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BACKGROUND: Previous cohort studies have suggested an association between cerebral small vessel disease (cSVD) and "unexplained dizziness". The causality of this link remains uncertain, but it would be of significant clinical importance, considering the substantial number of patients presenting with unexplained dizziness is large. We aimed to investigate the causal effect of cSVD-related phenotypes on unexplained dizziness using a Mendelian randomization approach. METHODS: Genetic instruments for each cSVD-related phenotype - white matter hyperintensity (WMH) volume, lacunar stroke (LS), perivascular spaces (PVS), and cerebral microbleeds (CMBs) - as well as unexplained dizziness were identified through large-scale genome-wide association studies. We conducted 2-sample Mendelian randomization analyses. The random-effects inverse-variance weighted (IVW) method was chosen for the primary analysis. For sensitivity analyses, we employed the weighted-median, MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out analysis methods were implemented for the sensitivity analyses. RESULTS: We successfully identified a significant causal effect of WMH volume on unexplained dizziness (odds ratio [95% CI], 1.12 [1.01-1.23]). However, we were unable to detect any significant causal effects of the other cSVD-related phenotypes on unexplained dizziness, with odds ratios [95% CI] of 1.03 [0.98-1.09] for LS, 0.75 [0.55-1.02] for white matter PVS, 1.02 [0.68-1.52] for basal ganglia PVS, 0.80 [0.43-1.51] for hippocampal PVS, 0.95 [0.90-1.00] for lobar CMBs, and 0.97 [0.92-1.01] for mixed CMBs respectively. The results from the sensitivity analyses were generally consistent with those of the primary analyses. CONCLUSIONS: This MR study supports a causal relationship between WMH, a phenotype associated with cSVD, and the risk of unexplained dizziness, but does not support such a relationship between other cSVD-related phenotypes and unexplained dizziness. These findings require further validation through randomized controlled trials, larger cohort studies, and MR studies based on more extensive GWASs.
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Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant inherited arterial disease, with lacunar infarction resulting from intracranial small vessel lesions being the most prevalent clinical manifestation of CADASIL. However, large-scale cerebral infarction caused by intracranial non-small vessels occlusion is relatively uncommon, and reports of vascular intervention and long-term antiplatelet drug treatment for patients with CADASIL and large-scale cerebral infarction are rarer. Methods: We reported a 52 year-old male who experienced a significant cerebral infarction due to an occlusion in the second segment of the left middle cerebral artery, 4 months subsequent to being diagnosed with CADASIL. Following the benefit and risk assessment, the patient underwent intracranial vascular thrombectomy and balloon dilation angioplasty. Subsequently, he was administered dual antiplatelet therapy for 3 months, followed by mono antiplatelet therapy. Results: After undergoing intracranial vascular intervention and receiving antiplatelet therapy, significant improvement in the symptoms were observed. The National Institutes of Health Stroke Scale score decreased from 6 to 2 points, and no bleeding lesions were detected on the head computed tomography during regular follow-up visits after discharge. Conclusion: Our case highlights the possibility that patients with CADASIL may also encounter extensive cerebral infarction resulting from stenosis or occlusion of intracranial non-small vessels. Considering the specific circumstances of the patient, intravascular intervention and antiplatelet therapy can be regarded as viable treatment options for individuals with CADASIL.
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BACKGROUND: Tenecteplase is an effective thrombolytic agent for eligible patients with stroke who are treated within 4.5 hours after the onset of stroke. However, data regarding the effectiveness of tenecteplase beyond 4.5 hours are limited. METHODS: In a trial conducted in China, we randomly assigned patients with large-vessel occlusion of the middle cerebral artery or internal carotid artery who had salvageable brain tissue as identified on perfusion imaging and who did not have access to endovascular thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or standard medical treatment 4.5 to 24 hours after the time that the patient was last known to be well (including after stroke on awakening and unwitnessed stroke). The primary outcome was the absence of disability, which was defined as a score of 0 or 1 on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability), at day 90. The key safety outcomes were symptomatic intracranial hemorrhage and death. RESULTS: A total of 516 patients were enrolled; 264 were randomly assigned to receive tenecteplase and 252 to receive standard medical treatment. Less than 2% of the patients (4 in the tenecteplase group and 5 in the standard-treatment group) underwent rescue endovascular thrombectomy. Treatment with tenecteplase resulted in a higher percentage of patients with a modified Rankin scale score of 0 or 1 at 90 days than standard medical treatment (33.0% vs. 24.2%; relative rate, 1.37; 95% confidence interval, 1.04 to 1.81; P = 0.03). Mortality at 90 days was 13.3% with tenecteplase and 13.1% with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage within 36 hours after treatment was 3.0% and 0.8%, respectively. CONCLUSIONS: In this trial involving Chinese patients with ischemic stroke due to large-vessel occlusion, most of whom did not undergo endovascular thrombectomy, treatment with tenecteplase administered 4.5 to 24 hours after stroke onset resulted in less disability and similar survival as compared with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage appeared to be higher. (Funded by the National Natural Science Foundation of China and others; TRACE-III ClinicalTrials.gov number, NCT05141305.).
Subject(s)
Fibrinolytic Agents , Ischemic Stroke , Tenecteplase , Tissue Plasminogen Activator , Humans , Tenecteplase/therapeutic use , Tenecteplase/adverse effects , Fibrinolytic Agents/therapeutic use , Fibrinolytic Agents/adverse effects , Fibrinolytic Agents/administration & dosage , Male , Middle Aged , Tissue Plasminogen Activator/therapeutic use , Tissue Plasminogen Activator/adverse effects , Female , Aged , Ischemic Stroke/drug therapy , Ischemic Stroke/surgery , Thrombectomy , Time-to-Treatment , Intracranial Hemorrhages/etiology , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/surgeryABSTRACT
Small extracellular vesicles (sEVs) contain abundant circular RNAs (circRNAs) and are involved in cellular processes, particularly hypoxia. However, the process that packaging of circRNAs into neuronal sEVs under hypoxia is unclear. This study revealed the spatial mechanism of the Fused in Sarcoma protein (FUS) that facilitates the loading of functional circRNAs into sEVs in hypoxia neurons. It is found that FUS translocated from the nucleus to the cytoplasm and is more enriched in hypoxic neuronal sEVs than in normal sEVs. Cytoplasmic FUS formed aggregates with the sEVs marker protein CD63 in cytoplasmic stress granules (SGs) under hypoxic stress. Meanwhile, cytoplasmic FUS recruited of functional cytoplasmic circRNAs to SGs. Upon relief of hypoxic stress and degradation of SGs, cytoplasmic FUS is transported with those circRNAs from SGs to sEVs. Validation of FUS knockout dramatically reduced the recruitment of circRNAs from SGs and led to low circRNA loading in sEVs, which is also confirmed by the accumulation of circRNAs in the cytoplasm. Furthermore, it is showed that the FUS Zf_RanBP domain regulates the transport of circRNAs to sEVs by interacting with hypoxic circRNAs in SGs. Overall, these findings have revealed a FUS-mediated transport mechanism of hypoxia-related cytoplasmic circRNAs loaded into sEVs under hypoxic conditions.
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BACKGROUND: Edaravone dexborneol is believed to be a novel cytoprotective drug, demonstrating a synergistic combination of antioxidative and anti-inflammatory properties in animal models. The Treatment of Acute Ischaemic Stroke with Edaravone Dexborneol (TASTE) trial demonstrated its superior efficacy over edaravone alone for acute ischaemic stroke (AIS) patients. However, its efficacy in individuals undergoing endovascular therapy (EVT) remains uncertain. AIM: To clarify the rationale and design of the TASTE II (TASTE-2) trial. DESIGN: The TASTE-2 is a multicentre, double-blind, randomised, placebo-controlled trial designed to evaluate the efficacy and safety of edaravone dexborneol in patients with AIS and large-vessel occlusion in the anterior circulation. The eligible participants, presenting with a National Institute of Health Stroke Scale score between 6 and 25 (range 0-42, with larger values suggesting severe neurological dysfunction) and an Alberta Stroke Program Early Computed Tomography Score ranging from 6 to 10 (range 0-10, with smaller values suggesting larger infarction) within the initial 24 hours after symptom onset, will be randomly allocated to either the edaravone dexborneol group or the placebo group in equal proportions prior to thrombectomy. The treatment will be continuously administered for a duration of 10-14 days. A follow-up period of 90 days will be implemented for all participants. STUDY OUTCOMES: The primary efficacy outcome is defined as achieving favourable functional independence, measured by a modified Rankin Scale of 0-2 at 90 days. The primary safety outcome focuses on the incidence of serious adverse events. DISCUSSION: The TASTE-2 trial will provide evidence to determine whether the administration of edaravone dexborneol in AIS patients undergoing EVT could yield significant improvements in neurological function.
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Background: We aim to explore the effect of the score for the targeting of atrial fibrillation (STAF) combined with the serum D-dimer (DD) level in screening acute ischemic stroke patients with atrial fibrillation (AF). Methods: This study is a retrospective case observation study. This study consecutively selected patients with acute ischemic stroke who were hospitalized in the Department of Neurology at Zhuhai Hospital Affiliated with Jinan University from February 2019 to February 2021. Venous blood was drawn from all patients within 24 hours of hospitalization for DD detection. In accordance with the medical records, the patients were classified into an AF group and a non-AF group and were scored according to the STAF standard. A combined test method was used to estimate the diagnostic screening value of the STAF combined with the DD value for acute ischemic stroke patients with AF.
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Given the epidemiological studies investigating the relationship between birthweight and dementia are limited. Our study aimed to explore the association between birthweight and the risk of dementia, cognitive function, and brain structure. We included 275,648 participants from the UK Biobank, categorizing birthweight into quartiles (Q1 ≤ 2.95 kg; Q2 > 2.95 kg, ≤ 3.32 kg; Q3 > 3.32 kg, ≤ 3.66 kg; Q4 > 3.66 kg), with Q3 as the reference. Cox regression models and restricted cubic splines estimated the relationship between birthweight and the risk of all causes of dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VD). Multivariable linear regression models assessed the relationship between birthweight, cognitive function, and MRI biomarkers. Over a median follow-up of 13.0 years, 3103 incident dementia cases were recorded. In the fully adjusted model, compared to Q3 (> 3.32 kg, ≤ 3.66 kg), lower birthweight in Q1 (≤ 2.95 kg) was significantly associated with increased risk of ACD (HR = 1.18, 95%CI 1.06-1.30, P = 0.001) and VD (HR = 1.32, 95%CI 1.07-1.62, P = 0.010), but no significant association with AD was found. Continuous birthweight showed a U-shaped nonlinear association with dementia. Lower birthweight was associated with worse performance in cognitive tasks, including reaction time, fluid intelligence, numeric, and prospective memory. Additionally, certain brain structure indices were identified, including brain atrophy and reductions in area, thickness, and volume of regional subcortical areas. Our study emphasizes the association between lower birthweight and increased dementia risk, correlating cognitive function and MRI biomarkers of brain structure, suggesting that in utero or early-life exposures might impact cognitive health in adulthood.
Subject(s)
Birth Weight , Dementia , Magnetic Resonance Imaging , Humans , Female , Male , Dementia/epidemiology , Prospective Studies , Aged , Middle Aged , United Kingdom/epidemiology , Cognition/physiology , Risk Factors , Incidence , Brain/diagnostic imaging , Brain/pathology , Alzheimer Disease/epidemiology , Alzheimer Disease/diagnostic imaging , Proportional Hazards ModelsABSTRACT
Huntington disease (HD) is a neurodegenerative disease caused by the abnormal expansion of a polyglutamine tract resulting from a mutation in the HTT gene. Oxidative stress has been identified as a significant contributing factor to the development of HD and other neurodegenerative diseases, and targeting anti-oxidative stress has emerged as a potential therapeutic approach. CHCHD2 is a mitochondria-related protein involved in regulating cell migration, anti-oxidative stress, and anti-apoptosis. Although CHCHD2 is highly expressed in HD cells, its specific role in the pathogenesis of HD remains uncertain. We postulate that the up-regulation of CHCHD2 in HD models represents a compensatory protective response against mitochondrial dysfunction and oxidative stress associated with HD. To investigate this hypothesis, we employed HD mouse striatal cells and human induced pluripotent stem cells (hiPSCs) as models to examine the effects of CHCHD2 overexpression (CHCHD2-OE) or knockdown (CHCHD2-KD) on the HD phenotype. Our findings demonstrate that CHCHD2 is crucial for maintaining cell survival in both HD mouse striatal cells and hiPSCs-derived neurons. Our study demonstrates that CHCHD2 up-regulation in HD serves as a compensatory protective response against oxidative stress, suggesting a potential anti-oxidative strategy for the treatment of HD.
Subject(s)
Huntington Disease , Induced Pluripotent Stem Cells , Neurodegenerative Diseases , Animals , Mice , Humans , Huntington Disease/metabolism , Neurodegenerative Diseases/metabolism , Up-Regulation/genetics , Induced Pluripotent Stem Cells/metabolism , Oxidative Stress , Huntingtin Protein/genetics , Huntingtin Protein/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
BACKGROUND AND PURPOSE: Glucose-to-glycated hemoglobin ratio (GAR) is considered a more reliable marker of stress hyperglycemia by correcting for basal blood glucose levels. This study aimed to investigate the extent to which GAR is associated with 3 month and 1 year all-cause mortalities in patients with acute ischemic stroke (AIS) undergoing mechanical thrombectomy (MT). METHODS: We retrospectively followed 553 AIS patients who underwent MT. The degree of stress hyperglycemia was quantified as the GAR, defined as fasting plasma glucose (mmol/L)/hemoglobin A1c (HbA1c) (%) on the second day after admission. According to the GAR quartiles, the patients were further categorized into four groups (group 1-group 4). We assessed the association between GAR and all-cause mortalities, clinical outcomes during hospitalization and function outcomes at 3 months. The associations between stress hyperglycemia and all-cause mortalities were analyzed using a Cox proportional-hazards model, while other outcomes were analyzed using multiple logistic regression analysis. RESULTS: The follow-up lasted a median of 18 months (range 0-66 months). The 3 month mortality rate was 9.58% (n = 53) and the 1 year mortality rate was 18.62% (n = 103). The Kaplan-Meier analysis revealed a significant inverse relationship between GAR and mortality (P < 0.001). In the Cox proportional-hazards model at 3 months, compared with group1, group 4 of GAR was associated with a significant increase in the risk of 3 month mortality (hazard ratio [HR] = 4.11, 95% confidence interval [CI] 1.41-12.0, P = 0.01) after adjusting for potential covariates. On multivariate logistic regression analysis, GAR was strongly associated with an increased risk of 3 month poor function outcome. CONCLUSIONS: Stress hyperglycemia, quantified by a higher GAR, is associated with all-cause mortality and poor functional outcomes in patients with AIS who undergo MT. Furthermore, GAR may contribute to improving the predictive efficiency of all-cause mortality in patients with AIS after MT, especially short-term all-cause mortality.
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BACKGROUND: The relationship between feelings of tense, as a significant emotional distress, and dementia remains unclear. This study aimed to evaluate the association between feelings of tense and dementia. METHODS: In UK Biobank, feelings of tense were measured with a standard item. The primary outcome was all cause of dementia (ACD) and its subtypes (Alzheimer's disease (AD), vascular dementia (VD), and other dementia). Cox regression models analyzed the association between feelings of tense and dementia risk, while linear regression examined the correlation with neuroimaging outcomes. The potential association and joint effects of AD and tenseness were evaluated based on the established genetic risk score (GRS). RESULTS: During a median follow-up of 12.7 years among 482,360 participants, 7331 dementia cases were identified. Individuals with feelings of tense had a significantly increased risk of ACD (HR, 1.194; 95 % CI: 1.115-1.278), VD (HR, 1.164; 95 % CI: 1.007-1.346), and other dementia (HR, 1.181; 95 % CI: 1.081-1.289), but not AD in multi-adjusted models. This association persisted across various sensitivity analyses and exhibited some heterogeneity in subgroup analyses. Furthermore, feelings of tense are associated with total brain volume shrinkage, higher white matter hyperintensities, and decreased partial subcortical volume, particularly in the hippocampus. No interaction between tenseness and AD genetic susceptibility was observed (P for interaction =0.346). LIMITATIONS: Our study only considered feelings of tense measured at a one-time point. CONCLUSIONS: Our findings demonstrate a significant association between feeling of tense and elevated dementia risk, indicating that tenseness could serve as a modifiable psychological determinant for dementia.
Subject(s)
Alzheimer Disease , Humans , Prospective Studies , Alzheimer Disease/epidemiology , Alzheimer Disease/etiology , Brain , Emotions , NeuroimagingABSTRACT
Previous researchers have tried to explore the association between folate/folic acid intake and dementia incidence, but the results remain controversial. We evaluated the associations of folate/folic acid supplementation alone and in combination with other B vitamins on dementia risk and brain structure. A total of 466â 224 UK Biobank participants were investigated. Cox proportional hazards models were used to assess the associations between folate/folic acid supplementation status and the risk of Alzheimer's disease (AD) and vascular dementia (VD). Multivariable linear regression models were employed to evaluate the association between folate/folic acid supplementation status and brain structure. In the final model, folate/folic acid supplementation alone was significantly associated with a higher risk of AD (hazard ratio [HR]â =â 1.34, 95% confidence interval [CI]â =â 1.06-1.69, pâ =â .015) and VD (HRâ =â 1.61, 95% CIâ =â 1.21-2.13, pâ =â .001). Folate/folic acid supplementation alone was associated with a reduction in the hippocampus (ßâ =â -95.25 mm3, 95% CIâ =â -165.31 to -25.19 mm3, pâ =â .014) and amygdala (ßâ =â -51.85 mm3, 95% CIâ =â -88.02 to -15.68 mm3, pâ =â .012). The risk of AD and VD, as well as brain structure, in the group with combined folate/folic acid supplementation and other B vitamins did not show a statistically significant difference compared to the reference group (all pâ >â .05). Folate/folic acid supplementation alone is significantly associated with a higher risk of AD and VD, as well as adverse alterations in brain structure. However, when combined with other B vitamins, these detrimental effects can be counteracted.
Subject(s)
Dementia , Vitamin B Complex , Humans , Folic Acid , Dietary Supplements , Biological Specimen Banks , UK Biobank , Brain/diagnostic imaging , Dementia/epidemiology , Dementia/prevention & control , Dementia/etiologyABSTRACT
OBJECTIVE: To investigate the potential relationship between common nonsteroidal anti-inflammatory drugs (NSAIDs), genetic susceptibility and all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VD) among individuals experiencing chronic pain. METHODS: This study was based on 194,758 chronic pain participants form UK biobank with a median follow-up of 13.7 years. Participants were categorized into different NSAIDs painkiller regimen groups: No NSAIDs group, Aspirin group, Ibuprofen group, Paracetamol group, and 2-3 NSAIDs group. Cox proportional risk models were used to examine the correlation between regular NSAIDs usage and the risk of ACD, AD, and VD. In addition, we further performed subgroup analyses and sensitivity analyses. RESULTS: 1) Compared to the No NSAIDs group, the aspirin group (HR = 1.12, 95% CI:1.01-1.24, P < 0.05), the paracetamol group (HR = 1.15, 95% CI:1.05-1.27, P < 0.01), and the 2-3 NSAIDs group (HR = 1.2, 95% CI:1.08-1.33, P < 0.05) showed a higher risk of ACD. Furthermore, the 2-3 NSAIDs group was also associated with a higher risk of VD (HR = 1.39, 95% CI: 1.08-1.33, P < 0.05). 2) At high dementia GRS participants with chronic pain, the paracetamol group (HR = 1.2, 95% CI: 1.03-1.43, P < 0.05) and the NSAIDs group (HR = 1.3, 95% CI: 1.07-1.59, P < 0.05) were associated with a higher risk of ACD compared to the no painkiller group. 3) There was no significant association between ibuprofen use and higher risk of dementia. CONCLUSION: In individuals with chronic pain, the use of aspirin and paracetamol was associated with a higher risk of ACD, whereas the use of ibuprofen was not significantly associated with a higher risk of ACD.
Subject(s)
Alzheimer Disease , Chronic Pain , Humans , Acetaminophen/adverse effects , Prospective Studies , Ibuprofen/adverse effects , Chronic Pain/drug therapy , UK Biobank , Biological Specimen Banks , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Aspirin/therapeutic use , Alzheimer Disease/drug therapy , Genetic Predisposition to DiseaseABSTRACT
BACKGROUND: Genetic factors, diet and inflammation are associated with the development of dementia. In this study, we aimed at evaluating the impact of the dietary inflammatory index (DII) scores and genetic susceptibility on the development of dementia. METHODS: This prospective study involved 207,301 participants aged between 39 and 72 years from UK biobank. A web-based 24-h dietary questionnaire was collected at least once from participants between 2006 and 2012. The DII was calculated based on inflammatory effect score of nutrients. Individual AD-GRS (Alzheimer's disease genetic risk score) was calculated. Incident dementia was ascertained through hospital or death records. RESULTS: Of all 207,301 participants, 468 incident cases of all-cause dementia (165 AD, 91 VD and 26 FTD) were reported during a follow-up period of 11.4 years. The participants in the highest quintile (Q) of DII scores reported a higher risk for all-cause dementia (Q5 vs. Q3, hazard ratio (HR) = 1.702; 95% CI: 1.285-2.255) and VD (Q5 vs. Q3, HR = 2.266, 95% CI: 1.133-4.531) compared to participants in the Q3. Besides, when compared with the Q1, there was a higher risk for AD in the subjects of Q5 (Q5 vs. Q1, HR = 1.590; 95% CI: 1.004-2.519). There was a non-linear relationship between DII score and all-cause incidence (P for non-linear = 0.038) by restricted cubic splines. Subgroup analysis found that the increased risk for all-cause dementia and AD was more pronounced in the elderly, women, and higher educated population. Cox regression models indicated that compared with the participants who had a low AD-GRS risk and in the lowest tertile of DII, participants had a high AD-GRS and the highest tertile of DII were associated with a higher risk of AD (HR = 1.757, 95% CI: 1.082-2.855, P = 0.023). CONCLUSIONS: The DII scores were independently associated with an augmented risk for all-cause dementia, AD and VD. Additionally, high AD-GRS with higher DII scores was significantly associated with a higher risk of AD.
Subject(s)
Alzheimer Disease , UK Biobank , Aged , Humans , Female , Adult , Middle Aged , Prospective Studies , Follow-Up Studies , Biological Specimen Banks , Diet/adverse effects , Inflammation/epidemiology , Inflammation/genetics , Genetic Predisposition to Disease , Risk FactorsABSTRACT
Microvasculature of the retina is considered an alternative marker of cerebral vascular risk in healthy populations. However, the ability of retinal vasculature changes, specifically focusing on retinal vessel diameter, to predict the recurrence of cerebrovascular events in patients with ischemic stroke has not been determined comprehensively. While previous studies have shown a link between retinal vessel diameter and recurrent cerebrovascular events, they have not incorporated this information into a predictive model. Therefore, this study aimed to investigate the relationship between retinal vessel diameter and subsequent cerebrovascular events in patients with acute ischemic stroke. Additionally, we sought to establish a predictive model by combining retinal veessel diameter with traditional risk factors. We performed a prospective observational study of 141 patients with acute ischemic stroke who were admitted to the First Affiliated Hospital of Jinan University. All of these patients underwent digital retinal imaging within 72 hours of admission and were followed up for 3 years. We found that, after adjusting for related risk factors, patients with acute ischemic stroke with mean arteriolar diameter within 0.5-1.0 disc diameters of the disc margin (MAD0.5-1.0DD) of ≥ 74.14 µm and mean venular diameter within 0.5-1.0 disc diameters of the disc margin (MVD0.5-1.0DD) of ≥ 83.91 µm tended to experience recurrent cerebrovascular events. We established three multivariate Cox proportional hazard regression models: model 1 included traditional risk factors, model 2 added MAD0.5-1.0DD to model 1, and model 3 added MVD0.5-1.0DD to model 1. Model 3 had the greatest potential to predict subsequent cerebrovascular events, followed by model 2, and finally model 1. These findings indicate that combining retinal venular or arteriolar diameter with traditional risk factors could improve the prediction of recurrent cerebrovascular events in patients with acute ischemic stroke, and that retinal imaging could be a useful and non-invasive method for identifying high-risk patients who require closer monitoring and more aggressive management.
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BACKGROUND: Current drug treatments for dementia aren't effective. Studying gene-environment interactions can help develop personalized early intervention strategies for Alzheimer's disease (AD). However, no studies have examined the relationship between screen-based sedentary activities and genetic susceptibility to AD risk, and further understanding of the causal relationship is also crucial. METHODS: This study included 462,524 participants from the UK Biobank with a follow-up of 13.6 years. Participants' screen-based sedentary activities time was categorized into three groups based on recorded time: ≥ 4 h/day, 2-3 h/day, and ≤ 1 h/day. Cox proportional risk models were used to analyze the association between computer use/TV viewing groups and the risk of all-cause dementia, AD and vascular dementia (VD). Generalized linear model (GLM) were used to examine the relationship between screen-based sedentary activities and brain structure. Bidirectional Mendelian randomization (MR) was used to validate the causal relationship between TV viewing and AD. RESULTS: Compared to TV viewing ≤ 1 h/day, 1)TV viewing 2-3 h/day was correlated with a higher risk of all-cause dementia (HR = 1.09, 95% CI:1.01-1.18, P < 0.05), and TV viewing ≥ 4 h/day was associated with a higher risk of all-cause dementia (HR = 1.29, 95% CI: 1.19-1.40, P < 0.001), AD (HR = 1.25, 95% CI:1.1-1.42, P < 0.001), and VD (HR = 1.24, 95% CI: 1.04-1.49, P < 0.05); 2) TV viewing ≥ 4 h/day was correlated with a higher AD risk at intermediate (HR = 1.34, 95% CI: 1.03-1.75, P < 0.001) and high AD genetic risk score (AD-GRS) (HR = 2.18, 95% CI: 1.65-2.87, P < 0.001);3) TV viewing 2-3 h/day [ß = (-94.8), 95% CI: (-37.9) -(-151.7), P < 0.01] and TV viewing ≥ 4 h/day [ß = (-92.94), 95% CI: (-17.42) -(-168.46), P < 0.05] were correlated with a less hippocampus volume. In addition, a causal effect of TV viewing times was observed on AD analyzed using MR Egger (OR = 5.618, 95%CI:1.502-21.013, P < 0.05). CONCLUSIONS: There was a causal effect between TV viewing time and AD analyzed using bidirectional MR, and more TV viewing time exposure was correlated with a higher AD risk. Therefore, it is recommended that people with intermediate and high AD-GRS should control their TV viewing time to be less than 4 h/ day or even less than 1 h/day.
Subject(s)
Alzheimer Disease , Dementia, Vascular , Humans , Longitudinal Studies , Exercise , Dementia, Vascular/etiology , Dementia, Vascular/genetics , Alzheimer Disease/epidemiology , Alzheimer Disease/genetics , Biological Specimen Banks , United Kingdom/epidemiologyABSTRACT
In the United States (US), the Surveillance, Epidemiology, and End Results (SEER) program is the only comprehensive source of population-based information that includes stage of cancer at the time of diagnosis and patient survival data. This program aims to provide a database about cancer incidence and survival for studies of surveillance and the development of analytical and methodological tools in the cancer field. Currently, the SEER program covers approximately half of the total cancer patients in the US. A growing number of clinical studies have applied the SEER database in various aspects. However, the intrinsic features of the SEER database, such as the huge data volume and complexity of data types, have hindered its application. In this review, we provided a systematic overview of the commonly used methodologies and study designs for retrospective epidemiological research in order to illustrate the application of the SEER database. Therefore, the goal of this review is to assist researchers in the selection of appropriate methods and study designs for enhancing the robustness and reliability of clinical studies by mining the SEER database.
Subject(s)
Neoplasms , Research Design , Humans , United States/epidemiology , Retrospective Studies , Reproducibility of Results , SEER ProgramABSTRACT
Few studies have investigated the properties and protein composition of small extracellular vesicles (sEVs) derived from neurons under hypoxic conditions. Presently, the extent of the involvement of these plentiful sEVs in the onset and progression of ischemic stroke remains an unresolved question. Our study systematically identified the characteristics of sEVs derived from neurons under hypoxic conditions (HypEVs) by physical characterization, sEV absorption, proteomics and transcriptomics analysis. The effects of HypEVs on neurites, cell survival, and neuron structure were assessed in vitro and in vivo by neural complexity tests, magnetic resonance imaging (MRI), Golgi staining, and Western blotting of synaptic plasticity-related proteins and apoptotic proteins. Knockdown of Fused in Sarcoma (FUS) small interfering RNA (siRNA) was used to validate FUS-mediated HypEV neuroprotection and mitochondrial mRNA release. Hypoxia promoted the secretion of sEVs, and HypEVs were more easily taken up and utilized by recipient cells. The MRI results illustrated that the cerebral infarction volume was reduced by 45% with the application of HypEVs, in comparison to the non- HypEV treatment group. Mechanistically, the FUS protein is necessary for the uptake and neuroprotection of HypEVs against ischemic stroke as well as carrying a large amount of mitochondrial mRNA in HypEVs. However, FUS knockdown attenuated the neuroprotective rescue capabilities of HypEVs. Our comprehensive dataset clearly illustrates that FUS-mediated HypEVs deliver exceptional neuroprotective effects against ischemic stroke, primarily through the maintenance of neurite integrity and the reduction of mitochondria-associated apoptosis.
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Objective: To prospectively assess whether air pollution, including PM2.5, PM10, and NOx, is associated with the risk of all-cause dementia, Alzheimer's disease (AD), and vascular dementia, and to investigate the potential relationship between air pollution and genetic susceptibility in the development of AD. Methods and results: Our study included 437,932 participants from the UK Biobank with a median follow-up period of over 10 years. Using a Cox proportional hazards model, we found that participants exposed to PM2.5 levels of ≥10 µg/m3 had a higher risk of developing all-cause dementia (HR = 1.1; 95% CI: 1.05-1.28; p < 0.05) compared to the group exposed to PM2.5 levels of <10 µg/m3. However, there was no significant association between PM10 levels of ≥15 µg/m3 and the risk of all-cause dementia, AD, or vascular dementia when compared to the group exposed to PM10 levels of <15 µg/m3. On the other hand, participants exposed to NOx levels of ≥50 µg/m3 had a significantly higher risk of all-cause dementia (HR = 1.14; 95% CI: 1.02-1.26; p < 0.05) and AD (HR = 1.26; 95% CI: 1.08-1.48; p < 0.05) compared to the group exposed to NOx levels of <50 µg/m3. Furthermore, we examined the combined effect of air pollution (PM2.5, PM10, and NOx) and Alzheimer's disease genetic risk score (AD-GRS) on the development of AD using a Cox proportional hazards model. Among participants with a high AD-GRS, those exposed to NOx levels of ≥50 µg/m3 had a significantly higher risk of AD compared to those in the group exposed to NOx levels of <50 µg/m3 (HR = 1.36; 95% CI: 1.03-1.18; p < 0.05). Regardless of air pollutant levels (PM2.5, PM10, or NOx), participants with a high AD-GRS had a significantly increased risk of developing AD. Similar results were obtained when assessing multiple variables using inverse probability of treatment weighting (IPTW). Conclusion: Our findings indicate that individuals living in areas with PM2.5 levels of ≥10 µg/m3 or NOx levels of ≥50 µg/m3 are at a higher risk of developing all-cause dementia. Moreover, individuals with a high AD-GRS demonstrated an increased risk of developing AD, particularly in the presence of NOx ≥ 50 µg/m3.
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BACKGROUND: Atherosclerosis (AS) and tumours are the leading causes of death worldwide and share common risk factors, detection methods and molecular markers. Therefore, searching for serum markers shared by AS and tumours is beneficial to the early diagnosis of patients. METHODS: The sera of 23 patients with AS-related transient ischaemic attack were screened by serological identification of antigens through recombinant cDNA expression cloning (SEREX), and cDNA clones were identified. Pathway function enrichment analysis was performed on cDNA clones to identify their biological pathways and determine whether they were related to AS or tumours. Subsequently, gene-gene and protein-protein interactions were performed and AS-associated markers would be discovered. The expression of AS biomarkers in human normal organs and pan-cancer tumour tissues were explored. Then, immune infiltration level and tumour mutation burden of various immune cells were evaluated. Survival curves analysis could show the expression of AS markers in pan-cancer. RESULTS: AS-related sera were screened by SEREX, and 83 cDNA clones with high homology were obtained. Through functional enrichment analysis, it was found that their functions were closely related to AS and tumour functions. After multiple biological information interaction screening and the external cohort validating, poly(A) binding protein cytoplasmic 1 (PABPC1) was found to be a potential AS biomarker. To assess whether PABPC1 was related to pan-cancer, its expression in different tumour pathological stages and ages was screened. Since AS-associated proteins were closely related to cancer immune infiltration, we investigated and found that PABPC1 had the same role in pan-cancer. Finally, analysis of Kaplan-Meier survival curves revealed that high PABPC1 expression in pan-cancer was associated with high risk of death. CONCLUSIONS: Through the findings of SEREX and bioinformatics pan-cancer analysis, we concluded that PABPC1 might serve as a potential biomarker for the prediction and diagnosis of AS and pan-cancer.
ABSTRACT
OBJECTIVE: The impact of thrombus migration (TM) prior to endovascular thrombectomy (EVT) on clinical outcomes and revascularisation rates remains unknown. We aimed to examine whether preinterventional TM modifies the treatment effects of direct EVT versus bridging EVT in acute large vessel occlusion patients. METHODS: All patients undergoing catheter angiography in the Direct Intra-arterial thrombectomy in order to Revascularise acute ischaemic stroke patients with large vessel occlusion Efficiently in Chinese Tertiary hospitals: A Multicentre randomised clinical Trial were included. TM was determined by radiologists unaware of the study by analysing discrepancies between computed tomographic angiography at baseline and first-run digital subtraction angiography before EVT. The primary outcome was the score on the modified Rankin scale (mRS) assessed at 90 days. RESULTS: Of 627 included patients, the TM rate was 11.3% (71/627). In the multivariable logistic regression model, baseline National Institutes of Health Stroke Scale score (adjusted OR 0.956, 95% CI 0.916 to 0.999; p=0.043) and intravenous thrombolysis (adjusted OR 2.614, 95% CI 1.514 to 4.514; p<0.001) were independently associated with TM. The patients with TM were less likely to be completely recanalised than those without TM (21.27% vs 36.23%, p=0.040). The interaction of TM and the EVT treatment effect did not significantly affect mRS shift analysis (p=0.687) or mRS scores of 0 to 1 (p=0.436). CONCLUSION: Preinterventional TM does not modify the treatment effects of direct versus bridging EVT on functional outcomes in patients with acute ischaemic stroke with anterior large vessel occlusion. TM leads to a lower complete recanalisation rate.