Identifying modifiable factors and their joint effect on brain health: an exposome-wide association study.

Considerable uncertainty remains regarding the associations of multiple factors with brain health. We aimed to conduct an exposome-wide association study on neurodegenerative disease and neuropsychiatry disorders using data of participants from the UK Biobank. Multivariable Cox regression models with the least absolute shrinkage and selection operator technique as well as principal component analyses were used to evaluate the exposures in relation to common disorders of central nervous system (CNS). Restricted cubic splines were conducted to explore potential nonlinear correlations. Then, weighted standardized scores were generated based on the coefficients to calculate the joint effects of risk factors. We also estimated the potential impact of eliminating the unfavorable profiles of risk domains on CNS disorders using population attributable fraction (PAF). Finally, sensitivity analyses were performed to reduce the risk of reverse causality. The current study discovered the significantly associated exposures fell into six primary exposome categories. The joint effects of identified risk factors demonstrated higher risks for common disorders of CNS (HR = 1.278 ~ 3.743, p < 2e-16). The PAF varied by exposome categories, with lifestyle and medical history contributing to majority of disease cases. In total, we estimated that up to 3.7 ~ 64.1% of disease cases could be prevented.This study yielded modifiable variables of different categories and assessed their joint effects on common disorders of CNS. Targeting the identified exposures might help formulate effective strategies for maintaining brain health.

CAIDE Score, Alzheimer's Disease Pathology, and Cognition in Cognitively Normal Adults: The CABLE Study.

Background: Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score serves as a credible predictor of an individual's risk of dementia. However, studies on the link of the CAIDE score to Alzheimer's disease (AD) pathology are scarce. Objective: To explore the links of CAIDE score to cerebrospinal fluid (CSF) biomarkers of AD as well as to cognitive performance. Methods: In the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, we recruited 600 cognitively normal participants. Correlations between the CAIDE score and CSF biomarkers of AD as well as cognitive performance were probed through multiple linear regression models. Whether the correlation between CAIDE score and cognitive performance was mediated by AD pathology was researched by means of mediation analyses. Results: Linear regression analyses illustrated that CAIDE score was positively associated with tau-related biomarkers, including pTau (p <  0.001), tTau (p <  0.001), as well as tTau/Aß42 (p = 0.008), while it was in negative association with cognitive scores, consisting of MMSE score (p <  0.001) as well as MoCA score (p <  0.001). The correlation from CAIDE score to cognitive scores was in part mediated by tau pathology, with a mediation rate varying from 3.2% to 13.2% . Conclusions: A higher CAIDE score, as demonstrated in our study, was linked to more severe tau pathology and poorer cognitive performance, and tau pathology mediated the link of CAIDE score to cognitive performance. Increased dementia risk will lead to cognitive decline through aggravating neurodegeneration.

Amyloid pathology mediates the associations between plasma fibrinogen and cognition in non-demented adults.

Though previous studies revealed the potential associations of elevated levels of plasma fibrinogen with dementia, there is still limited understanding regarding the influence of Alzheimer's disease (AD) biomarkers on these associations. We sought to investigate the interrelationships among fibrinogen, cerebrospinal fluid (CSF) AD biomarkers, and cognition in non-demented adults. We included 1996 non-demented adults from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study and 337 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The associations of fibrinogen with AD biomarkers and cognition were explored using multiple linear regression models. The mediation analyses with 10 000 bootstrapped iterations were conducted to explore the mediating effects of AD biomarkers on cognition. In addition, interaction analyses and subgroup analyses were conducted to assess the influence of covariates on the relationships between fibrinogen and AD biomarkers. Participants exhibiting low Aß42 were designated as A+, while those demonstrating high phosphorylated tau (P-tau) and total tau (Tau) were labeled as T+ and N+, respectively. Individuals with normal measures of Aß42 and P-tau were categorized as the A-T- group, and those with abnormal levels of both Aß42 and P-tau were grouped under A+T+. Fibrinogen was higher in the A+ subgroup compared to that in the A- subgroup (p = 0.026). Fibrinogen was higher in the A+T+ subgroup compared to that in the A-T- subgroup (p = 0.011). Higher fibrinogen was associated with worse cognition and Aß pathology (all p < 0.05). Additionally, the associations between fibrinogen and cognition were partially mediated by Aß pathology (mediation proportion range 8%-28%). Interaction analyses and subgroup analyses showed that age and ApoE ε4 affect the relationships between fibrinogen and Aß pathology. Fibrinogen was associated with both cognition and Aß pathology. Aß pathology may be a critical mediator for impacts of fibrinogen on cognition.

Associations between cardiometabolic multimorbidity and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: the CABLE study.

BACKGROUND: Cardiometabolic multimorbidity is associated with an increased risk of dementia, but the pathogenic mechanisms linking them remain largely undefined. We aimed to assess the associations of cardiometabolic multimorbidity with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology to enhance our understanding of the underlying mechanisms linking cardiometabolic multimorbidity and AD. METHODS: This study included 1464 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Cardiometabolic diseases (CMD) are a group of interrelated disorders such as hypertension, diabetes, heart diseases (HD), and stroke. Based on the CMD status, participants were categorized as CMD-free, single CMD, or CMD multimorbidity. CMD multimorbidity is defined as the coexistence of two or more CMDs. The associations of cardiometabolic multimorbidity and CSF biomarkers were examined using multivariable linear regression models with demographic characteristics, the APOE ε4 allele, and lifestyle factors as covariates. Subgroup analyses stratified by age, sex, and APOE ε4 status were also performed. RESULTS: A total of 1464 individuals (mean age, 61.80 years; age range, 40-89 years) were included. The markers of phosphorylated tau-related processes (CSF P-tau181: ß = 0.165, P = 0.037) and neuronal injury (CSF T-tau: ß = 0.065, P = 0.033) were significantly increased in subjects with CMD multimorbidity (versus CMD-free), but not in those with single CMD. The association between CMD multimorbidity with CSF T-tau levels remained significant after controlling for Aß42 levels. Additionally, significantly elevated tau-related biomarkers were observed in patients with specific CMD combinations (i.e., hypertension and diabetes, hypertension and HD), especially in long disease courses. CONCLUSIONS: The presence of cardiometabolic multimorbidity was associated with tau phosphorylation and neuronal injury in cognitively normal populations. CMD multimorbidity might be a potential independent target to alleviate tau-related pathologies that can cause cognitive impairment.

PUFAs add fuel to Crohn's disease-associated AIEC-induced enteritis by exacerbating intestinal epithelial lipid peroxidation.

Polyunsaturated fatty acids (PUFAs) have been shown to exacerbate Crohn's disease (CD) by promoting lipid peroxidation (LPO) of intestinal epithelial cells (IECs). Dysbiosis of the gut microbiota may play a crucial role in this process. CD patients often exhibit an increased abundance of Escherichia coli (E. coli) in the gut, and the colonization of adherent-invasive E. coli (AIEC) is implicated in the initiation of intestinal inflammation in CD. However, the impact of AIEC on LPO remains unclear. In this study, we observed that AIEC colonization in the terminal ileum of CD patients was associated with decreased levels of glutathione peroxidase 4 (GPX4) and ferritin heavy chain (FTH) in the intestinal epithelium, along with elevated levels of 4-Hydroxynonenal (4-HNE). In vitro experiments demonstrated that AIEC infection reduced the levels of GPX4 and FTH, increased LPO, and induced ferroptosis in IECs. Furthermore, arachidonic acid (AA) and docosahexaenoic acid (DHA) supplementation in AIEC-infected IECs significantly aggravated LPO and ferroptosis. However, overexpression of GPX4 rescued AIEC-induced LPO and ferroptosis in IECs. Our results further confirmed that AIEC with AA supplementation, associated with excessive LPO and cell death in IECs, worsened colitis in the DSS mouse model and induced enteritis in the antibiotic cocktail pre-treatment mouse model in vivo. Moreover, treatment with ferrostatin-1, a ferroptosis inhibitor, alleviated AIEC with AA supplementation-induced enteritis in mice, accompanied by reduced LPO and cell death in IECs. Our findings suggest that AIEC, in combination with PUFA supplementation, can induce and exacerbate intestinal inflammation, primarily through increased LPO and ferroptosis in IECs.

Associations of cardiovascular risk factors and lifestyle behaviors with neurodegenerative disease: a Mendelian randomization study.

Previous observational studies reported that midlife clustering of cardiovascular risk factors and lifestyle behaviors were associated with neurodegenerative disease; however, these findings might be biased by confounding and reverse causality. This study aimed to investigate the causal associations of cardiovascular risk factors and lifestyle behaviors with neurodegenerative disease, using the two-sample Mendelian randomization design. Genetic variants for the modifiable risk factors and neurodegenerative disease were extracted from large-scale genome-wide association studies. The inverse-variance weighted method was used as the main analysis method, and MR-Egger regression and leave-one-out analyses were performed to identify potential violations. Genetically predicted diastolic blood pressure (DBP: OR per 1 mmHg, 0.990 [0.979-1.000]), body mass index (BMI: OR per 1 SD, 0.880 [0.825-0.939]), and educational level (OR per 1 SD, 0.698 [0.602-0.810]) were associated with lower risk of late-onset Alzheimer's disease (LOAD), while genetically predicted low-density lipoprotein (LDL: OR per 1 SD, 1.302 [1.066-1.590]) might increase LOAD risk. Genetically predicted exposures (including LDL and BMI) applied to familial AD showed the same effect. The association of LDL was also found with Amyotrophic lateral sclerosis (ALS) (LDL: OR per 1 SD, 1.180 [1.080-1.289]). This MR analysis showed that LDL, BMI, BP, and educational level were causally related to AD; a significant association between LDL and ALS risk, as well as the potential effect of sleep duration on PD risk, were also revealed. Targeting these modifiable factors was a promising strategy of neurodegenerative disease prevention.

Plasma ß2-microglobulin and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: the CABLE study.

BACKGROUND: Previous studies have suggested a correlation between elevated levels of ß2-microglobulin (B2M) and cognitive impairment. However, the existing evidence is insufficient to establish a conclusive relationship. This study aims to analyze the link of plasma B2M to cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers and cognition. METHODS: To track the dynamics of plasma B2M in preclinical AD, 846 cognitively healthy individuals in the Chinese Alzheimer's Biomarker and LifestylE (CABLE) cohort were divided into four groups (suspected non-AD pathology [SNAP], 2, 1, 0) according to the NIA-AA criteria. Multiple linear regression models were employed to examine the plasma B2M's relationship with cognitive and CSF AD biomarkers. Causal mediation analysis was conducted through 10,000 bootstrapped iterations to explore the mediating effect of AD pathology on cognition. RESULTS: We found that the levels of plasma B2M were increased in stages 1 (P = 0.0007) and 2 (P < 0.0001), in contrast to stage 0. In total participants, higher levels of B2M were associated with worse cognitive performance (P = 0.006 for MMSE; P = 0.012 for MoCA). Moreover, a higher level of B2M was associated with decreases in Aß1-42 (P < 0.001) and Aß1-42/Aß1-40 (P = 0.015) as well as increases in T-tau/Aß1-42 (P < 0.001) and P-tau/Aß1-42 (P < 0.001). The subgroup analysis found B2M correlated with Aß1-42 in non-APOE ε4 individuals (P < 0.001) but not in APOE ε4 carriers. Additionally, the link between B2M and cognition was partially mediated by Aß pathology (percentage: 8.6 to 19.3%), whereas tau pathology did not mediate this effect. CONCLUSIONS: This study demonstrated the association of plasma B2M with CSF AD biomarkers as well as a possible important role of Aß pathology in the association between B2M and cognitive impairment, particularly in cognitively normal individuals. The results indicated that B2M could be a potential biomarker for preclinical AD and might have varied functions throughout various stages of preclinical AD progression.

Crohn's disease-associated AIEC inhibiting intestinal epithelial cell-derived exosomal let-7b expression regulates macrophage polarization to exacerbate intestinal fibrosis.

The interaction between adherent-invasive Escherichia coli (AIEC) and intestinal macrophages is implicated in the pathogenesis of Crohn's disease (CD). However, its role in intestinal fibrogenesis and the underlying molecular mechanisms are poorly understood. In addition, miRNAs such as let-7b may participate in AIEC-macrophage interactions. In this study, we identified that the colonization of AIEC in the ileum was associated with enhanced intestinal fibrosis and reduced let-7b expression by enrolling a prospective cohort of CD patients undergoing ileocolectomy. Besides, AIEC-infected IL-10-/- mice presented more severe intestinal fibrosis and could be improved by exogenous let-7b. Mechanistically, intestinal macrophages were found to be the main target of let-7b. Transferring let-7b-overexpressing macrophages to AIEC-infected IL-10-/- mice significantly alleviated intestinal fibrosis. In vitro, AIEC suppressed exosomal let-7b derived from intestinal epithelial cells (IECs), instead of the direct inhibition of let-7b in macrophages, to promote macrophages to a fibrotic phenotype. Finally, TGFßR1 was identified as one target of let-7b that regulates macrophage polarization. Overall, the results of our work indicate that AIEC is associated with enhanced intestinal fibrosis in CD. AIEC could inhibit exosomal let-7b from IECs to promote intestinal macrophages to a fibrotic phenotype and then contributed to fibrogenesis. Thus, anti-AIEC or let-7b therapy may serve as novel therapeutic approaches to ameliorate intestinal fibrosis.

What is the context?Adherent-invasive Escherichia coli (AIEC) plays an important role in the pathogenesis of Crohn's disease (CD) and has a strong association with intestinal fibrosis in animal models. However, how these bacteria contribute to intestinal fibrosis in CD patients is still unclear.The plasticity of macrophages is crucial in immune tolerance and tissue repair in the gastrointestinal tract, and the abnormal interaction between macrophages and gut bacteria triggers the fibrogenesis in the intestine.The association between the miRNA let-7b and fibrosis process has been widely reported in many tissues, except the intestine.What is new?AIEC colonization in the terminal ileum is associated with severe intestinal fibrosis in CD patients and the let-7b plays an anti-fibrotic role in intestinal fibrosis.Intestinal macrophages are the key modulator of AIEC-induced fibrosis and can be promoted to an antifibrotic phenotype through let-7b-targeted TGFßR1 inhibition.AIEC suppresses intestinal epithelial cell-derived exosomal let-7b to promote intestinal macrophages to a fibrotic phenotype, rather than a direct effect on macrophage regulation.What is the impact? Anti-AIEC and let-7b therapy may serve as potential therapeutic strategies to reduce intestinal fibrosis in CD in the future.

Cerebral Small Vessel Disease Burden Predicts Neurodegeneration and Clinical Progression in Prodromal Alzheimer's Disease.

BACKGROUND: Cerebral small vessel disease (CSVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). OBJECTIVE: This study aimed to comprehensively investigated the associations of CSVD burden with cognition and AD pathologies. METHODS: A total of 546 non-demented participants (mean age, 72.1 years, range, 55-89; 47.4% female) were included. The longitudinal neuropathological and clinical correlates of CSVD burden were assessed using linear mixed-effects and Cox proportional-hazard models. Partial least squares structural equation model (PLS-SEM) was used to assess the direct and indirect effects of CSVD burden on cognition. RESULTS: We found that higher CSVD burden was associated with worse cognition (MMSE, ß= -0.239, p = 0.006; MoCA, ß= -0.493, p = 0.013), lower cerebrospinal fluid (CSF) Aß level (ß= -0.276, p < 0.001) and increased amyloid burden (ß= 0.048, p = 0.002). In longitudinal, CSVD burden contributed to accelerated rates of hippocampus atrophy, cognitive decline, and higher risk of AD dementia. Furthermore, as the results of PLS-SEM, we observed both significant direct and indirect impact of advanced age (direct, ß= -0.206, p < 0.001; indirect, ß= -0.002, p = 0.043) and CSVD burden (direct, ß= -0.096, p = 0.018; indirect, ß= -0.005, p = 0.040) on cognition by Aß-p-tau-tau pathway. CONCLUSION: CSVD burden could be a prodromal predictor for clinical and pathological progression. Simultaneously, we found that the effects were mediated by the one-direction-only sequence of pathological biomarker changes starting with Aß, through abnormal p-tau, and neurodegeneration.

Exosomal miR-103a-3p from Crohn's Creeping Fat-Derived Adipose-Derived Stem Cells Contributes to Intestinal Fibrosis by Targeting TGFBR3 and Activating Fibroblasts.

BACKGROUND AND AIMS: Mesenteric adipose tissue hypertrophy is a hallmark of Crohn's disease [CD], and creeping fat [CF] is unique to CD. Adipose-derived stem cells [ASCs] from inflammatory tissue exhibited altered biological functions. The role of ASCs isolated from CF in intestinal fibrosis and the potential mechanism remain unclear. METHODS: ASCs were isolated from CF [CF-ASCs] and disease-unaffected mesenteric adipose tissue [Ctrl-ASCs] of patients with CD. A series of in vitro and in vivo experiments were conducted to study the effects of exosomes from CF-ASCs [CF-Exos] on intestinal fibrosis and fibroblast activation. A micro-RNA microarray analysis was performed. Western blot, luciferase assay and immunofluorescence were performed to further detect the underlying mechanisms. RESULTS: The results indicated that CF-Exos promoted intestinal fibrosis by activating fibroblasts in a dose-dependent manner. They continuously promoted progression of intestinal fibrosis even after dextran sulphate sodium withdrawal. Further analysis showed that exosomal miR-103a-3p was enriched in CF-Exos and participated in exosome-mediated fibroblast activation. TGFBR3 was identified as a target gene of miR-103a-3p. Mechanistically, CF-ASCs released exosomal miR-103a-3p and promoted fibroblast activation by targeting TGFBR3 and promoting Smad2/3 phosphorylation. We also found that the expression of miR-103a-3p in diseased intestine was positively associated with the degree of CF and fibrosis score. CONCLUSION: Our findings show that exosomal miR-103a-3p from CF-ASCs promotes intestinal fibrosis by activating fibroblasts via TGFBR3 targeting, suggesting that CF-ASCs are potential therapeutic targets for intestinal fibrosis in CD.

Recognizing and monitoring infectious sources of schistosomiasis by developing deep learning models with high-resolution remote sensing images.

BACKGROUND: China is progressing towards the goal of schistosomiasis elimination, but there are still some problems, such as difficult management of infection source and snail control. This study aimed to develop deep learning models with high-resolution remote sensing images for recognizing and monitoring livestock bovine, which is an intermediate source of Schistosoma japonicum infection, and to evaluate the effectiveness of the models for real-world application. METHODS: The dataset of livestock bovine's spatial distribution was collected from the Chinese National Platform for Common Geospatial Information Services. The high-resolution remote sensing images were further divided into training data, test data, and validation data for model development. Two recognition models based on deep learning methods (ENVINet5 and Mask R-CNN) were developed with reference to the training datasets. The performance of the developed models was evaluated by the performance metrics of precision, recall, and F1-score. RESULTS: A total of 50 typical image areas were selected, 1125 bovine objectives were labeled by the ENVINet5 model and 1277 bovine objectives were labeled by the Mask R-CNN model. For the ENVINet5 model, a total of 1598 records of bovine distribution were recognized. The model precision and recall were 81.9% and 80.2%, respectively. The F1 score was 0.81. For the Mask R-CNN mode, 1679 records of bovine objectives were identified. The model precision and recall were 87.3% and 85.2%, respectively. The F1 score was 0.87. When applying the developed models to real-world schistosomiasis-endemic regions, there were 63 bovine objectives in the original image, 53 records were extracted using the ENVINet5 model, and 57 records were extracted using the Mask R-CNN model. The successful recognition ratios were 84.1% and 90.5% for the respectively developed models. CONCLUSION: The ENVINet5 model is very feasible when the bovine distribution is low in structure with few samples. The Mask R-CNN model has a good framework design and runs highly efficiently. The livestock recognition models developed using deep learning methods with high-resolution remote sensing images accurately recognize the spatial distribution of livestock, which could enable precise control of schistosomiasis.

Renal function and neurodegenerative diseases : a two-sample Mendelian randomization study.

BACKGROUND: Observational studies showed renal function had associations with Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia (LBD) and multiple sclerosis (MS). However, it is unknown whether these associations are causal. METHODS: We use a two-sample Mendelian randomization (MR) analysis to investigate causal relationships between renal function and 6 neurodegenerative diseases (NDDs): AD (including familial AD), PD, LBD, frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and MS. Blood urea nitrogen (BUN), chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) were used to measure renal function. The inverse-variance weighted (IVW) was the predominant estimation method. The results were further validated using sensitivity analysis (i.e. MR Egger regression, Cochran Q statistic of IVW, and leave-one-out method). RESULTS: There was no indication of any causative relationship of BUN, CKD, or eGFR with AD, familial AD, PD, LBD, FTD and ALS (all P values >0.05). The IVW analysis demonstrated a causal relationship between eGFR and MS [odds ratio (OR), 4.89; 95% confidence interval (CI), 1.43 to 16.71; P = 0.01] that was not verified in the MR-Egger and weighted median (all P values >0.05). However, no causal association of MS with BUN (OR, 0.91; 95% CI, 0.40-2.07; P = 0.82) and CKD (OR,1.04; 95% CI, 0.88-1.23; P = 0.66) was found. There was no single SNP that affects the overall trend. CONCLUSIONS: Our study showed that reduced eGFR was related to MS. The value of this study is that it provides a direction for further research on the relationship between reduced eGFR and MS.

Hypoxic ASCs-derived Exosomes Attenuate Colitis by Regulating Macrophage Polarization via miR-216a-5p/HMGB1 Axis.

BACKGROUND: Exosomes derived from mesenchymal stem cells have shown therapeutic effects for colitis. As a more clinically accessible resource, the therapeutic potential of exosomes from adipose-derived stem cells (ASCs) has not been fully elucidated, and whether hypoxia precondition could improve the therapeutic effect of ASC-derived exosomes in colitis remains elusive. METHODS: In this study, exosomes were derived from ASCs under normoxia (NExos) and hypoxia (HExos) and were identified by detecting their morphology, size distribution, and exosome surface markers. The concentration of inflammation-related cytokines was detected by ELISA, and macrophage phenotype-related genes were determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blot, and immunofluorescence. A miRNA microarray sequencing analysis was conducted to confirm the differentially expressed miRNAs. Dextran sulfate sodium-induced colitis was employed as an in vivo assay. RESULTS: Administration of NExos alleviated inflammation by modulating the balance of macrophages both in cellular assays and in vivo experiments, and HExos showed higher therapeutic efficiency than NExos. The miR-216a-5p in HExos was significantly enriched and promoted macrophage M2 polarization through transfer to macrophages by exosomes. The miR-216a-5p was confirmed to target the 3'-UTR of HMGB1. Mechanistically, hypoxia-induced ASCs release miR-216a-5p in an exosomal way that induced macrophage M2 polarization by regulating the HMGB1/TLR4/NF-κB signaling pathway. CONCLUSIONS: Exosomal miR-216a-5p released from hypoxia-prime ASCs showed higher therapeutic efficiency than NExos in experimental colitis by promoting the M2 macrophage phenotype, which indicated that hypoxia prime may represent a promising approach to optimizing the function of ASC-derived exosomes.

Exosomal miR-216a-5p released from hypoxia-prime ASCs showed higher therapeutic efficiency than NExos in experimental colitis by promoting the M2 macrophage phenotype, which indicated that hypoxia prime may represent a promising approach to optimize the function of ASC-derived exosomes.

Association between air pollution and CSF sTREM2 in cognitively normal older adults: The CABLE study.

OBJECTIVES: Ambient air pollution aggravates the process of Alzheimer's disease (AD) pathology. Currently, the exact inflammatory mechanisms underlying these links from clinical research remain largely unclear. METHODS: This study included 1,131 cognitively intact individuals from the Chinese Alzheimer's Biomarker and LifestylE database with data provided on cerebrospinal fluid (CSF) AD biomarkers (amyloid beta-peptide 42 [Aß42], total tau [t-tau], and phosphorylated tau [p-tau]), neuroinflammatory (CSF sTREM2), and systemic inflammatory markers (high sensitivity C-reactive protein and peripheral immune cells). The 2-year averaged levels of ambient fine particulate matter with diameter <2.5 µm (PM2.5 ), nitrogen dioxide (NO2 ), and ozone (O3 ) were estimated at each participant's residence. Multiple-adjusted models were approached to detect associations of air pollution with inflammatory markers and AD-related proteins. RESULTS: Ambient 2-year averaged exposure of PM2.5 was associated with changes of neuroinflammatory markers, that is, CSF sTREM2 (ß = -0.116, p = 0.0002). Similar results were found for O3 exposure among the elderly (ß = -0.111, p = 0.0280) or urban population (ß = -0.090, p = 0.0144). No significant evidence supported NO2 related to CSF sTREM2. For potentially causal associations with accumulated AD pathologies, the total effects of PM2.5 on CSF amyloid-related protein (CSF Aß42 and p-tau/Aß42) were partly mediated by CSF sTREM2, with proportions of 14.22% and 47.15%, respectively. Additional analyses found inverse associations between peripheral inflammatory markers with PM2.5 and NO2 , but a positive correlation with O3 . INTERPRETATION: These findings demonstrated a strong link between PM2.5 exposure and microglial dysfunction. Furthermore, CSF sTREM2 as a key mediator modulated the influences of PM2.5 exposure on AD amyloid pathologies.

Heart fatty acid-binding protein is associated with phosphorylated tau and longitudinal cognitive changes.

Background: Perturbation of lipid metabolism is associated with Alzheimer's disease (AD). Heart fatty acid-binding protein (HFABP) is an adipokine playing an important role in lipid metabolism regulation. Materials and methods: Two datasets separately enrolled 303 and 197 participants. First, we examine the associations of cerebrospinal fluid (CSF) HFABP levels with cognitive measures [including Mini-Mental State Examination (MMSE), Clinical Dementia Rating sum of boxes (CDRSB), and the cognitive section of Alzheimer's Disease Assessment Scale] and AD biomarkers (CSF amyloid beta and tau levels). Second, we examine the longitudinal associations of baseline CSF HFABP levels and the variability of HFABP with cognitive measures and AD biomarkers. Structural equation models explored the mediation effects of AD pathologies on cognition. Results: We found a significant relationship between CSF HFABP level and P-tau (dataset 1: ß = 2.04, p < 0.001; dataset 2: ß = 1.51, p < 0.001). We found significant associations of CSF HFABP with longitudinal cognitive measures (dataset 1: ADAS13, ß = 0.09, p = 0.008; CDRSB, ß = 0.10, p = 0.003; MMSE, ß = -0.15, p < 0.001; dataset 2: ADAS13, ß = 0.07, p = 0.004; CDRSB, ß = 0.07, p = 0.005; MMSE, ß = -0.09, p < 0.001) in longitudinal analysis. The variability of HFABP was associated with CSF P-tau (dataset 2: ß = 3.62, p = 0.003). Structural equation modeling indicated that tau pathology mediated the relationship between HFABP and cognition. Conclusion: Our findings demonstrated that HFABP was significantly associated with longitudinal cognitive changes, which might be partially mediated by tau pathology.

The Prevalence of Concomitant Skip Small Bowel Lesions in Crohn's Disease and Their Effects on Reoperation in Patients Undergoing Ileocolic Resection.

AIMS: Concomitant lesions in the small intestine are common in Crohn's disease (CD). This study aimed to detect the incidence of small bowel (SB) lesions in patients undergoing surgical resection for symptomatic ileocolic disease and whether concomitant SB lesions are associated with reoperation due to recurrent CD. METHODS: In this observational, historical cohort study, consecutive patients with CD undergoing primary ileocolic resection (ICR) from 2007 to 2019 were included. Clinical variables and intraoperative findings were extracted from a prospectively maintained database and analyzed by Cox proportional hazards regression models for identifying risk factors of reoperation. RESULTS: Of the 404 patients included, there were 202 (50%) patients having concomitant SB lesions, and 108 of them underwent concurrent surgical intervention for SB lesions whereas 94 did not. The presence of concomitant SB lesions was a risk factor for reoperation (p = 0.041). Subgroup analysis indicated that patients with concomitant uncomplicated SB lesions left in situ had a comparable rate of reoperation (p = 0.605) whereas patients having concomitant complicated SB lesions undergoing simultaneous surgical intervention showed a higher reoperation rate (P = 0.006) when compared with those without concomitant SB lesions. Interestingly, the adverse effects of concomitant SB lesions can be reversed in the setting of postoperative anti-TNF agents [HR 0.2; 95% CI (0.04-0.9); P=0.040]. CONCLUSIONS: Concomitant SB lesion(s), especially those complicated lesions, could be a risk factor for postoperative surgical recurrence in patients undergoing ICR. Active postoperative management strategies such as anti-TNF agents should be provided for these patients.

Risk of Dementia in Cancer Survivors: A Meta-Analysis of Population-Based Cohort Studies.

BACKGROUND: A negative association between cancer and Alzheimer's disease (AD) was revealed. OBJECTIVE: We aimed to further explore the dementia risk among cancer survivors and then among cancer survivors who received cancer treatment in subsequent subgroup analyses. METHODS: Databases of PubMed, Embase, and Cochrane Library were systematically searched from inception to April 1, 2021, following PRISMA and MOOSE guidelines. Relative risks (RR) of dementia were pooled by a random-effects model stratifying the data by potential confounding factors to explore the heterogeneity. This study is registered with PROSPERO, number CRD42021250654. RESULTS: A total of 36 studies were included in this meta-analysis, of which 16 studies were about the risk of dementia in cancer survivors, and 20 studies were about the risk of dementia in survivors who accepted cancer treatment. The pooled RR reached 0.89 ([95% CI = 0.82-0.97], I2 = 97.9%) for dementia and 0.89 ([0.83-0.95], I2 = 92.6%) for AD in cancer survivors compared with non-cancer controls. Notably, both dementia risk and AD risk significantly decreased in survivors of colon, leukemia, small intestine, and thyroid cancers (RR ranged from 0.64 to 0.92). Furthermore, prostate cancer patients treated with androgen deprivation therapy exhibited a significantly increased risk of dementia (RR:1.18 [1.09-1.27], I2 = 89.5%) and AD (RR:1.17 [1.08-1.25], I2 = 81.3%), with evidence of between-study heterogeneity. CONCLUSION: Currently, available evidence suggests that the risk of dementia among cancer survivors is decreased. However, large-scale prospective cohort studies are warranted to further prove the association.

Towards a global One Health index: a potential assessment tool for One Health performance.

BACKGROUND: A One Health approach has been increasingly mainstreamed by the international community, as it provides for holistic thinking in recognizing the close links and inter-dependence of the health of humans, animals and the environment. However, the dearth of real-world evidence has hampered application of a One Health approach in shaping policies and practice. This study proposes the development of a potential evaluation tool for One Health performance, in order to contribute to the scientific measurement of One Health approach and the identification of gaps where One Health capacity building is most urgently needed. METHODS: We describe five steps towards a global One Health index (GOHI), including (i) framework formulation; (ii) indicator selection; (iii) database building; (iv) weight determination; and (v) GOHI scores calculation. A cell-like framework for GOHI is proposed, which comprises an external drivers index (EDI), an intrinsic drivers index (IDI) and a core drivers index (CDI). We construct the indicator scheme for GOHI based on this framework after multiple rounds of panel discussions with our expert advisory committee. A fuzzy analytical hierarchy process is adopted to determine the weights for each of the indicators. RESULTS: The weighted indicator scheme of GOHI comprises three first-level indicators, 13 second-level indicators, and 57 third-level indicators. According to the pilot analysis based on the data from more than 200 countries/territories the GOHI scores overall are far from ideal (the highest score of 65.0 out of a maximum score of 100), and we found considerable variations among different countries/territories (31.8-65.0). The results from the pilot analysis are consistent with the results from a literature review, which suggests that a GOHI as a potential tool for the assessment of One Health performance might be feasible. CONCLUSIONS: GOHI-subject to rigorous validation-would represent the world's first evaluation tool that constructs the conceptual framework from a holistic perspective of One Health. Future application of GOHI might promote a common understanding of a strong One Health approach and provide reference for promoting effective measures to strengthen One Health capacity building. With further adaptations under various scenarios, GOHI, along with its technical protocols and databases, will be updated regularly to address current technical limitations, and capture new knowledge.

Risk Factors for Worsening of Bone Loss in Patients Newly Diagnosed with Inflammatory Bowel Disease.

Background: Bone loss is common in patients with inflammatory bowel disease (IBD). The aim of the present study was to determine the prevalence of metabolic bone disease in patients newly diagnosed with IBD and to identify the risk factors for bone loss over time. Methods: We performed a retrospective, both cross-sectional and longitudinal, study to extract the risk factors of bone loss (including osteopenia and osteoporosis) in patients newly diagnosed with IBD, using dual-energy X-ray absorptiometry (DXA). Results: A total of 639 patients newly diagnosed with IBD that had at least one DXA were included in the cross-sectional study. Osteopenia and osteoporosis were diagnosed in 24.6% and 5.4% of patients, respectively. Age at diagnosis, body mass index, and serum phosphorus were identified as independent factors associated with bone loss at baseline. A total of 380 of the 639 IBD patients (including 212 CD patients and 168 UC patients) with at least a second DXA scan were included in the longitudinal study. 42.6% of the patients presented a worsening of bone loss in the follow-up study. Menopause, albumin, and use of corticosteroids were identified as independent factors associated with worsening of bone loss. Conclusions: Metabolic bone disease is common in IBD patients, and there is a significant increase in prevalence of bone loss over time. Postmenopausal female, malnourished patients, and those requiring corticosteroid treatment are at risk for persistent bone loss. Therefore, BMD measurements and early intervention with supplementation of calcium and vitamin D are recommended in IBD patients with high-risk factors.

Mesenteric Adipose Tissue Contributes to Intestinal Fibrosis in Crohn's Disease Through the ATX-LPA Axis.

BACKGROUND AND AIMS: Intestinal fibrostenosis is an important cause of surgical intervention in patients with Crohn's disease [CD]. Hypertrophic mesenteric adipose tissue [MAT] is associated with the disease process of CD. The purpose of this study was to investigate the contribution of MAT to intestinal fibrosis. METHODS: MAT from surgical specimens of fibrostenotic CD patients and controls was collected for measurement of the levels of autotaxin [ATX] and lysophosphatidic acid [LPA]. ATX was inhibited in vivo in DNBS [dinitrobenzene sulfonic acid]-induced colitis mice, which were evaluated for colonic inflammation and fibrosis. 3T3-L1 cells and primary colonic fibroblasts were used in vitro to investigate the interaction between MAT and intestinal fibrosis, as well as the molecular mechanism underlying this interaction. RESULTS: MAT adjacent to the fibrostenotic intestine in CD patients showed an activated ATX-LPA axis. An in vivo study indicated that inhibition of ATX was associated with the improvement of morphology and function of diseased MAT, which was combined with ameliorated intestinal inflammation and fibrosis in DNBS-instilled mice. In vitro studies showed that hypoxia stimulated adipocyte ATX expression and that LPA stabilized adipocyte HIF-1α protein, forming an ATX-LPA-HIF-1α amplification loop and aggravating adipocyte dysfunction. LPA secreted by adipocytes bound to LPA1 on the surface of fibroblasts, promoted their proliferation and differentiation, and increased the expression of fibrosis-related factors. CONCLUSIONS: The ATX-LPA axis regulated intestinal fibrosis by influencing the proliferation and differentiation of intestinal fibroblasts. Inhibiting this axis may be a therapeutic target for intestinal fibrosis in CD.