Gerrit Maximilian Grosse

Stroke triggers a multifaceted and dynamic immune response, engaging both innate and adaptive mechanisms that evolve in distinct spatial patterns. While these processes contribute to tissue repair and debris clearance, they also drive secondary injury, shape long-term recovery, and predispose patients to life-threatening complications such as infections and recurrent vascular events. Importantly, preexisting systemic inflammation and immune alterations may interact with the poststroke immune cascade, amplifying risk for complicating outcomes. Despite recent advances, the translation of immunomodulatory therapies remains limited, highlighting the need for a better understanding of immune mechanisms in human stroke. Blood-based biomarkers, including cytokines, chemokines, alarmins, and immune cell profiles, have not only emerged as promising tools to monitor the poststroke immune response but also as potential therapeutic targets. At the same time, advanced neuroimaging techniques are opening new avenues to visualize blood-brain barrier breakdown, microglial activation, and other hallmarks of cerebral inflammation. Together, these circulating and imaging biomarkers offer complementary insights into the evolving brain-immune crosstalk after stroke. This review synthesizes current concepts of poststroke immune responses, systemic interactions, and the role of established and emerging blood-based and imaging biomarkers. We highlight the translational potential of integrative biomarker strategies to improve individualized prognosis, guide precision therapies, and ultimately bridge the gap between mechanistic discovery and clinical application.

Background: Stroke is a leading cause of disability and death worldwide, and despite advances in therapies, recurrence rates remain substantial, reflecting incomplete understanding of the biological mechanisms underlying recurrence. Methods: The CRESCENDO consortium compiled ischaemic stroke cohorts from Germany, Spain, and Switzerland, comprising 4,854 patients with peripheral venous blood sampled within 24 hours after ischemic stroke. Proteomic profiling of 5,416 targets was performed on 175 patients selected via a classifier-guided enrichment strategy using the Olink Explore HT platform, comparing cases with and without 90-day recurrent events.Findings: Differential abundance analysis confirmed aetiology-specific patterns consistent with known stroke biology. Stratifying by aetiology revealed distinct recurrence-associated signatures: in large artery atherosclerosis, recurrence was associated with downregulation of NTRK2 and ITGB1, proteins implicated in neurotrophic signaling and structural repair; in cardioembolic stroke, recurrence was associated with upregulation of LGALS3, MIF, GPX4, and ANXA1, consistent with inflammatory and oxidative activation. Interpretation: Early post-stroke proteomic profiling identified aetiology-specific proteins associated with 90-day recurrence, detectable within 24 hours of onset and encompassing both previously reported and novel candidates. Molecular stratification by stroke subtype may offer a more informative basis for risk assessment than pan-aetiology approaches. Further external validation is required to assess the potential of these proteins as biomarkers or therapeutic targets.

Introduction: Recent studies in stroke patients from predominantly Asian populations have underscored the significance of trimethylamine N-oxide (TMAO) as a valuable blood biomarker for predicting incident strokes and major adverse cardiovascular events (MACE). However, its prognostic role after ischemic stroke in other populations is not yet comprehensively investigated. Patients and methods: We measured plasma TMAO levels in 1726 acute ischemic stroke patients (within 24 h from symptom onset) from the multicenter BIOSIGNAL cohort. Using cox and logistic regression models adjusting for demographic and vascular risk factors, we investigated the association of TMAO with recurrent stroke, MACE within 365 days and functional outcome at 90 days after stroke. Results: TMAO levels were not associated with any risk of recurrent stroke (n = 108, unadj. HR per unit increase of log (TMAO) 1.15, 95% CI 0.88–1.51, adjust. HR 1.07, 95% CI 0.78–1.47) or MACE (n = 309, unadj. HR of log (TMAO) 1.10,95% CI 0.91–1.3, adjust. HR 0.90, 95% CI 0.74–1.09). There was an univariable positive association between higher TMAO plasma levels and unfavorable functional outcome, this association remained statistically significant in the multivariable analysis (unadj. OR of log (TMAO) 1.56, 95% CI 1.34–1.81, adjust. OR 1.28, 95% CI 1.04–1.57). Conclusion: In this large cohort of acute stroke patients from a predominantly White population, TMAO had no independent association with either recurrent stroke, or MACE or death. In univariable, and multivariable analysis, there was a significant association between TMAO and unfavorable functional outcome, which might not be clinically significant due to its low effect size. Therefore, TMAO seems not to be a clinically relevant biomarker for risk stratification after stroke.

Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage (ICH) in older patients and an important contributor to cognitive decline and recurrent hemorrhagic stroke. Diagnosis of CAA is commonly based on MRI findings interpreted according to established criteria. Recently, the simplified Edinburgh criteria were proposed as a CT-based alternative to detect CAA in patients presenting with lobar ICH, potentially enabling faster diagnosis in emergency settings. The aim of this study was to evaluate the diagnostic accuracy of the simplified Edinburgh criteria in patients undergoing neurosurgical hematoma evacuation using histopathologically proven CAA as reference standard. We conducted a retrospective case-control study including all patients admitted to Hannover Medical School between February 2013 and December 2023 with lobar ICH who underwent hematoma evacuation. During surgery, brain tissue samples were collected and processed by β-amyloid (Aβ) immunohistochemistry and Congo red staining. Samples lacking intact vessel wall architecture were excluded. CAA severity was graded according to the Vonsattel rating. Preoperative cranial CT scans were analyzed by a board-certified neuroradiologist blinded to clinical and histologic information, applying the simplified Edinburgh criteria. Interrater reliability between a neuroradiologist, neurologist, and medical student was also assessed. Overall, 84 patients were included, of whom 58 had biopsy-proven CAA. The median age was 76 years (interquartile range 72-81) in the CAA-positive group and 69 years (interquartile range 54-76.5) in the CAA-negative group; women accounted for 57% and 35%, respectively. Substantial interrater agreement was observed when applying the simplified Edinburgh criteria. However, these criteria showed limited discrimination between CAA-positive and CAA-negative patients (area under the curve 0.617; 95% CI 0.486-0.749; sensitivity 64%; specificity 58%). Logistic regression adjusted for age significantly improved discrimination (area under the curve 0.784; 95% CI 0.662-0.905). Congo red staining alone demonstrated a sensitivity of only 65% compared with immunohistochemistry. Validation of the simplified Edinburgh criteria in patients with surgically treated ICH revealed limited diagnostic accuracy, emphasizing the need for histopathologic confirmation when available because imaging alone may not be sufficient for reliable CAA diagnosis in this population. Limitations include the retrospective design, single-center setting, and restriction to patients with surgically treated ICH. This study provides Class II evidence that the CT scan features of the simplified Edinburgh criteria have limited diagnostic accuracy to detect CAA in patients with lobar hematoma.

Introduction: Recent studies in stroke patients from predominantly Asian populations have underscored the significance of trimethylamine N-oxide (TMAO) as a valuable blood biomarker for predicting incident strokes and major adverse cardiovascular events (MACE). However, its prognostic role after ischemic stroke in other populations is not yet comprehensively investigated. Patients and methods: We measured plasma TMAO levels in 1726 acute ischemic stroke patients (within 24 h from symptom onset) from the multicenter BIOSIGNAL cohort. Using cox and logistic regression models adjusting for demographic and vascular risk factors, we investigated the association of TMAO with recurrent stroke, MACE within 365 days and functional outcome at 90 days after stroke. Results: TMAO levels were not associated with any risk of recurrent stroke ( n = 108, unadj. HR per unit increase of log (TMAO) 1.15, 95% CI 0.88–1.51, adjust. HR 1.07, 95% CI 0.78–1.47) or MACE ( n = 309, unadj. HR of log (TMAO) 1.10,95% CI 0.91–1.3, adjust. HR 0.90, 95% CI 0.74–1.09). There was an univariable positive association between higher TMAO plasma levels and unfavorable functional outcome, this association remained statistically significant in the multivariable analysis (unadj. OR of log (TMAO) 1.56, 95% CI 1.34–1.81, adjust. OR 1.28, 95% CI 1.04–1.57). Conclusion: In this large cohort of acute stroke patients from a predominantly White population, TMAO had no independent association with either recurrent stroke, or MACE or death. In univariable, and multivariable analysis, there was a significant association between TMAO and unfavorable functional outcome, which might not be clinically significant due to its low effect size. Therefore, TMAO seems not to be a clinically relevant biomarker for risk stratification after stroke.

Systemic inflammatory processes are crucial in the pathophysiology of ischemic stroke. The Prognostic biomarkers are essential for guiding clinical decision-making. Vasile et al. review the role of copeptin, a stable peptide derived from vasopressin, in acute ischemic stroke. Their systematic overview of the current evidence confirms that copeptin levels on admission predict both short-and long-term outcomes, as well as the efficacy of revascularization therapies, supporting its integration into prognostic models.Recent advances in epidemiological and genetic research have identified novel risk factors and biomarker candidates for stroke. In a large-scale, 10-year prospective cohort study, Li et al. evaluated the Triglyceride-Glucose (TyG) index as a predictor of stroke incidence in a Chinese population. Their findings demonstrate that a higher TyG index, reflecting insulin resistance, is independently associated with increased risk of total and ischemic stroke, but not hemorrhagic stroke, underscoring the importance of metabolic health in stroke prevention, Arginine derivatives are considered biomarkers of endothelial (dys-)function. Pihlasviita et al. describe plasma symmetric dimethylarginine (SDMA) as a metabolite biomarker that distinguishes severe acute ischemic stroke from hemorrhagic stroke within the first 90 minutes after symptom onset. Elevated SDMA levels were also linked to cardioembolic stroke and poor outcomes, highlighting its promise in diagnostic algorithms and tailored management.fatty acid side chains have causal relationships with intracerebral and subarachnoid hemorrhages. Lipids containing arachidonic acid chains therefore could be protective, while those with linoleic acid chains increase risk, offering new mechanistic insights and potential therapeutic targets.Finally, Chen et al. employ a comprehensive genetic approach to explore the causality between lipidomic and immune cell profiles and ischemic stroke subtypes. Their analysis identifies genetic links between specific immune cell phenotypes, and large artery, small vessel, and cardioembolic stroke. Mediation analyses highlight the role of immune cells in the lipid-stroke pathway, suggesting new avenues for personalized prevention and intervention.Quality assurance in acute stroke interventions is addressed by Lieschke and Foerch, who propose serum S100B as a surrogate marker for astroglial tissue damage after mechanical thrombectomy. The authors discuss how S100B levels measured post-intervention correlate with infarct size and functional outcome, offering a potential objective metric for benchmarking endovascular therapy success.Similarly, Freitas et al. demonstrate that neuron-specific enolase (NSE) measured 48 hours after reperfusion therapy is strongly associated with 90-day functional outcomes in ischemic stroke patients. Higher NSE levels correlate with worse neurological disability, suggesting its utility as a prognostic tool for patient stratification.Distinguishing hemorrhagic from ischemic strokes is still not possible without imaging, but would have enormous relevance for faster process times in stroke therapy. Paul et al. show that serum glial fibrillary acidic protein (GFAP) is markedly elevated in intracerebral hemorrhage compared to ischemic stroke, even in the hyperacute phase. GFAP levels also reflect the extent of tissue injury and time from onset, supporting its use in early subtype differentiation and assessment of tissue damage.Together, the work collected in this Research Topic represents a significant step forward in the quest for reliable blood-based biomarkers in stroke. From GFAP and S100B to copeptin, NSE, and beyond, these investigations illuminate new for faster diagnosis, more accurate prognosis, and individualized patient care. As the field continues to advance, the integration of these biomarkers into clinical practice holds the promise of transforming management and improving outcomes for patients worldwide. However, despite the exciting progress reflected in these studies, challenges remain. A considerable obstacle in biomarker studies often remains the limited statistical power and lack of external validation. Therefore, all efforts towards harmonization in cross-center projects are essential to advance the field.We thank all contributing authors for their rigorous and innovative work and hope this collection will inspire further research and translation into clinical practice.RS, RGK, JEW, TU, and GMG edited the Research Topic and drafted and revised the editorial manuscript. All authors have read and approved the final version of the manuscript.

Background: Oral anticoagulation is highly effective in preventing ischemic events in patients with atrial fibrillation. Still, a considerable number of patients have an acute ischemic stroke or transient ischemic attack despite anticoagulation. In this study, we investigated the association of prior antithrombotic regimens with stroke severity, volume, and hemorrhagic transformation. Methods and Results: This is a post hoc analysis of the prospective, multicenter, observational PRODAST (Prospective Record of the Use of Dabigatran in Patients With Acute Stroke or TIA) study, which was conducted in 86 stroke units in Germany between July 2015 and November 2020. In 9030 patients with atrial fibrillation who had an acute ischemic stroke or transient ischemic attack within 7 days before enrollment, we analyzed the association of anticoagulants in comparison to lack of prevalent antithrombotic treatment with clinical stroke severity, infarct size, and risk for hemorrhagic transformation. A total of 4479 patients had prior anticoagulation at the time of index event. After adjustment for confounders (arterial hypertension, diabetes, heart failure, age, and sex), patients with prior anticoagulation had less severe strokes (−2.5 National Institutes of Health Stroke Scale points [95% CI, −2.8 to −2.2]), smaller infarct sizes (−23 mL [95% CI, −44 mL to −2 mL], n=4041), and reduced odds for hemorrhagic transformation (5% versus 10%; odds ratio, 0.48 [95% CI, 0.40–0.57]) compared with patients without antithrombotic treatment. These findings were confirmed using sensitivity analyses accounting for thrombolysis and mechanical thrombectomy, as well as timing of brain imaging. Antiplatelet therapy had hardly any association with the end points compared with no antithrombotic pretreatment. Conclusions: Prior anticoagulation was not only associated with less severe stroke and smaller infarct size but also with a reduced risk of hemorrhagic transformation compared with no antithrombotic pretreatment. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02507856.

Background: Timely treatment of ischaemic stroke with intravenous thrombolysis (IVT) and endovascular treatment (EVT) depends on efficient communication within a multiprofessional team. Mobile applications can streamline communication and documentation processes in acute stroke care. Objective: This study aims to implement a mobile app to facilitate digital documentation and communication in acute stroke care and evaluate its impact on documentation rates and treatment times. Furthermore, a user experience survey was performed to gather information about the app usage in an acute medical process. Design: The study is designed as an observational post-market clinical follow-up cohort study. Methods: The mobile app ‘Join’ was implemented in a tertiary stroke care centre. Feasibility was assessed by monitoring documentation rates and process times, that is, ‘door-to-needle time’ (DNT) and ‘door-to-groin time’ (DGT). All patients treated for suspected stroke or transitory ischaemic attack were included in a 6-month period prior to (T1) and a 3-month period after (T2) implementation of the Join app. User experience was evaluated through a standardized survey including technical features. Results: The interface between the mobile application, hospital information, picture archiving and communication, and quality assurance system as well as various magnetic resonance imaging/computer tomography scanners was implemented for acute stroke care. A total of 504 stroke patients was treated, 334 in T1 and 170 in T2. Of these, 65 received IVT and 87 received endovascular treatment (EVT). DNT (T1 vs T2, 27.5 vs 32 min, p = 0.987) and DGT (T1 vs T2, 50 vs 61.5 min, p = 0.481) were numerically longer during T2. Documentation rates increased threefold for all patients and 1.5 times for those receiving recanalization therapy. The survey revealed that documentation (76%) and case information retrieval (52%) were the most used app features, while other functionalities were less frequently utilized. Conclusion: Implementing a mobile app facilitated real-time digital documentation accessible to the entire stroke care team. The introduction of the app did not improve treatment times for patients receiving acute recanalizing therapies. We recommend systematic training programmes to promote user acceptance and effective use.

Introduction: Factor Xa (FXa) inhibitors are superior to vitamin K antagonists (VKAs) in terms of avoiding hemorrhagic complications. However, no robust data are available to date as to whether this also applies to the early phase after stroke. In this prospective registry study, we aimed to investigate whether anticoagulation with FXa inhibitors in the early phase after acute ischemic stroke or transient ischemic attack (TIA) is associated with a lower risk of major bleeding events compared with VKAs. Materials and methods: The Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) study is a prospective, multicenter, observational, post-authorization safety study at 86 German stroke units between July 2015 and November 2020. Primary outcome was a major bleeding event during hospital stay. Secondary endpoints were recurrent strokes, recurrent ischemic strokes, TIA, systemic/pulmonary embolism, myocardial infarction, death and the composite endpoint of stroke, systemic embolism, life-threatening bleeding and death. Results: In total, 10,039 patients have been recruited. 5,874 patients were treated with FXa inhibitors and 1,050 patients received VKAs and were eligible for this analysis. Overall, event rates were low. We observed 49 major bleeding complications during 33,297 treatment days with FXa-inhibitors (rate of 14.7 cases per 10,000 treatment days) and 16 cases during 7,714 treatment days with VKAs (rate of 20.7 events per 10,000 treatment days), translating into an adjusted hazard ratio (aHR) of 0.70 (95% confidence interval (95% CI): 0.37–1.32) in favor of FXa inhibitors. Hazards for ischemic endpoints (63 vs 17 strokes, aHR: 0.96 (95% CI: 0.53–1.74), mortality (33 vs 6 deaths, aHR: 0.87 (95% CI: 0.33–2.34)) and the combined endpoint (154 vs 39 events, aHR: 0.99 (95% CI: 0.65–1.41) were not substantially different. Discussion and conclusion: This large real-world study shows that FXa inhibitors appear to be similarly effective in terms of bleeding events and ischemic endpoints compared to VKAs in the early post-stroke phase of hospitalization. However, the results need to be interpreted with caution due to the low precision of the estimates.

The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies¹. Risk is particularly high in patients with atherosclerosis, with more than 10% of patients experiencing early recurrent events^1,2. However, despite the enormous medical burden of this clinical phenomenon, the underlying mechanisms leading to increased vascular risk and recurrent stroke are largely unknown. Here, using a novel mouse model of stroke-induced recurrent ischaemia, we show that stroke leads to activation of the AIM2 inflammasome in vulnerable atherosclerotic plaques via an increase of circulating cell-free DNA. Enhanced plaque inflammation post-stroke results in plaque destabilization and atherothrombosis, finally leading to arterioarterial embolism and recurrent stroke within days after the index stroke. We confirm key steps of plaque destabilization also after experimental myocardial infarction and in carotid artery plaque samples from patients with acute stroke. Rapid neutrophil NETosis was identified as the main source of cell-free DNA after stroke and NET–DNA as the causative agent leading to AIM2 inflammasome activation. Neutralization of cell-free DNA by DNase treatment or inhibition of inflammasome activation reduced the rate of stroke recurrence after experimental stroke. Our findings present an explanation for the high recurrence rate after incident ischaemic events in patients with atherosclerosis. The detailed mechanisms uncovered here provide clinically uncharted therapeutic targets for which we show high efficacy to prevent recurrent events. Targeting DNA-mediated inflammasome activation after remote tissue injury represents a promising avenue for further clinical development in the prevention of early recurrent events.