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Introduction: We assess the risk of stroke in individuals with and without a migraine diagnosis, adjusting for demographic variables and stroke risk factors using participant information from the All of Us database. Method: Diagnoses of migraine, stroke and comorbidities were identified using ICD9 and ICD10 codes. A multivariable logistic regression analysis was performed to assess the association between migraine and risk of stroke adjusting for comorbidities including hypertension, atrial fibrillation, hyperlipidemia, diabetes, tobacco use, depression and demographics (age, sex at birth, race and ethnicity). To compare the prevalence of stroke between individuals with and without migraine, odds ratios using a 95% confidence interval (CI) were calculated. Results: Within the All of Us database, 31,444 individuals received a migraine diagnosis (female=25,374/81%, male=5,391/17%, other=679/2%; mean (std) age=54.9 (15.6)) and 379,283 did not have a migraine diagnosis (female=222,104/59%, male=149,182/39%, other=7,997/2%; mean (SD) age=55.9 (17.2)), see Figure 1 for detailed demographics. The migraine cohort had a greater proportion of women (81% vs 59%, p<0.001), a higher proportion of white individuals (61% vs. 55%, p<0.001) fewer African American individuals (15% vs. 19%, p<0.001) and a lower proportion of individuals who were 61 or older (39% vs 45%, p<0.001) compared to the non-migraine cohort. Compared to the non-migraine cohort, individuals with migraine had significantly higher rates of comorbidities, including depression (13% vs. 4%, p<0.001), diabetes (16% vs. 7%), tobacco use (23% vs. 9%, p<0.001), hyperlipidemia (48% vs. 22%, p<0.001), hypertension (57% vs. 27%, p<0.001), and atrial fibrillation (7% vs. 4%, p<0.001). A multivariate regression model adjusted for differences between cohort demographics and comorbidities found that individuals with migraine had 2.14 higher odds of overall stroke compared to the non-migraine cohort (OR 2.14, 95% CI [ 2.04, 2.24]. Discussion: After adjusting for cohort imbalances in demographics and comorbidities, individuals with migraine had a 2.14 times higher risk of stroke compared to those without a migraine diagnosis. Our analysis, using data from the All of Us database, confirms previous findings and suggests that while comorbidities are more prevalent in those with migraine, they do not fully account for the increased stroke risk.

Background: Angiographic shape of occlusion, like the clot meniscus sign and the claw-sign, have been reported to potentially impact recanalization rate and clinical outcome in patient undergoing mechanical thrombectomy for acute ischemic strokes. Method: Following PRISMA guidelines, a systematic literature search was conducted across PubMed, Scopus, and Web of Science databases. Patients were grouped into clot meniscus/claw sign positive and negative groups based on the definitions obtained from each study. Primary outcomes included technical success, with a meta-analysis performed using a random-effects model to calculate proportions and odds ratios (OR) with 95% confidence intervals (Cl). Results: We included seven studies recruiting 1572 patients. The results indicated that the positive and negative groups had comparable first-pass effect (OR: 1.95; 95%CI: 0.76 – 5.01; P = 0.167) and final recanalization (OR: 1.36; 95%CI: 0.81 – 2.27; P = 0.248) rates. However, the rate of having a favorable functional outcome was significantly higher in the positive than negative sign groups (OR: 1.91; 95%CI: 1.25 – 2.92; P < 0.003). Within the sign-positive population, the use of contact aspiration was associated with a significantly higher rate of recanalization compared to using a stent retriever (OR: 0.18; 95%CI: 0.07 – 0.49; P < 0.001). This result did not translate into a clinical impact, as both stent retriever and contact aspiration showed comparable rates of functional independence at three months (OR: 0.22; 95%CI: 0.02 – 2.33; P = 0.210). Conclusion: The presence of the clot meniscus/claw sign is not associated with recanalization outcomes after thrombectomy. However, it might be a good sign to predict which thrombectomy technique might be associated with better recanalization, although current evidence might need further confirmation.

Introduction: The lack of understanding about the genetic and molecular basis of young stroke (<55 years of age) has hindered development of diagnostic, management, and therapeutic approaches. Whole exome sequencing (WES) can be leveraged as a tool for studying etiological processes underlying stroke. At the time of study inception, this is the single largest WES study in this unique young stroke population to uncover elusive stroke etiologies. Methods: The Mayo Clinic TAPESTRY database is a research program conducting whole exome sequencing of 100,000 participants. Of these, 406 participants met the criteria for young stroke (18-54 years of age) based on ICD-9 and ICD-10 diagnostic codes. Controls were TAPESTRY participants without a stroke-related ICD diagnosis. Cases were matched for age, gender, and race for a 1:4 case-control ratio. Ischemic stroke etiology was classified using TOAST classification. To uncover genetic mechanisms, a gene centric approach was used to identify variants in our cohort. A list of 66 genes known to be associated with young stroke was curated based on existing genetic databases. Various filtration strategies were used to identify potentially damaging variants (graphic 1). Results: There were 406 cases (363 ischemic and 43 hemorrhagic; 291 female; age at stroke onset 39.8±10.4; 368 were White) and 3,857 controls. TOAST classification yielded 20 patients with large artery atherosclerosis, 58 cardioembolic, 10 small vessel disease, 148 other determined (58 patent foramen ovale, 50 dissection, 48 hypercoagulable state, 11 Moyamoya, 11 vasculitis, 10 fibromuscular dysplasia), and 165 undetermined etiologies. Several individuals had multiple competing etiologies. Of cerebral hemorrhages, there were 6 aneurysmal, 6 arteriovenous malformation, 5 hypertensive, 2 substance abuse, 3 trauma, and 21 other etiologies. Across the entire cohort, 35,054 variants were found within the 66 genes identified from the literature. Filtration identified 48 potentially damaging variants across 30 genes in 44 patients (20 cryptogenic and 21 other: 12 patent foramen ovale, 5 vasculitis, 4 dissection, 4 cardioembolic) that were absent in controls. Conclusion: WES is a powerful tool that can be used to uncover potential genetic mechanisms in the young stroke population. An improved understanding of etiologies would improve diagnostics and pave the way for new preventive and therapeutic approaches, thus improving the overall care of young stroke patients.

Introduction: Coagulation factor XI (FXI) inhibitors have shown a better safety profile than other anticoagulants, offering similar reductions in ischemic stroke (IS) risk with a lower risk of intracerebral hemorrhage (ICH). The APOE ε4 genotype is associated with increased risks of both IS and ICH, likely due to its effects on lipid levels, intracranial atherosclerosis, and cerebral amyloid angiopathy. We hypothesized that APOE ε4 carriers would gain greater therapeutic benefit from genetically reduced FXI levels compared to non-carriers. Methods: We conducted a two-stage Mendelian randomization (MR) analysis using the random-effects, inverse-variance weighted method. First, we estimated the effect of genetically proxied FXI inhibition on IS and ICH risk in the general population using summary data from genome-wide association studies of FXI levels (16,169 participants), IS (1,503,898 controls and 110,182 cases), and ICH (3,745 controls and 3,226 cases). Second, we performed stratified analyses to estimate the effect of genetically determined FXI levels on IS (10,343 cases and 476,838 controls) and ICH (2,236 cases and 484,945 controls) risk across APOE ε4 carriership strata (0, 1, or 2 alleles) using UK Biobank data. Results: In the general population, random-effects, inverse-variance weighted MR analyses showed that every 1 unit decrease in natural log-transformed FXI levels was associated with a 37% reduction in IS risk (OR:0.63; 95%CI:0.52–0.77; p <0.001) without a significant increase in ICH risk (OR:0.86; 95%CI:0.37–2.00; p =0.73). Stratified MR analyses indicated that genetically determined reductions in FXI levels had varying protective effects on IS risk based on APOE ε4 status: 31% in non-carriers (OR:0.69, 95%CI:0.53–0.91; p =0.008), 43% in carriers of 1 allele (OR:0.57, 95%CI:0.36–0.91; p =0.02), and 75% in carriers of 2 alleles (OR:0.25, 95%CI:0.06–1.06; p =0.06). Similar MR analyses showed no significant increase in ICH risk with genetically determined reductions in FXI levels in any APOE ε4 strata (all p >0.38, Figure 1). Conclusion: This two-stage genetic study provides causal evidence that lower FXI levels reduce IS risk in the general population, with an even stronger effect among APOE ε4 carriers, while not increasing ICH risk. These results indicate that FXI inhibitors might be a safer and more effective alternative to other anticoagulants among APOE ε4 carriers, who are known to be at higher risk for both ischemic and hemorrhagic events.

Introduction: Posterior reversible encephalopathy syndrome (PRES) has been defined based on classic risk factors, clinical characteristics, and evidence of reversibility. Radiographic evidence of vasogenic edema, which is best seen on MRI, is considered a cornerstone of the diagnosis. Yet, severity of clinical presentation does not correlate with extent of edema on MRI. We sought to explore whether PRES can present with negative MRI by comparing clinical features between cases of PRES with classic MRI findings and cases of hypertensive encephalopathy without MRI changes. Methods: Patients diagnosed with hypertensive encephalopathy from August 1, 2008 to December 31, 2017 were identified retrospectively and matched by age (+/- 5 years) and sex in a 2:1 ratio to patients retrospectively identified as having PRES from January 1 st , 2002 to November 30 th , 2017. All patients had undergone MRI, and images were reviewed. A detailed review of clinical information from the medical records was performed and included analysis of presenting symptoms, risk factors, and medical history. Results: We identified 16 cases of hypertensive encephalopathy and 32 age and sex matched controls with PRES on MRI. There were no statistically significant differences in the odds of presentation with headache (OR=1.372, 95% CI [0.458, 4.106]), encephalopathy (OR=2.303, 95% CI [0.433, 12.236]), visual disturbance (OR= 0.826, 95% CI [0.185, 3.697]), or focal neurologic deficit (OR=4.000, 95% CI [0.767, 20.872]). Seizures were more common at presentation in patients with typical PRES with vasogenic edema (OR=0.082, 95% CI [0.010, 0.664]). There was no significant difference in baseline creatine (OR= 0.874, 95% CI [0.424, 1.799]), admission creatine (OR= 1.215, 95% CI [0.819, 1.803]), or odds of acute kidney injury (OR=2.90, 95% CI [0.679, 12.449]). There were no statistically significant differences in the odds of having a past medical history of malignancy (OR= 0.295, 95% CI [0.076, 1.152]), transplant (OR= 3.347, 95% CI [0.594, 18.880]), or autoimmune disease (OR= 0.400, 95% CI [0.104, 1.532]). Resolution to baseline was the norm and occurred similarly in both groups. Conclusions: Most presenting symptoms and key risk factors were not significantly different between cases of hypertensive encephalopathy without vasogenic edema on MRI and typical PRES, arguing that the diagnosis of PRES, at least in the setting of acute severe hypertension, should not depend on MRI confirmation.

Background: The bovine aortic arch is a vascular variant in which the left common carotid artery originates from the brachiocephalic trunk rather than directly from the aortic arch. The bovine anatomical variation may alter the blood flow dynamics, potentially contributing to the formation and progression of carotid plaques. In this study, we evaluated the association of the bovine aortic arch and the severity of carotid stenosis. Methods: In this retrospective study, we included patients with carotid artery disease undergoing carotid endarterectomy (CEA) and pre-surgical computed tomography angiography (CTA). CTAs were reviewed to assess the carotid stenosis and the anatomy of the aortic arch. The left carotid artery was classified as normal if it originated from the aortic arch and as bovine if it originated from the brachiocephalic trunk (Figure 1) . Unlimited propensity score matching was performed to balance baseline characteristics between patients with bovine and normal anatomies. The Mann-Whitney U test was applied to compare carotid stenosis between bovine and normal arteries. Results: A total of 203 patients (bovine:23, normal:180) were initially enrolled. Using propensity score matching, 20 patients with bovine anatomy were matched to 45 patients with normal anatomy (Figure 2) . Among the 65 patients included, 47 (74.6%) were male, with a median age of 70 [IQR:65.0-76.0] years. Left-sided carotid artery disease was more prevalent in the bovine compared to normal group (N=12, 66.7% vs. N=16, 36.4%; p=0.030). Additionally, the severity of carotid stenosis in CEA-treated side was higher in patients with bovine arch compared to normal controls (82.5% [76.2-88.7] vs. 70.0% [50.0-95.0]; p=0.030) (Figure 3) . Conclusions: The association of a bovine aortic arch with more severe carotid stenosis suggests that this anatomical variant may be a marker for increased cerebrovascular risk.

Background: Artificial intelligence (AI) stroke imaging software is becoming mainstay in many hub-and-spoke hospitals. Brainomix 360 Stroke software is the market leader in Europe focused on leveraging simple imaging (non-contrast computerized topography (NCCT) and CT angiography (CTA)) and has recently been FDA-cleared for use in the USA. We evaluated the implementation of Brainomix 360 AI Stroke software in the 17 spoke, multi-state Mayo Clinic Health System (MCHS) telestroke network. Methods: This prospective study compared decision and treatment times before and after Brainomix AI implementation, as well as clinician feedback and simulated decision making to better understand any changes seen. Patients were included if they underwent telestroke evaluation at an MCHS emergency department within 90 days of implementation (2/9/2024-8/8/2024), and excluded if they were already admitted to the hospital or if video evaluation was not performed. Data collection included demographics, clinical decisions and treatment times. Qualitative surveys were conducted at baseline and evaluation end, as well as simulated decision making in 20 de-identified cases randomized to with/without AI through an online portal. Results: A total of 907 patients were included (444 pre- and 463 post-implementation, 287 (32%) with ischemic stroke final diagnosis). Median NIHSS was 2. IVT was recommended in 20.3% (27/148 ischemic stroke patients) pre- and 25.9% (36/139) post-implementation. EVT was recommended in 16.2% (24/148) pre and 14.4% (20/139) post. AI use was associated with trends of faster telestroke activation to IVT decision (36 vs 32 mins, p=0.6), IVT administration (47 vs 40 minutes, p=0.6), and EVT decision (36 vs 33 minutes, p=0.5). In the simulation, imaging interpretation was significantly faster when randomized to AI use (3.4 vs 2.1 mins, p<0.001) and associated with improved physician confidence (62 vs 88%, p=0.004). Qualitative feedback from 14/24 neurologists showed the greatest perceived value was improved confidence of treatment decisions (43%) and faster triaging (36%). Most value was gained from e-ASPECTS (NCCT) and LVO modules. Conclusion: This service evaluation highlighted the opportunity to improve efficiency of decision making even in the setting of a well-developed telestroke system. The impact was underpinned by the improved speed and confidence of imaging interpretation reflected in an offline simulation and qualitative feedback.

Background: Previous reports have established a relationship between asymptomatic high-grade carotid artery stenosis (CAS) and impaired cognition. Different forms of cardiac disease have also been associated with cognitive impairment and dementia. The effect of concurrent high-grade CAS and cardiac disease on cognition is unknown. We hypothesize the presence of comorbid cardiac disease has a synergistic effect on cognitive impairment in patients with asymptomatic CAS. Methods: Patients with ≥80% internal carotid artery stenosis with no history of stroke were recruited from inpatient and outpatient practices at a single, large, comprehensive stroke center. Patients with vs without comorbid cardiac disease (coronary artery disease [CAD], CAD with history of coronary artery bypass graft [CABG] or percutaneous intervention [PCI], heart failure [HF], atrial fibrillation [AF], or valvular disease [aortic or mitral]) were identified. Cognitive assessments were performed using a battery of 14 standardized tests of attention, memory, processing speed, visual construction, language and executive function. Z-scores were generated based on age-specifc norms. Multivariable linear regression was used to compare test-specific Z-scores in patients with vs without cardiac disease controlling for age, sex, years of education and depression. Results: Thirty-three patients with asymptomatic CAS were identified (21 males, age 74+/-10 years, education=16+/-3 years). Twenty-six (79%) had cardiac disease. Patients with comorbid cardiac disease had significantly lower Z-scores across multiple tests of memory compared to patients without cardiac disease (Fig). After adjusting for age, sex, years of education and depression, significant differences persisted in tests of memory in patients with CAD [Hopkins Recognition Memory Test, β= -1.127 (95% CI: -2.234, -0.020), P=0.046], CABG [Hopkins Learning Trial Memory Test, β= -1.441 (95% CI: -2.532, -0.350), P=0.012], and valvular disease [Hopkins Learning Trials Memory Test, β= -1.121 (95% CI: -2.224, -0.018), P=0.047]. Conclusion: Cardiac disease is common among patients with asymptomatic high-grade carotid stenosis and may have a synergistic effect on impairments in memory in a manner not mediated by stroke. Further work is needed to confirm these relationships and their longterm implications on vascular brain health.

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.

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.