Li’aN Huang

BACKGROUND: Glucagon-like peptide-1 receptor agonists reduce major adverse cardiovascular events in type 2 diabetes. Although body mass index does not seem to modify these effects, whether insulin resistance influences treatment efficacy remains unclear. METHODS: This post hoc analysis of the LAMP trial (Liraglutide in Acute Minor Ischemic Stroke or High-Risk Transient Ischemic Attack Patients With Type 2 Diabetes Mellitus; a multicenter, open-label, randomized controlled trial conducted at 27 hospitals in China between June 25, 2019, and December 27, 2023) included patients with minor ischemic stroke or high-risk transient ischemic attack and type 2 diabetes. Participants were randomized (1:1) to liraglutide plus standard therapy or standard therapy alone. IR was assessed using the homeostasis model assessment of IR, with a cutoff of 2.5 based on prior studies in Asian populations. Treatment-by-IR interactions were evaluated using Cox models. Absolute risk reduction was calculated as the difference in event rates between groups and was based on crude estimates. RESULTS: Among 636 enrolled patients, 510 were included in this analysis (mean age, 65 years; 64.7% male; follow-up, 3 months). A significant interaction between treatment and insulin resistance was observed for both stroke recurrence and composite vascular events ( P for interaction=0.02 for both). Among patients with homeostasis model assessment of IR ≥2.5, liraglutide reduced stroke recurrence (5.8% versus 18.1%; absolute risk reduction, 12.3% [95% CI, 5.6%–19.0%]; number needed to treat=8) and vascular events (5.8% versus 19.2%; absolute risk reduction, 13.4% [95% CI, 6.6%–20.2%]; number needed to treat=8). No significant benefit was observed in those with homeostasis model assessment of IR <2.5. CONCLUSIONS: IR may be an important determinant of the therapeutic efficacy of liraglutide in patients with acute minor ischemic stroke or high-risk transient ischemic attack and type 2 diabetes. IR-based stratification may help optimize the use of glucagon-like peptide-1 receptor agonists in secondary stroke prevention and guide personalized vascular risk management. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03948347.

TAR DNA-binding protein (TDP-43) is a multifunctional protein that binds DNA and RNA within the nucleus. In neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), TDP-43 is mislocalized to the cytoplasm, forming inclusions. Current TDP-43 transgenic mouse models generally fail to exhibit significant cytoplasmic accumulation and loss of nuclear TDP-43, which hampers the investigation of cytoplasmic TDP-43 pathology. We previously discovered that primate-specific caspase-4 (CASP4) can cleave TDP-43, producing truncated fragments that are mislocalized to the cytoplasm. Here we show that a transgenic mouse model that expresses human CASP4 and recapitulates the cytoplasmic mislocalization of endogenous TDP-43 and motor dysfunction in an age-dependent manner. Moreover, CASP4 mice exhibited gene expression changes and neuropathology similar to patients with sporadic ALS. Inhibition of CASP4 by its antisense oligonucleotide ameliorated TDP-43 pathology and subsequent neurotoxicity in CASP4 mice. Thus, CASP4 mice present a valuable animal model for exploring endogenous TDP-43-mediated pathogenesis and therapeutics.

Background Shift work is highly prevalent globally, yet evidence linking it to ischemic cerebrovascular disease remains inconsistent. Existing studies are limited by unsystematic quantification of night shift exposure and outcome definitions failing to capture the clinical continuum of ischemic events. We performed a large prospective cohort study using refined shift pattern classification and acute ischemic cerebrovascular syndrome (AICS) as the primary end point to enable a robust evaluation of the association between shift patterns and ischemic cerebrovascular disease. Methods 204,261 participants with employment information from the UK Biobank were included. Cox proportional hazards regression was used to assess associations between current shift work and AICS risk, with cross-classification by shift status and job duration. We further quantified average lifetime night shift frequency and cumulative duration among participants with complete occupational histories. Transient ischemic attack (TIA) and ischemic stroke (IS) were analyzed separately to identify the main driver of AICS and potential heterogeneity. Results During a median follow-up exceeding 14 years, irregular shift work was significantly associated with elevated AICS risk (HR 1.118, 95% CI 1.019–1.227, P = 0.019), while always night shift work was not (HR 0.904, 95% CI 0.707–1.157, P = 0.423). AICS risk was driven by irregular shift patterns rather than duration. Lifetime night shift frequency and duration showed significant dose–response relationships with AICS. Conclusions Irregular shift work increases AICS risk relative to non-shift work, and lifetime night shift exposure exhibits a clear dose–response effect. IS constitutes the primary driver of the composite AICS end point.

Background: Nurr1, an orphan nuclear receptor that lacks an endogenous ligand, plays a key role in hippocampal function, synaptic plasticity, and cognitive processes. It is linked to various central nervous system diseases; however, its association with chronic cerebral hypoperfusion (CCH)‐induced cognitive impairment remains unclear. This study investigated whether the Nurr1 agonist, amodiaquine (AQ), can enhance synaptic plasticity and alleviate cognitive deficits caused by CCH. Methods: A CCH rat model was created using the bilateral common carotid arterial occlusion method, followed by a 2‐week AQ treatment (20 mg/kg, every 12 h, through intraperitoneal injection). Learning and spatial memory were assessed using the Morris water maze (MWM), Y‐maze, and object recognition tests. Cerebral blood flow (CBF) in the cortex and hippocampus was measured using arterial spin labeling (ASL) with 3.0T magnetic resonance imaging (MRI), and white matter fiber density was assessed using diffusion tensor imaging (DTI). Hippocampal neuron morphology and count were examined using Nissl and NeuN staining, while dendritic spine morphology and density in CA1 and CA3 hippocampal regions were analyzed using Golgi staining. Results: Experiments with the water maze, Y‐maze, and object recognition tests demonstrated that CCH rats treated with AQ exhibited improved long‐term and short‐term memory and spatial recognition compared to the control group, with benefits persisting after two and 6 weeks. MRI DTI sequences revealed that AQ reversed the decline in white matter fiber density observed in CCH model rats compared to the sham group. Golgi staining confirmed that AQ protected the dendritic spines of the neurons damaged in the CCH model. Conclusion: Administrating Nurr1 agonist AQ demonstrated a sustained ameliorative effect on cognitive deficits in CCH rats. This effect is potentially mediated through the mitigation of hippocampal neuronal loss and improvement of dendritic spine integrity.

Background: The relationship between cerebral small vessel diseases (CSVD) and deep medullary veins (DMV) has been the subject of only a limited number of studies to date, with the majority of research focusing on the correlation between DMV and cognitive function in patients with CSVD. The present study aims to quantitatively evaluate the relationship between DMV and CSVD imaging markers, utilizing an artificial intelligence neuroimaging system to achieve this objective. Furthermore, an investigation was conducted into the correlation between DMV disruption and cognitive impairment.Methods: This cross-sectional study enrolled patients with CSVD imaging markers who were admitted to the Department of Neurology at our hospital. The quantitative assessment of CSVD imaging markers, encompassing white matter hyperintensities (WMH), lacunar infarction (LI), and cerebral microbleeds (CMB), was conducted employing the AccuBrain^® neuroimaging system. The DMV was evaluated using susceptibility-weighted imaging (SWI) with a semi-quantitative scale. The Montreal Cognitive Assessment (MoCA) score was evaluated for each patient.Results: The study’s sample population comprised 171 patients. Multivariate ordinal logistic regressions indicated that DMV score was significantly associated with WMH volume, LI count, and CMB count (p < 0.05). In the context of multivariate linear regression analysis, a significant negative correlation was observed between the DMV score and the MoCA score, with the latter being adjusted for confounding variables such as age, education, gender, and smoking history (p = 0.003). The application of path analysis revealed a significant correlation between the DMV score and the MoCA score, which indicates that WMH volume plays a mediating role in this relationship, thereby offering a novel perspective on cognitive function and neurodegenerative processes.Conclusion: DMV score is associated with the severity of WMH, CMB, and LI, as well as cognitive performance decline, implicating that cerebral venule damage may play a role in the development of CSVD and related cognitive impairment.

Background: The mild hypothermia for thrombolysis in patients with cerebral infarction caused by acute large‐vessel occlusion is superior to the standard medical treatment. Aims: The safety and effectiveness of cytoprotection and prognosis from the hypothermia is under investigation. Methods: Twenty‐five patients with acute occlusion of intracranial large vessels treated with endovascular thrombolysis of hypothermic saline infusion within 24 h at the onset of the disease were enrolled as a treatment group. As a control group, 166 patients suffering from acute large‐vessel occlusion and infused with normal temperature saline at the hospital during the same period were selected. The patients were paired according to gender, age, pathogenesis, offending vessel, risk factors, and combined underlying diseases. The baseline data were recorded and compared between the two groups. The pre‐ and postprocedure contents and prognosis of patients were recorded and compared for safety assessment. Results: Twenty pairs of patients were rigorously matched into the final statistical analysis. There was a significant decrease in the hematocrit difference of treatment group compared with the control group. However, we found no significant differences between the two groups regarding 7‐day postoperative NIHSS scores, incidence of pneumonia, rate of CT abnormalities in the immediate postoperative period, the rate of 7‐day postoperative head CT hemorrhage, the occurrence of severe cerebral edema, and 90‐day postoperative mRS scores. Conclusions: Targeted intravascular subcryogenic temperature combined with arterial thrombolysis is safe for the treatment of large‐vessel occlusive cerebral infarction, but the treatment fails to improve outcomes in the acute large vessel occlusive cerebral infarction patients.

Background: We aimed to investigate the phenomenon of thrombolysis resistance in tenecteplase and its underlying causes and evaluate whether DNase‐1 (deoxyribonuclease I) targeting neutrophil extracellular traps (NETs) could enhance the thrombolytic efficiency of tenecteplase. Methods: Fresh thrombi were retrieved from 25 patients with acute ischemic stroke via endovascular thrombectomy, and 50 artificial blood clots were generated by recalcifying whole blood from healthy donors for ex vivo thrombolysis experiments by tenecteplase±DNase‐1. Fibrinolytic resistance was analyzed via histology and scanning electron microscope. Thrombolytic rates were calculated. NETs were observed with immunofluorescence colocalization of NET markers. In vivo experiment was performed in mice with photothrombotic stroke, to evaluate the effects of tenecteplase+DNase‐1 versus tenecteplase on cerebral blood flow, infarct volume, and neurological deficits. Results: The NET‐rich outer shell remained after tenecteplase thrombolysis in thrombi and blood clots. Additive DNase‐1 enhanced the thrombolytic efficiency of tenecteplase, resulting in faster thrombolytic rates and lower weights of thrombus (31% versus 48%; P P P P P =0.003) at 24 hours. Conclusions: The shell structure of a thrombus, particularly the NETs, may play an important role in fibrinolytic resistance to tenecteplase. Additive DNase‐1 may enhance the thrombolytic efficiency of tenecteplase.

Cardiometabolic diseases (CMDs) including type 2 diabetes, heart disease, and stroke, increase the risk of dementia. However, the correlation between CMDs and dementia in different subgroups and the underlying pathophysiological mechanisms linking CMDs with dementia warrant further investigation. This prospective cohort study included a total of 287,748 individuals from the UK Biobank. The outcome measures included all-cause dementia (ACD), Alzheimer’s disease (AD) and vascular dementia (VD). Cox regression models and subgroup analyses were used to assess the association between CMD status and dementia, while mediation analysis was evaluated potential roles of inflammatory/metabolic markers in the observed associations. Compared with those without CMD, those with CMD multimorbidity had an elevated risk of ACD (hazard ratio [HR]: 2.27, 95% confidence interval [95% CI]: 1.95–2.63), AD (HR: 1.49, 95% CI: 1.13–1.97), and VD (HR: 3.70, 95% CI: 2.93–4.69). According to the subgroup analyses, the positive correlations between CMDs and ACD, as well as AD, were stronger in individuals who were under the age of 60 or female. Mediation analysis indicated that neutrophils mediated 2.43% of the association of CMDs with ACD, while glucose and hemoglobin A1c mediated 9.22% and 11.85% of the association of CMDs with ACD, respectively. This study further expands the research on cardiometabolic multimorbidity and dementia, highlighting the need for focused attention on specific populations, such as younger individuals and women. Additionally, inflammatory and metabolic biomarkers, as potential mediators, provide critical insights into the complex pathophysiological mechanisms.