Objectively Measured Physical Activity Is Inversely Associated With Nonalcoholic Fatty Liver Disease: The Rotterdam Study.

INTRODUCTION: The disease burden of nonalcoholic fatty liver disease (NAFLD) increases rapidly, in line with the obesity pandemic. Physical activity has been linked to a lower risk of NAFLD. However, the impact of different intensities of activity and sedentary behavior and whether their effects on NAFLD are explained by metabolic health remain unclear. METHODS: We performed cross-sectional analyses within the population-based Rotterdam Study cohort. Abdominal ultrasound and accelerometry data were collected between 2009 and 2014. NAFLD was defined as hepatic steatosis diagnosed by ultrasound, in the absence of secondary causes for steatosis: viral hepatitis, steatogenic drugs, and excessive alcohol. We categorized accelerometry data into sedentary time and light, moderate, and vigorous physical activities. RESULTS: We included 667 participants (aged 63.3 ± 6.3 years, 53% female individuals), and 34.3% had NAFLD. Total physical activity was associated with lower NAFLD prevalence adjusted for demographic, lifestyle, and socioeconomic factors (odds ratio: 0.958 per 10 min/d, 95% confidence interval [CI]: 0.929-0.986). More intensive physical activity was more strongly associated with lower NAFLD prevalence: odds ratios for light, moderate, and vigorous physical activities were 0.931 (95% CI: 0.882-0.982), 0.891 (95% CI: 0.820-0.967), and 0.740 (95% CI: 0.600-0.906) per 10 min/d, respectively. These associations were explained by metabolic health, particularly homeostatic model assessment of insulin resistance (proportion mediated: 0.59, P < 0.001) and waist circumference (proportion mediated: 1.08, P < 0.001). Beyond this indirect effect, no direct effect could be demonstrated (P = 0.282-0.827). DISCUSSION: Physical activity at each intensity is inversely associated with NAFLD prevalence, with larger effects for higher intensities of physical activity. This association is mediated by better metabolic health, mainly lower insulin resistance and waist circumference. Physical activity should therefore be incorporated into NAFLD disease management and prevention programs.

Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses.

BACKGROUND: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. METHODS: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. RESULTS: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. CONCLUSIONS: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.

The bidirectional relationship between brain structure and physical activity: A longitudinal analysis in the UK Biobank.

Physical activity is a protective factor against brain atrophy, while loss of brain volume could also be a determinant of physical activity. Therefore, we aimed to explore the bidirectional association of physical activity with brain structures in middle-aged and older adults from the UK Biobank. Overall, 3027 participants (62.45 ± 7.27 years old, 51.3% females) had data at two time points. Hippocampal volume was associated with total (ß=0.048, pFDR=0.016) and household (ß=0.075, pFDR<0.001) physical activity. Global fractional anisotropy (ß=0.042, pFDR=0.028) was also associated with household physical activity. In the opposite direction, walking was negatively associated with white matter volume (ß=-0.026, pFDR=0.008). All these associations were confirmed by the linear mixed models. Interestingly, sports at baseline were linked to hippocampal and frontal cortex volumes at follow-up but these associations disappeared after adjusting for multiple comparisons (pall>0.104). In conclusion, we found more consistent evidence that a healthier brain structure predicted higher physical activity levels than for the inverse, more established relationship.

The Cross-sectional and Longitudinal Association Between Thyroid Function and Depression: A Population-Based Study.

CONTEXT: An association of thyroid function with mood disorders has been widely suggested, but very few studies have examined this association longitudinally. OBJECTIVE: We assessed the cross-sectional and longitudinal association between thyroid function and depression in a population-based cohort. METHODS: A total of 9471 individuals were included in cross-sectional analyses, of whom 8366 had longitudinal data. At baseline, we assessed thyroid function using serum samples (thyrotropin [TSH], free thyroxine (FT4), and thyroid peroxidase antibodies) and depressive symptoms using the Centre for Epidemiologic Studies Depression (CES-D) scale. Incident depressive events (n = 1366) were continuously followed up with the CES-D and clinical interviews. We analyzed the cross-sectional association of thyroid function and thyroid disease with depressive symptoms using linear and logistic regression, and the longitudinal association with Cox proportional hazard models for depressive events. RESULTS: Lower TSH levels and lower and higher FT4 levels were cross-sectionally associated with more depressive symptoms with a B value of -0.07 per 1 unit increase of natural log-transformed TSH (95% CI -0.11; -0.04). Furthermore, hypothyroidism was cross-sectionally associated with less depressive symptoms and hyperthyroidism with more depressive symptoms. Longitudinally, there was a U-shaped association between FT4 and incident depressive events but only in euthyroid participants. CONCLUSION: We show a cross-sectional association between thyroid (dys)function with depressive symptoms, and a U-shaped association between FT4 and incident depressive events in euthyroid individuals. Our findings suggest an association of thyroid function with the risk of developing depression, albeit small. Reverse causation and additional underlying factors may also contribute to the association.

Weight-Bearing Physical Activity, Lower-Limb Muscle Mass, and Risk of Knee Osteoarthritis.

Importance: It has been demonstrated that total physical activity is not associated with risk of osteoarthritis. However, the association of different types of physical activity with incident knee osteoarthritis remains unclear. Objective: To determine whether weight-bearing recreational physical activities are associated with increased risk of incident knee osteoarthritis. Design, Setting, and Participants: This prospective cohort study used data from the Rotterdam Study (1996 to 2009), including participants with knee x-ray measurements at baseline and follow-up examinations. Participants with knee osteoarthritis at baseline were excluded. Residents aged 45 years and older of the Ommoord district in the city of Rotterdam in The Netherlands were invited to join the Rotterdam Study (78% response rate). Analysis was conducted in June 2023. Exposure: Total, weight-bearing, and non-weight-bearing recreational physical activities collected by questionnaires at baseline. Main Outcomes and Measures: Incident radiographic knee osteoarthritis measured by knee x-ray was the primary outcome, and incident symptomatic knee osteoarthritis defined by x-ray and knee pain questionnaire was the secondary outcome. The association of different types of recreational physical activity with radiographic knee osteoarthritis was examined using logistic regression within generalized estimating equation framework after adjusting for potential confounders. A prespecified stratification analysis was planned on the basis of lower-limb muscle mass index (LMI) tertiles, measured by dual-energy x-ray absorptiometry. Results: A total of 5003 individuals (2804 women [56.0%]; mean [SD] age, 64.5 [7.9] years) were included. The knee osteoarthritis incident rate was 8.4% (793 of 9483 knees) for a mean (SD) follow-up time of 6.33 (2.46) years. Higher weight-bearing activity was associated with increased odds of incident knee osteoarthritis (odds ratio [OR], 1.22; 95% CI, 1.10-1.35; P < .001), but non-weight-bearing activity was not (OR, 1.04; 95% CI, 0.95-1.15; P = .37). In the analysis stratified by LMI tertiles, the association of weight-bearing activity with incident osteoarthritis was found only among 431 patients in the lowest LMI tertile (OR, 1.53; 95% CI, 1.15-2.04; P = .003), but not among patients in the middle or high LMI tertile. Conclusions and Relevance: The findings of this study suggest that weight-bearing activity is associated with incident knee osteoarthritis in people with low levels of lower-limb muscle mass, which might be a promising avenue for tailored advice for physical activity.

Uncovering psychiatric phenotypes using unsupervised machine learning: A data-driven symptoms approach.

BACKGROUND: Current categorical classification systems of psychiatric diagnoses lead to heterogeneity of symptoms within disorders and common co-occurrence of disorders. We investigated the heterogeneous and overlapping nature of symptom endorsement in a population-based sample across three of the most common categories of psychiatric disorders: depressive disorders, anxiety disorders, and sleep-wake disorders using unsupervised machine learning approaches. METHODS: We assessed a total of 43 symptoms in a discovery sample of 6,602 participants of the population-based Rotterdam Study between 2009 and 2013, and in a replication sample of 3,005 participants between 2016 and 2020. Symptoms were assessed using the Center for Epidemiologic Studies Depression Scale, the Hospital Anxiety and Depression Scale, and the Pittsburgh Sleep Quality Index. Hierarchical clustering analysis was applied on test items and participants to investigate common patterns of symptoms co-occurrence, and further quantitatively investigated with clustering methods to find groups that may represent similar psychiatric phenotypes. RESULTS: First, clustering analyses of the questionnaire items suggested a three-cluster solution representing clusters of "mixed" symptoms, "depressed affect and nervousness", and "troubled sleep and interpersonal problems". A highly similar clustering solution was independently established in the replication sample. Second, four groups of participants could be separated, and these groups scored differently on the item clusters. CONCLUSIONS: We identified three clusters of psychiatric symptoms that most commonly co-occur in a population-based sample. These symptoms clustered stable over samples, but across the topics of depression, anxiety, and poor sleep. We identified four groups of participants that share (sub)clinical symptoms and might benefit from similar prevention or treatment strategies, despite potentially diverging, or lack of, diagnoses.

Mechanisms Linking Physical Activity with Psychiatric Symptoms Across the Lifespan: A Systematic Review.

BACKGROUND: Physical activity has been suggested as a protective factor against psychiatric symptoms. While numerous studies have focused on the magnitude of physical activity's effect on psychiatric symptoms, few have examined the potential mechanisms. OBJECTIVE: The current review aimed to synthesize scientific evidence of the mechanisms through which physical activity might reduce psychiatric symptoms across the lifespan. METHODS: We included articles that were published before March 2022 from five electronic databases (MEDLINE, Web of Science, PsycINFO, Embase, and Cochrane). A qualitative synthesis of studies was conducted. The risk of bias assessment was performed using The Joanna Briggs Institute Critical Appraisal Tool for Systematic Reviews. Studies were included if they explored the possible mechanisms through which physical activity influences psychiatric symptoms (i.e., internalizing and externalizing symptoms) across the lifespan. RESULTS: A total of 22 articles were included (three randomized controlled trials, four non-randomized controlled trials, three prospective longitudinal studies, and 12 cross-sectional studies). Overall, most of the studies focused on children, adolescents, and young adults. Our findings showed that self-esteem, self-concept, and self-efficacy were the only consistent paths through which physical activity influences psychiatric symptoms (specifically depressive and anxiety symptoms) across the lifespan. There were insufficient studies to determine the role of neurobiological mechanisms. CONCLUSIONS: Overall, future physical activity interventions with the purpose of improving mental health should consider these mechanisms (self-esteem, self-concept, self-efficacy) to develop more effective interventions. CLINICAL TRIAL REGISTRATION: The protocol of this study was registered in the PROSPERO database (registration number CRD42021239440) and published in April 2022.

Neurobiological, Psychosocial, and Behavioral Mechanisms Mediating Associations Between Physical Activity and Psychiatric Symptoms in Youth in the Netherlands.

Importance: Understanding the mechanisms by which physical activity is associated with a lower risk of psychiatric symptoms may stimulate the identification of cost-efficient strategies for preventing and treating mental illness at early life stages. Objective: To examine neurobiological, psychosocial, and behavioral mechanisms that mediate associations of physical activity with psychiatric symptoms in youth by testing an integrated model. Design, setting, and participants: Generation R is an ongoing prospective population-based cohort study collecting data from fetal life until young adulthood in a multiethnic urban population in the Netherlands. Pregnant women living in Rotterdam with an expected delivery date between April 2002 and January 2006 were eligible for participation along with their children born during this time. Data were collected at a single research center in the Erasmus Medical Center Sophia Children's Hospital. For the current study, data were analyzed from 4216 children with complete data on both exposure and outcome at ages 6, 10, and 13 years. Data were analyzed from January 2021 to November 2022. Exposures: Physical activity was ascertained at age 6 years (visit 1) via parent report and included weekly frequency and duration of walking or cycling to or from school, physical education at school, outdoor play, swimming, and sports participation. Main Outcomes and Measures: Psychiatric symptoms (internalizing and externalizing symptoms) were assessed at age 6 years (visit 1) and at age 13 years (visit 3) using the Child Behavior Checklist. Several mechanisms were explored as mediators, measured at age 10 years (visit 2). Neurobiological mechanisms included total brain volume, white matter microstructure, and resting-state connectivity assessed using a 3-T magnetic resonance imaging scanner. Psychosocial mechanisms included self-esteem, body image, and friendship. Behavioral mechanisms included sleep quality, diet quality, and recreational screen time. Pearson correlations between physical activity measures and psychiatric symptoms were calculated, with false discovery rate correction applied to account for the number of tests performed. Mediation analyses were performed when a correlation (defined as false discovery rate P < .05) between exposure and outcome was observed and were adjusted for confounders. Results: Among the 4216 children included in this study, the mean (SD) age was 6.0 (0.4) years at visit 1, and 2115 participants (50.2%) were girls. More sports participation was associated with fewer internalizing symptoms (ß for direct effect, -0.025; SE, 0.078; P = .03) but not externalizing symptoms. Self-esteem mediated the association between sports participation and internalizing symptoms (ß for indirect effect, -0.009; SE, 0.018; P = .002). No evidence was found for associations between any other neurobiological, psychosocial, or behavioral variables. No association was found between other types of physical activity and psychiatric symptoms at these ages. Conclusions and Relevance: The integrated model presented in this cohort study evaluated potential mechanisms mediating associations between physical activity and psychiatric symptoms in youth. Self-esteem mediated an association between sports participation in childhood and internalizing symptoms in adolescence; other significant mediations were not observed. Further studies might explore whether larger effects are present in certain subgroups (eg, children at high risk of developing psychiatric symptoms), different ages, or structured sport-based physical activity interventions.

Physical activity levels and brain structure in middle-aged and older adults: a bidirectional longitudinal population-based study.

Physical activity has been suggested as modifiable factor that might contribute to improving cognitive and brain function during aging. However, previous studies were mainly of cross-sectional design and did not consider effects of time or potential reverse causality. We aimed to investigate the bidirectional associations of physical activity with brain structure in middle-aged and older adults. Overall, 4365 participants (64.01 ± 10.82 years; 56% women) from the Rotterdam Study had physical activity and brain structure assessed on at least one of 2 timepoints ('baseline': 2006-2012 or 'follow-up': 2012-2017, median duration between visits: 5 years). Physical activity was assessed through the LASA Physical Activity Questionnaire. T1-weighted MRI and diffusion tensor imaging were used to quantify brain volumes and white matter microstructure, respectively. Cross-lagged panel models were performed to estimate bidirectional associations, and linear mixed-effects models to investigate the consistency of findings. Larger total brain volume (ß = 0.067, 95%-confidence interval 0.035;0.099, pFDR = 0.001), gray matter volume (ß = 0.063, 0.031;0.096, pFDR = 0.002), and white matter volume (ß = 0.051, 0.020;0.083, pFDR = 0.013) at baseline were associated with higher levels of sports at follow-up. Lower global mean diffusivity at baseline was associated with higher levels of walking at follow-up (ß = -0.074, -0.111;-0.037, pFDR = 0.001). No associations were found between physical activity levels at baseline and brain metrics at follow-up. In conclusion, larger brain volumes and white matter microstructure at baseline were associated with individuals remaining more physically active at follow-up. Overall, this study identified older adults with potentially advanced brain aging status as being at higher risk of physical inactivity over time, and therefore as potential target group for prevention and novel intervention strategies.

Time spent in physical activity, sedentary behavior, and sleep: Associations with self-rated sleep quality in middle-aged and older adults.

OBJECTIVES: We examined the associations of estimated allocations of time spent in physical activity, sedentary behavior and sleep with self-rated sleep quality. METHODS: Between 2011 and 2016, 1918 participants (mean age 71 ± 9 years, 51% women) from the population-based Rotterdam Study were included. Durations of light physical activity, moderate-to-vigorous physical activity, sedentary behavior, and sleep were assessed by accelerometry, self-rated sleep quality with the Pittsburgh Sleep Quality Index. Associations were assessed with compositional isotemporal substitution analyses. RESULTS: Spending 30 minutes more in sedentary behavior (adjusted mean difference in PSQI score: 0.21, 95% confidence interval [0.15; 0.28] or in light physical activity (adjusted mean difference in PSQI score: 0.25 [0.03; 0.46], and 30 minutes less in sleep, was associated with poorer sleep quality. CONCLUSIONS: Our findings suggest reducing sedentary behavior and increasing sleep duration might be a potential intervention target to improve sleep quality in this population of middle-aged and older adults.

Social and emotional loneliness in a large sample of Dutch adults aged 19-65: Associations with risk factors.

Loneliness is common in adults of all ages. Prior research among older adults has shown that social loneliness (feelings of missing a wider social network) and emotional loneliness (missing an intimate relationship) differ in risk factors. Therefore, this study examined risk factors of social and emotional loneliness among adults aged 19-65 years. This study was conducted within the framework of a community-based health study in the northwest of the Netherlands in 2016. Cross-sectional data of 7,885 participants were analysed using structural equation modelling. Social and emotional loneliness were measured using the validated scale of de Jong-Gierveld. Socio-demographic and health-related risk factors were self-reported. Multiple socio-demographic, health indicators and health behaviours were associated with higher scores on both types of loneliness, although the predictive power of multiple risk factors differed by type. Additionally, female gender, younger age, medium or high educational level and smoking were associated with lower social loneliness scores specifically, while having a paid job and lower body mass index were associated with lower emotional loneliness scores. To conclude, associations with risk factors were partly consistent across social and emotional loneliness, however, some important differences have been shown. These differences are important to consider when developing targeted prevention and intervention strategies.

Substitutions of physical activity, sedentary behaviour and sleep: associations with mental health in middle-aged and elderly persons.

BACKGROUND: Physical activity, sedentary behaviour and sleep are potential risk factors of mental health disorders, but previous studies have not considered the dependency between these activity domains. Therefore, we examined the associations of reallocations of time among older adults' physical activity, sedentary behaviour and sleep with depressive and anxiety symptoms using compositional isotemporal substitution analyses. METHODS: We included 1943 participants (mean age 71 years, SD: 9; 52% women) from the population-based Rotterdam Study. Between 2011 and 2016, we collected accelerometer data (mean duration 5.8 days, SD: 0.4) on physical activity, sedentary behaviour and sleep and self-reported data on depressive symptoms and anxiety. RESULTS: A reallocation of 30 min more moderate-to-vigorous physical activity was associated with a -0.55 (95% CI -1.04 to -0.06) points lower depressive symptoms score when replacing sleep and a -0.59 (95% CI -1.06 to -0.12) points lower score when replacing sedentary behaviour, but not when replacing light physical activity (-0.70, 95% CI -1.63 to 0.24). No associations were found for anxiety. CONCLUSION: Replacing sedentary behaviour or sleep with more moderate-to-vigorous physical activity was associated with less depressive symptoms, suggesting that mainly intensive types of physical activity are important for middle-aged and older adults in relation to depressive symptoms.

The interrelationship of chronic cough and depression: a prospective population-based study.

Background: Chronic cough is a debilitating medical condition that is often complicated by psychomorbidities such as depressive symptoms. Nevertheless, little is known about the impact of chronic cough on the risk of developing depression. Therefore, we investigated the association between chronic cough and prevalent, incident and recurrent depression in a population-based sample of middle-aged and older persons. Methods: Within the Rotterdam Study, a population-based cohort, we defined chronic cough as reporting daily coughing for ⩾3 months. Depression was assessed using the Center for Epidemiologic Studies Depression scale, clinical interviews and medical records. Associations between chronic cough and depression were determined with linear, logistic and Cox regression analyses. Results: The study included 5877 participants (mean±sd age 72±8 years, 59% female) who contributed 37 287 person-years of follow-up. At baseline, participants with chronic cough reported more depressive symptoms (adjusted standardised mean difference 0.15, 95% CI 0.07-0.22) compared to those without chronic cough. Over time, chronic cough was associated with an increased risk of depression in participants with a history of depression (hazard ratio (HR) 1.45, 95% CI 1.13-1.84), but not in those without a history of depression (HR 0.91, 95% CI 0.68-1.22). Conclusions: Adults with chronic cough have a disproportionate burden of depressive symptoms and an increased risk of recurrent depression. This highlights the importance of screening for depression in patients with chronic cough.

Mechanisms linking physical activity with psychiatric symptoms across the lifespan: a protocol for a systematic review.

INTRODUCTION: Persistent psychiatric symptomatology during childhood and adolescence predicts vulnerability to experience mental illness in adulthood. Physical activity is well-known to provide mental health benefits across the lifespan. However, the underlying mechanisms linking physical activity and psychiatric symptoms remain underexplored. In this context, we aim to systematically synthesise evidence focused on the mechanisms through which physical activity might reduce psychiatric symptoms across all ages. METHODS AND ANALYSIS: With the aid of a biomedical information specialist, we will develop a systematic search strategy based on the predetermined research question in the following electronic databases: MEDLINE, Embase, Web of Science, Cochrane and PsycINFO. Two independent reviewers will screen and select studies, extract data and assess the risk of bias. In case of inability to reach a consensus, a third person will be consulted. We will not apply any language restriction, and we will perform a qualitative synthesis of our findings as we anticipate that studies are scarce and heterogeneous. ETHICS AND DISSEMINATION: Only data that have already been published will be included. Then, ethical approval is not required. Findings will be published in a peer-reviewed journal and presented at conferences. Additionally, we will communicate our findings to healthcare providers and other sections of society (eg, through regular channels, including social media). PROSPERO REGISTRATION NUMBER: CRD42021239440.

Trajectories and Determinants of Physical Activity during COVID-19 Pandemic: A Population-Based Study of Middle-Aged and Elderly Individuals in The Netherlands.

Physical inactivity is a major public health problem, and there are concerns this might have increased during the COVID-19 pandemic. We aimed to identify distinct trajectories of physical activity over a 6-week period after the first restrictive measures and to explore determinants of these trajectories in a population-based cohort of middle-aged and elderly in the Netherlands (n = 5777). We observed that at least 59% of participants did not meet the World Health Organization recommendations for physical activity. Using latent class trajectory analyses over three time points, we identified five distinct trajectories, including four steady trajectories at different levels (very low, low, medium and high) and one increasing trajectory. Using multinomial logistic regression analyses, we observed that, compared to the 'steadily high' trajectory, participants in the 'steadily very low' trajectory were more often older, lower educated, reporting poorer physical health, more depressive symptoms, consuming a less healthy diet, smoking, and lower alcohol use, and were less often retired. A similar pattern of determinants was seen for those in the increasing trajectory, albeit with smaller effect sizes. Concluding, we observed low levels of physical activity that generally remained during the pandemic. The determinants we described can help identify groups that require additional preventive interventions.