AQP4 Endocytosis-Lysosome Degradation Mediated by MMP-9/ß-DG Involved in Diabetes Cognitive Impairment.

Cognitive impairment is considered to be one of the important comorbidities of diabetes, but the underlying mechanisms are widely unknown. Aquaporin-4 (AQP4) is the most abundant water channel in the central nervous system, which plays a neuroprotective role in various neurological diseases by maintaining the function of glymphatic system and synaptic plasticity. However, whether AQP4 is involved in diabetes-related cognitive impairment remains unknown. ß-dystroglycan (ß-DG), a key molecule for anchoring AQP4 on the plasma membrane of astrocytes and avoiding its targeting to lysosomes for degradation, can be cleaved by matrix metalloproteinase-9 (MMP-9). ß-DG deficiency can cause a decline in AQP4 via regulating its endocytosis. However, whether cleavage of ß-DG can affect the expression of AQP4 remains unreported. In this study, we observed that diabetes mice displayed cognitive disorder accompanied by reduction of AQP4 in prefrontal cortex. And we found that bafilomycin A1, a widely used lysosome inhibitor, could reverse the downregulation of AQP4 in diabetes, further demonstrating that the reduction of AQP4 in diabetes is a result of more endocytosis-lysosome degradation. In further experiments, we found diabetes caused the excessive activation of MMP-9/ß-DG which leaded to the loss of connection between AQP4 and ß-DG, further inducing the endocytosis of AQP4. Moreover, inhibition of MMP-9/ß-DG restored the endocytosis-lysosome degradation of AQP4 and partially alleviated cognitive dysfunction in diabetes. Our study sheds new light on the role of AQP4 in diabetes-associated cognitive disorder. And we provide a promising therapeutic target to reverse the endocytosis-lysosome degradation of AQP4 in diabetes, such as MMP-9/ß-DG.

An ACC-VTA-ACC positive-feedback loop mediates the persistence of neuropathic pain and emotional consequences.

The central mechanisms underlying pain chronicity remain elusive. Here, we identify a reciprocal neuronal circuit in mice between the anterior cingulate cortex (ACC) and the ventral tegmental area (VTA) that mediates mutual exacerbation between hyperalgesia and allodynia and their emotional consequences and, thereby, the chronicity of neuropathic pain. ACC glutamatergic neurons (ACCGlu) projecting to the VTA indirectly inhibit dopaminergic neurons (VTADA) by activating local GABAergic interneurons (VTAGABA), and this effect is reinforced after nerve injury. VTADA neurons in turn project to the ACC and synapse to the initial ACCGlu neurons to convey feedback information from emotional changes. Thus, an ACCGlu-VTAGABA-VTADA-ACCGlu positive-feedback loop mediates the progression to and maintenance of persistent pain and comorbid anxiodepressive-like behavior. Disruption of this feedback loop relieves hyperalgesia and anxiodepressive-like behavior in a mouse model of neuropathic pain, both acutely and in the long term.

Association between the triglyceride-glucose index and cognitive impairment in China: a community population-based cross-sectional study.

INTRODUCTION: Insulin resistance (IR) is a feature of metabolic syndrome and plays an important role in cognitive impairment (CI). The triglyceride-glucose (TyG) index is a convenient and cost-effective surrogate for assessing IR. This study aimed to assess the association between the TyG index and CI. METHODS: This community population-based cross-sectional study used a cluster-sampling methodology. All participants underwent the education-based Mini-Mental State Examination (MMSE), and those with CI were identified using standard thresholds. The fasting blood triglyceride and glucose levels were measured in the morning, and the TyG index was calculated as ln (½ fasting triglyceride level [mg/dL] × fasting blood glucose level [mg/dL]). Multivariable logistic regression and subgroup analysis were used to assess the relationship between the TyG index and CI. RESULTS: This study included 1484 subjects, of which 93 (6.27%) met the CI criteria. Multivariable logistic regression showed that CI incidence increased by 64% per unit increase in the TyG index (odds ratio [OR] = 1.64, 95% confidence interval [CI]: 1.02-2.63, p = 0.042). CI risk was 2.64-fold higher in the highest TyG index quartile compared to the lowest TyG index quartile (OR = 2.64, 95% CI: 1.19-5.85, p = 0.016). Finally, interaction analysis showed that sex, age, hypertension, and diabetes did not significantly affect the association between the TyG index and CI. CONCLUSION: The present study suggested that an elevated TyG index was associated with a higher CI risk. Subjects with a higher TyG index should manage and treat at an early stage to alleviate the cognitive decline.

Exploring the association between air pollution and Parkinson's disease or Alzheimer's disease: a Mendelian randomization study.

The correlation between air pollution and neurodegenerative diseases has garnered growing attention. Although observational studies have indicated a potential link between air pollution and neurodegenerative disease, establishing a causal relationship remains uncertain. To address this gap, we performed a two-sample Mendelian randomization analysis utilizing genetic instruments. This analysis aimed to investigate the causal connections between PM2.5, PM10, NO2, and NOX exposure and the occurrence of Parkinson's disease (PD) and Alzheimer's disease (AD). We implemented a series of filtering steps to identify suitable genetic instruments that demonstrated significant associations (P < 5 × 10-8) with PM2.5, PM10, NO2, and NOX. These instruments were derived from a comprehensive genome-wide association study (GWAS) encompassing up to 456,380 participants in the UK Biobank. To obtain summary statistics for PD (N = 482,730) and AD risk (N = 63,926), we utilized the most recent GWAS datasets available. For our primary analysis, we employed the inverse-variance weighted approach for two-sample MR. A multivariable MR (MVMR) was also performed to verify the impact of air pollution exposure on the risk of PD and AD. To ensure the robustness of our findings, sensitivity analyses and heterogeneity assessments were performed. In two-sample MR, by employing the inverse-variance weighted method, our result suggested that genetically NO2 exposure showed a significant association with an elevated risk of PD (OR = 4.07, 95% CI: 1.13 to 19.62, P = 0.034) and genetically PM10 exposure exhibited a significant association with a heightened risk of AD (OR = 1.93, 95% CI: 1.03-3.59, P = 0.040). Further MVMR analysis demonstrated that the causal effect between NO2 and PD disappeared (OR = 3.489, 95% CI: 0.01 to 2.1e + 03, P = 0.703), and only PM10 was associated with an increased risk of AD (OR = 6.500, 95% CI: 1.10 to 38.51, P = 0.039). Sensitivity analysis showed no detectable heterogeneity and pleiotropy (P > 0.05). Our findings demonstrate that NO2 and PM10 exposure may contribute to a risk of PD and AD, respectively. Future research is necessary to elucidate potential physiopathological mechanisms.

The protective effects of EGCG was associated with HO-1 active and microglia pyroptosis inhibition in experimental intracerebral hemorrhage.

Intracerebral hemorrhage (ICH), which has high mortality and disability rate is associated with microglial pyroptosis and neuroinflammation, and the effective treatment methods are limited Epigallocatechin-3-gallate (EGCG) has been found to play a cytoprotective role by regulating the anti-inflammatory response to pyroptosis in other systemic diseases. However, the role of EGCG in microglial pyroptosis and neuroinflammation after ICH remains unclear. In this study, we investigated the effects of EGCG pretreatment on neuroinflammation-mediated neuronal pyroptosis and the underlying neuroprotective mechanisms in experimental ICH. EGCG pretreatment was found to remarkably improved neurobehavioral performance, and decreased the hematoma volume and cerebral edema in mice. We found that EGCG pretreatment attenuated the release of hemin-induced inflammatory cytokines (IL-1ß, IL-18, and TNF-α). EGCG significantly upregulated the expression of heme oxygenase-1 (HO-1), and downregulated the levels of pyroptotic molecules and inflammatory cytokines including Caspase-1, GSDMD, NLRP3, mature IL-1ß, and IL-18. EGCG pretreatment also decreased the number of Caspase-1-positive microglia and GSDMD along with NLRP3-positive microglia after ICH. Conversely, an HO-1-specific inhibitor (ZnPP), significantly inhibited the anti-pyroptosis and anti-neuroinflammation effects of EGCG. Therefore, EGCG pretreatment alleviated microglial pyroptosis and neuroinflammation, at least in part through the Caspase-1/GSDMD/NLRP3 pathway by upregulating HO-1 expression after ICH. In addition, EGCG pretreatment promoted the polarization of microglia from the M1 phenotype to M2 phenotype after ICH. The results suggest that EGCG is a potential agent to attenuate neuroinflammation via its anti-pyroptosis effect after ICH.

Public acceptability of lumbar puncture in the diagnosis of Alzheimer's disease: a questionnaire-based single center study in China.

AIM: To investigate public acceptability of lumbar puncture in the diagnosis of Alzheimer's disease and to find out the factors influencing patient decision. METHODS: We administered a questionnaire to participants who were native to Xi'an using the "Sojump" application. Participants were required to answer the questionnaire on their cell phones following the instructions. The questions of the questionnaire were divided into four categories, including demographic data, awareness of lumbar puncture, attitudes toward lumbar puncture for the diagnosis of Alzheimer's disease, and reasons for negative attitude. Logistic regression was used to analyze the factors influencing the attitude toward lumbar puncture testing. RESULTS: A total of 1050 valid questionnaires were collected, including 403 (38.4%) from non-medical personnel and 647 (61.6%) from medical personnel. Among them, 35.7% of the participants knew about lumbar puncture examinations. Regarding the attitude, 862 participants (82.1%) had a positive attitude toward lumbar puncture in the diagnosis of Alzheimer's disease, and 508 (58.9%) of them considered lumbar puncture to be helpful in confirming the diagnosis. Multivariate analysis revealed that factors associated with a positive attitude in the non-medical group included age (OR=0.963, P=0.003, 95% CI: 0.939-0.987), education level (OR=2.073, P=0.037, 95% CI: 1.044-4.114), monthly income (OR=1.340, P=0.031, 95% CI: 1.028-1.748), and type of occupation (OR=1.569, P=0.038, 95% CI: 1.026-2.400). Factors associated with a positive attitude in the medical group included place of residence (OR=9.182, P=0.036, 95% CI: 1.151-73.238), monthly income (OR=4.008, P=0.002, 95% CI: 1.689-9.511), and hospital level (OR=38.311, P < 0.001, 95% CI: 14.323-102.478). CONCLUSIONS: More than 80% of the public has a positive attitude towards lumbar puncture in the diagnosis of Alzheimer's disease, suggesting high acceptability. However, the attitude toward lumbar puncture is depend on age, education level, economic status, and type of occupation.

Wearable multisource quantitative gait analysis of Parkinson's diseases.

As the motor symptoms of Parkinson's disease (PD) are complex and influenced by many factors, it is challenging to quantify gait abnormalities adequately using a single type of signal. Therefore, a wearable multisource gait monitoring system is developed to perform a quantitative analysis of gait abnormalities for improving the effectiveness of the clinical diagnosis. To detect multisource gait data for an accurate evaluation of gait abnormalities, force sensitive sensors, piezoelectric sensors, and inertial measurement units are integrated into the devised device. The modulation circuits and wireless framework are designed to simultaneously collect plantar pressure, dynamic deformation, and postural angle of the foot and then wirelessly transmit these collected data. With the designed system, multisource gait data from PD patients and healthy controls are collected. Multisource features for quantifying gait abnormalities are extracted and evaluated by a significance test of difference and correlation analysis. The results show that the features extracted from every single type of data are able to quantify the health status of the subjects (p < 0.001, ρ > 0.50). More importantly, the validity of multisource gait data is verified. The results demonstrate that the gait feature fusing multisource data achieves a maximum correlation coefficient of 0.831, a maximum Area Under Curve of 0.9206, and a maximum feature-based classification accuracy of 88.3%. The system proposed in this study can be applied to the gait analysis and objective evaluation of PD.

Wearable sensors and features for diagnosis of neurodegenerative diseases: A systematic review.

Objective: Neurodegenerative diseases affect millions of families around the world, while various wearable sensors and corresponding data analysis can be of great support for clinical diagnosis and health assessment. This systematic review aims to provide a comprehensive overview of the existing research that uses wearable sensors and features for the diagnosis of neurodegenerative diseases. Methods: A systematic review was conducted of studies published between 2015 and 2022 in major scientific databases such as Web of Science, Google Scholar, PubMed, and Scopes. The obtained studies were analyzed and organized into the process of diagnosis: wearable sensors, feature extraction, and feature selection. Results: The search led to 171 eligible studies included in this overview. Wearable sensors such as force sensors, inertial sensors, electromyography, electroencephalography, acoustic sensors, optical fiber sensors, and global positioning systems were employed to monitor and diagnose neurodegenerative diseases. Various features including physical features, statistical features, nonlinear features, and features from the network can be extracted from these wearable sensors, and the alteration of features toward neurodegenerative diseases was illustrated. Moreover, different kinds of feature selection methods such as filter, wrapper, and embedded methods help to find the distinctive indicator of the diseases and benefit to a better diagnosis performance. Conclusions: This systematic review enables a comprehensive understanding of wearable sensors and features for the diagnosis of neurodegenerative diseases.

Nonlinear relationship between pulse pressure and risk of cognitive impairment: A 4-year community-based cohort study in Xi'an, China.

OBJECTIVES: It has been known that pulse pressure (PP) is a risk factor for cardiovascular disease and stroke, however, the relationship between PP and cognitive impairment is unclear. METHODS: This was a community-based cohort study. Participates were followed-up for 4 years and new-onset cognitive impairment was diagnosed. Multivariable logistic regression and restricted cubic spline (RCS) were used to investigate the relationship between PP and cognitive impairment. Propensity score matching (PSM) and sensitivity analysis among ApoEε4 non-carriers were performed to confirm the results. RESULTS: 1462 participants were included at baseline and 1173 completed the follow-up. There were 42 (3.5%) new-onset cognitive impairment of whom 31 were diagnosed with MCI and 11 with dementia during the follow-up. Multivariable logistic regression analysis showed that PP was positively associated with cognitive impairment (OR = 2.853, 95% CI 1.079-7.548, p = 0.035), and RCS suggested a non-linear relationship (Pnon-linear = 0.034). The risk of cognitive impairment merely changed when the PP was below about 46.7 mmHg and increased rapidly thereafter. After the covariates were well balanced using PSM (standardized mean differences <0.1 for all covariates), logistic regression analysis revealed the risk of cognitive impairment was still higher for those with high PP (OR = 3.369, 95% CI 1.202-9.441, p = 0.021). Sensitivity analysis showed consistent results with primary analysis. CONCLUSION: PP is associated with cognitive impairment in a non-linear manner among middle-aged and elderly. The risk of cognitive impairment increases rapidly when PP exceeds about 46.7 mmHg, which may be informative for subsequent research of PP control ranges.

Loganin attenuates neuroinflammation after ischemic stroke and fracture by regulating α7nAChR-mediated microglial polarization.

Fracture in acute stage of ischemic stroke can increase inflammatory response and enhance stroke injury. Loganin alleviates the symptoms of many inflammatory diseases through its anti-inflammatory effect, but its role in ischemic stroke and fracture remains to be explored. Here, mice were handled with permanent middle cerebral artery occlusion (pMCAO) followed by tibial fracture 1 day later to establish a pMCAO+fracture model. Loganin or Methyllycaconitine (MLA, a specific a7nAchR inhibitor) were intragastrically administered 2 or 0.5 h before pMCAO, respectively. And mouse motor function and infarct volume were evaluated 3 days after pMCAO. We found that loganin alleviated the neurological deficit, cerebral infarction volume, and neuronal apoptosis (NeuN+ TUNEL+ ) in mice with pMCAO+fracture. And loganin suppressed pMCAO+fracture-induced neuroinflammation by promoting M2 microglia polarization (Iba1+ CD206+ ) and inhibiting M1 microglia polarization (Iba1+ CD11b+ ). While administration with MLA reversed the protective effect of loganin on pMCAO+fracture-induced neurological deficit and neuroinflammation. Next, LPS was used to stimulate BV2 microglia to simulate pMCAO+fracture-induced inflammatory microenvironment in vitro. Loganin facilitated the transformation of LPS-stimulated BV2 cells from M1 pro-inflammatory state (CD11b+ ) to M2 anti-inflammatory state (CD206+ ), which was antagonized by treatment with MLA. And loganin induced autophagy activation in LPS-stimulated BV2 cells by activating a7nAchR. Moreover, treatment with rapamycin (an autophagy activator) neutralized the inhibitory effect of MLA on loganin induced transformation of BV2 cells to M2 phenotype. Furthermore, BV2 cells were treated with LPS, LPS + loganin, LPS + loganin+MLA, or LPS + loganin+MLA+ rapamycin to obtain conditioned medium (CM) for stimulating primary neurons. Loganin reduced the damage of primary neurons caused by LPS-stimulated BV2 microglia through activating a7nAchR and inducing autophagy activation. In conclusion, loganin played anti-inflammatory and neuroprotective roles in pMCAO + fracture mice by activating a7nAchR, enhancing autophagy and promoting M2 polarization of microglia.

Diabetes influences the fusion of autophagosomes with lysosomes in SH-SY5Y cells and induces Aß deposition and cognitive dysfunction in STZ-induced diabetic rats.

Diabetes has been regarded as an independent risk factor for Alzheimer's disease (AD). Our previous study found that diabetes activated autophagy, but lysosome function was impaired. Autophagy-lysosome dysfunction may be involved in Aß deposition in diabetic cognitive impairment. In the present study, we used STZ-induced diabetic rats and SH-SY5Y cells to investigate whether diabetes inhibits autophagosome fusion with lysosomes. We found that in the in vivo study, STZ-induced diabetic rats exhibited cognitive dysfunction, and the lysosome function-related factors CTSL, CTSD, and Rab7 were decreased (P < 0.05). In an in vitro study, the mRFP-GFP-LC3 assay showed that the fusion of autophagosomes with lysosomes was partly blocked in SH-SY5Y cells. High glucose treatment downregulated the number of autophagolysosomes, downregulated CTSD, CTSL, and Rab7 expression (P < 0.05), and then influenced the function of ACP2 to partly block the fusion of autophagosomes and lysosomes to inhibit Aß clearance. These findings indicate that high glucose treatment affected lysosome function, interfered with the fusion of autophagosomes with lysosomes, and partly blocked autophagic flux to influence Aß clearance.

Associations among Body Mass Index, Waist-to-Hip Ratio, and Cognitive Impairment Tend to Follow an Opposite Trend and Are Sex Specific: A Population-Based Cross-Sectional Study in a Rural Area of Xi'an, China.

INTRODUCTION: The relationship between obesity and cognitive impairment (CI) is highly heterogeneous in previous studies, which may be due to insufficient consideration of anthropometric indicators and sex. This study compared the cross-sectional relationships among body mass index (BMI), waist-to-hip ratio (WHR), and CI among people aged ≥40 years, and sex-specific relationships were also considered. METHODS: This was a population-based cross-sectional study with a cluster sampling design. CI was defined as a Mini-Mental State Examination score lower than the cutoff value. Multivariate logistic regression was used. BMI and WHR were fitted as both restricted cubic splines and categorical data. Stratified analysis and interaction analysis were performed to explore the sex-specific relationship. RESULTS: A total of 1,792 subjects (40.5% male) were analyzed, and 230 were confirmed to have CI. The relationships among BMI, WHR, and CI were significant (poverall = 0.023, pnonlinear = 0.097; poverall = 0.017, pnonlinear = 0.078, respectively) but exhibited an opposite trend in the total population in the analyses with BMI and WHR as restricted cubic splines. Further categorical analyses showed that subjects with a BMI <23 kg/m2 tended to have a higher risk of CI than those with BMI ≥23 kg/m2 (16.2% vs. 11.8%, p = 0.017; OR = 1.366 [0.969-1.926], p = 0.075), and subjects with a WHR >0.92 had a significantly higher risk of CI than those with a WHR ≤0.92 (11.7% vs. 16.2%, p = 0.011; OR = 1.619 [1.161-2.258], p = 0.005). In addition, the relationship between a low BMI and CI was more significant in males (p = 0.034), while the relationship between a high WHR and CI was more significant in females (p = 0.002). Further studies are needed to confirm the sex differences because of the marginal significance result in the interaction analysis (p = 0.051 for interaction term BMI × sex; p = 0.056 for interaction term WHR × sex). CONCLUSION: The relationships among BMI, WHR, and CI exhibit an opposite trend. A low BMI or high WHR was positively associated with CI, which was more prominent in males for a low BMI and females for a high WHR.

Pulse Pressure Is Associated with Rapid Cognitive Decline over 4 Years: A Population-Based Cohort Study.

Aiming to investigate the relationship between pulse pressure (PP) and cognitive decline, cognitively normal subjects from a community-based longitudinal cohort were followed-up for 4 years. The Mini-Mental State Examination (MMSE) was used to evaluate global cognitive function, and a ≥2-point decrease in the MMSE score from baseline was defined as cognitive decline. Restricted cubic spline, multivariable linear regression and logistic regression were used to investigate the relationship between PP and cognitive decline. A total of 1173 participants completed the follow-up, and 205 (17.5%) met the criteria for cognitive decline. Restricted cubic splines showed no nonlinear relationship between PP and ΔMMSE (Poverall = 0.037, Pnon-linear = 0.289) or cognitive decline (Poverall = 0.003, Pnon-linear = 0.845). Multivariable linear regression analysis showed that PP was positively related to ΔMMSE (b = 0.021, p = 0.020). Multivariable logistic regression analysis showed that PP was positively associated with cognitive decline (OR = 1.020, p = 0.023). A stratified analysis found an association between PP and cognitive decline in participants who were aged ≤65 years, male, and APOEε4 noncarriers and who had school education ≤6 years or hypertension. A sensitivity analysis after propensity-score matching did not alter our findings. These findings highlight that elevated PP is associated with rapid cognitive decline, particularly in males, middle-aged, low-educated, hypertensive individuals and APOEε4 noncarriers.

CYP4 subfamily V member 2 (CYP4V2) polymorphisms were associated with ischemic stroke in Chinese Han population.

BACKGROUND: CYP4 subfamily V member 2 (CYP4V2) polymorphisms are related to venous thromboembolism. However, the influence of CYP4V2 polymorphisms on the susceptibility to ischemic stroke (IS) remains undetermined. METHODS: We selected and genotyped five polymorphisms of CYP4V2 in 575 cases and 575 controls to test whether CYP4V2 variants were associated with the risk for IS in a Chinese Han population. Genotyping of CYP4V2 polymorphisms was performed using the Agena MassARRAY platform. Logistic regression analysis was used to assess the association between CYP4V2 polymorphisms and IS risk by calculating odds ratios (ORs) and 95% confidence interval (CI). False-positive report probability analysis was applied to assess the noteworthy relationship of the significant findings. RESULTS: CYP4V2 rs1398007 might be a risk factor for IS (OR = 1.34, 95% CI 1.05-1.71, p = 0.009). Specially, confounding factors (age, gender, smoking and drinking status) might affect the relationship between rs1398007 and IS susceptibility. Moreover, rs1053094 and rs56413992 were associated with IS risk in males. Multifactor dimensionality reduction analysis showed the combination of rs13146272 and rs3736455 had the strongest interaction effect (information gain value of 0.40%). Furthermore, genotypes of rs1398007 (p = 0.006) and rs1053094 (p = 0.044) were associated with the levels of high-density lipoprotein cholesterol (HDL-C) among healthy controls. CONCLUSION: Our results first provided evidence that CYP4V2 rs1398007 might be a risk factor for IS, which provides instructive clues for studying the mechanisms of CYP4V2 to the pathogenesis of IS.

Protocol of End-PSCI trial: a multicenter, randomized controlled trial to evaluate the effects of DL-3-n-butylphthalide on delayed-onset post stroke cognitive impairment.

BACKGROUND: Delayed-onset post stroke cognitive impairment (PSCI) results from secondary neurodegeneration induced by stroke. Whereas targeted prevention or treatment strategies are still missing due to lack of evidences. This trial aims to evaluate the preventive effects of DL-3-n-butylphthalide (NBP) on delayed-onset PSCI. METHODS: Effects of NBP on Delayed-onset Post Stroke Cognitive Impairment (End-PSCI) is a prospective, parallel-group, open-label, multicenter, randomized controlled trial with blinded outcome assessment. Hospital patients with acute cerebral infarction (within 2 weeks of onset) will be randomized into either standard medical therapy group or standard medical therapy combined NBP treatment group (NBP 200 mg, three times per day for 24 weeks). The primary outcome is the difference of incidence of delayed-onset PSCI between two groups. The secondary outcomes include difference of white matter degeneration, cognitive scores and prevalence of early-onset PSCI between two groups. DISCUSSION: End-PSCI trial will provide evidences for NBP preventing delayed-onset PSCI. The secondary outcomes will also provide valuable insights into the pathogenesis of delayed-onset PSCI and mechanism of NBP's actions. TRIAL REGISTRATION: Trialsearch.who.int , ChiCTR2000032555, 2020/5/2, prospectively registered.

Sleep disturbance is associated with mild cognitive impairment: a community population-based cross-sectional study.

BACKGROUND: Sleep is conducive to the elimination of brain metabolites and the recovery of brain function. However, the relationship between sleep disturbance and Mild Cognitive Impairment is not fully been determined. METHODS: This was a community population-based cross-sectional study. A total of 1,443 participants from a village in the suburbs of Xi'an, China were enrolled in 2017. Sleep quality was evaluated using the Pittsburgh sleep quality index (PSQI), and sleep disturbance was defined as a PSQI score > 5. Mini-Mental State Examination (MMSE) was used to assess cognitive function and Mild Cognitive Impairment(MCI) was defined as the MMSE score less than cutoff values and meets the diagnostic criteria. Univariate and multivariate analyses were used to analyze the relationships between sleep disturbance and MCI. RESULTS: Among 1,443 subjects, 69(4.78%) had MCI, and 830 (57.52%) had sleep disturbance. In bivariate analysis, MCI was associated with sleep disturbance (ρ = 0.094, P<0.001). In the binary logistic regression, MCI was positively associated with the sleep disturbance (OR = 2.027, 95%CI = 1.112-3.698, P = 0.021). In the internal constitution of PSQI, MCI was negatively associated with the habitual sleep efficiency (OR = 0.447, 95%CI = 0.299-0.669, P < 0.001). Compared with waking up before or at 7 am, waking up after 7 am (OR = 0.555, 95%CI = 0.309-0.995, P = 0.048), or 8 am (OR = 0.296, 95%CI = 0.097-0.902, P = 0.032) was probably more likely to have normal cognition. However, people who slept more than 8 h a day might be more likely to suffer from MCI (OR = 5.560, 95%CI = 1.419-21.789, P = 0.014). CONCLUSION: Sleep disturbance is associated with Mild Cognitive Impairment. However, the causal relationship between them is not clear. It needs to be further studied.

Effects of Simvastatin on Plasma Amyloid-ß Transport in Patients with Hyperlipidemia: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Abnormal blood lipids are associated with cognitive impairment and amyloid-ß (Aß) deposition in the brain. However, the effects of statins on Alzheimer's disease (AD) have not been determined. OBJECTIVE: Considering that plasma Aß are related to Aß deposition in the brain, we investigated the effects of simvastatin on plasma Aß transport. METHODS: This was a randomized, double-blind, placebo-controlled trial. One hundred and twenty patients with hyperlipidemia were randomly assigned to receive 40 mg of simvastatin per day or matching placebo for 12 weeks (sixty patients per group). Plasma Aß, sLRP1, sRAGE, and lipid levels were measured at baseline and at the 6-week and 12-week visits. RESULTS: The ITT database ultimately included 108 participants (placebo group: n = 53; simvastatin group: n = 55) and 64 (59.3%) were women, ranging in age from 45 to 75 years (mean 57.2±6.9 years). Multiple linear regression analysis showed that, after 12 weeks of follow-up, compared with the placebo group, ΔAß42 levels (the change of Aß42 levels from baseline at week 12) increased more and ΔsRAGE levels decreased more in the simvastatin group (Aß42: ß= 5.823, p = 0.040; sRAGE: ß= -72.012, p = 0.031), and a significant negative association was found between ΔAß42 and ΔsRAGE levels (ß= -0.115, p = 0.045). In addition, generalized estimation equation analysis showed that triglycerides levels were negatively correlated with Aß40 (ß= -16.79, p = 0.023), Aß42 (ß= -6.10, p = 0.001), and sRAGE (ß= -51.16, p = 0.003). CONCLUSION: Daily oral simvastatin (40 mg/day) in patients with hyperlipidemia for 12 weeks can significantly increase plasma Aß42 levels compared with placebo, which was associated with reduced triglycerides and sRAGE levels, indicating that statins may affect plasma Aß transport.

Resting heart rate is associated with novel plasma atherosclerosis biomarkers.

BACKGROUND: Resting heart rate (RHR) is a strong predictor of adverse cardiovascular outcomes. Both soluble low-density lipoprotein receptor-related protein-1 (sLRP1) and soluble receptor for advanced glycation end products (sRAGE) are novel plasma biomarkers for atherosclerosis. In this study, we examined the potential associations between RHR and plasma sLRP1 and sRAGE levels and whether any associations might be modified by apolipoprotein E (APOE) ε4 carrier status. METHODS: This cross-sectional study included 941 apparently healthy adults aged 40 years or older. Plasma sLRP1 and sRAGE levels were measured by a commercial enzyme-linked immunosorbent assay. APOE gene polymorphisms were analyzed by a polymerase chain reaction and Sanger sequencing. RESULTS: RHR was a significant determinant of log-transformed sLRP1 (ß = 0.004; 95% confidence interval [CI], 0.002-0.007; P = 0.001) and log-transformed sRAGE (ß = 0.005; 95% CI, 0.002-0.007; P <0.001) independently of age, sex, body mass index, blood pressure, blood glucose, blood lipids, lifestyle, and medical history. Additionally, APOE ε4 carrier status was inversely associated with log-transformed plasma sLRP1 level (ß = -0.072; 95% CI, -0.130 to -0.015; P = 0.01) and did not modify the relationship between RHR and plasma sLRP1 level. CONCLUSIONS: An elevated RHR was associated with increased sLRP1 and sRAGE values, which was not modified by APOE genotype. The underlying mechanism of this effect may be relevant to the progression of atherosclerosis.

The Relationship Between Pre-existing Coronary Heart Disease and Cognitive Impairment Is Partly Explained by Reduced Left Ventricular Ejection Fraction in the Subjects Without Clinical Heart Failure: A Cross-Sectional Study.

Background: Coronary heart disease (CHD) is closely associated with cognitive impairment, especially in severe cases of heart failure. However, it is unclear whether cardiac systolic function plays a role in the relationship between pre-existing CHD and cognitive impairment in subjects without clinical heart failure. Methods: In total, 208 subjects from the First Affiliated Hospital of Xi'an Jiaotong University were recruited from June 2014 to January 2015, and were divided into CHD (n = 118) and non-CHD (n = 90) groups according to the inclusion and exclusion criteria. The global cognitive function of all subjects was assessed by the Mini-Mental State Examination (MMSE) and cognitive impairment was defined as the score lower than the cutoff value. Left ventricular ejection fraction (LVEF) was measured using transthoracic echocardiograms. The relationship among pre-existing CHD, LVEF, and cognitive impairment was analyzed by multivariate logistic regression. Results: In total, 34 subjects met the criteria of cognitive impairment. Univariate analysis showed that the cognitive impairment prevalence in the CHD group was significantly higher than that in the non-CHD group (22.0 vs. 8.9%, p = 0.011). Multivariate logistic analysis revealed that CHD was significantly associated with a higher risk of cognitive impairment (odds ratio [OR] = 3.284 [95% CI, 1.032-10.450], p = 0.044) after adjusting for confounds except for LVEF. However, the OR of CHD decreased (OR = 2.127 [95% CI, 0.624-7.254], p = 0.228) when LVEF was further corrected as a continuous variable, and LVEF was negatively associated with the risk of cognitive impairment (OR = 0.928 [95% CI, 0.882-0.976], p = 0.004). Conclusion: Pre-existing CHD is associated with a higher risk of cognitive impairment, and such an association can be considerably explained by reduced LVEF. An impaired cardiac systolic function may play a key role in the relationship between CHD and cognitive impairment among patients with pre-heart failure conditions.