thirty-two patients who underwent debranching TEVAR and twenty-six who underwent CEA were enrolled. In patients who underwent debranching TEVAR, the rCBF increased from 48.4 to 53.5 ml/min/100g in patients anesthetized with volatile anesthetics and decreased from 55.1 to 32.8 ml/min/100g in patients anesthetized with intravenous anesthetics, as shown in the Figure. There was a significant difference between both anesthetics (p=0.034) but no significant difference between both anesthetics with CEA (p=0.93).

Conclusion:
In patients undergoing debranching TEVAR, volatile anesthetics may be preferable to intravenous anesthetics during carotid clamping.
Abstract WP270: Clonal Hematopoiesis of Indeterminate Potential (CHIP): Relationship With Ischemic Stroke Etiology
Authors: Lazaro Carlos , Lozano Prudencio , Montoro Julia , Palomo Laura , Pellin Claudia , Rizzo Federica , Campos Jose Manuel , Garcia-Tornel Alvaro , Juega Jesus M , PAGOLA Jorge , Molina Carlos A , Rubiera Marta
Published: February 2024

Clonal Hematopoiesis of Indeterminate Potential (CHIP) is defined by the presence of somatic mutations in peripheral blood cells without evidence of a hematological neoplasm. It has recently been associated with cardiovascular disease and stroke. The objective of our study is to evaluate the relationship of CHIP with the etiology of the ischemic stroke and how its measurement could contribute to the study of stroke causes.

Material and Methods:
Prospective observational study of consecutive patients who suffered an ischemic stroke between September 2021 and August 2022. After complete work-up, patients were classified as cardioembolic (CE), atherothrombotic (AT) and cryptogenic (CRIP) stroke; those who presented a double mechanism, incomplete study or were affected by an active neoplasia were excluded from the study. During hospital admission, 13 genes related to CHIP were analyzed, through targeted next generation sequencing. A variant allele fraction of >2% was considered positive.

Results:
Samples from 78 patients (50% women, mean age 73.5 years) were analyzed and etiologically classified as: 37 CE (47.5%), 33 AT (42.3%) and 8 CRIP (10.3 %). Twenty-one patients had CHIP (31.3%), of which the predominating mutations were: DNMT3A (47.6%), TET2 (28.5%) and SFRS3 (14.2%). Patients diagnosed with CE stroke had a higher frequency of CHIP (p=0.046): CE 14/37 (37.8%) vs. AT 6/33 (18.2%) vs. CRIP 1/8 (12.5%); specifically of the TET2 mutation (p=0.015): CE 6/37 (16.2%) vs. AT 0/33 (0%) vs. CRIP 0/8 (0%). In the multivariate analysis, the TET2 mutation was associated with CE etiology after adjusting by age, coronary artery disease, and classic cardiovascular risk factors (OR 8.1; CI 1.35-48.47; p=0.012).

Conclusions:
CHIP is frequently found in patients with ischemic stroke. The presence of the TET2 mutation is associated with CE stroke and could constitute a new risk factor and contribute to a more accurate etiological stroke diagnosis.
Abstract WP275: Longitudinal Biomarker Analysis in Patients With Ischemic Stroke: Exploratory Targeted and Omics Assessments From a Phase 2a Clinical Trial
Authors: Szapacs Matthew , Mollon Jen , Challagundla Malleswari , Forst Elise , Hu Min , Schulz Michael , Vasanthakumar Aparna , Smith Elaine
Published: February 2024

Introduction:
Elezanumab (EZB), a monoclonal antibody specific to repulsive guidance molecule A (RGMa), is under investigation to treat acute ischemic stroke. Biomarker evidence in ischemic stroke and for the RGMa pathway is limited.

Methods:
This blinded, in-study analysis from a 52-week phase 2a, multicenter, randomized (1:1; EZB:placebo) clinical trial (NCT04309474) included patients aged 30-90 years with an acute ischemic stroke (onset ≤ 24 hours before baseline), and a NIHSS score of 7-21. Blinded analyses did not distinguish between treatment arms. Healthy adult controls were procured outside this trial. Blood samples were taken post-stroke across 52 weeks, or 1 time (baseline) for healthy adults. Plasma concentrations of neurodegenerative markers neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAP) were measured (validated Simoa Human Neurology 4-Plex A assay; Quanterix). Protein, mRNA, and miRNA were assessed with omics approaches.

Results:
This preliminary analysis included 34 patients with stroke (mean [SD] age 67.1 [12.3] years, 58.8% male) and 31 healthy adults (61.8 [8.0] years, 71.0% male). The mean (SD) baseline NIHSS total score was 10.9 (4.3). NfL and GFAP concentrations were elevated on day 1 in patients with stroke vs healthy adults (healthy adults are included for reference only). Mean concentrations of NfL were 48.7 pg/mL vs 13.9 pg/mL, respectively; mean concentrations of GFAP were 746.0 pg/mL vs 137.2 pg/mL, respectively. In patients with stroke, agnostic to treatment, peak NfL and GFAP elevations occurred at day 28 and days 2-4, respectively; NfL and GFAP concentrations were lower at week 52 than day 1.

Conclusions:
Preliminary blinded analysis of plasma markers of neurodegeneration confirm increased NfL and GFAP levels during acute stroke, which diminish over time with different temporal patterns. Final unblinded results will provide a robust natural time course of specific biomarkers of neurodegeneration including GAP43. Forthcoming analyses evaluate broad panels of proteins, mRNA, and miRNA markers. Identifying relevant post stroke biomarkers with directed and exploratory omics may allow development of validated assays to assess efficacy and support decision making in clinical trials.
Abstract WP277: Stroke Etiology in Young Adults With Substance Abuse
Authors: Patel Himanshu , Heshmati Keyvan , Ryan Kathleen A , Yarbrough Karen L , Mixon Lakeisha M , Williams Devin E , Kittner Steven J , Cronin Carolyn A
Published: February 2024

Introduction:
Recent public health trends suggest increasing rates of substance abuse among young people. Substance use has been associated with an increased risk of stroke, and specifically, cocaine use is known to more likely cause lacunar and cardioembolic strokes. However, less is known about the stroke etiology with other substances.

Methods:
We conducted a retrospective review of stroke patients between the ages of 18 to 50 years presenting to our Young Stroke Center between April 2022 through August 2023. For each case, data including basic demographics and medical history were collected, and stroke etiology was determined by a vascular neurologist. Patients with substance use at the time of stroke were compared to all non-substance use related stroke and analyzed with respect to TOAST stroke etiology. Substance use was defined as use of opioids, cocaine, marijuana, or alcohol abuse. Analysis was performed with logistic regression adjusting for age, sex, and race.

Results:
Of 187 patients in the registry, 25 patients had substance use at time of stroke compared with 162 patients with non-substance use related stroke. There were 10 marijuana, 4 opioid, 0 cocaine, 3 alcohol abuse and 8 polysubstance use (including 3 cocaine) cases. There were no significant differences in age at time of stroke (36.9 ± 7.1 vs. 38.8 ± 8.2 years) and race (50.0% vs. 53.4% Black) between substance use and non-substance use related stroke groups, respectively. There was a significantly higher proportion of males with substance use (62.5% vs. 31.9% male; OR [95% CI]: 4.0 [1.6-10.0]). In the substance use group, a higher proportion had cardioembolic stroke etiology (20.8% vs. 9.2%; OR [95% CI]: 4.1 [1.2-14.0]); however, there was no significant difference with respect to the other TOAST stroke etiologies. In patients with active substance use and cardioembolic stroke etiology, heart failure with reduced ejection fraction and atrial fibrillation were the etiologies found.

Conclusion:
Our findings indicate that among young individuals with active substance use at the time of their stroke, cardioembolic etiology appears to be more likely than in young stroke patients without substance use. This underscores the need for comprehensive cardiac evaluation in this population.
Abstract WP278: Trends in GLP1RA and SGLT2i Use in Ischemic Stroke Patients With Diabetes
Authors: Yanus Matthew R , Salemi Angela , Bhavsar Riya , Zhang Tony , McCane Charles D , Pan Alan P , Vahidy Farhaan , Gadhia Rajan R
Published: February 2024

Background:
The current AHA stroke prevention guidelines give Class 1 recommendations that patients with AIS and diabetes should receive glucose-lowering agents with cardiovascular benefit to reduce risk of MACE. The ADA recommends in patients with ASCVD, when prevention of further vascular events is the priority, a GLP1RA should be added; and when concern for heart failure or chronic kidney disease is the priority, a SGLT2i should be added.

Objective:
Among a cohort of patients with diabetes presenting with AIS, we analyzed rates of GLP1RA and SGLT2i use during hospitalization and/or outpatient follow-up.

Methods:
A retrospective review of AIS patients at a comprehensive stroke center between May 2016 and October 2022 was conducted using an institutional registry. Patients were identified to have diabetes as derived by the Charlson Comorbidity Index ICD 10 codes E10 through E14. We then identified patients receiving GLP1RA or SGLT2i and evaluated trends over time.

Results:
4131 patients were identified of which 2045 (49.4%) had a diagnosis of diabetes. Of these patients 60/2045 (2.9%) were on GLP1RA while 35/2045 (1.7%) were on SGTLi for total of 4.6%. Annual trends were 2016 6/220 (2.7%) and 1/220 (0.4%), in 2017 6/347 (1.7%) and 3/347 (0.8%), in 2018 6/377 (1.6%) and 5/377 (1.3%), in 2019 3/240 (1.2%) and 1/240 (0.4%), in 2020 9/335 (2.7%) and 10/335 (3.0%), in 2021 11/322 (3.4%) and 10/322 (3.1%), in 2022 19/205 (9.2%) and 5/205 (2.4%) for GLP1RA and SGLT2i, respectively.

Conclusions:
In this retrospective analysis of 4131 AIS cases, use of GLP1RA and SGLT2i prior to 2019 remained around 2-3%. Following publication of the 2021 stroke prevention guidelines, GLP1RA use increased in 2022 to 9%. However, the study highlights the still-low rates of use of secondary MACE prevention despite Class 1 recommendations. This analysis serves as a call to attention that improving treatment of diabetes with ASCVD risk-reduction is a potential area of improvement.
Abstract WP287: AI-ECG Algorithm Outperforms CHA2DS2-VASc in Prediction of Occult Atrial Fibrillation Detection on Prolonged Cardiac Monitoring Following Cerebral Infarction
Authors: Holmes Carmen R , Ahmed Ahmed , Mangold Kathryn , Noseworthy Peter A , Graff-Radford Jonathan , Rabinstein Alejandro A , English Stephen
Published: February 2024

Introduction:
Patients diagnosed with ischemic stroke routinely undergo prolonged cardiac telemetry (PCT) to evaluate for occult atrial fibrillation (AF), but this approach is limited by high cost and low yield. Clinical scores including CHA2DS2-VASc and CHARGE-AF can risk stratify patients but lack desired accuracy. Therefore, we aimed to evaluate an artificial intelligence (AI)-enabled ECG algorithm to predict AF detected by PCT after index stroke.

Methods:
This retrospective study included all adult patients with ischemic stroke evaluated at Mayo Clinic with baseline electrocardiogram (ECG) and PCT between 2018-2020. We recorded demographics, CHA2DS2-VASc score, CHARGE-AF score, stroke etiology, duration of PCT, and if PCT detected AF. ECGs were analyzed using the AI-ECG algorithm to determine AF likelihood. Stroke etiology was adjudicated using TOAST and embolic stroke of undetermined source (ESUS) definitions. The ability of the AI-ECG algorithm, CHA2DS2-VASc, and CHARGE-AF to predict AF detected by PCT was assessed via receiver operating characteristics analysis, calculating the area under curve (AUC) (c-statistic). Sensitivity and specificity analyses were performed for each tool using optimal cutoffs (using maximum Youden indices).

Results:
863 patients were included; median age was 69 years, 496 (57.5%) were male, and 561 (65%) patients were categorized as ESUS. PCT detected AF in 85 (9.8%) patients. Median duration of cardiac telemetry was 30 (IQR 25-30) days. Sensitivity and specificity analyses are outlined in Table 1. The AI-ECG algorithm outperformed the CHA2DS2-VASc score (AUC 0.690 vs. 0.597, p=0.013), but was similar to the CHARGE-AF score (AUC 0.690 vs 0.651, p=0.233).

Conclusions:
Our AI-ECG algorithm demonstrated improved ability to predict AF detection on PCT after index stroke when compared to the CHA2DS2-VASc score, but was similar in performance to the CHARGE-AF score. All three methods had suboptimal accuracy.
Abstract WP298: Intracisternal Bolus Administration of Stanniocalcin-2 Promotes Post-Stroke Recovery in a Translational Aged Rodent Model
Authors: Azadian Matine M , Markarian Eric , Macedo Nicholas T , George Paul M
Published: February 2024

Stanniocalcin-2 (STC-2) is a glycoprotein implicated in multiple physiological pathways, including calcium and phosphate homeostasis, cell proliferation, and anti-inflammatory responses. The molecular mechanisms by which STC-2 functions in the brain and its specific roles in various neurological processes are not well-defined. We have previously shown that intraventricular administration of STC-2 post-stroke increases endogenous stem cell production and improves functional recovery in an adult rodent model of distal middle cerebral artery occlusion (dMCAO). To further investigate the translatability and preclinical efficacy of STC-2 as a protein therapeutic, we intracisternally administered recombinant STC-2 one week post-dMCAO in aged rats (18-24 months) and comprehensively assessed recovery over a 6 week period via sensorimotor, locomotor, and cognitive tasks. Our results indicate that just two bolus intracisternal injections of STC-2 improved stroke recovery in a battery of behavioral assessments in comparison to a control group (n=9 per group, unpaired t-tests with Welch's correction, see Figure 1A-D). Improved sensorimotor recovery (as assessed by vibrissae-forepaw and hind-rearing tests), locomotor recovery (as assessed by an open field test), and cognitive recovery (as assessed by a novel object recognition test) were observed. Further research is required to delve into the underlying molecular mechanisms responsible. Nevertheless, we are optimistic about the substantial translational prospects of this study. Our findings have the potential to pave the way for a novel protein therapeutic for the treatment of stroke deficits.
Abstract WP299: Encephalomyosynangiosis Promotes Mature Angiogenesis After Ischemic Stroke
Authors: Verma Rajkumar , Gamiotea Daylin , Yadav Sanjeev Kumar , Patel Vraj , Bulsara Ketan R
Published: February 2024

Backgrounds:
Current treatments for ischemic stroke patients is ineffective. The brain's inherent ability to self-heal post ischemic stroke is hampered by inadequate blood supply to the affected region. Encephalomyosynangiosis (EMS), a neurosurgical intervention, has proven successful in promoting angiogenesis in patients with Moyamoya disease. We have earlier shown that EMS can increase angiogenesis after stroke in the implanted region, it is not known if those blood vessels are stable or mature. Given that EMS provide balanced growth factors, we therefore hypothesized that EMS enhances stable or mature cerebral angiogenesis in the cortical region surrounding the muscle graft.

Methods:
Following a 60-minute period of transient middle cerebral artery occlusion (MCAo), mice were assigned randomly to either MCAo alone or MCAo followed by EMS (3-4 hours post MCAo).. Mice were sacrificed at 7, 21, or 70 days post MCAo. A mouse angiogenesis and proteomic profile array was employed to quantify the expression of angiogenic and neuromodulating proteins. Immunohistochemistry was utilized to visualize the bonding of the graft with the brain cortex, changes in vessel density, and pericyte coverage to assess the degree of normal or mature angiogenesis.

Results and Conclusions:
Preliminary data indicate successful graft implantation and a significantly increased vessel density (P<0.05 compared to the MCAo alone) in proximity to the muscle graft, signifying increased angiogenesis after stroke. EMS-treated mice exhibited an early improvement in sensory motor deficits post-stroke. Analysis of the angiogenesis and proteomic profile array data unveiled a downregulation of antiangiogenic factors (such as interleukin-10 and Fetuin A) and an upregulation of pro-angiogenic cytokines or growth factors (including Fibroblast Growth Factor and C-X-C Motif Chemokine 12) in the EMS group. Co-immunostaining of the endothelial cell marker (Lectin) with the pericyte marker Platelet-Derived Growth Factor Receptor Beta (PDGFRβ) after 70 days of EMS suggested the stability and maturity of new blood vessels. In summary, the EMS procedure appears effective, holding promise for enhanced stable angiogenesis which may help to expedite recovery following ischemic stroke.
Abstract WP301: STAT3 Inhibition Reduces Infarct and Neuroinflammation in Experimental Stroke
Authors: Zhang Wenri , Alkayed Nabil J , Davis Catherine M
Published: February 2024

Signal Transducer and Activator of Transcription 3 (STAT3) activation is increased in the brain following cerebral ischemia. STAT3, a transcription factor, is a positive regulator of cell survival and is implicated in cytoprotection following ischemia in multiple cell types, including neurons and endothelial cells. We hypothesized that pharmacological inhibition of STAT3 activation in mice during the reperfusion phase after middle cerebral artery occlusion (MCAO) will lead to increased infarct size. We subjected mice to 1-hour MCAO, following which they received STAT3 inhibitor Stattic (20 mg/kg), or vehicle, for 24 hours delivered subcutaneously via osmotic pump. Twenty-four hours later, infarct was measured by TTC and inflammatory cells were measured by flow cytometry. For experiments involving splenectomy, spleens were surgically removed 14 days prior to MCAO surgery. Surprisingly, we found that STAT3 inhibition reduces infarct after MCAO, with infarct in the hemisphere reducing from 49.90 ± 2.44 % in vehicle to 32.86 ± 1.55 % in Stattic-treated mice. Since STAT3 is involved in inflammatory processes, as well as cytoprotection, this led us to hypothesize that the reduction in infarct we observe may be due to decreased inflammation. We carried out FACS analysis and observed that Stattic inhibits MCAO-induced infiltration of B-, T- and dendritic cells into the brain. Neutrophil and monocyte infiltration into the brain were unaffected by Stattic. Since MCAO is known to induce splenic atrophy, with spleen size being inversely proportional to infarct volume, we measured spleen weights. Interestingly Stattic-treated mice had larger spleens (66.31 ± 5.40 g) compared to vehicle-treated mice (46.43 ± 4.60 g), indicating a dampened peripheral immune response upon inhibition of STAT3. Furthermore, Stattic was no longer effective in reducing infarct size in splenectomized mice. We conclude that pharmacological inhibition of STAT3 reduces infarct following MCAO, with the mechanism of protection involving differential regulation of the peripheral immune response.
Abstract WP308: TGFBR2 Knockdown Improves Cognitive Function and Breathing in AD Mice
Authors: IQBAL ZAHID , El Hamamy Ahmad , Le Ngoc Mai , Ranjan Arya , Qi Li , Tan Chunfeng , McCullough Louise D , Li Jun
Published: February 2024

Introduction:
Respiratory disorders, including sleep apnea, are an independent risk factor for the development of cognitive dysfunction and dementia. Disordered breathing occurs frequently in patients with AD (Alzheimer’s Disease). Disruption of the brainstem breathing centers, including the Retro-trapezoid nucleus (RTN), leads to breathing disorders. Our previous work showed that upregulation of Transforming Growth Factor Beta Receptor 2 (TGFBR2) signaling in the RTN leads to respiratory dysfunction in mice. The present study investigated if inhibiting TGFBR2 selectively in the RTN region could improve breathing and cognitive function in AD mice.

Methods:
We used 20 WT and 20 TG2576 mice (15 months old). Mice were randomly assigned into two sub-groups; treatment with a shTGFBR2 vector (knockdown) or vector control with scrambled shRNA. After baseline behavior and breathing testing, lentiviral stereotaxic injections of vehicle and shTGFBR2 were done directly into the RTN. After 6 weeks, behavior and breathing testing was performed, and then brain tissues were collected for histological analysis. All the data are presented as Mean±SEM.

Results:
Tg2576 mice had significantly higher number of apnea (7.91±0.95) than WT mice (4.10±0.85) with a
p
-value of 0.0079. When injected with shTGFBR2 into the RTN, Tg2576 had improved recognition of a novel object (69.24%±5.75) as compared to the Tg2576 vehicle-treated group (51.02%±4.88) in the NORT (
p
=0.0213). They also showed a significant improvement in the latency to escape (64.94±15.56) compared to the Tg2576 vehicle-treated group (136.4±20.90) in the Barnes maze (
p
=0.0109). The number of apneas was also significantly reduced in TG2675 mice treated with shTGFBR2 in the RTN (3.33±0.69), when compared to the Tg2576 vehicle-treated group (8.22±1.30) with a
p
-value of 0.0029.

Conclusions:
Our study revealed that the knockdown of TGFBR2 in the RTN, a brainstem nucleus involved in respiratory control, improved both the cognitive and breathing phenotypes in AD-model mice. Our work suggests that improving respiratory control and reducing apnea in AD may be a potential treatment for the disease. This is especially relevant as new treatments for central apnea, such as phrenic nerve stimulation, are available.
Abstract WP309: UDP-Glucose Exacerbates Neuronal Apoptosis via Its Receptor P2y14 After Subarachnoid Hemorrhage in Rats
Authors: Kanamaru Hideki , Takemoto Yushin , Huang Lei , Sherchan Prativa , Zhu Shiyi , Dong Siyuan , Suzuki Hidenori , Tang Jiping , Zhang John H
Published: February 2024

Introduction:
Subarachnoid hemorrhage (SAH) is a severe subtype of stroke that can lead to poor outcomes. Recent studies reported that uridine diphosphate glucose (UDP-G), one of the intermediates in glucose/glycogen metabolism, can be released from damaged cells and proceed with pathologic conditions by activating the purinergic P2Y14 receptor. This study aimed to elucidate the role of brain UDP-G/P2Y14 signaling after SAH.

Hypothesis:
The inhibition of the brain UDP-G/P2Y14 signaling pathway would attenuate neuronal apoptosis and neurological deficits after SAH in rats.

Methods:
A total of 200 adult male Sprague Dawley rats were used. Endovascular perforation method was used to induce SAH. The time course changes of CSF UDP-G, brain protein levels of UDP-G converting enzyme UDP-G pyrophosphorylase-2 (UGP2) and P2Y14 receptors, as well as the brain cell types expressing P2Y14 were examined. A selective P2Y14 receptor inhibitor PPTN hydrochloride or exogenous UDP-G was administered intranasally 1 hour after SAH. SAH grading, neurological evaluation, immunofluorescence, TUNEL staining, Nissl staining, western blot, and liquid chromatography-mass spectrometry were performed.

Results:
Endogenous CSF UDP-G and brain UGP2 were increased at 3 hours and 6 hours after SAH. The protein level of the brain P2Y14 receptor was not changed temporally and was mainly expressed in neurons 24 hours after SAH. PPTN hydrochloride decreased but exogenous UDP-G aggravated the number of TUNEL-positive neurons, brain protein levels of proapoptotic molecules such as cleaved caspase 3, and modified Garcia neurological score at 24 hours after SAH. Early inhibition of P2Y14 receptor signaling by PPTN hydrochloride preserved the numbers of Nissl staining identified surviving neurons in the hippocampus, amygdala, and cortex with improved water maze learning performance and depressive-like behavior at 1-month post-SAH.

Conclusion:
Brain UDP-G/P2Y14 receptor signaling activation plays a detrimental role after SAH, as a part of glucose metabolic pathology at the tissue level. P2Y14 receptor inhibitor reduced neuronal apoptosis and improved neurological deficits after SAH, which may serve as potential therapeutics in treating patients with SAH.
Abstract WP310: Pharmacological Inhibition of 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3) is Neuroprotective in an Acute Mouse Model of Ischemic Stroke
Authors: Gunraj Rachel E , Larochelle Jonathan , Yang Changjun , Liu Lei , Stansbury Sofia , Candelario-Jalil Eduardo
Published: February 2024

Background:
A major hallmark of stroke is the dysregulation of normal metabolic functions. In the ischemic environment, cells shift towards glycolysis, a metabolic pathway associated with a prolonged inflammatory response and delayed apoptotic cell death. One primary driver of glycolysis is 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). This enzyme is upregulated after injury and synthesizes fructose-2,6-biphosphate, an allosteric regulator of phosphofructokinase-1, which catalyzes the first rate-limiting step in glycolysis. Studies in other disease models support a neuroprotective effect of PFKFB3 inhibition.

Hypothesis:
Because aberrant glycolysis contributes to inflammation and cell death and PFKFB3 upregulates glycolysis after injury, inhibition of PFKFB3 is neuroprotective in stroke.

Methods:
We administered a 45-minute transient middle cerebral artery occlusion in male C57BL/6J mice, followed by treatment with a highly selective PFKFB3 inhibitor AZ67 (N=10) or vehicle (N=11). The vehicle or the inhibitor (30mg/kg) were administered starting at the onset of reperfusion via the jugular vein with three repeated retro-orbital doses over the course of 48h. Open field, vertical grid, weight test, and neural deficit scorings were conducted at 24 and 48h post-stroke, after which the mice were euthanized by perfusion with saline and stained with TTC to quantify infarct size.

Results:
Our findings show a neuroprotective effect of PFKFB3 inhibition in ischemic stroke with improved functional and behavioral recovery and smaller infarct sizes. These results support the hypothesis that PFKFB3 inhibitors may be used as a novel pharmacological treatment for reducing delayed cell death after ischemic stroke. Future studies are underway to investigate the molecular mechanisms and cell types involved in the protection conferred by PFKFB3 blockade in the context of ischemic stroke.
Abstract WP325: Peripheral Blood Mononuclear Cells Preconditioned by Oxygen-Glucose Deprivation Regulate Microglial Polarization by Secretome After Cerebral Ischemia
Authors: Hatakeyama Masahiro , Otsu Yutaka , Akiyama Natsuki , Kanayama Takkeshi , Ninomiya Itaru , ONODERA Osamu , Shimohata Takayoshi , Kanazawa Masato
Published: February 2024

Introduction:
We previously reported that oxygen-glucose deprivation (OGD) decreased the expression of exosomal miR155-5p from peripheral blood mononuclear cells (PBMCs) and that the administration of PBMCs preconditioned by OGD (OGD-PBMCs) enhanced the VEGF expression from the resident microglia, leading to tissue remodeling in ischemic rats. However, the effect of exosomal miR155-5p downregulation on PBMCs and microglia is still unclear.

Hypothesis:
OGD-PBMCs polarize PBMCs and microglia towards a tissue-protective phenotype by secretome.

Methods:
We prepared PBMCs from human blood by centrifugation and cultured PBMCs under OGD conditions for 18 h. We transferred the conditioned media from OGD-PBMCs to PBMCs under normoxic conditions and evaluated protective marker SSEA-3 expression by flow cytometric analysis. Next, we cocultured OGD-PBMCs and microglia under normoxic conditions with or without miR-155-5p antisense oligonucleotide (ASO) inhibitor before performing western blotting to assess the VEGF expression levels in the microglia. Finally, we administered normoxic PBMC treated with miR155-5p ASO inhibitor to rats 7 d after cerebral ischemia and performed microscopic analysis to evaluate VEGF expression.

Results:
The frequency of stem cell marker SSEA-3-positive cells in PBMCs incubated with conditioned media from OGD-PBMCs was more prominent than that in PBMCs incubated with normal glucose media (P = 0.028). The VEGF expression levels in the microglia cocultured with OGD-PBMCs increased compared to that without OGD-PBMCs (P = 0.025). Moreover, VEGF expression levels in the microglia cocultured with OGD-PBMCs were higher with miR-155-5p ASO than without it (P = 0.049). miR-155-5p ASO-treated PBMC administration increased VEGF expression 21 d after administration in ischemic rats (28 d after cerebral ischemia). VEGF expression was not observed in ischemic rats without administration.

Conclusions:
OGD-PBMCs may cause phenotype conversion in resident microglia by the secretome, including reduction of exosomal miR-155-5p, after cerebral ischemia.
Abstract WP34: Quantitative Radiological Analysis and Clinical Outcomes of Urgent Bypass for Hemodynamic Compromised Patients With Acute Ischemic Stroke
Authors: Lee Si Un
Published: February 2024

Objective:
This study aimed to demonstrate the effectiveness of urgent extracranial-to-intracranial bypass (EIB) in acute ischemic stroke (AIS) through quantitative analysis of computed tomography perfusion (CTP) results using RAPID software.

Methods:
We retrospectively analyzed 41 patients who underwent urgent EIB for AIS under strict operation criteria. The quantitative data from CTP images were reconstructed to analyze changes in pre- and postoperative perfusion status in terms of objective numerical values using RAPID software. Short- and long-term clinical outcomes, including complications and neurological status, were also analyzed.

Results:
Postoperatively, the volume of time-to-max (Tmax) >6 s decreased significantly; it continued to improve significantly until 6 months postoperatively (preoperative, 78 ml (median); immediate postoperative, 23 ml; postoperative 6 months, 7 ml; p = .000). Ischemic core-penumbra mismatch volumes were also significantly improved until 6 months postoperatively (preoperative, 72 ml (median); immediate postoperative, 23 ml; postoperative 6 months, 5 ml; p = .000). In addition, the patients’ neurological condition improved significantly (
p
<0.001). Only 1 patient (2.3%) showed progression of infarction.

Conclusion:
Urgent EIB using strict indications can be a feasible treatment for IAT-ineligible patients with AIS due to large vessel occlusion or stenosis.