Background: Cerebral small vessel disease (CSVD) is a major cause of vascular cognitive impairment (VCI), yet diagnosis remains difficult due to heterogeneous patient profiles and complex manifestations. This study aimed to develop and validate AI-based tools for distinguishing normal cognition (NC) and mild cognitive impairment (MCI) in CSVD. Methods: Two CSVD cohorts were analyzed: (1) a nationwide multicenter dataset (N=4185) with standardized demographic and clinical variables; and (2) a single-center dataset from Beijing Tiantan Hospital (N=74) including demographic, structural MRI, heart rate variability, EEG, hemodynamic, functional MRI (fMRI), and diffusion tensor imaging (DTI) features. Cognitive status was determined by Montreal Cognitive Assessment (MoCA) scores. Models were developed using the tabular prior-data fitted network (TabPFN) and conventional machine learning methods (Random Forest, XGBoost, LightGBM). Performance was assessed with stratified five-fold cross-validation and independent testing, using area under the ROC curve (AUC). Secondary analyses in the single-center cohort examined associations between multimodal features and domain-specific outcomes: verbal fluency test (VFT-composite), color trails test part 1 (CTT-1), and Stroop test part 3. Results: In the nationwide cohort, TabPFN achieved the best performance (AUC=0.821), slightly surpassing XGBoost (AUC=0.795), while requiring no feature selection. In the single-center multimodal dataset, RF outperformed TabPFN (AUC=0.841, accuracy=68.9%), likely due to small sample size and class imbalance. Adding imaging and physiological features improved classification over demographic-only inputs, especially in MCI patients. For domain-specific outcomes, advanced neuroimaging (fMRI, DTI) contributed most. AUCs were 0.83 for VFT-composite, 0.836 for CTT-1, and 0.854 for Stroop part 3. Conclusions: AI-based models support auxiliary diagnosis of MCI in CSVD. Nationwide TabPFN models provide scalable screening, while multimodal single-center models allow refined evaluation. Advanced imaging and physiological features enhance domain-specific cognitive assessment, informing targeted diagnostic and intervention strategies.

IntroductionCerebral small vessel disease (CSVD) and motoric cognitive risk syndrome (MCR) are both associated with adverse outcomes in older adults. Factors associated with MCR in CSVD remain poorly understood. We aimed to explore factors associated with MCR and its components (slow gait and subjective cognitive complaints [SCCs]) in CSVD, and to evaluate exploratory association-based multivariable models.MethodsThis cross-sectional study included CSVD patients aged ≥55 years without possible dementia based on education-adjusted MoCA screening from the cognitive subgroup of a national registry. Demographics, clinical variables, physical activity, and CSVD neuroimaging markers were assessed. MCR was defined as co-existing slow gait (age- and sex-adjusted) and SCCs (single-item memory complaint from the 15-item Geriatric Depression Scale). Logistic regression and receiver operating characteristic analyses were performed to identify associated factors and evaluate models. Firth penalized logistic regression and bootstrap internal validation were additionally performed to assess sparse-data bias and optimism in model discrimination.ResultsAmong 225 patients (mean age 65.4 years, 54.2% male), MCR prevalence was 16.4%. In multivariable models, MCR was associated with lower average systolic blood pressure and high total CSVD burden, while physical inactivity showed a positive but imprecise association because of sparse exposure. SCCs were associated with greater juxtacortical white matter hyperintensity volume and higher total CSVD burden. Slow gait was associated with dyslipidemia, poorer functional status, and higher basal ganglia perivascular spaces. The comprehensive exploratory model integrating demographic, clinical, and neuroimaging factors achieved areas under the curve of 0.732 for MCR, 0.733 for SCCs, and 0.770 for slow gait; the corresponding optimism-corrected AUCs were 0.691, 0.696, and 0.725, respectively.ConclusionIn this exploratory cross-sectional analysis, MCR in CSVD patients showed associations with vascular, lifestyle-related, and neuroimaging markers. However, given the small number of MCR events, the single-item SCC assessment, the lack of temporality, and the limited persistence of associations after FDR correction, these findings should be interpreted as hypothesis-generating.

BACKGROUND AND OBJECTIVES:Previous studies have shown a beneficial effect of clopidogrel-aspirin and intensive statin therapy in acute ischemic stroke; however, the synergistic effect of the 2 treatments is still unclear. The aim of this study was to investigate the effect of combining clopidogrel-aspirin and immediate intensive statin in patients with acute mild ischemic stroke or transient ischemic attack (TIA). METHODS:We performed a multicenter, randomized, double-blind, placebo-controlled trial with a 2-by-2 factorial design across 222 hospitals in China. Eligible participants were patients with acute mild ischemic stroke or TIA of a presumed atherosclerotic cause within 72 hours of symptom onset. Patients were randomly assigned to receive clopidogrel plus aspirin or aspirin alone and an immediate or delayed intensive statin. The primary efficacy outcome was a new stroke (ischemic or hemorrhagic) within 90 days, and the primary safety outcome was moderate-to-severe bleeding. RESULTS:Between September 17, 2018, and October 15, 2022, 6,100 patients were enrolled (median age, 65 years; 64.2% male), of whom 1,525 each were assigned to the 4 groups. New stroke within 90 days occurred in 116 patients (7.6%) in the clopidogrel-aspirin plus immediate intensive statin group (hazard ratio [HR] 0.76, 95% CI 0.60-0.97), in 106 patients (7.0%) in the clopidogrel-aspirin plus delayed statin group (HR 0.69, 95% Cl 0.54-0.89), and in 129 patients (8.5%) in the aspirin plus immediate statin group (HR 0.85, 95% Cl 0.67 to 1.07), compared with 150 patients (9.9%) in the aspirin plus delayed intensive statin group. Moderate-to-severe bleeding occurred in 17 (1.1%) in the clopidogrel-aspirin plus immediate statin group (p = 0.047), 10 (0.7%) in the clopidogrel-aspirin plus delayed statin group (p = 0.46), and 6 (0.4%) in the aspirin plus immediate statin group (p = 0.80), compared with 7 (0.5%) in the aspirin plus delayed statin group. DISCUSSION:Among patients with mild ischemic stroke or TIA of presumed atherosclerotic cause, the combination of clopidogrel-aspirin and delayed intensive statin was superior to aspirin plus delayed intensive statin in reducing the risk of new stroke, an effect that was mainly driven by clopidogrel-aspirin and not significantly different from that of clopidogrel-aspirin plus immediate statin. The combination treatment had a low but increased risk of moderate-to-severe bleeding. TRIAL REGISTRATION INFORMATION:ClinicalTrials.gov identifier: NCT03635749. CLASSIFICATION OF EVIDENCE:This study provides Class I evidence that in patients with mild ischemic stroke or TIA of presumed atherosclerotic cause, the combination of clopidogrel-aspirin plus delayed intensive statin was superior to aspirin plus delayed intensive statin in reducing the 90-day risk of new stroke.

Background/Objectives: Cerebral small vessel disease (CSVD) is an important contributor to motor impairment. Cortical cerebral microinfarct (CCMI) is an emerging imaging marker of CSVD. Although its association with cognitive impairment has been well established, its relationship with motor function remains unclear. We explored associations of CCMI with motor performance at baseline and 1-year follow-up in this secondary analysis of data from the China Imaging-based Biobank of Cerebral Small Vessel Diseases. Methods: CCMI was assessed on baseline brain magnetic resonance imaging. Motor function was assessed at baseline and at 1-year follow-up. Outcomes were gait speed, poor balance performance (Short Physical Performance Battery balance score ≤ 2), abnormal gait (Scale for the Assessment and Rating of Ataxia gait score ≥ 2), and repeated chair-stand time. Gait speed was the primary outcome and all other motor outcomes were secondary. Multivariable linear and logistic regression models were used, with Benjamini-Hochberg correction applied to secondary outcomes. Results: The analysis included 192 patients, of whom 74 had 1-year follow-up motor data. At baseline, 55 patients (28.65%) had CCMI. Compared with patients without CCMI, those with CCMI had lower gait speed [0.92 (0.75-1.12) vs. 1.05 (0.87-1.16) m/s]. They also had higher prevalences of poor balance performance (29.09% vs. 14.60%) and abnormal gait (63.64% vs. 36.50%). However, fully adjusted analyses provided no conclusive evidence of baseline associations. At 1-year follow-up, CCMI was associated with slower gait speed after adjustment for demographic factors, baseline gait speed, and total CSVD burden (adjusted β -0.16, 95% CI -0.24 to -0.08; p < 0.001). CCMI was also nominally associated with longer repeated chair-stand time (adjusted β 2.07, 95% CI 0.39-3.75; nominal p = 0.02; adjusted p = 0.06), but this association did not survive correction for multiple comparisons. Conclusions: CCMI was associated with slower gait speed at 1-year follow-up in patients with CSVD. This finding is hypothesis-generating and requires confirmation.

BACKGROUND:Free fatty acid (FFA) serves as an important link between metabolic risk factors and atherosclerotic vascular disease. In this post hoc analysis of the Intensive Statin and Antiplatelet Therapy for Acute High Risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial, we aimed to investigate whether serum FFA concentration was associated with prognosis of acute ischemic stroke. METHODS:Data was obtained from the INSPIRES trial, which was a randomized, double-blind, placebo-controlled, multicenter two-by-two factorial trial at 222 hospitals in China. Fasting venous blood samples were collected from all subjects within 24 hours after randomization. Enrolled patients were divided into 4 groups according to the FFA quartiles. RESULTS:A total of 5813 participants were included, with the median age of 65 years, and 35.9% were women. The median FFA level was 0.45 (interquartile range, 0.31-0.61) mmol/L. After adjusting for potential covariates, elevated FFA level was associated with higher risk of new stroke at 3 months (Q4 vs. Q1: HR 1.85, 95% CI 1.41 to 2.43) and poor functional outcome (Q3 vs. Q1: RR 1.66, 95% CI 1.19 to 2.32; Q4 vs. Q1: RR 1.73, 95% CI 1.37 to 2.16). FFA as a continuous variable was associated with a new stroke and poor functional outcome. Similar results were observed for the outcomes of composite vascular events, ischemic stroke and all-cause mortality. CONCLUSIONS:Elevated baseline serum FFA level was associated with an increased risk of new stroke, as well as composite vascular events, ischemic stroke, and poor functional outcome at 3-month follow-up in patients with acute ischemic stroke.

AIMS:A subgroup analysis of the Intensive Statin and Antiplatelet Therapy for High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial to evaluate intensive statin effects in patients with ischemic stroke by glycemic status. METHOD:Patients were stratified into three subgroups based on glycemic status: without type 2 diabetes mellitus (T2DM), with newly diagnosed T2DM, with a history of T2DM. The primary outcomes included stroke and moderate-to-severe bleeding, whereas secondary outcomes comprised composite vascular events, poor functional outcomes, and any bleeding within 90 days. RESULTS:Among 6100 patients, 4038 were without T2DM, 404 had a newly diagnosed T2DM, and 1658 had a history of T2DM. No significant risk reduction of stroke was observed with immediate versus delayed statin therapies across glycemic subgroups (p for interaction = 0.29). Compared to delayed-intensive statin, immediate-intensive statin treatment was associated with reduced risk of poor functional outcome in non-T2DM patients (adjusted relative risk 0.71, 95% CI 0.57-0.90; p = 0.004), but no benefit in those with newly diagnosed T2DM or those with a history of T2DM (p for interaction = 0.003). There was no glycemic status by treatment interaction for risk of bleeding or composite vascular event. CONCLUSIONS:Patients without T2DM derived greater benefit in functional outcomes from immediate-intensive statin after ischemic stroke than those with T2DM.

Patients with established cardiovascular disease (CVD) may have a higher risk of recurrent stroke and a higher prevalence of antiplatelet resistance than those without CVD. This study investigated the efficacy and safety of dual antiplatelet therapy (DAPT) with clopidogrel plus aspirin in patients with established CVD. This is a secondary post hoc analysis of the Intensive Statin and Antiplatelet Therapy for Acute High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial. Patients with mild ischemic stroke (IS) or high-risk transient ischemic attack (TIA) of presumed atherosclerotic cause were randomized to receive either DAPT or aspirin alone within 72 h after symptom onset. Established CVD was defined as a prior diagnosis of IS, coronary artery disease, TIA, or peripheral arterial disease. The primary efficacy and safety outcomes were the occurrence of new stroke and moderate-to-severe bleeding within 90 days. This study included 6100 patients, with a mean age of 63.7 ± 9.6 years and 35.8% of female. DAPT was associated with a reduced risk of new stroke (hazard ratio [HR] = 0.67, 95%CI: 0.54–0.85, P < 0.001) in non-CVD patients but not in those with established CVD (HR = 0.97, 95%CI: 0.73–1.28, P = 0.82), compared with aspirin (P for interaction = 0.04). Moderate-to-severe bleeding did not differ by antiplatelet treatments across CVD subgroups (P for interaction = 0.32). In the INSPIRES trial, patients with established CVD may benefit less from clopidogrel–aspirin in reducing the risk of recurrent stroke within 90 days than those without CVD after mild IS or high-risk TIA. Trial registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03635749.

Background:Prior studies have linked the microbiota to brain diseases, whereas the longitudinal effects of the oral microbiota on cortical thinning and cognitive impairments in cerebral small vessel disease (CSVD) remain unexplored. Methods:We recruited 120 CSVD patients and 40 healthy controls (HCs). The subgingival plaque microbiota was sequenced by a metagenomic approach. Cortical thickness was assessed using GM-centile, an age- and sex-normalized MRI metric. Differential microbial taxa and KEGG orthologs (KOs) between groups were identified using MaAsLin2. Associations between key differential taxa with CSVD-specific cortical thinning were examined using the Spearman test, and those with MoCA score and plasma inflammatory markers (CRP and lymphocyte counts) were examined by linear regression models. Mediation models evaluated the indirect role of cortical thinning in the relationship between microbial abundance and cognitive function. Generalized estimation equations validated the longitudinal effects of the microbiota on cortical thinning progression. Result:We identified distinct oral microbiota dysbiosis in CSVD, including depletion of g_Selenomonas and g_Leptotrichia and enrichment of g_Treponema. The abundance of these microbes was correlated with longitudinal cortical thinning in the frontal gyrus, insular lobes, and inferotemporal gyrus. Enrichment analysis revealed that CSVD-enriched KOs were linked to the upregulation of LPS-mediated pro-inflammatory pathways, while those depleted were associated with the reduced biosynthesis of neuroprotective short-chain fatty acids (SCFAs). g_Leptotrichia abundance showed negatively correlation with CRP (p = 0.045). Mediation analyses indicated that the association between g_Leptotrichia depletion and baseline cognitive impairment was mediated by bilateral insular cortical thinning (both p < 0.05). Additionally, the association between g_Leptotrichia depletion and one-year cognitive decline was mediated by superior frontal cortical thinning (p = 0.033). Conclusions:Oral microbiota dysbiosis in CSVD patients reflects a pro-inflammatory state, characterized by enhanced LPS synthesis and reduced SCFAs production. This dysbiosis is associated with CSVD-specific cortical thinning in regions vulnerable to neuroinflammation, which in turn mediates cognitive impairment.

Purpose:To investigate the associations between retinal parameters and cognitive impairment and identify retinal biomarkers for detecting cognitive dysfunction in patients with cerebral small vessel disease (CSVD). Methods:This cross-sectional study enrolled 125 patients with CSVD-related white matter hyperintensities. Participants were independent in daily activities and free of significant ophthalmic diseases. Cognition was assessed using the Mini-Mental State Examination (MMSE). Multimodal retinal imaging was employed to evaluate retinal structural and vascular features, including peripapillary retinal nerve fibre layer (pRNFL) and ganglion cell complex thicknesses and vessel densities (VDs) of the radial peripapillary capillary (RPC) network, macular superficial retinal capillary plexus (SRCP), and deep RCP (DRCP). The central retina vascular diameter, mean angle, angle tortuosity, arc length tortuosity, and fractal dimension of the retinal arteries and veins were quantified using a fully automated vessel segmentation and parameter calculation method. Linear and logistic regression models were applied to assess the associations between retinal parameters with general cognitive domains (general cognition, memory, visuospatial space, attention and numeracy, language, and orientation). Receiver operating characteristic (ROC) curves and areas under the ROC curve (AUCs) were used to evaluate the predictive performance of the retinal biomarkers. Results:A smaller central retinal arteriolar equivalent/central retinal venular equivalent ratio [odds ratio (OR) = 0.013, p = 0.035] and lower VDs in whole macular SRCP (OR = 0.864, p = 0.029), perifoveal SRCP (OR = 0.862, p = 0.027), perifoveal superior SRCP (OR = 0.855, p = 0.014), perifoveal nasal SRCP (OR = 0.833, p = 0.008), and inside-disc capillary RPC network (OR = 0.901, p = 0.028) were significantly associated with lower MMSE scores. Attention and orientation scores were significantly correlated with the VDs of the SRCP (β = 0.734, p = 0.027 and β = -9.460, p = 0.037, respectively) and DRCP (β = -0.553, p = 0.004 and p = 0.044, respectively), whereas visuospatial and language function scores were associated with the VD of the inside-disc RPC network (β = 0.018, p = 0.026 and β = 0.068, p = 0.012, respectively). The VDs of the whole macular, perifoveal, perifoveal superior, and nasal SRCPs achieved AUCs of 0.71-0.74 for screening cognitive impairment. Conclusion:Specific retina parameters are associated with cognitive decline in patients with CSVD. These findings suggest that multimodal retinal evaluation might provide an objective, imaging-based adjunct to conventional subjective cognitive tests for screening cognitive impairment in patients with CSVD. Clinical trial registration:https://www.chictr.org.cn/, identifier ChiCTR 2100043346.

BACKGROUNDS:White matter hyperintensities (WMH), a marker of cerebral small vessel disease, are associated with cardiovascular risk factors and disease. However, the extent to which these associations are driven by shared genetic architecture remains unclear. METHODS:Using data from 44 996 UK Biobank participants, we evaluated associations between WMH subtypes (total WMH, deep WMH, and periventricular WMH) and polygenic risk scores (PRSs) for 35 diseases and traits. Associations were tested using χ2 and multivariable linear regression models. Cox models assessed whether WMH burden modified cardiovascular risk across genetic risk strata. Multiomics data were examined to identify biomarkers jointly associated with WMH and disease-specific PRSs. RESULTS:Higher WMH burden was associated with increased PRSs for cardiovascular disease (CVD), hypertension, ischemic stroke, and blood pressure, with the strongest associations observed for total WMH. WMH burden was prospectively associated with higher CVD incidence among individuals with high CVD PRS (hazard ratio, 2.54 [95% CI, 1.44-4.45]), but not among those with low PRS. For hypertension, WMH burden was associated with increased risk in both PRS strata, with stronger associations in individuals with high hypertension PRS, indicating additive contributions of genetic susceptibility and WMH burden. Lifestyle influences varied by genetic background: longer sleep duration and lower body mass index were protective only with low CVD PRS. Multiomics analyses identified 46 circulating biomarkers jointly associated with WMH and CVD PRSs, predominantly related to lipid metabolism. CONCLUSIONS:The association between WMH burden and cardiovascular-related disease risk is influenced by genetic background, supporting precision risk stratification and prevention in clinical practice.

Metabolic dysfunction-associated steatohepatitis (MASH) is a systemic metabolic disease involving coordinated alterations across multiple organs. Here, we established a diet-induced murine model of MASH and performed integrated transcriptomic, proteomic, and metabolomic profiling across seven metabolic tissues and the circulation, encompassing the liver, white and brown adipose tissues, skeletal muscle, gallbladder, pancreas, and plasma. Multi-omics analyses identified coordinated molecular changes across tissues, including altered immune, metabolic, and fibrotic programs. Metabolomic profiling further revealed widespread changes in lipid and amino acid metabolism, together with altered gut-derived metabolites in tissues and plasma. Several candidates showing concordant transcript and protein changes in mouse tissues, particularly in the liver, were also supported by independent human liver datasets. This study provides a multi-tissue, multi-omics resource for diet-induced MASH and offers a framework for investigating molecular interactions among metabolically connected organs.

BACKGROUND:Patients with different hypertension status could potentially respond differently to the treatment of clopidogrel-aspirin owing to thrombosis, antiplatelet resistance, and platelet reactivity. AIMS:The aim of the study is to examine the efficacy and safety of clopidogrel-aspirin in patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) according to different hypertension status. METHODS:In the Intensive Statin and Antiplatelet Therapy for Acute High-Risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial, patients were randomized to either clopidogrel-aspirin or aspirin group. The primary outcome was any new ischemic or hemorrhagic stroke within 90 days. Hypertension status was classified into two categories based on medical history: patients with or without hypertension. RESULTS:Among 6100 patients with complete data of hypertension status, 3915 (64.2%) were men. Clopidogrel-aspirin compared with aspirin was associated with reduced incidence of new stroke in patients without hypertension (hazard ratio (HR): 0.62, 95% confidence interval (CI): 0.44-0.86, p = 0.004), but not in patients with hypertension (HR: 0.87, 95% CI: 0.71-1.07, p = 0.18; p = 0.085 for interaction). CONCLUSIONS:In this study, patients without hypertension may have more benefit from receiving treatment with clopidogrel-aspirin than those with hypertension. This finding can be used as an enrichment strategy in the future secondary stroke prevention randomized clinical trials of dual antiplatelet therapy. TRIAL REGISTRATION:The INSPIRES trial was registered at http://www. CLINICALTRIALS:gov (unique identifier: NCT03635749).

ObjectiveTo explore the key genes of ferroptosis involved in renal tubulointerstitium of diabetic kidney disease （DKD） and its clinical relevance by bioinformatics analysis.MethodsDKD and non-DKD datasets of renal tubulointerstitial tissue were obtained to identify differentially expressed genes （DEGs）， and DKD-specific ferroptosis-related genes. Functional enrichment and protein-protein interaction network （PPI） analyses were conducted. After screening key genes， clinical correlation analysis and quantitative real-time PCR （qPCR） were performed for validation. The relationship between key genes and immune microenvironment was explored.ResultsA total of 37 ferroptosis-associated DEGs in DKD were screened， and they were mainly enriched in metabolic， lipid peroxidation， and inflammatory response signaling pathways. Among the 37 ferroptosis-related genes， 5 genes （PTEN， VEGFA， HSPA5， MAPK8， CD44， ATM） were identified as DKD-specific ferroptosis-associated genes. qPCR showed that the mRNA level of PTEN was significantly up-regulated and that of VEGFA was significantly down-regulated in high glucose-treated human kidney proximal tubular epithelial （HK-2） cells. Nephroseq data showed that the mRNA expression level of VEGFA was positively correlated with glomerular filtration rate （GFR）， and the Person correlation coefficient （r value） was 0.67 （P<0.05）. It was negatively correlated with urinary protein and serum creatinine， with the r value of -0.79 （P<0.05）. The mRNA levels of HSPA5 and PTEN were negatively correlated with GFR in DKD patients， with r values of -0.60 and -0.90， respectively （P<0.05）. The mRNA level of ATM was positively correlated with serum creatinine， with the r value of 0.53 （P<0.05）. The mRNA level of VEGFA was positively correlated with memory T cells， with the r value of 0.69 （P<0.05）.ConclusionsVEGFA and PTEN may be specific molecules involved in ferroptosis in DKD， and may participate in the occurrence and development of DKD via regulating lipid metabolism， oxidative stress， and inflammatory response.

Rosuvastatin (RVS) is an HMG-CoA reductase inhibitor with lipid-lowering properties. This study aims to investigate the role of RVS in plaque formation in atherosclerosis (AS) and its functional mechanism. ApoE-/- mice were fed a high-fat diet to generate a mouse model of AS. RVS treatment reduced serum levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol in atherosclerotic mice, alleviated oxidative stress, and ameliorated lipid deposition, plaque formation, and fibrosis in the mouse aortic tissues. In vitro, it reduced reactive oxygen species and suppressed the proliferation and migration of oxidized low-density lipoprotein-challenged human vascular smooth muscle cells (HVSMCs). REST corepressor 1 (RCOR1) was identified as a target protein upregulated by RVS. It was found to repress transcription of decidual protein induced by progesterone 1 (DEPP1/C10ORF10) by binding to its promoter. Silencing of RCOR1 negated the AS-ameliorating effects of RVS in mice and HVSMCs. However, the AS-like symptoms in mice and HVSMC activity were suppressed by the additional C10ORF10 silencing. In conclusion, this study demonstrates that RVS alleviates oxidative stress and reduces atherosclerotic plaque formation by increasing RCOR1-mediated transcriptional repression of C10ORF10.

Cerebral small vessel disease (CSVD) is a common condition among the elderly population. In patients with CSVD, imaging markers, motor function, and cognition are closely interrelated. This study aimed to analyze the effect of cognition on the association between CSVD burden and motor function. This cross-sectional study included 134 patients with CSVD, recruited from the China Imaging-based Biobank of Cerebral Small Vessel Diseases (CIBB-CSVD) at Beijing Tiantan Hospital between January 2020 and May 2023. We obtained demographic and medical profiles, as well as the Montreal Cognitive Assessment (MoCA) score, Short Physical Performance Battery (SPPB) score, a four-point CSVD burden score determined through magnetic resonance imaging (MRI), and gait parameters evaluated using the Codamotion analysis system from all participants. The mean age of all CSVD patients was 60 ± 12 years. The median scores for the CSVD burden, MoCA, SPPB and modified Rankin Scale (mRS) were 3 (2, 4), 20 (16, 24), 11 (9, 12) and 0 (0, 1), respectively. Significant correlations were observed between age and the CSVD burden score, MoCA score, SPPB score, speed, and stride length (P < 0.05). Patients with higher CSVD burden scores exhibited significantly lower SPPB scores, reduced speed, shorter stride length, and decreased hip and knee range of motion (ROM), as revealed by both univariable linear regression and multivariable regression analyses adjusted for age (P < 0.05). However, after further adjustment for MoCA score, only the association between CSVD burden score and SPPB score remained statistically significant (P < 0.05). Mediation analysis indicated that the MoCA score significantly mediated the associations between CSVD burden score and both SPPB score and knee ROM. The proportion of the effect mediated by the MoCA score was 33.835

OBJECTIVE:The objective was to investigate the efficacy and safety of clopidogrel-aspirin versus aspirin alone in patients after ischemic stroke by glycemic status using data from the Intensive Statin and Antiplatelet Therapy for Acute High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial. METHODS:Patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) were randomized to clopidogrel-aspirin or aspirin alone. They were categorized into 3 subgroups according to glycemic status based on medical history and diagnosis by a clinician during hospitalization: without type 2 diabetes mellitus, with newly diagnosed type 2 diabetes, and with a history of type 2 diabetes mellitus. The primary efficacy and safety outcomes were new stroke and moderate-to-severe bleeding risk within 90-day follow-up. RESULTS:A total of 6,100 patients were enrolled (3,050 in each arm), with a median age of 65 years (interquartile range [IQR], 57-71) and 2,185 female (35.8%). Clopidogrel-aspirin treatment was associated with a reduction in recurrent stroke compared with aspirin alone in patients without type 2 diabetes mellitus (6.3% vs 8.4%; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.59-0.94; p = 0.01) and those with newly diagnosed type 2 diabetes mellitus (5.8% vs 13.0%; HR, 0.30; 95% CI, 0.14-0.66; p = 0.002), but not in those with a history of type 2 diabetes mellitus (10.0% vs 9.9%; HR, 0.98; 95% CI, 0.72-1.33; p = 0.88) (p for interaction = 0.03). Moderate-to-severe bleeding events did not differ significantly by treatment across glycemic subgroups. INTERPRETATION:In the INSPIRES trial, patients without or with type 2 diabetes mellitus derived greater benefit from clopidogrel-aspirin than those with a history of type 2 diabetes mellitus after mild ischemic stroke or high-risk TIA. TRIAL REGISTRATION:INSPIRES, NCT03635749. Registered 15 August 2018, https://clinicaltrials.gov/search?cond=NCT03635749. ANN NEUROL 2025;98:174-182.

Background Previous studies have shown that obesity is associated with an increased risk of various cardiovascular diseases. The Body Roundness Index (BRI) is a novel indicator for assessing body fat and visceral fat. However, the relationship between BRI and all-cause and cardiovascular mortality in individuals with hypertension remains unclear. This study aims to investigate the association between BRI and all-cause and cardiovascular mortality among US adults with hypertension. Methods This study utilized data from the National Health and Nutrition Examination Survey (NHANES) (1999–2018). The study population consisted of 20,532 hypertensive adults. Cox proportional hazards models were used to assess the association between BRI and all-cause and cardiovascular mortality. A generalized additive model were employed to evaluate potential nonlinear relationships between BRI and mortality. Results Among the 20,532 hypertensive adults (mean age: 59.5 ± 15.9 years), a total of 5,044 (25.4%) participants died during follow-up. BRI exhibited a U-shaped association with all-cause mortality, with an inflection point at 5.09. Below the inflection point, each unit increase in BRI was associated with a decreased risk of all-cause mortality (HR = 0.82, 95% CI: 0.79–0.86, P < 0.0001); above the inflection point, each unit increase in BRI was associated with an increased risk (HR = 1.05, 95% CI: 1.04–1.07, P < 0.0001). A similar U-shaped relationship was observed for cardiovascular mortality, with an inflection point at 4.97 (HR = 0.87 [0.80, 0.94], P = 0.0006 below the inflection point; HR = 1.23 [1.12, 1.36], P < 0.0001 above the inflection point). After adjusting for age, sex, race, and education level, both the lowest and highest BRI tertiles were associated with higher all-cause mortality. Conclusion Among US adults with hypertension, BRI demonstrates a U-shaped relationship with all-cause and cardiovascular mortality. Further research is needed to validate these findings.

BACKGROUND:The aim of this study was to investigate the clinical outcomes of clopidogrel-aspirin therapy initiated between 24 and 72 hours from the symptom onset among patients with minor stroke or transient ischemic attack stratified by CYP2C19 loss-of-function allele status. METHODS:This was a prespecified secondary analysis of the INSPIRES trial (Intensive Statin and Antiplatelet Therapy for Acute High-Risk Intracranial or Extracranial Atherosclerosis), which was a randomized clinical trial conducted across 222 centers in China from September 2018 to October 2022. Two loss-of-function alleles (CYP2C19*2, CYP2C19*3) and 1 gain-of-function allele (CYP2C19*17) were genotyped in the INSPIRES study. Patients with CYP2C19 loss-of-function allele carriers were patients with either CYP2C19*2 or CYP2C19*3. All participants were randomized to receive clopidogrel-aspirin or aspirin treatment, and those started treatment between 24 and 72 hours from the symptom onset were included in this study. The primary efficacy outcome was new stroke within 90 days. The primary safety outcome was moderate-to-severe bleeding. Cox proportional hazards models were performed to estimate the interaction between treatment assignment and CYP2C19 loss-of-function allele status for the primary outcomes. RESULTS:Among 5003 patients, 2911 (58.2%) patients were loss-of-function carriers, and 2092 (41.8%) patients were noncarriers. Relative to aspirin alone, clopidogrel-aspirin reduced the rate of new stroke in the noncarriers (hazard ratio, 0.67 [95% CI, 0.49-0.91]; P=0.01) but not in the carriers (hazard ratio, 0.96 [95% CI, 0.73-1.25], P=0.74; P=0.09 for interaction). For the safety outcome, moderate-to-severe bleeding did not vary significantly between the carriers (hazard ratio, 1.83 [95% CI, 0.68-4.95]; P=0.23) and noncarriers (hazard ratio, 2.07 [95% CI, 0.62-6.88], P=0.23; P=0.88 for interaction). CONCLUSIONS:Clopidogrel-aspirin treatment presented a priority to aspirin in reducing the risk of new stroke in CYP2C19 loss-of-function noncarriers when administered between 24 and 72 hours after stroke onset. These findings supported the necessity of CYP2C19 genotyping in the choice of antiplatelet therapy with an extended treatment window to 72 hours. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03635749.