[This corrects the article DOI: 10.3389/fphar.2021.642925.].

Background Transcranial magnetic stimulation (TMS) is an effective therapy for patients with Alzheimer’s Disease (AD), potentially modulating aberrant functional connectivity. Electroencephalography (EEG) microstates represent transient large-scale resting networks and have emerged as candidate markers for AD. However, their modulation by repetitive TMS (rTMS) and intermittent theta burst stimulation (iTBS) protocols remains to be elucidated. Methods Resting-state EEG was recorded from 28 AD patients at baseline and following the 1st, 7th, and 14th sessions of rTMS or iTBS treatment. Polarity-insensitive modified k-means clustering was used to segment EEGs into constituent microstates, which were then subjected to source localization to identify their corresponding cortical regions. Longitudinal changes within subjects in clinical status and microstate parameters (duration, occurrence, coverage, transition probability) were evaluated with one-way repeated-measures analysis of variance, and differences between rTMS and iTBS groups were assessed using t-tests. Results Four microstates (MS A-D) were identified from EEG data. rTMS predominantly induced sustained suppression of MS-B, whereas iTBS elicited early-phase increases in MS-C activity. Clinical symptoms improvement following TMS correlated with increased MS-C and decreased MS-B activity. Source localization revealed rTMS predominantly modulated MS-B generators in the occipital cortex (impacting visual and dorsal attention networks), while iTBS preferentially engaged MS-C generators in the parietal cortex (affecting sensorimotor and frontoparietal networks). Conclusions We identified distinct EEG microstates and their underlying cortical generators associated with clinical improvement in AD following treatment with rTMS and iTBS protocols. The results demonstrate protocol-specific spatiotemporal modulation profiles and temporal dynamics, highlighting differential neural mechanisms of rTMS and iTBS.

Background Cerebral amyloid angiopathy (CAA) is associated with a high risk of recurrence of intracerebral hemorrhage (ICH). This study aimed to identify risk factors of CAA-related ICH recurrence, especially focused on CAA-characteristic neuroimaging markers.Methods Consecutive survivors of spontaneous lobar ICH for probable CAA, possible CAA, and mixed cerebral small vessel disease (CSVD) were enrolled at Tianjin Huanhu Hospital between 2017 and 2024. Baseline clinical data and magnetic resonance imaging (MRI) findings were collected. Posterior confluent white matter hyperintensities (WMH-PC), which means WMHs predominantly posterior to the ventricular horns, extending more than 5 mm in the deep white matter. Other MRI features included multispot white matter hyperintensities (WMH-MS), cortical superficial siderosis (cSS), perivascular spaces (PVS), and acute convexity subarachnoid hemorrhage (cSAH) in the present study. Participants were prospectively followed for recurrent symptomatic ICH or death. Kaplan-Meier and Cox-regression models were used to assess associations with ICH recurrence risk.Results The cohort included 254 survivors of spontaneous ICH, with median age of 68.5 years (interquartile range [IQR]: 63.0-76.0) and 63.0% male. WMH-PC was present in 124 patients (48.8%). Hundred and seventy patients (66.9%) were probable CAA-related ICH. Over a median follow-up period of 20.0 months (IQR: 8.0-38.0), 53 patients (20.9%) experienced recurrent ICH. In the probable CAA-related ICH group, WMH-PC (adjusted hazard ratio [aHR]: 2.548; 95% confidence interval [CI]: 1.251-5.193); cSS (aHR: 2.340; 95% CI: 1.126-4.860); and CSO-PVS (aHR: 2.751; 95% CI: 1.219-6.207) were associated with increased risk of ICH recurrence; after adjusted for the MRI features, only CSO-PVS (aHR: 2.278; 95% CI: 1.075-4.828) remained independently associated with an increased risk of ICH recurrence. The effect of combined WMH-PC and cSS on the recurrence of ICH in cases of probable CAA was synergistic (aHR: 3.160; 95% CI: 1.579-6.325).Conclusions WMH-PC, cSS and CSO-PVS are risk factors associated with ICH recurrence and WMH-PC in combination with cSS demonstrates a synergistic effect on increased ICH recurrence risk in patients with probable CAA.

Background:Growing evidence suggests that both ApoE genotype and metabolic disturbances including insulin resistance (IR) and obesity constitute risk factors for Alzheimer's disease (AD). However, large-scale studies investigating whether ApoE genotype interacts with metabolic abnormalities to indirectly impair cognitive function in AD remain scarce. Objective:This cross-sectional study aimed to explore the associations between ApoE genotype, metabolic disturbances [IR assessed by triglyceride-glucose (TyG) index and body mass index (BMI)], and cognitive function in AD patients. Methods:We analyzed 1,162 clinically diagnosed probable AD patients from the Cognitive Impairment Clinic at Tianjin Huanhu Hospital. Participants were categorized by ApoE ε4 carrier status. Metabolic parameters were evaluated using the TyG index and BMI. Mediation effect models were employed to assess the relationships between ApoE genotype, metabolic indices, and cognitive function. Results:ApoE ε4 carriers exhibited significantly lower BMI (P < 0.001) and higher TyG index (P < 0.001) compared to non-ApoE ε4 carriers. Significant TyG index elevation in ApoE ε4 carriers was observed in AD patients with Mini-Mental State Examination (MMSE) > 20 (P = 0.0036) and MMSE 10-20 (P = 0.009). Mediation analysis revealed that ApoE ε4 exerted 73.4% of its negative effect on cognition through direct pathways, while 9.7 and 16.9% were mediated through BMI reduction and TyG elevation, respectively. Conclusion:ApoE ε4 carriers demonstrate a distinct metabolic profile characterized by lower BMI and elevated TyG index, associated with poorer cognitive performance. Our findings suggest that ApoE ε4 may indirectly influence AD cognition through metabolic pathways, highlighting early interventions targeting ApoE-related metabolic dysregulation as potential strategies to delay AD progression.

BACKGROUND:The Frailty Index of Cumulative Deficits (FI-CD) is a key predictor of adverse health outcomes in older adults, but its utility for cross-study comparisons is limited due to assumptions of item homogeneity. METHODS:We constructed a Frailty Index based on Item Response Theory (FI-IRT) in frailty measures, including 51 health-related variables, in older adults from the China Health and Retirement Longitudinal Study (CHARLS) 2011-2020, the Health and Retirement Study (HRS) 2010-2020, and the Survey of Health, Aging, and Retirement in Europe (SHARE) 2010-2020. A two-parameter logistic (2PL) model estimated FI-IRT scores, and Cox/logistic regression assessed its associations with mortality. Several analyses tested its robustness to the variable set and population selection. RESULTS:The FI-IRT followed a slightly right-skewed, approximately normal distribution, with frailty prevalence of 16.3% (CHARLS), 28.5% (HRS), and 15.5% (SHARE). The FI-IRT showed a high level of agreement with the FI-CD, both on a continuous scale and a hierarchical scale. A higher FI-IRT was associated with an increased risk of all-cause mortality across all 3 cohorts (hazard ratios: 1.81-2.38, p < .001). When domain-specific variables were excluded, the FI-IRT continued to offer relatively stable estimations (intraclass correlation coefficient: 0.934; 95% CI, 0.933-0.934; p < .001). A high degree of consistency was observed between the FI-IRTs calculated from models constructed based on different subpopulations (Spearman's rank correlation coefficients: 0.971-0.999, p < .001; intraclass correlation coefficient: 0.945; 95% CI, 0.850-0.972; p < .001). CONCLUSIONS:The FI-IRT provides a useful, robust, and cross-study comparable measure of frailty.

BackgroundEmerging evidence supports the clinical utility of music therapy for Alzheimer's disease (AD), yet robust clinical evidence remains limited.ObjectiveThis study aimed to systematically evaluate the multidimensional effects of music therapy on individuals with AD and to identify optimal intervention parameters and cumulative duration thresholds to guide clinical implementation.MethodsWe conducted a systematic review using RevMan 5.4, analyzing 24 randomized controlled trials (n = 2316) from Chinese and English databases up to January 2025.ResultsCompared to controls, music therapy significantly improved cognition (MD = 2.14, 95%CI = 0.88∼3.41, p = 0.0009), reduced neuropsychiatric symptoms (SMD = -0.55, 95%CI = -0.99∼-0.12, p = 0.01) and anxiety (MD = -4.37, 95%CI = -6.68∼-2.06, p = 0.0002), enhanced quality of life (SMD = 0.51, 95%CI = 0.02∼1.01, p = 0.04), and alleviated caregiver burden (SMD = -0.75, 95%CI = -0.94∼-0.55, p < 0.00001). The optimal regimen involved: frequency >3 sessions/week (p = 0.002), duration <40 min/session (p = 0.03), and intervention period ≥12 weeks (p = 0.002). A staged care model progressing from individual to group-based approaches is recommended (all p < 0.05). Minimum cumulative intervention durations for symptom improvement were: ≥1440 min for quality of life, ≥1800 min for behavioral and psychological symptoms, and ≥3360 min for cognition (all p < 0.05).ConclusionsMusic therapy demonstrates multidimensional benefits for persons living with AD, with distinct cumulative dose thresholds required for improving specific clinical symptoms, providing valuable guidance for clinical practice.

This study aimed to investigate the expression and prognostic significance of genes associated with copper-induced cell death in glioblastoma multiforme (GBM). Using a suite of bioinformatics tools and databases, the researchers analyzed gene expression, survival rates, and immune infiltration in GBM. Complementary in vitro experiments were performed to evaluate the effects of LIPT1 inhibition on GBM cell behavior in the context of copper-induced cell death. The team further explored upstream mechanisms leading to LIPT1 overexpression in GBM, specifically focusing on transcription factors and the role of ubiquitination degradation. The findings indicated a significant upregulation of LIPT1 in GBM, correlating with increased sensitivity to copper-induced cell death. Inhibition of LIPT1 was observed to exacerbate malignant behaviors in GBM cells post-copper exposure. Subsequent analysis pinpointed three transcription factors—CBX3, E2F6, and GTF2B—as regulators of LIPT1. Notably, GTF2B was also found to be co-expressed with LIPT1 and positively associated with recurrence-free survival in patients. ChIP-seq data analysis revealed significant GTF2B binding peaks near the LIPT1 promoter. Further exploration using UbiBrowser 2.0 identified E3 ubiquitin ligases that potentially target GTF2B, with RBX1 emerging as a viable anti-cancer target in GBM. Data from the UALCAN database showed a notable decrease in RBX1 protein expression in GBM tissues. Moreover, several ubiquitination modification sites were detected on the GTF2B protein. In conclusion, the study proposes a novel scientific hypothesis: RBX1 inhibits LIPT1 transcription by promoting the ubiquitin-mediated degradation of GTF2B, thereby suppressing copper-induced cell death in GBM cells. These findings offer new insights into the molecular mechanisms governing copper death sensitivity in GBM and identify potential therapeutic targets for further exploration.

Alzheimer's disease (AD) is associated with impaired connectivity in critical functional networks. This study investigated the effects of 20 Hz transcranial magnetic stimulation (TMS) on brain network mechanisms in 25 patients with AD, including 17 in the TMS group and 8 in the sham group. We analyzed resting-state functional magnetic resonance imaging data, using the amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) to quantify neural activity and identify regions of interest. Subsequently, changes in static and dynamic functional connectivity were analyzed based on these regions. The results showed that: (1)In the TMS group, significant increases in ALFF/fALFF were observed specifically in the right dorsolateral superior frontal gyrus (SFGdor.R) and the left anterior cingulate gyrus (ACG.L); (2)Enhanced static functional connectivity between the SFGdor.R and the right middle temporal gyrus was positively correlated with improvements in Montreal Cognitive Assessment scores, while reduced static functional connectivity between the ACG.L and the left inferior temporal gyrus was associated with gains in Boston Naming Test scores; (3)Improvements in both Montreal Cognitive Assessment scores and Mini Mental State Examination scores were linked to decreased dynamic functional connectivity variability between the ACG.L and the middle occipital gyrus. These findings suggest that TMS improves cognitive and behavioral performance in patients with AD through multiscale regulatory effects, and that this improvement may be associated with alterations in functional integration among brain regions as well as reduced variability of abnormal network dynamics, providing new insights into the mechanism of action of TMS in AD.

AIMS:Adverse ventricular remodeling following myocardial infarction contributes to heart failure. Following cardiac injury, quiescent fibroblasts trans-differentiate into myofibroblasts and produce extracellular matrix proteins to initiate ventricular remodeling. We investigated the role of Suv39h1, a lysine methyltransferase, in this process. METHODS:Myocardial infarction was induced by permanent ligation of the left anterior descending (LAD) coronary artery. RESULTS:Suv39h1 expression was up-regulated in cardiac fibroblasts isolated from mice subjected to the LAD procedure compared to the sham procedure mirroring the induction of Periostin, a myofibroblast marker. Reporter assay and chromatin immunoprecipitation (ChIP) assay showed that C/EBPβ was recruited to the Suv39h1 promoter to mediate Suv39h1 trans-activation by pro-fibrogenic stimuli in fibroblasts. Genetic deletion of Suv39h1 from either quiescent fibroblasts or activated fibroblasts (myofibroblasts) in mice attenuated cardiac fibrosis and rescued the decline of heart function following myocardial infarction. Importantly, administration of a small-molecule Suv39h1 inhibitor F5446 ameliorated cardiac fibrosis and partially normalized heart function in mice following myocardial infarction. RNA-seq identified several potential Suv39h1 targets that might contribute to fibroblast-myofibroblast transition. SIGNIFICANCE:In conclusion, our data demonstrate that Suv39h1 might play an important role regulating ventricular remodeling in ischemic cardiomyopathy.

Alzheimer’s disease (AD) is a prevalent degenerative neurological disorder with limited treatment options. Prior studies reported specific metabolites and inflammatory proteins to be related to AD risk. However, the intricate relationship between inflammatory proteins, blood metabolites, and AD risk in European population remains unclear. Genetic instruments for 1,091 metabolites and 736 inflammatory proteins were derived from two recent comprehensive genome-wide association studies. Univariable Mendelian Randomization was employed to assess potential causal effects of metabolites on AD risk, potential effects of inflammatory proteins on metabolites, and effects of inflammatory proteins on AD risk. Multivariable MR (MVMR) was further applied to disentangle direct effects of proteins and metabolites on AD. Twelve metabolites were identified to be associated with AD risk, and 226 inflammatory proteins demonstrated likely to be causal effects on these 12 metabolites. Further examining the associations between such inflammatory proteins and AD risk revealed 22 associations for which the effect directions from inflammatory proteins to metabolites, from metabolites to AD risk, and from inflammatory proteins to AD risk were aligned, suggesting inflammatory protein - metabolite - AD risk pathway. MVMR further highlighted four trios in which the effect directions were consistent with the UVMR results, supporting a metabolite‑mediated pattern. This large‑scale genetic analysis highlights specific metabolites as direct contributors to AD risk and suggests that certain inflammatory proteins may influence AD primarily through downstream metabolic pathways. Our findings offer potential novel therapeutic targets for AD intervention.

INTRODUCTION:We evaluated lecanemab's safety and cognitive outcomes in Chinese patients with Alzheimer's disease (AD) and the utility of blood-based biomarkers (BBMs) for treatment guidance. METHODS:A multicenter, real-world cohort enrolled 1042 patients receiving lecanemab, with 453, 359, 97 patients followed up at 3, 6, 12 months, respectively. Safety outcomes included amyloid-related imaging abnormalities (ARIA) and infusion-related reactions (IRRs), and the main clinical outcome was Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score change. RESULTS:Of 1,042 patients, ARIA occurred in 7.87%, and IRRs in 16.12%. Discontinuation was 16.51%, mainly due to financial burden. CDR-SB did not change at 12 months overall or in any subgroup. High-accuracy BBMs were the sole AD biomarker assay in 5.28%, with comparable outcomes. DISCUSSION:Lecanemab exhibited favorable 12-month safety, with no clear evidence of cognitive decline, and BBMs hold potential for treatment guidance. Further studies using a control group are now warranted.

Spontaneous intracerebral hemorrhage (ICH) is a highly lethal and disabling form of stroke, in which hematoma expansion (HE) is a major and potentially modifiable determinant of early neurological deterioration and poor functional outcome. Computed tomography (CT) remains the first-line imaging modality for acute ICH and provides essential information for early HE risk stratification. However, current evidence is dispersed across conventional CT signs, composite scores, radiomics, machine learning, and deep learning approaches, many of which have been reported descriptively without sufficient comparison of clinical utility, validation quality, or translational readiness. This review critically evaluates CT-based prediction of HE and adverse outcomes after spontaneous ICH. We compare contrast-enhanced markers, including the spot sign, leakage sign, and iodine sign, with non-contrast CT markers such as the blend sign, black hole sign, island sign, satellite sign, hypodensity sign, swirl sign, hematoma shape, and density heterogeneity, focusing on sensitivity, specificity, reproducibility, availability, and clinical applicability. We further assess composite prediction models and artificial intelligence approaches, emphasizing limitations related to small cohorts, overfitting, dataset heterogeneity, insufficient external validation, interpretability, and workflow integration. Given the scope of GeroScience, we also discuss how vascular aging, cerebral amyloid angiopathy, frailty, anticoagulant exposure, and age-associated vulnerability to secondary injury may influence HE risk and outcome prediction. Future progress will require interpretable, multimodal, prospectively validated models that integrate CT imaging, clinical variables, biomarkers, and aging-related factors to support individualized management of ICH.

BACKGROUND:Health recommender systems offer new opportunities to meet the personalized needs of people with dementia and their caregivers, but evidence on their effectiveness remains limited. OBJECTIVE:This study aimed to evaluate the effectiveness of a mobile application-based dementia care intelligent recommender system (DCIRS) among caregivers of people with dementia. METHODS:We conducted a RCT among family caregivers of people with dementia in China. Participants were randomly assigned to either the intervention group or a waitlist control group (n = 125 per group). Caregivers in the control group received no intervention during the study period, whereas those in the intervention group received access to a remote, mobile application-based DCIRS. Outcomes were assessed at baseline (T0), week 6 (T1), and week 12 (T2). The outcomes included distress related to care problems, caregiver burden, depressive symptoms, and the occurrence of safety-related events. Generalized estimating equations were used for analysis. RESULTS:The caregivers in intervention group showed significant reductions in distress scores for dressing, personal hygiene, communication, and behavioural and psychological care problems at both the 6th and 12th week assessments. Caregiver burden scores in the intervention group showed a continuous decline from baseline to week 6 (MD = -1.61) and further to week 12 (MD = -3.43) (P < .05). Within-group analyses showed that depressive symptom scores remained largely stable from baseline to week 6 and week 12 in both the intervention and control groups, with no significant pre-post changes detected. A significant between-group difference was found in the total number of safety-related events (P = .037). CONCLUSION:In summary, this RCT showed that the DCIRS may reduce caregivers' distress related to care problems and lessen caregiver burden. Although depressive symptoms did not improve significantly, further research is needed to assess long-term effects and clarify the mechanisms underlying remote, personalized interventions such as the DCIRS. REGISTRATION:The trial was registered at the Chinese Clinical Trials Registry (ChiCTR2200066087).

This article describes the cross‐cultural adaptation and psychometric testing of the Chinese version of the gains associated with caregiving (GAC) scale. This tool is designed to measure self‐reported gains experienced by caregivers of people with dementia. The adaptation process entailed back‐translation and validation by a committee of experts. Content validity was analyzed using the content validity coefficient, and construct validity was analyzed by exploratory factor analysis and confirmatory factor analysis. The reliability of the scale was evaluated by using Cronbach’s α coefficient and the test–retest reliability coefficient. With a cross‐sectional study design, we invited caregivers of people with dementia to complete the Chinese version of the GAC scale. Factor analysis suggested a four‐factor solution in which all 27 items were retained, accounting for 65.76% of the variance. Cronbach’s α was 0.968, and the test–retest reliability coefficient was 0.886. The Chinese version of the GAC scale appears to be a valid and reliable scale for assessing perceived gains among family caregivers of people with dementia.

BackgroundThe rapid increase in the global aging population poses a major public health challenge due to the prevalence of stroke. Constipation represents a significant complication of stroke, significantly impacting quality of life. The objective of this study is to investigate the incidence of constipation in acute stroke and to identify the factors that contribute to new-onset constipation (defined as constipation developing after stroke in patients with no prior history) after stroke.MethodsA total of 600 acute stroke patients were recruited for a cross-sectional study, with a questionnaire administered to each participant. This study included demographic characteristics, stroke type and focus, medical history, sleep quality, psychological problems, and the NIHSS and Barthel index (BI). Participants with constipation were evaluated for severity, medications, and stroke outcomes at discharge by the investigators.ResultsOf the 600 acute stroke patients, 126 (21%) reported a history of constipation. Furthermore, 278 patients (46.3%) demonstrated post-stroke constipation (PSC), while 184 patients (38.8%) experienced new-onset constipation following their stroke. The results indicated that hemorrhagic stroke, posterior circulation stroke, diabetes, osmotic diuretics, antacids, use of bedpans, Difficulty falling asleep, depression, and a higher NIHSS score at admission were significant risk factors for new-onset constipation. In patients demonstrating moderate severity, PSC correlated with adverse stroke outcomes at discharge.ConclusionThe incidence of constipation in acute stroke patients is higher than that in the general population. The results suggest that depression and Difficulty falling asleep may increase the risk of new-onset constipation. Moreover, after adjusting for confounders, new-onset constipation was independently associated with poor discharge outcome, particularly in patients with moderate stroke severity. Early identification of constipation risk in stroke patients can improve the development and optimization of rehabilitation protocols.Clinical trial registrationIdentifier ChiCTR2400080663.

Background:Post-stroke cognitive impairment (PSCI) is common and imposes a significant burden upon both families and society. There is limited information on biomarkers for PSCI. This study investigated the correlation between blood biomarkers and post-ischaemic stroke cognitive impairment, to identify potential blood biomarkers and their efficacy in predicting the disorder. Methods:This prospective study enrolled patients who had experienced their first acute ischaemic stroke between January 2024 and March 2025. Patients underwent blood tests within 24 h of admission, which measured plasma levels of Aβ1-40, Aβ1-42, glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), p-Tau181, p-Tau217, Aβ42/40, and p-Tau217/Aβ1-42. The cognitive function of the patients was assessed at the three-month follow-up visit using the Montreal Cognitive Assessment (MOCA) scale. Participants were divided into a cognitive impairment group and a cognitively normal group with a MoCA cutoff score of 22. Results:A total of 128 patients who had experienced a first ischaemic stroke were included in the analysis. At the three-month post-stroke follow-up, 69 patients (53.9%) were allocated to the PSCI group, with 59 patients (46.1%) in the cognitively normal group. After univariate and multivariate logistic regression analyses, plasma GFAP (OR = 1.0027, 95% CI = 1.0002-1.0053, p = 0.038) and plasma NFL (OR = 1.0046, 95% CI = 1.0006-1.0086, p = 0.025) were identified as independent risk factors for cognitive impairment following ischaemic stroke. Receiver operating characteristic (ROC) curves indicated area under the curve (AUC) values of 0.779 (95% CI = 0.700-0.858, p < 0.001) for plasma GFAP and 0.809 (95% CI = 0.733-0.885, p < 0.001) for plasma NFL, indicating good predictive performance for both parameters. The AUC for GFAP+NFL was 0.855 (95% CI = 0.792-0.918, p < 0.001), indicating superior predictive performance of the GFAP and NFL combination for PSCI post-ischaemic stroke cognitive impairment. Conclusion:Elevated plasma GFAP and NFL levels are associated with an increased risk of post-ischaemic stroke cognitive impairment. Plasma GFAP and NFL may represent potential biological markers for PSCI. The combination of the two parameters showed superior predictive efficacy for PSCI.

BACKGROUND:Despite successful mechanical thrombectomy (MT), approximately 50% of patients with large vessel occlusion (LVO) stroke experience poor outcomes due to reperfusion injury. Intra-arterial infusion of human serum albumin (HSA) may offer neuroprotective benefits; however, its safety and feasibility have not been established when delivered via the internal carotid artery. In this study we aimed to evaluate the safety and technical feasibility of HSA infusion through the guiding catheter placed during MT in patients with anterior circulation LVO stroke following successful reperfusion. METHODS:We conducted a prospective, single-center, open-label, pilot trial evaluating intra-arterial infusion of 20% HSA immediately after MT in patients with anterior circulation LVO stroke. The study included a 3+3 dose-escalation and a dose-expansion phase. Eligible patients achieved successful reperfusion (modified Thrombolysis in Cerebral Infarction score ≥2b) and received HSA infusion via the guiding catheter. Safety endpoints included 90-day mortality, symptomatic intracranial hemorrhage (sICH), and serious adverse events. Post-hoc analyses explored infarct volume, immune markers, and proteomic/metabolomic signatures. RESULTS:Between September 2023 and February 2024, 42 patients received intra-arterial HSA infusion. In the dose-escalation phase (n=27), two deaths and two mild infusion-related adverse events occurred, with no sICH. In the dose-expansion phase (n=15), one death and one case of sICH were reported, with no HSA-related adverse events. Post-hoc analysis showed that the HSA group had a significantly smaller infarct volume at 24 hours compared with controls. CONCLUSIONS:Intra-arterial infusion of 20% HSA in combination with MT is safe and feasible. Preliminary findings suggest a potential therapeutic benefit in reducing infarct volume. TRIAL REGISTRATION NUMBER:NCT05953623.

Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease for which no effective pharmacological treatments exist. Histone deacetylases (HDACs) have emerged as critical regulators of cardiovascular pathophysiology; however, the contributions of individual HDAC isoforms to AAA formation remain largely undefined. Here, we identified sirtuin 7 (SIRT7) as the most markedly downregulation isoform among 18 HDAC family members in human AAA tissues. Global and vascular smooth muscle cell (VSMC)-specific Sirt7 knockout exacerbated AAA formation, whereas SIRT7 overexpression attenuated aneurysm progression. Mechanistically, SIRT7 deacetylates serum response factor (SRF) at lysine 154, thereby preventing SRF nuclear-to-cytoplasmic translocation and ubiquitin-mediated degradation and preserving the VSMC contractile phenotype. Consequently, SIRT7 deficiency enhances SRF acetylation, accelerates its degradation, and promotes VSMC phenotypic switching, ultimately facilitating AAA progression. Pharmacological activation of SIRT7 with the NAD⁺ precursor nicotinamide mononucleotide attenuated aortic dilation. Collectively, our findings reveal a crucial role for SIRT7-mediated SRF-K154 deacetylation in limiting AAA progression and suggest that nicotinamide mononucleotide supplementation may represent a promising therapeutic strategy for AAA.

Background Abdominal aortic aneurysm (AAA) is a life-threatening aortic disease with a high mortality rate in cases of rupture, accompanied by abnormalities in metabolic processes. However, how polyamine metabolism is involved in AAA development remains largely unknown. Methods We used single-cell RNA sequencing (scRNA-seq) to analyze the polyamine metabolism pathway in multiple cell clusters within human AAA compared with nonaneurysmal samples. Results scRNA-seq analysis revealed higher activity of the polyamine metabolism pathway in multiple cell clusters within human AAA compared with nonaneurysmal samples. The messenger RNA expression levels of genes related to polyamine metabolism, such as ODC1 and SAT1, were also found to be elevated in various cell clusters of human AAA samples. Immunofluorescence assays confirmed an increased expression of ODC1 in AAA tissues relative to controls. Polyamine metabolomic analysis indicated that spermidine (SPD) levels were positively correlated with the diameters of AAA (R = 0.73; P = .04). In angiotensin II (Ang II)-induced AAA model of Apoe(-/-) mice, SPD treatment significantly decreased the incidence of aneurysm rupture compared with the control group (27% vs 62.5%; P < .0001). scRNA-seq of mouse aortic aneurysm tissues revealed a higher proportion of smooth muscle cells (SMCs) in the SPD-treated groups. Trajectory analysis suggested that the clusters of SMCs underwent the phenotype switch from the contractile SMCs to synthetic SMCs. Differential expressed gene analysis in the SMCs cluster showed that elastin (Eln) messenger RNA is the most markedly upregulated gene in SPD-treated group compared with controls. In both porcine pancreatic elastase-induced AAA mouse models and mouse vascular SMCs, Eln messenger RNA levels were significantly increased in SPD-treated groups than in control groups. ConclusionsWe found that polyamine metabolism is more active in AAA. As one of polyamines, SPD can prevent rupture of aortic aneurysms. Eln upregulation by SPD in SMCs may be the potential molecular mechanism.