Acute ischemic stroke is the leading cause of permanent disability and second leading cause of death worldwide. Over the past 10 years, mechanical thrombectomy has become a powerful technique for improving outcomes after large-vessel occlusion in patients with a small baseline infarct. Reperfusion in patients with extensive infarction has historically been considered futile or harmful. However, a recent series of trials showed that endovascular therapy benefits patients who present with extensive baseline infarction. These new data represent a paradigm shift in the approach to stroke therapy, leading to an expansion of indications. Therefore, more patients will benefit from mechanical thrombectomy. Furthermore, these data challenge current definitions of infarct and ischemia as seen on imaging. The data suggest a new era of reperfusion therapy that focuses on optimizing patient-specific approaches and developing adjunctive neuroprotectants and neurorestorative therapies.

Background: and Purpose Stroke impairs cognition and movement. Although clinical severity and infarct volume can predict functional outcomes, variability in patient responses requires advanced structural and functional connectivity methods. Disconnection markers were tested to predict functional outcomes after acute ischemic stroke using diffusion tensor imaging. Methods: A probabilistic approach was used to quantify brain damage from white matter (WM) disconnections affecting cortical areas, using lesion masking on a tractography atlas and parcellation of gray matter into functional network nodes. Forty-three patients with acute ischemic stroke were grouped according to functional improvement (change in modified Rankin Scale score from 3–5 at discharge to 0–2 at 3-month follow-up). Significantly different structural disconnection measures between the groups were combined into a principal component and included in a logistic regression model to evaluate prediction accuracy. Fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity, and mean diffusivity of the disconnected WM tracts were analyzed. Results: Baseline structural disconnections in the mid-posterior and central corpus callosum predicted poor functional outcomes at 3 months, and increased somatomotor network (SMN) disconnection severity correlated with poor recovery. Age, National Institutes of Health Stroke Scale score, and structural disconnections significantly predicted functional outcomes in logistic regression models. The first principal component analysis of the dysconnectivity measures explained 88% of the total variance and improved prediction accuracy from 53.8% to 76.9%. Differences in FA and RD in the region of interest of the corpus callosum between outcome groups were statistically significant. Conclusions Predictive outcome markers from probabilistic structural disconnection mapping in acute stroke emphasize preserving interhemispheric corpus callosum and SMN connections.

Early neurologic deterioration (END) is common and occurs within a few hours to days after an ischemic stroke. Traditionally, END has been treated as a collective entity, including the occurrence of new deficits (recurrence) and the aggravation of pre-existing neurologic deficits (progression). END arises from distinct mechanisms that require different therapeutic approaches. We reviewed clinical and experimental studies addressing the epidemiology, mechanisms, and treatment of END, focusing on differentiating END due to recurrence from END due to progression and on interventions including antiplatelet therapy, direct thrombin inhibition, and induced hypertension. Early recurrence is closely associated with thrombus growth and new ischemic events, particularly in atherothrombotic disease. Early recurrence is also common in patients with cancer-associated stroke. Thrombin and platelet activation play central roles under both conditions. In contrast, progression is mainly driven by infarct growth, that is, the evolution from incomplete infarction to complete infarction due to impaired perfusion, especially in lesions involving the subcortical fiber tracts. Therapeutic implications differ accordingly. Recurrence may respond to potent antithrombotic strategies, including combined antiplatelet and direct thrombin inhibition, whereas progression may benefit from induced hypertension. However, recurrence and progression often occur simultaneously, making clinical differentiation challenging. END should be conceptualized as a spectrum of clinical presentations arising from distinct mechanisms. Recognizing recurrence and progression as separate processes is essential for mechanism-oriented treatments. Future trials should adopt this framework to develop individualized strategies and improve outcomes in patients with acute stroke.

Pharmacogenomic variations may significantly influence responses to commonly prescribed stroke medications. Despite accumulating evidence, genetic testing has not yet been widely integrated into stroke care. This review summarizes current evidence and provides practical guidance for clinical implementation. Pharmacogenomic studies and clinical guidelines related to antiplatelet agents, anticoagulants, and statins were reviewed, with particular emphasis on East Asian populations. Substantial evidence supports genotype-guided use of clopidogrel (CYP2C19), warfarin (CYP2C9, VKORC1, CYP4F2), and statins (SLCO1B1, ABCG2). For aspirin, PTGS1/2 and PEAR1 variants have been investigated; however, current data remain insufficient for clinical application. Regarding direct oral anticoagulants (DOACs), candidate genes such as ABCB1 and CES1 demonstrate pharmacokinetic associations, though robust clinical outcome data are lacking. Distinct allele frequencies in East Asians—such as higher prevalence of CYP2C19 and ABCG2 variants—underscore the need for population-specific strategies. Beyond single-gene approaches, polygenic risk scores, pharmacogenomic panels, and integration with multi-omics data and artificial intelligence represent promising directions for personalized therapy. Pharmacogenomic testing can enhance stroke pharmacotherapy, particularly in populations with high frequencies of actionable variants. Broader implementation requires rapid testing platforms, clinician education, tailored clinical guidelines, and real-world validation of aspirin, DOACs, and multi-gene approaches. Future research should expand population-specific studies and integrate pharmacogenomics within the broader framework of precision medicine to ensure equitable clinical benefit.

Background: and Purpose Cardioembolic sources account for 20%–30% of acute ischemic strokes (AIS), often with high morbidity. Conventional imaging confirms etiology retrospectively but lacks insight into the dynamic behavior of embolic transport. We aimed to predict stroke laterality by integrating patient-specific computational fluid dynamics (CFD) simulations with robust Bayesian logistic regression modeling. Methods: Eight patients (median age 77.5 years; 2 females) with anterior circulation AIS of confirmed cardiac origin underwent high-resolution computed tomography angiography. Vascular geometries were segmented to generate CFD models simulating physiologic pulsatile flow. In each cardiac cycle, 1,000 massless particles were released at the aortic inlet. Two features were derived: x1 (long-term embolic bias over 10 seconds) and x2 (short-term embolic bias during the first cardiac cycle). These were used as predictors in a robust Bayesian logistic regression model. Results: The right internal carotid artery (ICA) received more embolic particles (mean 34/s) than the left ICA (mean 28/s). Patients with right-sided strokes had higher x1 (median 0.27 vs. -0.44) and lower x2 (median -0.82 vs. 0.56) than those with left-sided strokes. The model yielded posterior mean coefficients of 1.51 (95% credible interval [CrI]: -0.46 to 4.11) for x1 and -1.96 (95% CrI: -4.88 to 0.20) for x2, achieving complete separation of stroke patients by laterality in this pilot cohort. Conclusions The combination of CFD-based embolic modeling and Bayesian analysis accurately predicted stroke laterality in cardioembolic AIS, exposing distinct patient-specific embolic transport dynamics.

Background: and Purpose Therapeutic target selection in noninvasive brain stimulation for poststroke motor recovery typically relies on the interhemispheric inhibition model, which is effective for mildly affected patients but offers limited benefits for severely affected individuals. The mechanisms governing recovery from moderate-to-severe stroke remain poorly understood, which hinders the development of targeted interventions. Methods: We analyzed resting-state functional magnetic resonance imaging data from patients with unilateral subcortical stroke and moderate-to-severe upper limb deficits, both pre- and postintervention, along with data from healthy controls. We developed a novel dynamic lag analysis method for identifying recovery-related homotopic sensorimotor regions with altered interhemispheric interactions. To further uncover the global reorganization pathway, we developed dynamic lateralization approaches to detect large-scale functional connectivity (FC) alterations associated with the identified regions in transient lateralization states. Results: Dynamic time-lag analysis revealed significantly reduced synchronized states in the homotopic dorsal premotor cortex (PMd) post-intervention compared with pre-intervention, which correlated with motor recovery. Further dynamic lateralization analysis revealed a prolonged segregation state in patients, characterized by weakened interhemispheric and strengthened intrahemispheric interactions. In this state, patients showed decreased FC in the ipsilesional PMd and increased FC in the contralesional PMd with bilateral subcortical networks. These recoveryrelated alterations were absent in the traditional static analysis. Conclusions Dynamic analyses targeting interhemispheric interactions are valuable for understanding neural reorganization after stroke. The diminished interactions between the homotopic PMd indicate a compensatory mechanism. Importantly, a state-dependent compensatory pathway was identified, wherein the contralesional PMd assumes the functions of the ipsilesional PMd through enhanced interactions with subcortical structures, potentially guiding more effective interventions.

Background: and Purpose Whether perfusion-diffusion mismatch modifies treatment effect of mechanical thrombectomy (MT) for large strokes is poorly known. To address this question, we conducted a post hoc secondary analysis of the Large Stroke Therapy Evaluation (LASTE) randomized controlled trial (RCT). Methods: The LASTE RCT compared MT plus best medical treatment (BMT) to BMT alone in patients with large infarct (Alberta Stroke Program Early CT Score 0–5) in the 0–7-hour timewindow. This secondary analysis was restricted to patients with available baseline MR perfusionweighted imaging. We investigated the potential heterogeneity of MT treatment according to the presence of perfusion-diffusion mismatch, defined as a mismatch ratio ≥1.2, calculated as the time-to-maximum >6 seconds cerebral volume divided by ischemic core volume. The primary outcome was better functional outcome (favorable shift in the distribution of modified Rankin Scale [mRS] at 90 days, analyzed using generalized odds ratio [GenOR]). Results: A total of 102/324 patients were included, among whom 55 (54%) had a perfusiondiffusion mismatch. No significant treatment effect heterogeneity by diffusion-perfusion mismatch was observed for the primary outcome (GenOR for better functional outcome: 1.70 [95% confidence interval, CI, 0.95 to 3.05] and 1.04 [95% CI, 0.57 to 1.87] in patients with and without mismatch, respectively; ratio of GenORs: 1.63 [95% CI, 0.71 to 3.74]; P for heterogeneity=0.24) or for the secondary efficacy and safety outcomes. Conclusions Our study found no evidence of heterogeneity of treatment effect with respect to benefit or safety in patients with unrestricted infarct size at baseline treated with MT by presence of perfusion-diffusion mismatch. An individual participant-data meta-analysis of RCT is needed for definitive conclusions.