Lipid metabolism mediates the association between body mass index change and bone mineral density: The Taizhou imaging study.

BACKGROUND: Limited research explores the impact of body mass index (BMI) change on osteoporosis, regarding the role of lipid metabolism. We aimed to cross-sectionally investigate these relationships in 820 Chinese participants aged 55-65 from the Taizhou Imaging Study. METHODS: We used the baseline data collected between 2013 and 2018. T-score was calculated by standardizing bone mineral density and was used for osteoporosis and osteopenia diagnosis. Multinomial logistic regression was used to examine the effect of BMI change on bone health status. Multivariable linear regression was employed to identify the metabolites corrected with BMI change and T-score. Exploratory factor analysis (EFA) and mediation analysis were conducted to ascertain the involvement of the metabolites. RESULTS: BMI increase served as a protective factor against osteoporosis (OR = 0.79[0.71-0.88], P-value<0.001) and osteopenia (OR = 0.88[0.82-0.95], P-value<0.001). Eighteen serum metabolites were associated with both BMI change and T-score. Specifically, high-density lipoprotein (HDL) substructures demonstrated negative correlations (ß = -0.08 to -0.06 and - 0.12 to -0.08, respectively), while very low-density lipoprotein (VLDL) substructions showed positive correlations (ß = 0.09 to 0.10 and 0.10 to 0.11, respectively). The two lipid factors (HDL and VLDL) extracted by EFA acted as mediators between BMI change and T-score (Prop. Mediated = 8.16% and 10.51%, all P-value<0.01). CONCLUSION: BMI gain among Chinese aged 55-65 is beneficial for reducing the risk of osteoporosis. The metabolism of HDL and VLDL partially mediates the effect of BMI change on bone loss. Our research offers novel insights into the prevention of osteoporosis, approached from the perspective of weight management and lipid metabolomics.

Disease trajectory of high neuroticism and the relevance to psychiatric disorders: A retro-prospective cohort study.

BACKGROUND: Neuroticism is a psychological personality trait that has a significant impact on public health and is also a potential predisposing factor for adverse disease outcomes; however, comprehensive studies of the subsequently developed conditions are lacking. The starting point of disease trajectory in terms of genetic variation remains unclear. METHOD: Our study included 344,609 adult participants from the UK Biobank cohort who were virtually followed up from January 1, 1997. Neuroticism levels were assessed using 12 items from the Eysenck Personality Questionnaire. We performed a phenome-wide association analysis of neuroticism and subsequent diseases. Binomial tests and logistic regression models were used to test the temporal directionality and association between disease pairs to construct disease trajectories. We also investigated the association between polygenic risk scores (PRSs) for five psychiatric traits and high neuroticism. RESULTS: The risk for 59 diseases was significantly associated with high neuroticism. Depression, anxiety, irritable bowel syndrome, migraine, spondylosis, and sleep disorders were the most likely to develop, with hazard ratios of 6.13, 3.66, 2.28, 1.74, 1.74, and 1.71, respectively. The disease trajectory network revealed two major disease clusters: cardiometabolic and chronic inflammatory diseases. Medium/high genetic risk groups stratified by the PRSs of four psychiatric traits were associated with an elevated risk of high neuroticism. We further identified eight complete phenotypic trajectory clusters of medium or high genetic risk for psychotic, anxiety-, depression-, and stress-related disorders. CONCLUSION: Neuroticism plays an important role in the development of somatic and mental disorders. The full picture of disease trajectories from the genetic risk of psychiatric traits and neuroticism in early life to a series of diseases later provides evidence for future research to explore the etiological mechanisms and precision management.

Mobility-related brain regions linking carotid intima-media thickness to specific gait performances in old age.

BACKGROUND: Gait disturbance is common in older adults with vascular diseases. However, how carotid atherosclerosis affects gait remains poorly understood. The objectives were to investigate the associations between carotid intima-media thickness and specific gait performances and explore the potential role of brain structure in mediating these associations. METHODS: A cross-sectional analysis of data from the Taizhou Imaging Study was conducted, including 707 individuals who underwent both gait and carotid ultrasound examinations. Gait assessments include the Timed-Up-and-Go test, the Tinetti test, and quantitative gait assessment using a wearable device. Quantitative parameters were summarized into independent gait domains with factor analysis. Magnetic resonance images were obtained on a 3.0-Tesla scanner, and the volumes of fifteen brain regions related to motor function (primary motor, sensorimotor), visuospatial attention (inferior posterior parietal lobules, superior posterior parietal lobules), executive control function (dorsolateral prefrontal cortex, anterior cingulate), memory (hippocampus, entorhinal cortex), motor imagery (precuneus, parahippocampus, posterior cingulated cortex), and balance (basal ganglia: pallidum, putamen, caudate, thalamus) were computed using FreeSurfer and the Desikan-Killiany atlas. Mediation analysis was conducted with carotid intima-media thickness as the predictor and mobility-related brain regions as mediators. RESULTS: Carotid intima-media thickness was found to be associated with the Timed-Up-and-Go performance (ß = 0.129, p = 0.010) as well as gait performances related to pace (ß=-0.213, p < 0.001) and symmetry (ß = 0.096, p = 0.045). Besides, gait performances were correlated with mobility-related brain regions responsible for motor, visuospatial attention, executive control, memory, and balance (all FDR < 0.05). Notably, significant regions differed depending on the gait outcomes measured. The primary motor (41.9%), sensorimotor (29.3%), visuospatial attention (inferior posterior parietal lobules, superior posterior parietal lobules) (13.8%), entorhinal cortex (36.4%), and motor imagery (precuneus, parahippocampus, posterior cingulated cortex) (27.3%) mediated the association between increased carotid intima-media thickness and poorer Timed-Up-and-Go performance. For the pace domain, the primary motor (37.5%), sensorimotor (25.8%), visuospatial attention (12.3%), entorhinal cortex (20.7%), motor imagery (24.9%), and balance (basal ganglia: pallidum, putamen, caudate, thalamus) (11.6%) acted as mediators. CONCLUSIONS: Carotid intima-media thickness is associated with gait performances, and mobility-related brain volume mediates these associations. Moreover, the distribution of brain regions regulating mobility varies in the different gait domains. Our study adds value in exploring the underlying mechanisms of gait disturbance in the aging population.

Metagenomic association analysis of cognitive impairment in community-dwelling older adults.

The gut microbiota is reportedly involved in neurodegenerative disorders, and exploration of differences in the gut microbiota in different cognitive status could provide clues for early detection and intervention in cognitive impairment. Here, we used data from the Taizhou Imaging Study (N = 516), a community-based cohort, to compare the overall structure of the gut microbiota at the species level through metagenomic sequencing, and to explore associations with cognition. Interestingly, bacteria capable of producing short-chain fatty acids (SCFAs), such as Bacteroides massiliensis, Bifidobacterium pseudocatenulatum, Fusicatenibacter saccharivorans and Eggerthella lenta, that can biotransform polyphenols, were positively associated with better cognitive performance (p < 0.05). Although Diallister invisus and Streptococcus gordonii were not obviously related to cognition, the former was dominant in individuals with mild cognitive impairment (MCI), while the later was more abundant in cognitively normal (CN) than MCI groups, and positively associated with cognitive performance (p < 0.05). Functional analysis further supported a potential role of SCFAs and lactic acid in the association between the gut microbiota and cognition. The significant associations persisted after accounting for dietary patterns. Collectively, our results demonstrate an association between the gut microbiota and cognition in the general population, indicating a potential role in cognitive impairment. The findings provide clues for microbiome biomarkers of dementia, and insight for the prevention and treatment of dementia.

BMI trajectory of rapid and excessive weight gain during adulthood is associated with bone loss: a cross-sectional study from NHANES 2005-2018.

BACKGROUND: Studies have examined the effect of weight change on osteoporosis, but the results were controversial. Among them, few had looked at weight change over the life span. This study aimed to fill this gap and investigate the association between lifetime body mass index (BMI) trajectories and bone loss. METHODS: In this cross-sectional study, participants at age 50 and above were selected from the National Health and Nutrition Examination Survey (NHANES) 2005-2018. Dual-energy X-ray Absorptiometry was used to measure the bone mineral density at the femoral neck and lumbar spine. Standard BMI criteria were used, with < 25 kg/m2 for normal, 25-29.9 kg/m2 for overweight, and ≥ 30 kg/m2 for obesity. The latent class trajectory model (LCTM) was used to identify BMI trajectories. Multinomial logistic regression models were fitted to evaluate the association between different BMI trajectories and osteoporosis or osteopenia. RESULTS: For the 9,706 eligible participants, we identified four BMI trajectories, including stable (n = 7,681, 70.14%), slight increase (n = 1253, 12.91%), increase to decrease (n = 195, 2.01%), and rapid increase (n = 577, 5.94%). Compared with individuals in the stable trajectory, individuals in the rapid increase trajectory had higher odds of osteoporosis (OR = 2.25, 95% CI 1.19-4.23) and osteopenia (OR = 1.49, 95% CI 1.02-2.17). This association was only found in the lumbar spine (OR = 2.11, 95% CI 1.06-4.2) but not in the femoral neck. In early-stage (age 25-10 years ago) weight change, staying an obesity and stable weight seemed to have protective effects on osteoporosis (OR = 0.26, 95% CI 0.08-0.77) and osteopenia (OR = 0.46, 95% CI 0.25-0.84). Meanwhile, keeping an early-stage stable and overweight was related to lower odds of osteopenia (OR = 0.53, 95% CI 0.34-0.83). No statistically significant association between recent (10 years ago to baseline) weight change and osteoporosis was found. CONCLUSIONS: Rapid and excess weight gain during adulthood is associated with a higher risk of osteoporosis. But this association varies by skeletal sites. Maintaining stable overweight and obesity at an early stage may have potentially beneficial effects on bone health.

Education, neighborhood environment, and cognitive decline: Findings from two prospective cohort studies of older adults in China.

INTRODUCTION: The impacts of education on cognitive decline across different neighborhood environments (NEs) have rarely been studied. METHODS: We investigated and compared the associations between educational attainment and cognitive decline using data of 1286 participants from the Taizhou Imaging Study (TIS) and the Shanghai Aging Study (SAS). RESULTS: Compared with low-educated participants, in TIS with disadvantaged NE, high-educated participants manifested a significantly slower decline in global cognition (.062 Z score per year, P < .001), memory (.054 Z score per year, P < .05), and attention (.065 Z score per year, P < .01), whereas in SAS with advanced NE, highly educated individuals exhibited a slower decline only in attention (.028 Z score per year, P < .05). DISCUSSION: We observed the additive effect of educational attainment and NE on cognitive decline in older adults. Education is especially important for maintaining cognitive health in a disadvantaged environment.

Association between oral health and cognitive function among Chinese older adults: the Taizhou imaging study.

BACKGROUND: We aimed to investigate the association between oral health and cognitive function in a sample of older adults from a Chinese rural community. METHODS: The cross-sectional cognitive function of 677 individuals were assessed by Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). A comprehensive profile of the oral health status was evaluated by questionnaire and clinical examination. RESULTS: Multiple covariates-adjusted regression models demonstrated decayed teeth (DT) and decayed/missing/filled teeth (DMFT) were negatively associated with MoCA score (all p < 0.05). Calculus index (CI) and clinical attachment loss (CAL) were significantly associated with the lower MoCA, short-term memory and executive function score, respectively (all p < 0.05). Additionally, participants with missing teeth unrestored tend to get lower MMSE and MoCA scores (p < 0.05). The results also showed that increased DT and CI were modestly associated with higher odds of cognitive impairment (p < 0.05). CONCLUSIONS: There is an association between oral health and global cognition. Poor periodontal status was strongly associated with worse global cognition performance, especially in the short-term memory and executive domain for the aging population.

Genome-wide associated variants of subclinical atherosclerosis among young people with HIV and gene-environment interactions.

BACKGROUND: Genome-wide association studies (GWAS) have identified some variants associated with subclinical atherosclerosis (SCA) in general population but lacking sufficient validation. Besides traditional risk factors, whether and how would genetic variants associate with SCA among people with HIV (PWH) remains to be elucidated. METHOD: A large original GWAS and gene-environment interaction analysis of SCA were conducted among Chinese PWH (n = 2850) and age/sex-matched HIV-negative controls (n = 5410). Subgroup analyses by age and functional annotations of variants were also performed. RESULTS: Different from HIV-negative counterparts, host genome had a greater impact on young PWH rather than the elders: one genome-wide significant variant (rs77741796, P = 2.20 × 10-9) and eight suggestively significant variants (P < 1 × 10-6) were identified to be specifically associated with SCA among PWH younger than 45 years. Seven genomic loci and 15 genes were mapped to play a potential role on SCA among young PWH, which were enriched in the biological processes of atrial cardiac muscle cell membrane repolarization and molecular function of protein kinase A subunit binding. Furthermore, genome-wide interaction analyses revealed significant HIV-gene interactions overall as well as gene-environment interactions with alcohol consumption, tobacco use and obesity among PWH. The identified gene-environment interaction on SCA among PWH might be useful for discovering high-risk individuals for the prevention of SCA, particularly among those with tobacco use and alcohol consumption. CONCLUSION: The present study provides new clues for the genetic contribution of SCA among young PWH and is the starting point of precision intervention targeting HIV-related atherosclerosis.

The gut microbiome in subclinical atherosclerosis: a population-based multiphenotype analysis.

OBJECTIVES: An altered microbiota, which can be described quantitatively, has been identified as playing a pivotal role in host vascular physiology, and it may contribute to various diseases. The aim of this study was to better understand the role of the gut microbiota in vascular physiology in a subclinical elderly population, and to investigate how lifestyle affects the composition of host gut microbiota to further impact the pathogenesis of vascular diseases. METHODS: We performed a population-based faecal metagenomic study over 569 elderly asymptomatic subclinical individuals in rural China. An association network was built based on clinical measurements and detailed epidemiologic questionnaires, including blood chemistry, arterial stiffness, carotid ultrasonography, and metagenomic datasets. RESULTS: By analyzing the breadth, depth and impact of each node of the association network, we found carotid arterial atherosclerosis indices, including intima-media thickness (IMT), were essential in the network, and were significantly associated with living habits, socio-economic status, and diet. Using mediation analysis, we found that higher frequency of eating fresh fruits and vegetables, and more exercise significantly reduced carotid atherosclerosis in terms of IMT, peak systolic velocity and end-diastolic velocity values through the mediation of Alistepes, Oligella and Prevotella. Gut microbes explained 16.5% of the mediation effect of lifestyle on the pathogenesis of carotid atherosclerosis. After adjustment, Faecalicatena [odds ratio (OR) = 0.12 ∼0.65] was shown to be protective against the formation of carotid atherosclerosis, independently, while Libanicoccus (OR = 1.46 ∼4.20 ) was associated with increased carotid arterial IMT. KEGG/KO Kyoto Encyclopedia of Genes and Genomes/ KEGG Orthology (KEGG/KO) analyses revealed a loss of anti-inflammation function in IMT subjects. CONCLUSION: Our study revealed a Chinese population-wide phenotype-metagenomic association network and a mediation effect of gut microbiota on carotid artery atherosclerosis, hinting at potential therapeutic and preventive uses for microbiota in vascular diseases.

Lifestyle, multi-omics features, and preclinical dementia among Chinese: The Taizhou Imaging Study.

China has the largest number of patients with dementia in the world. However, dementia in the Chinese population is still poorly understood and under-researched. Given the differences in genetic, demographic, sociocultural, lifestyle, and health profiles among Chinese and other ethnic/racial groups, it is crucial to build appropriate infrastructure for long-term longitudinal studies to advance Chinese cognitive aging and dementia research. We initiated a community-based prospective cohort-the Taizhou Imaging Study (TIS)-to accelerate the understanding of dementia and cerebrovascular diseases in Chinese. This article presents the rationale, aims, study design, and organization of TIS. In addition, we described some examples of the types of studies such a resource might support. The TIS provides a new framework for facilitating Chinese dementia research, encompassing invaluable resources including detailed epidemiological, sociocultural, neuroimaging, and omics data.

The progress of gut microbiome research related to brain disorders.

There is increasing evidence showing that the dynamic changes in the gut microbiota can alter brain physiology and behavior. Cognition was originally thought to be regulated only by the central nervous system. However, it is now becoming clear that many non-nervous system factors, including the gut-resident bacteria of the gastrointestinal tract, regulate and influence cognitive dysfunction as well as the process of neurodegeneration and cerebrovascular diseases. Extrinsic and intrinsic factors including dietary habits can regulate the composition of the microbiota. Microbes release metabolites and microbiota-derived molecules to further trigger host-derived cytokines and inflammation in the central nervous system, which contribute greatly to the pathogenesis of host brain disorders such as pain, depression, anxiety, autism, Alzheimer's diseases, Parkinson's disease, and stroke. Change of blood-brain barrier permeability, brain vascular physiology, and brain structure are among the most critical causes of the development of downstream neurological dysfunction. In this review, we will discuss the following parts: Overview of technical approaches used in gut microbiome studiesMicrobiota and immunityGut microbiota and metabolitesMicrobiota-induced blood-brain barrier dysfunctionNeuropsychiatric diseases ■ Stress and depression■ Pain and migraine■ Autism spectrum disordersNeurodegenerative diseases ■ Parkinson's disease■ Alzheimer's disease■ Amyotrophic lateral sclerosis■ Multiple sclerosisCerebrovascular disease ■ Atherosclerosis■ Stroke■ Arteriovenous malformationConclusions and perspectives.

Functional regression method for whole genome eQTL epistasis analysis with sequencing data.

BACKGROUND: Epistasis plays an essential rule in understanding the regulation mechanisms and is an essential component of the genetic architecture of the gene expressions. However, interaction analysis of gene expressions remains fundamentally unexplored due to great computational challenges and data availability. Due to variation in splicing, transcription start sites, polyadenylation sites, post-transcriptional RNA editing across the entire gene, and transcription rates of the cells, RNA-seq measurements generate large expression variability and collectively create the observed position level read count curves. A single number for measuring gene expression which is widely used for microarray measured gene expression analysis is highly unlikely to sufficiently account for large expression variation across the gene. Simultaneously analyzing epistatic architecture using the RNA-seq and whole genome sequencing (WGS) data poses enormous challenges. METHODS: We develop a nonlinear functional regression model (FRGM) with functional responses where the position-level read counts within a gene are taken as a function of genomic position, and functional predictors where genotype profiles are viewed as a function of genomic position, for epistasis analysis with RNA-seq data. Instead of testing the interaction of all possible pair-wises SNPs, the FRGM takes a gene as a basic unit for epistasis analysis, which tests for the interaction of all possible pairs of genes and use all the information that can be accessed to collectively test interaction between all possible pairs of SNPs within two genome regions. RESULTS: By large-scale simulations, we demonstrate that the proposed FRGM for epistasis analysis can achieve the correct type 1 error and has higher power to detect the interactions between genes than the existing methods. The proposed methods are applied to the RNA-seq and WGS data from the 1000 Genome Project. The numbers of pairs of significantly interacting genes after Bonferroni correction identified using FRGM, RPKM and DESeq were 16,2361, 260 and 51, respectively, from the 350 European samples. CONCLUSIONS: The proposed FRGM for epistasis analysis of RNA-seq can capture isoform and position-level information and will have a broad application. Both simulations and real data analysis highlight the potential for the FRGM to be a good choice of the epistatic analysis with sequencing data.

Intake of dietary flavonoids in relation to bone loss among U.S. adults: a promising strategy for improving bone health.

Dietary flavonoids have been recommended for improving bone health due to their antioxidant, anti-inflammatory and osteogenic properties. However, the effectiveness of each flavonoid subclass in the prevention and treatment of osteoporosis remains controversial. The objective of the current study was to examine the association between the intake of flavonoid subclasses and bone loss in 10 480 U.S. adults in the National Health and Nutrition Examination Survey. We employed a multinomial logistic regression model to calculate the odds ratios (OR) and 95% confidence intervals (95% CI). The intake of flavones, isoflavones, and flavanones was beneficially associated with osteoporosis (ORQ5 vs. Q1 = 0.44; 95% CI: 0.30-0.64 for flavones; ORQ5 vs. Q1 = 0.53; 95% CI: 0.37-0.77 for isoflavones; ORQ5 vs. Q1 = 0.66; 95% CI: 0.45-0.97 for flavanones). A higher intake of flavones and flavanones was significantly associated with a lower risk of bone loss at the femoral neck rather than the lumbar spine. Notably, stratified analysis showed that genistein had a harmful association with osteopenia in the population with lower serum calcium levels, whereas it had a beneficial association with osteoporosis in the population with higher serum calcium levels. Multiple sensitivity analyses were performed to test the robustness of the results, including subgroup analysis, exclusion of individuals' use of anti-osteoporosis, corticosteroid, and estrogenic medications, adjusting more potential confounders and calculation of the E-value. Overall, incorporating this modifiable diet into an individual's lifestyle could provide potential possibilities to prevent and ameliorate osteoporosis.

Associations of sleep behaviors and genetic risk with risk of incident osteoporosis: A prospective cohort study of 293,164 participants.

BACKGROUND: Unhealthy sleep behaviors are associated with higher risks of osteoporosis (OP), while prospective evidence is limited. This study aimed to prospectively investigate this association, quantify the attributable burden of OP incidence reduction due to unhealthy sleep behaviors, and explore potential modifications by genetic risk factors. METHODS: This longitudinal cohort study was conducted utilizing data from the UK Biobank, comprising 293,164 participants initially free of OP and with requisite sleep behaviors data at baseline. We followed the participants after recruitment until November 30, 2022, to ascertain incident OP. We assessed the associations of five sleep behaviors including sleep duration, chronotype, insomnia, daytime napping, and morning wake-up difficulties, as well as sleep behavior patterns identified based on the above sleep behaviors, with the risk of OP, using Cox models adjusted for multiple confounders. The analyses were then performed separately among individuals with different OP susceptibility, indexed by standard polygenetic risk scores(PRS) for OP. Our secondary outcome was OP with pathologic fracture. Subgroup and sensitivity analyses were performed. Additionally, attributable risk percent in the exposed population (AR%) and population attributable fraction (PAF) of sleep behaviors were calculated. RESULTS: Over a median follow-up of 13.7 years, 8253 new-onset OP cases were documented. Unhealthy sleep behaviors, such as long or short sleep duration, insomnia, daytime napping, morning wake-up difficulties, and unhealthy sleep patterns, were associated with elevated risks of OP (HRs ranging from 1.14 to 1.46, all P-value <0.001) compared to healthy sleep behaviors. Similar associations were observed for OP with pathologic fractures. Insomnia exhibited the largest AR% of 39.98 % (95%CI: 36.46, 43.31) and PAF of 33.25 % (95%CI: 30.00, 36.34) among healthy sleep patterns and components. A statistically significant multiplicative interaction was noted between sleep behaviors and OP PRS on OP risk (all P-interaction <0.001). CONCLUSIONS: Four unhealthy sleep behaviors and sleep behavior patterns were associated to increased OP risk, with insomnia contributing the most to OP incidence, while genetic risk for OP modified this association. These findings underscore the crucial role of adhering to healthy sleep behaviors for effective OP prevention.

Bidirectional mediation of bone mineral density and brain atrophy on their associations with gait variability.

This mediation analysis aimed to investigate the associations among areal bone mineral density, mobility-related brain atrophy, and specific gait patterns. A total of 595 participants from the Taizhou Imaging Study, who underwent both gait and bone mineral density measurements, were included in this cross-sectional analysis. We used a wearable gait tracking device to collect quantitative gait parameters and then summarized them into independent gait domains with factor analysis. Bone mineral density was measured in the lumbar spine, femoral neck, and total hip using dual-energy X-ray absorptiometry. Magnetic resonance images were obtained on a 3.0-Tesla scanner, and the volumes of brain regions related to mobility were computed using FreeSurfer. Lower bone mineral density was found to be associated with higher gait variability, especially at the site of the lumbar spine (ß = 0.174, FDR = 0.001). Besides, higher gait variability was correlated with mobility-related brain atrophy, like the primary motor cortex (ß = 0.147, FDR = 0.006), sensorimotor cortex (ß = 0.153, FDR = 0.006), and entorhinal cortex (ß = 0.106, FDR = 0.043). Bidirectional mediation analysis revealed that regional brain atrophy contributed to higher gait variability through the low lumbar spine bone mineral density (for the primary motor cortex, P = 0.018; for the sensorimotor cortex, P = 0.010) and the low lumbar spine bone mineral density contributed to higher gait variability through the primary motor and sensorimotor cortices (P = 0.026 and 0.010, respectively).

Circulating Lipoproteins Mediate the Association Between Cardiovascular Risk Factors and Cognitive Decline: A Community-Based Cohort Study.

Cardiovascular health metrics are now widely recognized as modifiable risk factors for cognitive decline and dementia. Metabolic perturbations might play roles in the linkage of cardiovascular diseases and dementia. Circulating metabolites profiling by metabolomics may improve understanding of the potential mechanism by which cardiovascular risk factors contribute to cognitive decline. In a prospective community-based cohort in China (n = 725), 312 serum metabolic phenotypes were quantified, and cardiovascular health score was calculated including smoking, exercise, sleep, diet, body mass index, blood pressure, and blood glucose. Cognitive function assessments were conducted in baseline and follow-up visits to identify longitudinal cognitive decline. A better cardiovascular health was significantly associated with lower risk of concentration decline and orientation decline (hazard ratio (HR): 0.84-0.90; p < 0.05). Apolipoprotein-A1, high-density lipoprotein (HDL) cholesterol, cholesterol ester, and phospholipid concentrations were significantly associated with a lower risk of longitudinal memory and orientation decline (p < 0.05 and adjusted-p < 0.20). Mediation analysis suggested that the negative association between health status and the risk of orientation decline was partly mediated by cholesterol ester and total lipids in HDL-2 and -3 (proportion of mediation: 7.68-8.21%, both p < 0.05). Cardiovascular risk factors were associated with greater risks of cognitive decline, which were found to be mediated by circulating lipoproteins, particularly the medium-size HDL components. These findings underscore the potential of utilizing lipoproteins as targets for early stage dementia screening and intervention. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-023-00120-2.

Sleep Pattern, Genetic Susceptibility, and Abdominal Aortic Aneurysm in UK Biobank Participants: Large-Scale Cohort Study.

Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality. Objectives: The authors aimed to explore the associations between sleep patterns and genetic susceptibility to AAA. Methods: We included 344,855 UK Biobank study participants free of AAA at baseline. A sleep pattern was defined by chronotype, sleep duration, insomnia, snoring, and daytime sleepiness, and an overall sleep score was constructed with a range from 0 to 5, where a high score denotes a healthy sleep pattern. Polygenic risk score based on 22 single nucleotide polymorphisms was categorized into tertiles and used to evaluate the genetic risk for AAA. Cox proportional hazards regression models were used to assess the association between sleep, genetic factors, and the incidence of AAA. Results: During a median of 12.59 years of follow-up, 1,622 incident AAA cases were identified. The HR per 1-point increase in the sleep score was 0.91 (95% CI: 0.86-0.96) for AAA. Unhealthy sleep patterns, defined as a sleep score ranging from 0 to 3, were found to be associated with a higher risk of AAA for the intermediate (HR: 1.18, 95% CI: 1.06-1.31) and poor sleep patterns (HR: 1.40, 95% CI: 1.13-1.73), respectively, compared to the healthy pattern. Participants with poor sleep patterns and high genetic risks had a 2.5-fold higher risk of AAA than those with healthy sleep patterns and low genetic risk. Conclusions: In this large prospective study, healthy sleep patterns were associated with a lower risk of AAA among participants with low, intermediate, or high genetic risk.

Single extracellular vesicle surface protein-based blood assay identifies potential biomarkers for detection and screening of five cancers.

Extracellular vesicles (EVs) and EV proteins are promising biomarkers for cancer liquid biopsy. Herein, we designed a case-control study involving 100 controls and 100 patients with esophageal, stomach, colorectal, liver, or lung cancer to identify common and type-specific biomarkers of plasma-derived EV surface proteins for the five cancers. EV surface proteins were profiled using a sequencing-based proximity barcoding assay. In this study, five differentially expressed proteins (DEPs) and eight differentially expressed protein combinations (DEPCs) showed promising performance (area under curve, AUC > 0.900) in pan-cancer identification [e.g., TENM2 (AUC = 0.982), CD36 (AUC = 0.974), and CD36-ITGA1 (AUC = 0.971)]. Our classification model could properly discriminate between cancer patients and controls using DEPs (AUC = 0.981) or DEPCs (AUC = 0.965). When distinguishing one cancer from the other four, the accuracy of the classification model using DEPCs (85-92%) was higher than that using DEPs (78-84%). We validated the performance in an additional 14 cancer patients and 14 controls, and achieved an AUC value of 0.786 for DEPs and 0.622 for DEPCs, highlighting the necessity to recruit a larger cohort for further validation. When clustering EVs into subpopulations, we detected cluster-specific proteins highly expressed in immune-related tissues. In the context of colorectal cancer, we identified heterogeneous EV clusters enriched in cancer patients, correlating with tumor initiation and progression. These findings provide epidemiological and molecular evidence for the clinical application of EV proteins in cancer prediction, while also illuminating their functional roles in cancer physiopathology.

Analysis of gait pattern related to high cerebral small vessel disease burden using quantitative gait data from wearable sensors.

BACKGROUND AND OBJECTIVES: Sensor-based wearable devices help to obtain a wide range of quantitative gait parameters, which provides sufficient data to investigate disease-specific gait patterns. Although cerebral small vessel disease (CSVD) plays a significant role in gait impairment, the specific gait pattern associated with a high burden of CSVD remains to be explored. METHODS: We analyzed the gait pattern related to high CSVD burden from 720 participants (aged 55-65 years, 42.5 % male) free of neurological disease in the Taizhou Imaging Study. All participants underwent detailed quantitative gait assessments (obtained from an insole-like wearable gait tracking device) and brain magnetic resonance imaging examinations. Thirty-three gait parameters were summarized into five gait domains. Sparse sliced inverse regression was developed to extract the gait pattern related to high CSVD burden. RESULTS: The specific gait pattern derived from several gait domains (i.e., angles, phases, variability, and spatio-temporal) was significantly associated with the CSVD burden (OR=1.250, 95 % CI: 1.011-1.546). The gait pattern indicates that people with a high CSVD burden were prone to have smaller gait angles, more stance time, more double support time, larger gait variability, and slower gait velocity. Furthermore, people with this gait pattern had a 25 % higher risk of a high CSVD burden. CONCLUSIONS: We established a more stable and disease-specific quantitative gait pattern related to high CSVD burden, which is prone to facilitate the identification of individuals with high CSVD burden among the community residents or the general population.

Infant age inversely correlates with gut carriage of resistance genes, reflecting modifications in microbial carbohydrate metabolism during early life.

The infant gut microbiome is increasingly recognized as a reservoir of antibiotic resistance genes, yet the assembly of gut resistome in infants and its influencing factors remain largely unknown. We characterized resistome in 4132 metagenomes from 963 infants in six countries and 4285 resistance genes were observed. The inherent resistome pattern of healthy infants (N = 272) could be distinguished by two stages: a multicompound resistance phase (Months 0-7) and a tetracycline-mupirocin-ß-lactam-dominant phase (Months 8-14). Microbial taxonomy explained 40.7% of the gut resistome of healthy infants, with Escherichia (25.5%) harboring the most resistance genes. In a further analysis with all available infants (N = 963), we found age was the strongest influencer on the resistome and was negatively correlated with the overall resistance during the first 3 years (p < 0.001). Using a random-forest approach, a set of 34 resistance genes could be used to predict age (R 2 = 68.0%). Leveraging microbial host inference analyses, we inferred the age-dependent assembly of infant resistome was a result of shifts in the gut microbiome, primarily driven by changes in taxa that disproportionately harbor resistance genes across taxa (e.g., Escherichia coli more frequently harbored resistance genes than other taxa). We performed metagenomic functional profiling and metagenomic assembled genome analyses whose results indicate that the development of gut resistome was driven by changes in microbial carbohydrate metabolism, with an increasing need for carbohydrate-active enzymes from Bacteroidota and a decreasing need for Pseudomonadota during infancy. Importantly, we observed increased acquired resistance genes over time, which was related to increased horizontal gene transfer in the developing infant gut microbiome. In summary, infant age was negatively correlated with antimicrobial resistance gene levels, reflecting a composition shift in the gut microbiome, likely driven by the changing need for microbial carbohydrate metabolism during early life.