Background Status epilepticus (SE) is a life-threatening neurological emergency with high mortality, often leading to acute cerebral edema and chronic cognitive impairment. Its pathology involves both immune and vascular dysfunction. The complement C3/C3a receptor (C3/C3aR) signaling pathway has recently emerged as a key regulator of immune activation and blood-brain barrier (BBB) permeability. This study investigates whether bindarit, a potent anti-inflammatory drug, mitigates SE-induced brain injury through modulation of the C3/C3aR pathway. Methods SE modeling mice were randomized to receive daily bindarit or vehicle. To explore underlying mechanisms, C3aR antagonist (C3aRA) and recombinant C3a were used in additional groups. Post-SE brain injuries were assessed, including survival, memory performance, histopathology, brain edema, BBB integrity, neurovascular inflammation, microglia-astrocyte interactions, and microglial synaptic engulfment. Results We found that bindarit treatment improved survival and memory, reduced histological damage, alleviated brain edema, preserved BBB integrity, and attenuated endothelial inflammation in SE mice. It promoted a shift in microglia from a pro-inflammatory to an anti-inflammatory-associated features, reversed pathological microglia-astrocyte crosstalk, limited synaptic elimination, and restored microglial morphology. Mechanistically, bindarit inhibited neurotoxic astrocyte-derived C3 production and reduced C3aR expression in both microglia and endothelial cells. C3aRA produced comparable protective effects, whereas co-administration of C3a partially negated bindarit's benefits. Conclusions Bindarit confers robust neuroprotection in SE by preserving BBB integrity, attenuating neurovascular inflammation, reducing synaptic loss, and improving cognitive outcomes. These effects are mediated predominantly through inhibition of the C3/C3aR pathway, highlighting bindarit as a promising therapeutic candidate for SE.

The influence of age on the management of spontaneous intracranial hypotension (SIH), particularly epidural blood patch (EBP), remains unclear. This study aims to characterize age-related differences in clinical manifestation, neuroimaging features, and treatment outcomes. In this retrospective cohort study, we analyzed 54 SIH patients who underwent EBP at our center. Patients were classified into two groups based on the cohort median age (35 years). Demographic, clinical, neuroimaging features, and treatment outcomes were compared between the two groups. We further utilized Spearman correlation, locally weighted scatterplot smoothing, and multivariable linear regression to analyze the association between age and EBP volume. Several sensitivity analyses were conducted to assess the robustness of our findings. Among 54 enrolled patients, the injected volume of EBP was markedly larger in the older group (26.00 [19.12, 32.75] vs. 19.25 [15.00, 24.00] ml, P = 0.018). While Spearman correlation indicated a significant positive correlation existed between age and EBP volume (ρ = 0.388, P = 0.004), subgroup analysis revealed a dissociation: a strong linear correlation in the older group (ρ = 0.458, P = 0.018) contrasted with a non-significant, non-monotonic trend in the younger group (ρ = -0.034, P = 0.863). Linear regression analysis showed that age was positively associated with EBP volume (β = 2.899, 95

QuestionAmong patients with acute ischemic stroke without large or medium vessel occlusion or cardioembolic source, does intravenous tirofiban after an insufficient response to intravenous tenecteplase improve functional outcomes?FindingsIn this randomized trial of 359 patients, tirofiban significantly increased the proportion of patients with an excellent outcome (defined as a score of 0 or 1 on the modified Rankin Scale) at 90 days compared with placebo (63.8% vs 52.2%, respectively).MeaningThese findings suggest a potential benefit of adjunctive intravenous tirofiban after intravenous tenecteplase in this specific patient population and warrant further investigation. ImportanceAlthough recent trials have shown benefit with early tirofiban after thrombolysis, its efficacy remains uncertain in patients with acute ischemic stroke who do not have a large or medium vessel occlusion or a cardioembolic source and who show an inadequate clinical response to intravenous tenecteplase.ObjectiveTo assess the efficacy and safety of intravenous tirofiban administered after an inadequate response to intravenous tenecteplase in this specific patient population.Design, Setting, and ParticipantsInvestigator-initiated, randomized, double-blind, placebo-controlled trial conducted at 37 hospitals in China, enrolling 359 patients with acute ischemic stroke, without large or medium vessel occlusion or cardioembolic etiology, and with an insufficient clinical response to intravenous tenecteplase (defined as no significant change from baseline, neurological deterioration, or neurological fluctuation based on serial assessment of the National Institutes of Health Stroke Scale score within 4-24 hours after infusion). Recruitment took place between April 24, 2024, and July 16, 2025, with final follow-up on October 11, 2025.InterventionsIntravenous tirofiban (n = 177), administered as a 0.3-mu g/kg/min bolus over 30 minutes, followed by a continuous infusion of 0.075 mu g/kg/min for up to 47.5 hours, or matching placebo (n = 182), initiated within 4 to 24 hours after intravenous tenecteplase. Oral antiplatelet therapy (aspirin and/or clopidogrel) was started 24 hours after thrombolysis in the placebo group and 44 hours after thrombolysis in the tirofiban group and continued in all patients through 90-day follow-up.Main Outcomes and MeasuresThe primary outcome was an excellent outcome (defined as a score of 0 or 1 on the modified Rankin Scale; range, 0-6, with higher scores indicating more severe disability) at 90 days. Safety outcomes included incidence of symptomatic intracranial hemorrhage within 48 hours and 90-day mortality.ResultsAmong 359 patients randomized (mean age, 66 years; 141 females [39.3%]), 358 (99.7%) completed the trial. An excellent outcome at 90 days was observed in 113 patients (63.8%) in the tirofiban group and in 95 patients (52.2%) in the placebo group (risk ratio, 1.22; 95% CI, 1.02-1.46; P = .03). Symptomatic intracranial hemorrhage within 48 hours occurred in 1 patient (0.9%) in the tirofiban group and no patients in the placebo group; 90-day mortality was 0.6% and 1.6%, respectively.Conclusions and RelevanceAmong patients with acute ischemic stroke without large or medium vessel occlusion or a cardioembolic source who had an inadequate clinical response to intravenous tenecteplase, adjunctive intravenous tirofiban increased the likelihood of an excellent outcome at 90 days.Trial RegistrationClinicalTrials.gov Identifier: NCT05604638 This randomized trial assesses the effect of intravenous tirofiban vs placebo on 90-day outcome among patients with acute ischemic stroke and an inadequate clinical response to intravenous tenecteplase.

Endovascular treatment (EVT) is an effective treatment for patients with acute ischemic stroke (AIS); however, it remains to be determined if treatment with intravenous thrombolysis (IVT) prior to EVT confers any benefit in octogenarians and older. This study aimed to address if bridging tPA has improved functional outcomes or complications in patients 80 years and older. This multicentre retrospective cohort study included patients 80 years old and above who underwent endovascular therapy for large vessel occlusion acute ischaemic stroke in 10 compressive stroke centres across China and Singapore between 2018 and 2024. Clinical and procedural factors of patients in Singapore and China were compared using multivariate binary logistic regression. The primary outcome measured was 3-month functional independence defined as modified rankin scale (mRS) 0–2. Secondary outcomes included 3-month independent ambulation as defined as mRS 0–3, 3-month mortality rates and achieving successful recanalization. Data on intracranial haemorrhage was also collected. Bridging IVT was not associated with improvement in 3-month functional independence (24.47

Background This study aimed to develop and validate a practical and reliable tool for comprehensive assessment of brain lesions on immediate post‐endovascular therapy (EVT) noncontrast computed tomography (CT) and to predict 90‐day functional outcomes in patients with acute ischemic stroke. Methods We retrospectively reviewed consecutive patients with acute ischemic stroke undergoing EVT from 2 academic hospitals as the development cohort and used an independent national multicenter prospective cohort for external validation. The new score was derived from the Alberta Stroke Program Early CT Score (ASPECTS) on the immediate post‐EVT non‐contrast CT, integrating both hyperdensity and hypodensity signs, named comprehensive Alberta Stroke Program Early CT Score (Co‐ASPECTS). Unfavorable outcome was defined as modified Rankin Scale score of 3 to 6 at 90 days. Results A total of 1015 patients were included (development cohort: 542; validation cohort: 473). Co‐ASPECTS, formulated through equal‐weight summation of hyperdensity and hypodensity signs and consistent with the 0 to 10 score ASPECTS framework, was significantly associated with unfavorable outcomes (adjusted odds ratio, 0.45 [95% CI, 0.40–0.51]). It showed discrimination for functional outcome with a C‐statistic of 0.889 in the development cohort, outperforming conventional models including baseline ASPECTS and immediate post‐EVT ASPECTS that calculated based on hyperdensity or hypodensity signs alone. In the validation cohort, Co‐ASPECTS maintained robust performance (C‐statistic, 0.847). It also appeared to reflect both infarct burden and secondary injury, showing associations with final infarction and intracranial hemorrhage. Conclusions Co‐ASPECTS may serve as a promising tool with reliability and practicality for assessing brain lesions and predicting functional outcomes of patients with acute ischemic stroke who underwent EVT in clinical practice.

INTRODUCTION:Parenchymal haematoma (PH) is a potentially serious complication post endovascular treatment (EVT) and is associated with poor functional outcomes. It is unknown if modifiable factors can improve the outcomes of patients with PH. This study aimed to determine whether successful reperfusion is associated with favourable outcome in patients with ischemic stroke despite this complication. METHODS:In an international multi-centre study, favourable outcomes (mRS0-2) of patients achieving successful reperfusion (TICI 2b/3) were compared with outcomes of those with unsuccessful reperfusion. RESULTS:346 patients were included in the final analysis. 36 patients had unsuccessful reperfusion (10.4%) while 310 had successful reperfusion (89.6%). Amongst patients with PH post-EVT, successful reperfusion conferred better 3-month favourable outcomes (20.32% vs 5.56%; p=0.032) and lower mortality rates (40.32% vs 72.22%; p <0.001) compared with patients who had unsuccessful reperfusion. CONCLUSION:Successful reperfusion remains a strong predictor of favourable outcome and reduced mortality in ischemic stroke patients with parenchymal haematoma post endovascular treatment.

Cerebral edema is a severe complication following ischemic stroke. Recent studies have highlighted the crucial role of the glymphatic system (GS) in the clearance of water and macromolecules. GS dysfunction involving the disorders of AQP4 polarization may be crucial in the pathophysiology of cerebral edema. β-Hydroxybutyrate (BHB), the main component of the ketone body, has been shown to alleviate neurological deficits by restoring GS function in subarachnoid hemorrhage models and to reduce Aβ deposition in Alzheimer’s disease models. In this study we investigated the effects of BHB on cerebral edema following ischemic stroke and its mechanisms. The mice were fed a ketogenic diet (KD) or a normal diet for 4 weeks before transient middle cerebral artery occlusion (MCAO). Alternatively, the mice received BHB (5 g·kg−1·d−1) or vehicle post-MCAO. By using brain section analysis, transcranial macroimaging, two-photon in vivo imaging and MRI, we demonstrated that both KD and BHB treatment significantly enhanced GS function under normal and MCAO conditions. BHB reduced cerebral edema and infarct volume post-MCAO. Notably, delayed BHB treatment initiated 10 h post-MCAO still improved GS function, but did not influence infarct volume. Furthermore, we revealed that BHB increased α1-syntrophin expression and H3K27ac levels in α1-syntrophin (Snta1) enhancer, restoring AQP4 polarization. In addition, BHB also reduced HDAC3 expression and elevated p300 expression. These results suggest that a KD and BHB treatment enhance GS function in mice and that BHB also mitigates brain edema after MCAO. The potentiation of GS function by BHB is likely mediated by the inhibition of HDAC3 activity and the increase in p300 activity, which upregulate α1-syntrophin expression and restore AQP4 polarization.

Background The clinical benefits of early PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor use in patients with acute large vessel occlusion undergoing endovascular therapy (EVT) remain unclear. This study investigates whether early administration of PCSK9 inhibitors after EVT is associated with improved clinical outcomes. Methods In this retrospective cohort study, we consecutively screened patients with acute large vessel occlusion with successful EVT recanalization at 2 academic hospitals from January 2019 to March 2025. Participants were grouped based on receipt of evolocumab or alirocumab within 96 hours after EVT. Propensity score matching was performed to adjust for baseline covariates. The primary outcome was early artery reocclusion. Mediation analysis was conducted to explore potential links between PCSK9 inhibitors and clinical outcomes. Results Among 429 eligible patients (148 in the PCSK9 inhibitors group, 281 controls), 116 matched pairs were analyzed. The incidence of early artery reocclusion was significantly lower in the PCSK9 inhibitors group compared with controls (3.4% versus 12.9%; odds ratio [OR], 0.24 [95% CI, 0.08–0.75]; P=0.01). Moreover, a significantly greater proportion of patients in the PCSK9 inhibitors group achieved favorable outcomes at 90 days (modified Rankin Scale score 0–2: 77.6% versus 60.3%; OR, 2.28 [95% CI, 1.28–4.04]; P<0.01). Safety outcomes were comparable between the 2 groups. Mediation analysis suggested the benefit of PCSK9 inhibitors on functional outcomes was partially mediated by reduced EAR. Conclusions Early PCSK9 inhibitor use after EVT in patients with acute large vessel occlusion was linked to reduced EAR and better 90‐day outcomes without added adverse events.

Importance:Although recent trials have shown benefit with early tirofiban after thrombolysis, its efficacy remains uncertain in patients with acute ischemic stroke who do not have a large or medium vessel occlusion or a cardioembolic source and who show an inadequate clinical response to intravenous tenecteplase. Objective:To assess the efficacy and safety of intravenous tirofiban administered after an inadequate response to intravenous tenecteplase in this specific patient population. Design, Setting, and Participants:Investigator-initiated, randomized, double-blind, placebo-controlled trial conducted at 37 hospitals in China, enrolling 359 patients with acute ischemic stroke, without large or medium vessel occlusion or cardioembolic etiology, and with an insufficient clinical response to intravenous tenecteplase (defined as no significant change from baseline, neurological deterioration, or neurological fluctuation based on serial assessment of the National Institutes of Health Stroke Scale score within 4-24 hours after infusion). Recruitment took place between April 24, 2024, and July 16, 2025, with final follow-up on October 11, 2025. Interventions:Intravenous tirofiban (n = 177), administered as a 0.3-μg/kg/min bolus over 30 minutes, followed by a continuous infusion of 0.075 μg/kg/min for up to 47.5 hours, or matching placebo (n = 182), initiated within 4 to 24 hours after intravenous tenecteplase. Oral antiplatelet therapy (aspirin and/or clopidogrel) was started 24 hours after thrombolysis in the placebo group and 44 hours after thrombolysis in the tirofiban group and continued in all patients through 90-day follow-up. Main Outcomes and Measures:The primary outcome was an excellent outcome (defined as a score of 0 or 1 on the modified Rankin Scale; range, 0-6, with higher scores indicating more severe disability) at 90 days. Safety outcomes included incidence of symptomatic intracranial hemorrhage within 48 hours and 90-day mortality. Results:Among 359 patients randomized (mean age, 66 years; 141 females [39.3%]), 358 (99.7%) completed the trial. An excellent outcome at 90 days was observed in 113 patients (63.8%) in the tirofiban group and in 95 patients (52.2%) in the placebo group (risk ratio, 1.22; 95% CI, 1.02-1.46; P = .03). Symptomatic intracranial hemorrhage within 48 hours occurred in 1 patient (0.9%) in the tirofiban group and no patients in the placebo group; 90-day mortality was 0.6% and 1.6%, respectively. Conclusions and Relevance:Among patients with acute ischemic stroke without large or medium vessel occlusion or a cardioembolic source who had an inadequate clinical response to intravenous tenecteplase, adjunctive intravenous tirofiban increased the likelihood of an excellent outcome at 90 days. Trial Registration:ClinicalTrials.gov Identifier: NCT05604638.

Cox proportional hazards regression analysis of factors affecting OS in patients with gastric cancer.

Status epilepticus (SE) is a severe condition that results in uncontrollable cerebral edema and cognitive dysfunction. Recent studies suggest that the localization of aquaporin-4 (AQP4) in astrocytic endfeet plays a crucial role in regulating blood-brain water transport and cell volume control, particularly along perivascular pathways. However, the signaling mechanisms underlying AQP4 localization remain poorly understood. In this study, we utilized the genetically encoded fluorescent calcium (Ca2+) indicator GCaMp6f to investigate Ca2+ signals in astrocytic somata, processes, and endfeet during SE induction and observed enhanced Ca2+ signals in both the somata and perivascular endfeet of astrocytes. We employed genetic knockout of TRPM4 (Trpm4 -/- ) and glibenclamide treatment to explore the role of sulfonylurea receptor 1 transient receptor potential melastatin-4 (SUR1-TRPM4) channel in these Ca2+ responses. Both approaches significantly suppressed the Ca2+ signals in the astrocytic endfeet and reduced perivascular expression of the Ca2+-related signaling pathway sensor calmodulin (CaM). Furthermore, we found that AQP4 localization was no longer confined to the domains of astrocytic endfeet following SE. Inhibition of SUR1-TRPM4 through pharmacological blockade or gene deletion restored the subcellular localization of AQP4, reduced cerebral edema, and improved cognitive outcomes post-SE. Our findings suggest that SUR1-TRPM4 plays a pivotal role in regulating astrocytic Ca2+ signals and mediating the aberrant expression and subcellular localization of astrocytic AQP4 along perivascular pathways. Together, these findings demonstrate a novel molecular mechanism underscoring SUR1-TRPM4 therapy in the treatment of SE characterized by dysregulated Ca2+ signaling in astrocytic endfeet.

Kaplan–Meier survival curves for OS in TBA-positive and TBA-negative patients with gastric cancer.

Reduced CD8+ T-cell infiltration and altered CD4+/CD8+ ratio in TBA-positive gastric cancer tissues. ns, not significant.

Neuronal autoantibodies have been identified in immune-mediated encephalitis, most of which are related to paraneoplastic neurologic syndromes (PNS). We detected neuronal autoantibodies in patients with gastric cancer without PNS and illustrated their correlation with clinical prognosis. All serum samples were tested by the mouse brain tissue-based assay (TBA) using immunofluorescence for screening neuronal autoantibodies. Known PNS-related neuronal autoantibodies were detected by cell-based assay. A single-center cohort has been started in Nanfang Hospital. The T-cell status of the tumor microenvironment was assessed. Single-cell sequencing was performed with limited tumor samples. Patients were grouped into TBA-positive (n = 144) and TBA-negative (n = 179) groups by the TBA status. Further screening of TBA+ specimens using the cell-based assay method revealed known PNS-related autoantibodies in 13.2% (19/144) of cases. Additionally, TBA-positive patients with gastric cancer exhibited lower CD8+ T-cell infiltration in the tumor tissue. The survival analysis show that neuronal autoantibodies in patients (TBA-positive) were associated with shorter overall survival (OS; P = 0.014). In the multivariate survival analysis, TBA positivity was still associated with shortened OS after adjusting the major covariates (HR = 2.28; 95% confidence interval, 1.31-3.97; P = 0.004). Meanwhile, single-cell sequencing indicates that cell junction assembly and synapse organization may play important roles in biological process. In this cohort study, neuronal autoantibodies were highly prevalent among patients with gastric cancer and were associated with shortened OS and features of immunosuppression within the tumor microenvironment, suggesting a candidate for exploring therapeutic relevance, with further mechanistic studies needed for validation. SIGNIFICANCE:Neuronal autoantibodies are prevalent in patients with gastric cancer, and patients without neurologic symptoms are linked to shorter survival and immunosuppression. These results provide a new direction for prognostic biomarkers and targeted therapy exploration.

Delayed radiation-induced brain injury (RIBI) characterized by progressive cognitive decline significantly impacts patient outcomes after radiotherapy. The activation of NLRP3 inflammasome within microglia after brain radiation is involved in the progression of RIBI by mediating inflammatory responses. We have previously shown that sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) mediates microglial NLRP3-related inflammation following global brain ischemia. However, the role of SUR1-TRPM4 in RIBI remains unclear. Here, we found that whole-brain radiation induced up-regulation and assembly of SUR1-TRPM4, which further activated the NLRP3 inflammasome in microglia and caused persistent neuroinflammation in mice. Blocking SUR1-TRPM4 by glibenclamide or gene deletion of Trpm4 effectively prevented NLRP3-mediated neuroinflammation and alleviated RIBI. Utilizing the mouse model of RIBI and irradiated BV2 cells, we further demonstrated that irradiation caused mitochondrial damage to microglia, leading to violent release of reactive oxygen species (ROS), which enhanced the transcription of SUR1, TRPM4, and NLRP3 inflammasome-related molecules. Moreover, ROS up-regulated ten-eleven translocation 2 (TET2) to enhance TRPM4 expression by mediating the demethylation of the gene promoter, thereby facilitating the assembly of SUR1-TRPM4 in microglia. In summary, this study deciphers that SUR1-TRPM4 crucially mediates the persistent activation of microglial NLRP3 inflammasome under the action of ROS after whole-brain radiation, offering novel therapeutic strategies for delayed RIBI as well as other NLRP3-related neurological disorders involving excessive ROS production.

Background: Intracerebral hemorrhage (ICH) is the most lethal and devastating subtype of stroke. Basal ganglia hemorrhage and thalamic hemorrhage are the most common types of ICH, accounting for 50-70% of all ICH cases, leading to disability and death, and it involves the posterior limb of the internal capsule to varying degrees. In this study, we investigated the impact of varying degrees of the involvement of the posterior limb of the internal capsule on the prognosis of patients with basal ganglia and thalamic ICH and assessed whether it improves the predictive accuracy of the max-ICH score, an existing scale for ICH functional outcome. Methods: This is a multicenter, retrospective, observational study. We graded the involvement of the posterior limb of the internal capsule according to the degree of compression and injury (called iICH, ranging from 0 to 4). An unfavorable outcome was defined as a 90-day modified Rankin Scale (mRS) of > 2. Multivariate logistic regression analysis was used to identify independent risk factors associated with unfavorable prognosis. The discrimination was verified using receiver operating characteristic curve (ROC) analysis, while the calibration was verified by the Hosmer-Lemeshow test. Results: Of the 305 patients included, 188 from Nanfang Hospital were assigned to the development cohort, and 117 from Heyuan People's Hospital and Huadu District People's Hospital were assigned to the validation cohort. In the development cohort, iICH was identified as an independent factor of a 90-day unfavorable outcome, and the area under the ROC (AUC) was 0.774. When combined with the iICH, the AUC of max-ICH was significantly elevated from 0.816 to 0.866. Comparable results were found in the validation cohort. Conclusions: Increased involvement of the posterior limb of the internal capsule is associated with a worse outcome in patients with basal ganglia and thalamic ICH.

BACKGROUND:Collapsin response mediator protein (CRMP) consists of five subtypes (CRMP1-5), which share high homology and are expressed in the nervous system. Anti-CRMP2 and anti-CRMP5 antibodies (Abs) have been reported in autoimmune encephalitis (AE). This study retrospectively evaluated the diagnostic value of CRMP auto-Abs in patients with suspected immune-mediated encephalopathy/myelopathy. METHODS:Patients with encephalopathy/myelopathy attributed to autoimmune or infectious causes, as well as those with encephalopathy of unclear etiology, were recruited from our department between January 2017 and November 2019. Clinical data, as well as serum and/or cerebrospinal fluid (CSF) samples, were collected. Measurement of Abs against CRMPs in patient samples was performed using a cell-based assay (CBA) with HEK293 cells expressing CRMP proteins and confirmed by a tissue-based assay (TBA) with mouse brain sections. RESULTS:A total of 400 patients and 77 healthy controls were recruited. The male-to-female ratio of the patients was 0.88, and the average age was 39.22 ± 16.59 years. CBA testing was performed with 200 paired CSF and serum samples, along with 99 CSF samples and 101 serum samples. Of the patients, 22 (5.5%) presented with anti-CRMPs Abs. Anti-CRMP1 was the most commonly detected Ab (17/22, 77.3%), either alone or in combination with CRMP2 and CRMP3. Titers of anti-CRMPs Abs ranged from 1: 3.2 to 1:10 in CSF samples and 1:32 to 1:320 in serum samples. Patients with anti-CRMPs Abs experienced more headaches and had higher levels of chloride in CSF compared to those without anti-CRMPs Abs. Fourteen of the 22 patients with anti-CRMPs Abs were diagnosed with encephalitis, exhibiting a higher frequency of fever and headache, CSF pleocytosis, and more frequent treatment with immunotherapy, steroids, antibiotics, and antiviral therapy compared to non-inflammatory encephalopathy patients. CONCLUSION:Anti-CRMPs Abs may indicate immune-mediated neuronal damage in encephalopathy, including encephalitis, and may serve as potential biomarkers for neuronal injury.

Cryptogenic stroke represents 25%-40% of ischemic strokes, with many cases harboring unrecognized large artery atherosclerosis (LAA) requiring specific secondary prevention. In this multicenter pilot study, we developed a metabolomics-based machine learning model to identify LAA and predict plaque burden in cryptogenic stroke patients. Plasma metabolites from 572 acute ischemic stroke patients across three hospitals were analyzed using untargeted metabolomics. A two-stage machine learning approach was developed: Model 1 distinguished cardioembolic (CE) from non-CE stroke, and Model 2 separated LAA from small vessel occlusion (SVO). Models were integrated to directly predict LAA among all subtypes. Model 1 achieved exceptional performance distinguishing CE from non-CE (AUC = 0.998, accuracy = 97.9%), with pyruvate and glutamine as key discriminators. Model 2 differentiated LAA from SVO with AUC = 0.949, identifying pyroglutamate and 2-hydroxybutyrate as primary markers. The combined model predicted LAA with AUC = 0.821. Critically, cryptogenic stroke patients predicted as LAA showed significantly higher plaque burden than those predicted as CE/SVO (23.9% vs. 10.9%, p = 0.014), with increased neovascularization and ulcerative features. This metabolomics-based approach accurately identifies LAA in cryptogenic stroke patients and predicts atherosclerotic plaque burden, offering a novel diagnostic tool to guide personalized antithrombotic therapy selection. Trial Registration: Chinese Clinical Trial Registry registration number: ChiCTR1800015956.

This study aimed to elucidate the differences between patients with anti-glial fibrillary acidic protein (GFAP) antibodies who exhibited concurrent positivity for other neuro-antibodies and those who did not. Hospitalised patients demonstrating anti-GFAP antibody positivity in cerebrospinal fluid (CSF) were retrospectively collected and followed up from March 2019 to July 2022. Data including clinical features, laboratory results, imaging findings, therapy, and prognosis were extracted from the medical record system. Thirty-seven patients with positive anti-GFAP antibody in CSF were included. Ten patients exhibited concomitant other neuro-antibodies and were categorised as the “overlapping group”. Compared to the non-overlapping group, the incidence of seizures was significantly higher in the overlapping syndrome group (50