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Background: Acute stroke lesions become more hypodense on non-contrast CT as the ischemic injury matures. Lesions transition to established infarcts at which time recanalization treatment is thought to be futile, if not harmful. As it is not possible to directly quantify the degree of injury progression, eligibility for treatment is determined using temporal criteria. In this study we used an AI approach to segment and quantify the degree of hypoattenuation of acute stroke lesions on baseline CTs, and explored its impact on clinical outcome following mechanical thrombectomy. Methods: Imaging was collected from a multicentric registry (across 4 US and 5 EU sites) of consecutive large vessel occlusion (LVO) stroke patients who underwent mechanical thrombectomy. Baseline NCCT scans were processed using Brainomix 360 to automatically segment the ischemic core. Lesion hypoattenuation was then quantified by in-house software using the mean Net-Water-Uptake (NWU). Multivariate models were used to explore the association between NWU and clinical outcome (3-month modified Rankin scale–mRS), controlling for e-ASPECTS scores, age, and recanalization status. Interaction models were also used to examine the relationship between NWU e-ASPECTS scores. Results: Of the 1363 patients included (age: median 70, IQR: 50-79; 571 females), successful recanalization (mTICI 2b-3) was achieved for 1119 patients. Multivariate analysis found NWU (p=<.001, t=4.62; Fig1) to remain an independent predictor of outcome. There was a significant interaction effect between and ASPECTS score (p=0.029, Fig 2), suggesting that degree of hypoattenuation played a larger role in patients with lower aspects value. In subgroup analysis, NWU was not a significant predictor of outcome in patients that did not achieve successful recanalizion (mTICI 0-2a). Conclusions: These findings suggest that stroke lesion hypodensity measured using NWU might help identify patients at risk of futile recanalization, and that incorporating this information might be more relevant in patients with lower ASPECTS. The ability to determine treatment eligibility using information extracted from routine imaging would allow safe extension of treatment to patients with unclear onset time, and would account for differences in rates of infarct progression.

Introduction: Previous studies have established the safety and economic benefits of outpatient Transient Ischemic Attack (TIA) management, highlighting reduced expenses for outpatient evaluation. This context underscores the potential advantages of refined outpatient TIA management, a focus of our study, through the implementation of a novel expedited outpatient TIA workflow and assessment of its economic, administrative and clinical impact. Methods: We implemented a novel TIA pathway including streamlined assessments by emergency department (ED) physicians, a structured expedited set of diagnostic tests and outpatient follow-up with vascular neurologists within 48-72 hours of ED presentation. We conducted a retrospective cost-efficacy analysis, contrasting two phases: pre-implementation (standard ED-to-hospital admission TIA workflow from May 1, 2020 - December 31, 2020) and post-implementation (ED-to- outpatient TIA workflow from May 1, 2021 - December 31, 2021). We also compared the clinical outcomes of patients with a final diagnosis of TIA or minor ischemic stroke syndrome from the implementation cohort (May 2021-May 2022) with those from an ABCD2-matched inpatient TIA cohort evaluated in the pre-implementation period (2017-2021). Results: The newly implemented outpatient TIA workflow resulted in a 7% decrease in admissions to hospital observation status, 14.8% reduction in hospital admissions, whereas ED discharge rates rose by 20.4%. Within 8 months, these changes equated to 21 fewer hospitalizations or admissions, reducing costs by approximately $103,320 (Figure1). Laboratories, diagnostic imaging, and neurology evaluations were completed faster in the inpatient pathway. Both pathways had similar vascular risk factors and outcomes regarding final diagnosis, - diagnostic testing achieved, preventative treatments prescribed, stroke/TIA recurrences, re-admissions, TIA-related morbidity and mortality, and related ED return visits (Table 1). Conclusion: The deployment of an optimized outpatient TIA management workflow at Mayo Clinic Arizona had demonstrated improved administrative and cost efficiency, with similar clinical outcomes as inpatient TIA pathway. This investigation corroborates the efficacy of workflow enhancements in outpatient TIA settings and suggests a scalable model for analogous strategies in other medical centers.

Background: CT perfusion (CTP) imaging is an important tool for identifying candidates for mechanical thrombectomy (MT). This modality is increasingly available in regional facilities, but whether pre-transfer perfusion imaging studies may be relied upon for treatment decisions is unclear. We analyzed a cohort of stroke transfers to quantify changes in CTP imaging profiles over time. Methods: A cohort of confirmed ischemic stroke patients who received CTP before and after transfer to a large mid-western comprehensive stroke center (CSC) were identified. We compared perfusion mismatch (MM), core infarct volume (CIV), and favorability of imaging for mechanical thrombectomy (MT) candidacy (defined as the presence of LVO and MM/CIV ratio of >1.8) between studies. Regression models were used to examine predictors of CIV growth including hypoperfusion intensity ratio (HIR) and time between studies. Results: Over a 24-month period, 61 patients met inclusion criteria. Median age was 71 (IQR 60-80), 52% were female, median NIHSS was 14 (IQR 4-19), and most patients had occlusion of the internal carotid and/or middle cerebral arteries (77%). The median time from last known well (LKW) to initial CT was 148 minutes (IQR 71-620) and median time between imaging studies was 149 minutes (IQR 126-194). Median CIV growth was 0 mL (IQR 0-6) and 8% (5/61) had growth ≥25 mL. In linear regression, higher HIR predicted CIV growth (β=24.3, p=0.04), but time from LKW to presentation and time between imaging studies did not. Imaging studies taken at the regional and CSC sites demonstrated excellent agreement in classifying patients as candidates for MT (kappa 0.778 [95% CI: 0.611-0.944]). A favorable regional CTP profile was 93% sensitive for MT delivery at the CSC with a positive predictive value of 63%. Conclusion: In our cohort, CIV growth between facilities was minimal despite relatively long interfacility transport times and was predicted by the regional HIR. A favorable regional imaging profile demonstrated high agreement with the imaging result at the CSC and was strongly associated with MT treatment.

Introduction: The safety and efficacy of intravenous thrombolysis (IVT) in cervical artery dissection-related acute ischemic stroke (CeAD-AIS) remains unclear. We performed a retrospective study of data from the National Inpatient Sample investigating outcomes in CeAD-AIS patients treated with and without IVT. Methods: We included adult patients with CeAD-AIS hospitalized between 2016 to 2019. CeAD-AIS was defined by concurrent CeAD and AIS diagnoses, identified with ICD-10 codes. The primary outcome was home discharge. The safety outcomes were inpatient death and intracerebral hemorrhage (ICH). We used survey-weighted multivariable adjusted logistic regressions comparing the groups (IVT versus no IVT), followed by interaction analyses to examine for effect modifications based on age, medical history, stroke severity, and endovascular treatment. Results: Between 2016-2019, 1,360 (12.1%) of 11,285 CeAD-AIS patients received IVT. Patients treated with IVT- had higher NIH Stroke Scale (NIHSS) scores (median 8 [4-17] versus 3 [1-11]; p < 0.001). In adjusted analyses, treatment with IVT was associated with a greater odds of home discharge (adjusted odds ratio [aOR] 1.49; 95% confidence interval [CI] 1.09-2.05, p = 0.014), but not ICH (aOR 0.90, 95% CI 0.43-1.86, p = 0.773) or inpatient death (aOR 1.22, 95% CI 0.72-2.06, p = 0.454). In interaction analyses, stroke severity significantly interacted with IVT ( p for interaction = 0.001), where IVT was significantly associated with increased likelihood of home discharge in patients with moderate to severe strokes (NIHSS > 4) (aOR 2.28, 95% CI 1.59-3.26, p < 0.001) but not in those with mild stroke (NIHSS 0-4) (aOR 1.03 95% CI 0.62-1.70, p = 0.922). Conclusion: IVT improved the likelihood of home discharge in patients with CeAD-AIS without increasing the risk of inpatient death or ICH.

Introduction: Extracranial carotid artery pathology accounts for 15-20% of ischemic strokes. Advancements in magnetic resonance angiography (MRA) with vessel wall imaging (VWI) have enabled the identification of vulnerable plaques, aiding in risk stratification for neurovascular events. This pilot study aimed to identify proteins in plaques with and without vulnerable features on MRA with VWI. Hypothesis: There is a differential proteomic profile of vulnerable and non-vulnerable, thus, these can serve as potential biomarkers for disease progression, stroke prevention, and therapeutic targets. Methods: Consecutive patients undergoing carotid endarterectomy (CEA) were included in the study cohort with pre-operative MRA with VWI. A retrospective chart review was conducted to extract pertinent clinical data including cardiovascular risk factors and medications. The proteomic analysis involved Tandem Mass Tag (TMTpro) labeling of peptides, basic pH HPLC fractionation, and NanoLC-tandem mass spectrometry. Results: A total of sixteen plaques were retrieved from fifteen patients. There were 73.3% male patients. The most common comorbidities were hyperlipidemia (93.3%) and hypertension (80%). 31.2% of patients had symptomatic disease. Eleven plaques were vulnerable in preoperative MRI with VWI. From those, intraplaque hemorrhage was the most common feature (81.1%) . Proteomic analysis revealed 23 relevant proteins significantly elevated in vulnerable plaques, including Proteinase 3 (PRTN3), Phospholipid Transfer Protein (PLTP), and S100 Calcium-Binding Protein A12 (S100A12), with increased abundance exceeding two-fold changes or above (P<0.001). Conversely, three proteins exhibited reduced abundance in vulnerable plaques including Dynamin-3 (DNM3), Transmembrane Protein 181 (TMEM181), and Adducin-3 (ADD3) (P<0.05). All results are summarized in Figure 1A-C and Table I and II. Conclusion: This study contributes to the understanding of protein biomarkers associated with carotid plaque vulnerability, offering insights into disease progression, stroke prevention, and identification of potential therapeutic targets (Figure 1D) . Furthermore, these patients could benefit from early surgical intervention if these biomarkers were to be detected. We present a comprehensive study of multiple proteins with significant bioavailability in explanted plaque specimens that can serve as a foundation for identifying blood biomarkers for future validation studies.

Introduction: Four randomized clinical trials have not demonstrated the superiority of anticoagulation over antiplatelet therapy in the prevention of recurrent embolic stroke of undetermined source (ESUS). In this multicenter observational cohort study, we evaluated long-term outcomes associated with various antithrombotic strategies according to potential embolic sources. Methods: A multicenter retrospective observational cohort of consecutive adult patients with ESUS was queried (n=27 sites). Comparisons were made between patients treated with single or combination antiplatelet therapy versus anticoagulation (direct oral anticoagulant, vitamin K antagonist, low molecular weight heparin) with or without antiplatelet therapy initiated within 7 days of stroke. The primary composite outcome of recurrent stroke, major bleeding, or death was assessed using unadjusted and adjusted Cox proportional hazards regression, with clustering by site. Causal inference was assessed using inverse probability of treatment weighted regression adjustment (IPTWRA), accounting for propensity for antiplatelet treatment, with effect estimates summarized as the average treatment effect (ATE) over time (in days). Adjusted models accounted for age, stroke severity, vascular risk factors, and major categories of potential embolic sources. Results: Of the 2201 included patients (n=218 treated with anticoagulation) followed over a median of 564 days (interquartile range [IQR] 154-1124), the median age was 65y (IQR 54-74) and 49.8% were female. Patients treated with anticoagulation were older with more frequent previous stroke, concomitant left ventricular dysfunction, and more severe deficits. Over 4541 person-years of follow-up, the annualized incidence rate of the primary outcome was 14.6% (95% confidence interval [CI], 13.6%-15.8%). Compared to anticoagulation, antiplatelet(s) use was not associated with a lower risk of the primary outcome in the adjusted Cox model (HR 0.91, 95% CI, 0.64-1.29) or in the IPTWRA model (average treatment effect 0.14, 95% CI, -1376.6 to 1376.9). Major bleeding events trended toward significance in the adjusted Cox model (HR 0.51, 95% CI 0.25-1.04) but were no different with IPTWRA (ATE 58.9, 95% CI, -125.4 to 243.2). Conclusions: These results validate the observations of randomized trials indicating a lack of benefit of anticoagulation over antiplatelet therapy in ESUS. A more detailed analysis of heterogeneity of treatment effect is under way.

Background: Cerebral microbleeds (CMBs) are associated with incident dementia, but the impact of specific CMB patterns is unclear. CMBs in lobar regions suggest cerebral amyloid angiopathy (CAA), which is sometimes accompanied by superficial siderosis (SS), while subcortical CMBs indicate hypertensive origins. This study investigates the association between CMB patterns and dementia risk in the community-based longitudinal Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Methods: All ARIC-NCS participants with a 3T research MRI at visit 5 (2011-13; aged 67-90) without intracerebral hemorrhage or dementia were included. CMB and SS presence and location were coded from T2* GRE sequences. Individuals were classified into one of four patterns: no CMBs, only subcortical, mixed (lobar and/or SS + subcortical), and only lobar and/or SS. Incident dementia diagnoses were defined by cognitive testing (in-person and telephone), informant interviews, and hospital discharge codes or death certificates. Cox proportional-hazards models assessed the association between the presence, patterns, and frequency of CMBs (0,1,2,3+), presence of SS, and incident dementia from visit 5 through 2020. Model covariates included demographics, vascular risk factors, and imaging markers of small vessel disease. Results: Among 1609 participants, 364 had CMBs (Table 1). Participants with CMBs tended to be older and female compared to those without CMBs. Compared to individuals with no CMBs, presence of any CMBs was associated with an increased risk of dementia (Table 2). Compared to individuals without CMBs, individuals with only lobar CMBs and/or SS had an increased risk of incident dementia, as did individuals with mixed CMBs, but individuals with subcortical-only did not. Participants with ≥3 CMBs of any variant had an increased risk of incident dementia vs no CMBs. Although SS was infrequent, its presence (vs no SS) was associated with an elevated risk of dementia. Conclusion: CMBs, particularly in a mixed or lobar and/or SS-only pattern, are linked to an increased risk of incident dementia. The number of recurrent CMBs and any SS also showed an increased dementia risk. These data support that dementia risk is high in individuals with a CAA-type CMB pattern, but also emphasize that a mixed pattern, not typical of CAA alone, is associated with a high risk of dementia. Further studies should evaluate mechanisms by which these different patterns contribute to dementia.

Migraine with aura(MwA) is associated with an increased risk of stroke and adverse vascular outcomes compared to those with migraine without aura (MwoA). AI-ECG prediction models developed at our institution can evaluate the probability of atrial fibrillation (AF) and estimate a patient’s age based on a normal sinus rhythm (NSR) ECG. Delta age, AI-ECG estimated age minus chronological age, indicates endothelial dysfunction and is associated with cardiovascular mortality. We aim to assess how AI-ECG prediction model outputs, specifically the AF probability and delta age, are associated with adverse vascular outcomes in patients with migraine. Adult patients diagnosed with MwA and MwoA from 2000-2020 with at least one digital, standard 12-lead ECG were identified. The first ECG that showed NSR is used as the index ECG. Patients with any adverse vascular outcomes before the index ECG were excluded. Adverse vascular outcomes used as endpoints include acute ischemic stroke, acute myocardial infarction, deep vein thrombosis/pulmonary embolism, AF, and carotid artery dissection. A total of 31301 patients (13783 MwA, 17518 MwoA) were included in our analysis. The mean age at the time of the index ECG was 44.3 (14.5), and the average follow-up time was 71.6 (69.8) months. Based on the index ECG, the mean AF probability was significantly higher in MwA compared to MwoA (2.39 vs 2.06, p< 0.001), while the delta age was lower in MwA compared to MwoA (3.7 vs 4.2, p <.001). The prevalences of all vascular outcomes are summarized in Table 1. Multivariate Cox regression models showed that a higher AF prediction model output (every 10% increase), as well as a higher delta age (every 10-year increase), are associated with an increased risk of composite vascular outcomes (HR1.20, 95%CI 1.17-1.23, p<.001, and HR1.19, 95%CI 1.14-1.23, p < .001) [Table 2]. The Kaplan-Meier curve of adverse vascular outcome-free survival by AF prediction model output, using 1% as the cutoff (HR 1.49, 95% CI 1.41, 1.57, p<.001), and by delta age, using 2-year as the cutoff (HR 1.14, 95% CI 1.08, 1.21, p <. 001) are presented in Figure 1. Having aura, older age, male, coronary artery disease, congestive heart failure, diabetes, hypertension, and tobacco use were also associated with a higher risk of adverse vascular outcomes. Our results demonstrated the potential of using AI-ECG AF prediction model output and delta age to identify migraine patients at risk for adverse vascular outcomes.

Background: Emergency medical services (EMS) routing of stroke patients is challenging in rural settings. To address this, the American Stroke Association (ASA) has developed a template severity-based EMS triage algorithm to direct EMS to either the nearest stroke-ready versus the nearest Comprehensive Stroke Center (CSC) hospital, but its real-world impact is uncertain. Methods: This is an interim analysis of a before-and-after quality improvement study examining the impact of implementation of a severity-based EMS stroke destination protocol by three medical control authorities (MCAs) covering 4 rural counties in western Michigan. We defined optimal destination according to the ASA algorithm, which recommends bypass for patients within 24 of last known well if large vessel occlusion suspected and bypass will not delay thrombolysis. Chi square tests were used to compare optimal destination selection before and after implementation among EMS suspected stroke cases originating from the target counties. We also compared the time from EMS scene arrival to ischemic stroke (IS) treatment (thrombolysis or endovascular therapy [EVT]) before and after implementation using Wilcoxon Rank Sum tests. Results: From November 2021 to May 2024, EMS transported 616 suspected stroke cases, 272 (44.2%) of which ultimately received a diagnosis of ischemic stroke (IS) or transient ischemic attack. The protocol was implemented by each MCA in random order at months 21, 23, and 29, resulting in 73 MCA-months before and 17 after implementation, excluding a one-month washout for each MCA. Optimal hospital destinations were selected for 310/499 (62.1%) patients prior to the protocol and 86/117 (73.5%) after (p=0.021). Thrombolytics were administered to 57 patients (48 before and 9 after) and 46 (42 before and 4 after) received EVT. Median times from first EMS contact to needle decreased from 98 (interquartile range [IQR]: 79-107) to 77 (IQR: 75-85) minutes (p=0.012); median times from EMS contact to groin puncture increased nonsignificantly from 165 (IQR: 132-216) to 196 (IQR: 191-228) minutes (p=0.110). Conclusions: Interim analysis of implementation of a rural EMS severity-based triage algorithm for suspected stroke cases resulted in improved destination selection and faster thrombolysis but did not improve EVT treatment times. This analysis will be repeated once follow-up is completed in 7 months.

Background: There is an unmet need to better understand the likelihood of a good functional outcome in older and frailer populations undergoing endovascular therapy (EVT) following large-vessel occlusion (LVO) ischemic stroke. One approach is to improve the understanding of pre-morbid brain health (“brain frailty”) as a predictor of functional outcome. This study explored the relationship between the spatial pattern of brain atrophy and functional outcome to determine whether this is a predictor of outcomes following EVT. Methods: Patients with LVO from four hospitals in Europe and the USA were included. Three cohorts were used as a derivation cohort, and the fourth served for validation. Presenting CT imaging was processed using Brainomix in-house software to automatically localize and quantify atrophy (frailty-index). Masks from the derivation cohort were used to localize regions of atrophy significantly associated with poorer functional outcome (modified Ranking Scale 3-6) using a voxel-based, multivariate method (Sparse Canonical-Correlation-Analysis) (see Figure 1). For both derivation and validation cohorts, the degrees of overlap between each patient’s atrophy mask and the regions associated at a group level with poor outcome were calculated. This was used as an independent predictor of functional outcome in multivariate analysis adjusting for overall brain frailty-index, recanalization status, and ASPECT score Results: The derivation cohort consisted of 658 patients (mean age 69.6±15.0, median ASPECTS 9 [7-10]), while the validation cohort consisted of 447 patients (mean age 64.7 ±15.5, median ASPECTS 8 [5-10] ). Atrophy localized to the lateral ventricles and sylvian fissure was significantly associated with poorer outcomes (Figure 1). In both derivation and validation cohort, the presence of this spatial pattern of brain frailty (quantified using the degree of overlap) was an independent predictor of poor functional outcome (Table 1). Conclusion: A better understanding of pre-stroke brain health, such as the distribution of atrophy, may provide additional information to inform the prediction of outcome following LVO. This could improve patient selection for treatment following ischemic stroke through better prognostication and a more personalized approach to decision making.