Stroke is a major cause of death and permanent disability, which is described by abrupt loss of neuronal energy, oxidative injury, inflammation, and apoptosis, primarily mediated by mitochondrial dysfunction. Mitochondria are key regulators of stress responses, apoptosis, redox homeostasis, immune signaling and known as central signaling hubs, integrating pathways from multiple cellular compartments to maintain homeostasis. Among the major regulatory elements are protein kinase enzymes that modulate cell signaling by phosphorylating substrates. Several kinases, including members of the Akt, PKA, PKC, GSK-3β, PINK1, and MAPK families, dynamically translocate to mitochondria under physiological and pathological conditions. Once localized, they influence mitochondrial dynamics, bioenergetics, reactive oxygen species (ROS) production, and programmed cell death. Dysregulation of these functions has been implicated in impaired mitophagy, aberrant calcium signaling, and processes associated with the pathogenesis of various neurological disorders, particularly in those with acute brain injuries, such as acute ischemic stroke (AIS). Especially, mitochondrial kinase oxidative stress hallmarks of neuronal injury. In this review, we examine the role of mitochondrial-associated kinases in AIS, explore mechanisms of their translocation, downstream signaling effects, and their promise as druggable targets highlighting the importance of spatial dynamics of kinases and the need for precision therapies. Understanding these mechanisms may open new avenues for therapeutic intervention in neurological diseases with a focus on acute brain injury, by targeting mitochondrial signaling networks.

INTRODUCTION:The ATLAS trial was a prospective, multicenter, single-arm, investigational device exemption (IDE) study to evaluate the safety and effectiveness of the Neuroform Atlas Stent System for the treatment of wide-necked bifurcation aneurysms. This analysis presents the 36-month follow-up data for the anterior and posterior cohorts. METHODS:Of the 182 patients in the IDE anterior cohort, 146 consented to participate in the post-approval study (PAS) and, of the 116 patients in the IDE posterior cohort, 101 consented to participate in the PAS. The primary effectiveness endpoint was core laboratory adjudicated (Raymond-Roy 1; RR1) without retreatment or parent artery stenosis (>50%) at 36 months post-procedure. The primary safety endpoint was Clinical Event Committee-adjudicated major ipsilateral stroke or neurological death through 36 months. RESULTS:There were 146 patients in the anterior cohort and 101 patients in the posterior cohort. At 24 months the composite effectiveness endpoint was 77.3% (34/44) in the anterior cohort and 65.5% (19/29) in the posterior cohort and at 36 months these rates were 92.3% (24/26) and 75.0% (18/24), respectively. RR1 rates at 24 months were 84.1% (37/44) in the anterior cohort and 70.0% (21/30) in the posterior cohort; at 36 months they were 96.3% (26/27) and 79.2% (19/24), respectively. By 36 months the primary safety endpoint occurred in 4.1% (6/146) of patients in the anterior cohort and 5.0% (5/101) in the posterior cohort. CONCLUSION:The results of the long-term assessment of the Neuroform Atlas Stent System demonstrate favorable safety and effectiveness in the treatment of wide-necked bifurcation aneurysms without a single treated target aneurysm rupture beyond 12 months post-procedure.

INTRODUCTION:Emergent large vessel occlusion (ELVO) stroke is a severe ischemic subtype with high morbidity despite mechanical thrombectomy (MT). Current biomarkers inadequately capture the intracranial immune response driving stroke progression. Interleukin-7 (IL-7) is implicated in neuroinflammation but remains understudied in stroke. This study investigates intracranial and systemic IL-7 expression in patients with ELVO stroke, assessing its association with infarct burden and its potential as a prognostic biomarker. METHODS:Plasma samples were collected from patients with ELVO stroke during MT and from CVD control patients undergoing elective diagnostic cerebral angiography. Systemic and intracranial arterial blood was processed with a proximity extension assay (Olink Proteomics) to quantify IL-7 and other cytokines. Infarct and edema volumes were assessed using MRI or CT at 24 hours post-procedure. Spearman correlation and multivariable linear regression models adjusted for the National Institutes of Health Stroke Scale (NIHSS) score at admission were used to evaluate associations between IL-7 levels (intracranial, systemic, and the difference between compartments) and clinical outcomes. RESULTS:Intracranial IL-7 was independently associated with infarct volume (β=-42 052, P=0.0432; R²=0.232), demonstrating greater overall best fit than systemic IL-7 (P=0.8408) and systemic-intracranial differences (P=0.0857). Intracranial IL-7 was also correlated with infarct volume, edema, and NIHSS score at discharge. CONCLUSION:Intracranial IL-7 is a significant predictor of infarct burden in ELVO stroke, highlighting its role in localized immune responses. Systemic IL-7 lacked predictive value, suggesting spatially restricted IL-7 signaling within the ischemic environment. IL-7 may serve as a biomarker for stroke severity and a potential therapeutic target.

Background and Purpose Ischemic stroke comprises about 87% of all stroke cases in the US. 20% of these have a cardioembolic (CE) etiology, and 25% are still considered embolic strokes of undetermined sources (ESUS). ESUS strokes are associated with worse functional outcomes and survival rates, underscoring the need for understanding the clinical differences in stroke etiology. Methods We analyzed the Investigation of Clot in Ischemic Stroke and Hematoma Evacuation (INSIGHT) registry (NCT04693767, https://clinicaltrials.gov/study/NCT04693767), which includes n=388 patients total (n=208 CE, n=142 AFIB, n=180 non-CE). We analyzed 123 data features, spanning across domains including demographics, past medical history, baseline blood lab values, intraoperative data, and thrombus characteristics. We found correlations, univariate analyses, and LASSO machine learning models to predict etiology. Results We found several associations between clinical variables and stroke etiology. Higher baseline prothrombin time and INR (only among patients not on anticoagulants), baseline use of antiarrhythmics and antihypertensives, and a higher baseline mRS were associated with an increased risk of both overall CE and AFIB-specific etiologies. A higher baseline platelet and RBC count was associated with a decreased risk of AFIB stroke etiology. All of these results were significant (p<0.05) across multiple analysis methods. Lastly, our LASSO models predicted CE and AFIB-specific etiologies with an AUC of 0.71 and 0.73, respectively. Conclusions Several clinical features are strongly correlated with stroke etiology, and these can be combined in a machine learning model to predict stroke etiology.

Blood pressure management after intracerebral hemorrhage (ICH) is a key part of early care to reduce complications and improve outcomes. Blood pressure variability (BPV) affects outcomes independently of achieving a specific goal. This study evaluated a novel method for describing variability—area under the curve (AUC)—and applied the guideline-suggested range for systolic blood pressure (SBP) to a prospective cohort previously studied. This was a post-hoc analysis of ATACH2 trial data. Variation outside the SBP range (130–150 mmHg) during the first 24 h was measured via AUC and compared to endpoints such as mortality, modified Rankin Score, and renal adverse effects. Multivariate regression analysis evaluated factors related to early neurologic outcome. 38.2

BACKGROUND:Despite good rates of reperfusion with thrombectomy, rates of moderate to severe post-stroke disability remain high. Even with successful reperfusion, infarct growth occurs, leading to worsened outcomes. METHODS:This prospective cohort study integrates cone-beam CT (CBCT) perfusion imaging with intracranial microcatheter sampling during thrombectomy. A prototype CBCT perfusion platform was used to generate real-time perfusion maps, allowing delineation of core, penumbra, and normal perfusion. Sampling sites are co-registered using a 2D-3D fusion program, enabling precise sample localization. Intracranial and systemic blood samples were collected, followed by immediate arterial blood gas analysis. Clinical outcome measures were also assessed. Primary analyses investigated blood gas differences between sampling locations and their association with clinical outcomes. RESULTS:Intracranial samples from 82 patients exhibited lower pO2, pCO2, HCO3-, and base excess relative to systemic blood (P<0.001) with pH remaining stable across locations. When stratified by microcatheter location, intracranial pCO2 was significantly lower in ischemic core (31.5±1.5 mmHg) than penumbra (37±1.2 mmHg, P=0.007). Further, patients with elevated intracranial pCO2 demonstrated significantly lower discharge National Institutes of Health Stroke Scale (NIHSS) score (P=0.028), particularly pronounced within the penumbra (P=0.0093). These relationships were not observed in systemic blood sample analysis. CONCLUSION:This study is the first of its kind to evaluate the impact of perfusion on intracranial pathophysiology. The intracranial microenvironment during stroke is highly perfusion-specific, and intracranial hypocapnia is associated with parenchymal ischemia and worsened functional outcomes. Whether this implicates the vasodilatory effect of pCO2 or reflects an ischemic metabolic acidosis deserves further study but may provide avenues to reduce stroke injury.

BACKGROUND:The EMBOLISE trial (The Embolization of the Middle Meningeal Artery With Onyx Liquid Embolic System in the Treatment of Subacute and Chronic Subdural Hematoma) demonstrated that middle meningeal artery embolization as an adjunct to surgical drainage reduces recurrence of symptomatic subacute and chronic subdural hematomas. We performed a subgroup analysis of the EMBOLISE surgical cohort to determine how the timing of embolization relative to surgery impacted various outcomes. METHODS:We performed a post hoc subgroup analysis to examine the association of the timing of embolization relative to surgery with the primary end point (hematoma reoperation within 90 days), secondary end points (clinical and radiographic outcomes), and safety end points (serious adverse events, neurological death, all-cause death, and stroke). RESULTS:Middle meningeal artery embolization before surgery (embolization-first group) and middle meningeal artery embolization after surgery (surgery-first group) were performed in 107 and 78 patients, respectively. Demographics and baseline clinical characteristics of the 2 groups were similar. The core laboratory confirmed the procedure to be successful in all patients with similar rates of distal penetration of Onyx into middle meningeal artery branches at the end of the embolization procedure in both groups (49.5% and 48.7%, respectively, P>0.99). Six of 103 patients in the embolization-first group (5.8%) and none in the surgery-first group needed reoperation within 90 days (analysis with observed data, P=0.08). Hematoma volumes at 90 and 180 days were similar except for lower hematoma thickness in the surgery-first group (2.3±3.0 mm versus 4.4±5.6 mm, P=0.03) at 180 days. Clinical and safety outcomes at 30, 90, and 180 days were similar. CONCLUSIONS:Performing surgical drainage before embolization in patients with subacute and chronic subdural hematomas may help minimize treatment failures and enhance hematoma resolution. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04402632.

Background Chronic subdural hematomas (cSDHs) are associated with high recurrence risks following surgical evacuation. The EMBOLISE trial demonstrated that, compared with surgery alone, adjunctive middle meningeal artery embolization (MMAE) significantly reduced reoperation rates. However, given the limitations of the clinical end points of the trial, which may be subject to interrater variability and certain biases, the quantitative imaging metrics need to be evaluated. Purpose To evaluate the prespecified imaging end points of the EMBOLISE trial and assess the long-term resolution of cSDH through quantitative imaging analyses. Materials and Methods EMBOLISE was a multicenter, randomized, interventional trial conducted across 39 U.S. sites between December 2020 and August 2023. Prespecified secondary imaging end points included changes in hematoma volume and thickness and midline shifts from 24 hours to 90 days after the procedure at CT and MRI. The post hoc analyses performed herein extended the assessment to 180 days and included absolute hematoma metrics. Mixed-effects modeling was employed to adjust for confounders. Results Four hundred patients were enrolled in the EMBOLISE study, among whom 352 were included (mean age, 72 years ± 10.4 [SD]; 256 men). The mean cSDH volume was 126 mL at screening, with no intergroup differences. At 90 and 180 days, the MMAE plus surgery group had lower cSDH volumes (20.6 mL vs 28.9 mL [P = .03] and 19.4 mL vs 31.5 mL [P = .04], respectively). Mixed-effects models revealed a 6.9 mL (95% CI: -13.5, -0.40; approximately 25%) greater volume reduction and an 8.4 mL (95% CI: -15.2, -1.6; approximately 30%) lower absolute volume at 90 days in the MMAE group There was no evidence of a difference in the prespecified secondary imaging end points between the groups. Conclusion While the prespecified secondary imaging end points did not significantly differ, the absolute 90- and 180-day hematoma volumes were significantly lower in patients who received MMAE and surgery. Confounder-adjusted mixed-effects analysis indicated a greater reduction in hematoma volume with adjunctive MMAE. ClinicalTrials.gov identifier NCT04402632 © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Ramasamy and Baker in this issue.

OBJECTIVE:Normal pressure hydrocephalus (NPH) is a neurological condition characterized by impaired gait, cognitive decline, and urinary incontinence. Endovascular shunting using the eShunt Implant diverts cerebrospinal fluid (CSF) from basal cisterns to the internal jugular vein via a transvenous, transfemoral procedure. We report initial eShunt safety data for treatment of NPH through 90 days in a prospective, multicenter, single-arm trial. METHODS:NPH participants indicated for endovascular shunt placement were included after exhibiting positive gait response to lumbar CSF withdrawal and candidate anatomy. NPH symptoms at baseline and following eShunt Implant placement were assessed using the Timed Up & Go (TUG) test for gait, Montreal Cognitive Assessment (MoCA) for cognition, and Neurogenic Bladder Symptom Score-Short Form (NBSS-SF) for urinary symptoms. The primary endpoint was the rate of device and/or procedure-related serious adverse events (SAE) at 90-day follow-up. RESULTS:Sixty-six participants were treated with the eShunt Implant without immediate or delayed cerebral hemorrhage, over-drainage, infection or device-related SAEs. Two procedure-related SAEs (3.0%) occurred, one sigmoid sinus thrombosis and one femoral artery pseudoaneurysm, both resolved without surgical intervention. Matched-pair analysis showed statistically significant improvements in TUG time (37.2%; P<0.0001), MoCA score (+2.3; P<0.0001), and NBSS-SF score (-2.1; P<0.002). CONCLUSIONS:Endovascular shunting for NPH was feasible with a low rate of SAEs typically associated with conventional shunt surgery. An acceptable clinical response through 90 days was observed. These findings suggest further investigation of this minimally invasive, endovascular approach to NPH in a randomized controlled trial comparing to standard of care. TRIAL REGISTRATION NUMBER:ClinicalTrials.gov Identifiers: NCT05250505 and NCT05232838.

BACKGROUND:Previous studies have demonstrated that successful reperfusion does not always correlate with long-term functional benefit in patients with acute ischemic stroke (AIS) treated via endovascular therapy (EVT). We evaluated patient characteristics and clinical outcomes in patients with AIS who underwent EVT with successful reperfusion resulting in either beneficial recanalization (BR) or futile recanalization (FR). METHODS:The authors conducted a single-institution retrospective, observational study of patients with AIS who underwent EVT between January 2019 and January 2024. Baseline characteristics, procedural details, and clinical metrics were reviewed, and FR predictors were identified. RESULTS:Of 441 subjects, 151 (34.24%) experienced FR, with this cohort displaying a higher mean blood glucose level on admission compared with the BR cohort (168±87.77 mg/dL vs 143±70.48 mg/dL; P=0.0029). Multivariable logistic regression analysis found blood glucose on admission to be a significant independent predictor of FR (P=0.0081). Hyperglycemia (glucose≥126 mg/dL) carried a twofold higher risk of FR (OR 2.088, 95% CI 1.399 to 3.137, P=0.0003), whereas glucose exceeding 300 mg/dL carried a threefold increased risk (OR 3.321, 95% CI 1.367 to 8.565, P=0.0093). CONCLUSIONS:Rates of futile recanalization increased in a stepwise fashion as glucose levels on admission worsened in this study cohort. These findings suggest that early and rapid glucose management in patients with AIS undergoing EVT may improve outcomes and reduce the incidence of futile recanalization.

Abstract Background Women often experience greater disability after ischemic stroke than men, but the biological mechanisms underlying these differences remain unclear. Proteomic analysis may identify sex-specific molecular pathways that contribute to stroke rehabilitation and recovery. Methods We analyzed plasma samples from 141 patients enrolled in the Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC). Expression of 184 inflammatory and cardiometabolic proteins, measured proximal and distal to the clot, was quantified using Olink panels. Associations between protein expression and discharge outcomes – including the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS), and Montreal Cognitive Assessment (MoCA) – were evaluated with models including a sex by protein interaction term, adjusting for clinical and demographic covariates. Results The median age was 69 years, and 55% were women. After controlling the false discovery rate, systemic TGFBI was expressed at higher levels in men. Multiple proteins demonstrated sex-specific associations with discharge outcomes. For NIHSS, systemic PCOLCE and NT3, as well as intracranial FGF5, NT3, TNFSF14, and TWEAK, were differentially associated by sex, with higher expression generally linked to worse outcomes in women and protective trends in men. For mRS, systemic ICAM3 and TGFBI were associated with higher odds of poor mRS scores in women, while SELL showed a potential protective effect in men. Intracranial CD6 and LAP TGF-β1 also demonstrated sex-specific associations with mRS scores. No sex-specific associations were observed for MoCA. Conclusions Several sex dependent proteins were associated with post-stroke discharge outcomes. These findings suggest that sex-specific molecular responses could contribute to disparities in post-stroke recovery and highlight the importance of incorporating sex as a biological variable in biomarker studies as well as stratifying clinical trials based on sex.

Introduction: Delays in endovascular therapy for acute large vessel occlusion (LVO) stroke can contribute significantly to disability following successful recanalization. The implementation of an automated intelligence LVO detection and interdisciplinary communication platform can shorten times to treatment. Methods: We conducted a multicenter retrospective observational cohort study of consecutive adults with acute occlusion of the internal carotid, proximal middle cerebral, or basilar artery. Hub-and-spoke networks implementing Viz.ai queried electronic medical records 6 months prior to and 6 months following implementation of Viz.ai. Patients were included if they had a National Institutes of Stroke Scale (NIHSS) score ≥6, pre-stroke modified Rankin Scale 0-1, and presented within 24 hours of last known well (or unknown). The primary outcome was time from initial hospital contact to arterial puncture, which was compared between study periods using descriptive statistics, regression with robust standard errors clustered by site, and adjusted inverse probability of treatment weighting (IPTW) in which probability weights were used to reduce imbalance between study periods in a causal inference model. The model was adjusted for age, NIHSS, sex, comorbidities, overnight arrival, hub versus spoke arrival, academic quarter, and pre-stroke modified Rankin Scale which was imputed when missing using chained equations as an ordinal covariate. Results: Of the 474 included patients across 7 sites (n=215 post-Viz, 45.4%), the median age was 67 years (interquartile range [IQR] 57-77) and median NIHSS was 17 (IQR 11-22). Using descriptive statistics, there was a trend toward a shorter time from hospital contact to puncture during the post-Viz period (median 103min, IQR 68-146, vs. 106min, IQR 76-169, p=0.10). In unadjusted regression with robust errors, clustered by site, the trend persisted (β -26.3, 95% confidence interval [CI], -53.7 to 1.3, p=0.058). In the adjusted IPTW model, arrival during the post-Viz period was associated with a shorter adjusted average treatment effect (time difference) of 31 minutes (95% CI, 14 to 48 minutes, p<0.001) when compared to arrival during the pre-Viz period. Conclusions: Implementation of the Viz.ai platform led to a significant decrease in time to arterial puncture for patients with acute LVO. The degree to which these changes contributed to better clinical outcomes is being explored in subsequent analyses.

BACKGROUND:Randomized clinical trials have demonstrated that middle meningeal artery embolization (MMAe) reduces reoperation rates in surgically treated patients with subacute/chronic subdural hematoma (SDH). The effect of embolization on outcomes beyond reoperation remains to be determined. We analyzed the impact of reoperation and healthcare encounters among patients enrolled in the EMBOLISE trial. METHODS:Symptomatic subacute/chronic SDH patients were randomized to surgical evacuation alone (control) or surgical evacuation plus Onyx MMAe (treatment). Changes in modified Rankin Scale (mRS) scores, frequency of unscheduled follow-up visits, and radiographic evolution of hematomas in patients with versus without reoperation were analyzed. RESULTS:A total of 197 patients were randomly assigned to the treatment group and 203 to the control group. Patients who required reoperation compared with those who did not exhibited a ~threefold higher incidence of mRS >2 (37.0% vs 12.9%, P=0.0025) and an ~2.5 fold increase in mRS worsening (22.2% vs 9.5%, P=0.0503) at 180 days. In patients who did not receive MMAe, there was a ~threefold fold increase in rate of SDH recurrence/progression even among those who did not require reoperation (14.3% vs 5.3%, P=0.0045) and a ~twofold increase in unscheduled physician follow-up visits (27.1% vs 14.7%, P=0.0031). CONCLUSION:Among patients with symptomatic subacute/chronic SDH, reoperation was associated with increased rates of mRS worsening and higher mRS scores at follow-up. Adjunctive Onyx MMAe resulted in lower rates of hematoma recurrence/progression and fewer unscheduled physician follow-up visits. Thus, in addition to reducing surgical reoperation rates, adjunctive MMAe led to improved clinical outcomes and reduced healthcare encounters.

The ability to differentiate cerebrovascular disease (CVD) with plasma biomarkers could be an invaluable tool. CVD encompasses a spectrum of conditions that alter intracranial blood flow and activate endothelial cells (ECs), which results in a dysregulated blood brain barrier (BBB). Activated ECs upregulate and cleave many junctional proteins, including soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intracellular adhesion molecule-1 (sICAM-1), and von Willebrand factor (vWF). These junctional complexes regulate BBB permeability and infiltration of leukocytes that release interferon-gamma (IFN-gamma) for immune cell regulation. Key barriers to providing therapies for CVD are due to lack of biomarkers to differentiate pathologies. Utilizing extracellular vesicles (EVs), which are nanoparticles, released from all cell carrying cargo specific to their parent cells microenvironment, may provide insight into cerebrovascular changes before overt pathological and cognitive changes are present. Therefore, we unbanked plasma from the Blood And Clot Thrombectomy Registry And Collaboration” (BACTRAC; NCT03153683) and “Moyamoya and Stroke Tissue Evaluation and Repository” (MASTER) to measure EV sVCAM-1, sICAM-1, vWF and IFN-γ concentrations in aneurysms, emergent large vessel occlusions (ELVO), and Moyamoya. Moyamoya vasculopathy is a unique CVD that presents with internal carotid artery terminus stenosis and abnormal vascular collaterals. EVs were isolated using size exclusion chromatography, concentrated, and the protein ran on MSD assays. Aneurysms (n=17, 76.5% female), ELVO (n=20, 65% female), and Moyamoya (n=21, 66.7 % female) did not have significant differences in sex, body mass indexes, hypertension, smoking status or diabetes between groups. ELVOs were significantly older (72.75 ± 3.3 years) than Moyamoya (47.2.1 ±2.0, p<0.0001) and aneurysms (50.9 ± 5.5, p=0.01) and had significantly lower EV IFN-gamma (p=0.004). In ELVOs, lower EV IFN-gamma correlated to larger edema volumes (p=0.023, r=-0.821) and higher stroke severity (NIHSS, r=-0.812, p=0.05). Moyamoya EVs showed increased sVCAM-1 (p= 0.069) and sICAM (p=0.057), compared to aneurysm, with significantly lower (p=0.001) vWF, compared to aneurysms and ELVOs. Higher EV sICAM-1 trended (p=0.059, r=0.794) for better cognitive outcomes following ELVO. These data suggest that markers of BBB dysregulation in plasma EVs could provide some insight into type and severity of CVD.

Background: Acute ischemic stroke is a leading cause of death and disability in the U.S. Mechanical thrombectomy (MT) has transformed care for patients with small or moderate core infarcts and recently expanded to include those with large infarcts, demonstrating both functional and survival benefits. Despite this, many patients undergoing MT still experience significant disability or death. The discovery of novel adjuvant pharmacotherapies is increasingly critical as MT indications broaden. This study aimed to identify proteomic expression patterns in large core infarct patients undergoing MT to inform potential pharmacological intervention targets. Methods: The Blood And Clot Thrombectomy Registry And Collaboration (BACTRAC) tissue registry was reviewed for anterior circulation MT patients treated between June 2017-December 2023. Patients with an initial Alberta Stroke Program Early CT Score (ASPECTS) > 6 were compared to those with ASPECTS < 6. The primary outcome was the development of malignant cerebral edema (MCE), defined as edema with any degree of midline shift secondary to a completed infarct in the intracranial internal carotid or middle cerebral artery territories. Results: One hundred and thirty patients were eligible for out study of which 15 (11.5%) had ASPECTS <6. Patients with ASPECTS <6 were younger (60.5 vs 67.5 years, p=0.04) and more likely to have history of myocardial infarction (27% vs 4%, p=0.01), higher NIHSS on admission (26 vs 17, p<0.0001) and discharge (25 vs 7, p<0.0001) when compared to patients with ASPECTS > 6. Other baseline demographics were comparable. Ten patients (66.6%) with ASPECTS<6 developed MCE versus 11 patients (9.5%) with ASPECTS > 6 (p<0.0001). In MCE patients those with ASPECTS<6 had significantly higher expression of FGF 21, DPP4 and NT-3 (p=0.02, 0.04 and 0.04, respectively) and lower expression of IGFBP6 and TWEAK (P=0.006 and 0.03, respectively). Conclusion: Patients with large core infarcts (ASPECTS <6) undergoing MT are at a significantly higher risk of developing malignant cerebral edema. The differential expression of proteomic markers such as FGF 21, DPP4, NT-3, IGFBP6, and TWEAK in these patients suggests potential targets for pharmacological intervention. These findings highlight the need for further research into neuroprotective strategies to improve outcomes in this high-risk population.