Association of hippocampal subfield volumes with prevalence, course and incidence of depressive symptoms: The Maastricht Study.

BACKGROUND: Late-life depression has been associated with volume changes of the hippocampus. However, little is known about its association with specific hippocampal subfields over time. AIMS: We investigated whether hippocampal subfield volumes were associated with prevalence, course and incidence of depressive symptoms. METHOD: We extracted 12 hippocampal subfield volumes per hemisphere with FreeSurfer v6.0 using T1-weighted and fluid-attenuated inversion recovery 3T magnetic resonance images. Depressive symptoms were assessed at baseline and annually over 7 years of follow-up (9-item Patient Health Questionnaire). We used negative binominal, logistic, and Cox regression analyses, corrected for multiple comparisons, and adjusted for demographic, cardiovascular and lifestyle factors. RESULTS: A total of n = 4174 participants were included (mean age 60.0 years, s.d. = 8.6, 51.8% female). Larger right hippocampal fissure volume was associated with prevalent depressive symptoms (odds ratio (OR) = 1.26, 95% CI 1.08-1.48). Larger bilateral hippocampal fissure (OR = 1.37-1.40, 95% CI 1.14-1.71), larger right molecular layer (OR = 1.51, 95% CI 1.14-2.00) and smaller right cornu ammonis (CA)3 volumes (OR = 0.61, 95% CI 0.48-0.79) were associated with prevalent depressive symptoms with a chronic course. No associations of hippocampal subfield volumes with incident depressive symptoms were found. Yet, lower left hippocampal amygdala transition area (HATA) volume was associated with incident depressive symptoms with chronic course (hazard ratio = 0.70, 95% CI 0.55-0.89). CONCLUSIONS: Differences in hippocampal fissure, molecular layer and CA volumes might co-occur or follow the onset of depressive symptoms, in particular with a chronic course. Smaller HATA was associated with an increased risk of incident (chronic) depression. Our results could capture a biological foundation for the development of chronic depressive symptoms, and stresses the need to discriminate subtypes of depression to unravel its biological underpinnings.

Associations of an individual's need for cognition with structural brain damage and cognitive functioning/impairment: cross-sectional population-based study.

BACKGROUND: High cognitive activity possibly reduces the risk of cognitive decline and dementia. AIMS: To investigate associations between an individual's need to engage in cognitively stimulating activities (need for cognition, NFC) and structural brain damage and cognitive functioning in the Dutch general population with and without existing cognitive impairment. METHOD: Cross-sectional data were used from the population-based cohort of the Maastricht Study. NFC was measured using the Need For Cognition Scale. Cognitive functioning was tested in three domains: verbal memory, information processing speed, and executive functioning and attention. Values 1.5 s.d. below the mean were defined as cognitive impairment. Standardised volumes of white matter hyperintensities (WMH), cerebrospinal fluid (CSF) and presence of cerebral small vessel disease (CSVD) were derived from 3T magnetic resonance imaging. Multiple linear and binary logistic regression analyses were used adjusted for demographic, somatic and lifestyle factors. RESULTS: Participants (n = 4209; mean age 59.06 years, s.d. = 8.58; 50.1% women) with higher NFC scores had higher overall cognition scores (B = 0.21, 95% CI 0.17-0.26, P < 0.001) and lower odds for CSVD (OR = 0.74, 95% CI 0.60-0.91, P = 0.005) and cognitive impairment (OR = 0.60, 95% CI 0.48-0.76, P < 0.001) after adjustment for demographic, somatic and lifestyle factors. The association between NFC score and cognitive functioning was similar for individuals with and without prevalent cognitive impairment. We found no significant association between NFC and WMH or CSF volumes. CONCLUSIONS: A high need to engage in cognitively stimulating activities is associated with better cognitive functioning and less presence of CSVD and cognitive impairment. This suggests that, in middle-aged individuals, motivation to engage in cognitively stimulating activities may be an opportunity to improve brain health.

Retinal microvascular function and incidence and trajectories of clinically relevant depressive symptoms: the Maastricht Study.

BACKGROUND: Cerebral microvascular dysfunction may contribute to depression via disruption of brain structures involved in mood regulation, but evidence is limited. We investigated the association of retinal microvascular function, a proxy for microvascular function in the brain, with incidence and trajectories of clinically relevant depressive symptoms. METHODS: Longitudinal data are from The Maastricht Study of 5952 participants (59.9 ± 8.5 years/49.7% women) without clinically relevant depressive symptoms at baseline (2010-2017). Central retinal arteriolar equivalent and central retinal venular equivalent (CRAE and CRVE) and a composite score of flicker light-induced retinal arteriolar and venular dilation were assessed at baseline. We assessed incidence and trajectories of clinically relevant depressive symptoms (9-item Patient Health Questionnaire score ⩾10). Trajectories included continuously low prevalence (low, n = 5225 [87.8%]); early increasing, then chronic high prevalence (early-chronic, n = 157 [2.6%]); low, then increasing prevalence (late-increasing, n = 247 [4.2%]); and remitting prevalence (remitting, n = 323 [5.4%]). RESULTS: After a median follow-up of 7.0 years (range 1.0-11.0), 806 (13.5%) individuals had incident clinically relevant depressive symptoms. After full adjustment, a larger CRAE and CRVE were each associated with a lower risk of clinically relevant depressive symptoms (hazard ratios [HRs] per standard deviation [s.d.]: 0.89 [95% confidence interval (CI) 0.83-0.96] and 0.93 [0.86-0.99], respectively), while a lower flicker light-induced retinal dilation was associated with a higher risk of clinically relevant depressive symptoms (HR per s.d.: 1.10 [1.01-1.20]). Compared to the low trajectory, a larger CRAE was associated with lower odds of belonging to the early-chronic trajectory (OR: 0.83 [0.69-0.99]) and a lower flicker light-induced retinal dilation was associated with higher odds of belonging to the remitting trajectory (OR: 1.23 [1.07-1.43]). CONCLUSIONS: These findings support the hypothesis that cerebral microvascular dysfunction contributes to the development of depressive symptoms.

Social cohesion and associations with sedentary time, physical activity and dietary quality in The Maastricht Study.

INTRO: We aim to investigate the relationship between social cohesion and sedentary behavior (SB), total physical activity (PA), moderate-to-vigorous PA (MVPA), and dietary quality. Additionally, we assess whether these associations are independent of neighborhood walkability and the food environment. METHODS: A total of 7641 participants from The Maastricht Study in the Netherlands between the ages of 40 and 75 years were analyzed. Neighborhood social cohesion was obtained by participant questionnaire completed at baseline and measured by the Dutch Livability meter. Home addresses were linked to geographic information system (GIS) data from the Geoscience and Health Cohort Consortium (GECCO) to create neighborhood exposures of walkability and food environment. A thigh worn accelerometer collected data to measure sedentary time, total daily PA, and MVPA. Dietary quality was measured with a food frequency questionnaire. Multivariate linear regression analyses were adjusted for age, sex, socioeconomic position, neighborhood walkability, and food environment. RESULTS: Those living in the highest quartile area of perceived social cohesion had statistically significant lower levels of SB (Q4 B: -13.04; 95% CI = -20.23, -5.85), higher total PA (Q4 B: 4.39; 95% CI = 1.69, 7.10), and higher MVPA (Q4 B: 2.57; 95% CI = 0.83, 4.31) and better diet quality (Q4 B: 1.12; 95% CI = 0.24, 2.01) compared to the lowest quartile independent of walkability and food environment. Similar results were found using the Livability meter. CONCLUSION: We discovered neighborhood social cohesion as an important obesogenic determinant that should be considered in policymaking to encourage higher levels of PA and higher diet quality.

Data harmonization and federated learning for multi-cohort dementia research using the OMOP common data model: A Netherlands consortium of dementia cohorts case study.

BACKGROUND: Establishing collaborations between cohort studies has been fundamental for progress in health research. However, such collaborations are hampered by heterogeneous data representations across cohorts and legal constraints to data sharing. The first arises from a lack of consensus in standards of data collection and representation across cohort studies and is usually tackled by applying data harmonization processes. The second is increasingly important due to raised awareness for privacy protection and stricter regulations, such as the GDPR. Federated learning has emerged as a privacy-preserving alternative to transferring data between institutions through analyzing data in a decentralized manner. METHODS: In this study, we set up a federated learning infrastructure for a consortium of nine Dutch cohorts with appropriate data available to the etiology of dementia, including an extract, transform, and load (ETL) pipeline for data harmonization. Additionally, we assessed the challenges of transforming and standardizing cohort data using the Observational Medical Outcomes Partnership (OMOP) common data model (CDM) and evaluated our tool in one of the cohorts employing federated algorithms. RESULTS: We successfully applied our ETL tool and observed a complete coverage of the cohorts' data by the OMOP CDM. The OMOP CDM facilitated the data representation and standardization, but we identified limitations for cohort-specific data fields and in the scope of the vocabularies available. Specific challenges arise in a multi-cohort federated collaboration due to technical constraints in local environments, data heterogeneity, and lack of direct access to the data. CONCLUSION: In this article, we describe the solutions to these challenges and limitations encountered in our study. Our study shows the potential of federated learning as a privacy-preserving solution for multi-cohort studies that enhance reproducibility and reuse of both data and analyses.

Socioeconomic inequalities in health-related functioning among people with type 2 Diabetes: longitudinal analyses in the Maastricht Study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a common chronic disease that disproportionally affects disadvantaged groups. People with a low socioeconomic position (SEP) have increased risk of T2DM and people with a low SEP and T2DM have higher HbA1c-levels compared to people with T2DM and high SEP. The aim of this study is to analyze longitudinal socioeconomic differences in health-related functioning in people with T2DM. METHODS: Longitudinal data from 1,537 participants of The Maastricht Study with T2DM were used (32.6% female, mean (SD) age 62.9 (7.7) years). SEP was determined by baseline measures of education, occupation and income. Health-related functioning (physical, mental and social) was measured with the Short-Form Health Survey and the Impact on Participation and Autonomy survey (all scored from 0 to 100). Associations of SEP and health-related functioning were studied annually over a 10-year period (median (IQR) 7.0 (5.0) years, baseline 2010-2018) using linear mixed methods adjusting for demographics, HbA1c-levels and lifestyle factors. RESULTS: Participants with a low SEP had significantly worse health-related functioning compared to those with a high SEP. For example, participants with low income had lower scores for physical (-4.49[CI -5.77;-3.21]), mental (-2.61[-3.78,-1.44]) and social functioning (-9.76[-12.30;-7.23]) compared to participants with high income on a scale from 0 to 100. In addition, participants with a low education significantly declined more over time in mental (score for interaction education with time - 0.23[-0.37;-0.09]) and social functioning (-0.44[-0.77;-0.11]) compared to participants with high education. Participants with low and intermediate incomes significantly declined more over time in physical functioning (-0.17 [-0.34, -0.01 and - 0.18 [-0.36, 0.00]) compared to participants with high income. CONCLUSIONS: Among people with T2DM, those with a lower SEP had worse health-related functioning in general than people with a higher SEP. Additionally, people with T2DM and low education developed poorer mental and social functioning over time compared to people with T2DM and high education. People with T2DM and low or intermediate income declined more in physical functioning over time than those with high incomes. In addition to HbA1c-levels and lifestyle patterns, more attention is needed for socioeconomic differences in health-related functioning for people living with T2DM.

Thinner inner retinal layers are associated with lower cognitive performance, lower brain volume, and altered white matter network structure-The Maastricht Study.

INTRODUCTION: The retina may provide non-invasive, scalable biomarkers for monitoring cerebral neurodegeneration. METHODS: We used cross-sectional data from The Maastricht study (n = 3436; mean age 59.3 years; 48% men; and 21% with type 2 diabetes [the latter oversampled by design]). We evaluated associations of retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer thicknesses with cognitive performance and magnetic resonance imaging indices (global grey and white matter volume, hippocampal volume, whole brain node degree, global efficiency, clustering coefficient, and local efficiency). RESULTS: After adjustment, lower thicknesses of most inner retinal layers were significantly associated with worse cognitive performance, lower grey and white matter volume, lower hippocampal volume, and worse brain white matter network structure assessed from lower whole brain node degree, lower global efficiency, higher clustering coefficient, and higher local efficiency. DISCUSSION: The retina may provide biomarkers that are informative of cerebral neurodegenerative changes in the pathobiology of dementia.

(Pre)diabetes and a higher level of glycaemic measures are continuously associated with corneal neurodegeneration assessed by corneal confocal microscopy: the Maastricht Study.

AIMS/HYPOTHESIS: To assess the associations between glucose metabolism status and a range of continuous measures of glycaemia with corneal nerve fibre measures, as assessed using corneal confocal microscopy. METHODS: We used population-based observational cross-sectional data from the Maastricht Study of N=3471 participants (mean age 59.4 years, 48.4% men, 14.7% with prediabetes, 21.0% with type 2 diabetes) to study the associations, after adjustment for demographic, cardiovascular risk and lifestyle factors, between glucose metabolism status (prediabetes and type 2 diabetes vs normal glucose metabolism) plus measures of glycaemia (fasting plasma glucose, 2 h post-load glucose, HbA1c, skin autofluorescence [SAF] and duration of diabetes) and composite Z-scores of corneal nerve fibre measures or individual corneal nerve fibre measures (corneal nerve bifurcation density, corneal nerve density, corneal nerve length and fractal dimension). We used linear regression analysis, and, for glucose metabolism status, performed a linear trend analysis. RESULTS: After full adjustment, a more adverse glucose metabolism status was associated with a lower composite Z-score for corneal nerve fibre measures (ß coefficients [95% CI], prediabetes vs normal glucose metabolism -0.08 [-0.17, 0.03], type 2 diabetes vs normal glucose metabolism -0.14 [-0.25, -0.04]; linear trend analysis showed a p value of 0.001), and higher levels of measures of glycaemia (fasting plasma glucose, 2 h post-load glucose, HbA1c, SAF and duration of diabetes) were all significantly associated with a lower composite Z-score for corneal nerve fibre measures (per SD: -0.09 [-0.13, -0.05], -0.07 [-0.11, -0.03], -0.08 [-0.11, -0.04], -0.05 [-0.08, -0.01], -0.09 [-0.17, -0.001], respectively). In general, directionally similar associations were observed for individual corneal nerve fibre measures. CONCLUSIONS/INTERPRETATION: To our knowledge, this is the first population-based study to show that a more adverse glucose metabolism status and higher levels of glycaemic measures were all linearly associated with corneal neurodegeneration after adjustment for an extensive set of potential confounders. Our results indicate that glycaemia-associated corneal neurodegeneration is a continuous process that starts before the onset of type 2 diabetes. Further research is needed to investigate whether early reduction of hyperglycaemia can prevent corneal neurodegeneration.

Sex differences in body composition in people with prediabetes and type 2 diabetes as compared with people with normal glucose metabolism: the Maastricht Study.

AIMS/HYPOTHESIS: Obesity is a major risk factor for type 2 diabetes. However, body composition differs between women and men. In this study we investigate the association between diabetes status and body composition and whether this association is moderated by sex. METHODS: In a population-based cohort study (n=7639; age 40-75 years, 50% women, 25% type 2 diabetes), we estimated the sex-specific associations, and differences therein, of prediabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes (reference: normal glucose metabolism [NGM]) with dual-energy x-ray absorptiometry (DEXA)- and MRI-derived measures of body composition and with hip circumference. Sex differences were analysed using adjusted regression models with interaction terms of sex-by-diabetes status. RESULTS: Compared with their NGM counterparts, both women and men with prediabetes and type 2 diabetes had more fat and lean mass and a greater hip circumference. The differences in subcutaneous adipose tissue, hip circumference and total and peripheral lean mass between type 2 diabetes and NGM were greater in women than men (women minus men [W-M] mean difference [95% CI]: 15.0 cm2 [1.5, 28.5], 3.2 cm [2.2, 4.1], 690 g [8, 1372] and 443 g [142, 744], respectively). The difference in visceral adipose tissue between type 2 diabetes and NGM was greater in men than women (W-M mean difference [95% CI]: -14.8 cm2 [-26.4, -3.1]). There was no sex difference in the percentage of liver fat between type 2 diabetes and NGM. The differences in measures of body composition between prediabetes and NGM were generally in the same direction, but were not significantly different between women and men. CONCLUSIONS/INTERPRETATION: This study indicates that there are sex differences in body composition associated with type 2 diabetes. The pathophysiological significance of these sex-associated differences requires further study.

Lower heart rate variability, an index of worse autonomic function, is associated with worse beta cell response to a glycemic load in vivo-The Maastricht Study.

OBJECTIVE: We investigated, using population-based data, whether worse autonomic function, estimated from lower 24-hour heart rate variability (HRV), was associated with beta cell function, assessed from beta cell response during an oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: We used cross-sectional data from The Maastricht Study, a population-based cohort study (N = 2,007; age, mean ± SD:60 ± 8 years; 52% men; and 24% with type 2 diabetes). We used linear regression analyses with adjustment for potential confounders (demographic, cardiovascular, and lifestyle factors) to study the associations of time- and frequency-domain HRV (composite scores) with overall beta cell response (estimated from a composite score calculated from: C-peptidogenic index, overall insulin secretion, beta cell glucose sensitivity, beta cell potentiation factor, and beta cell rate sensitivity). In addition, we tested for interaction by sex and glucose metabolism status. RESULTS: After full adjustment, lower time- and frequency-domain HRV was significantly associated with lower overall beta cell response composite score (standardized beta, -0.055 [-0.098; -0.011] and - 0.051 [-0.095; -0.007], respectively). These associations were not modified by sex and there was no consistent pattern of interaction by glucose metabolism status. CONCLUSION: The present etiological study found that worse autonomic function, estimated from lower HRV, was associated with worse beta cell function, estimated from a composite score in a population-based sample which covered the entire spectrum of glucose metabolism. Hence, autonomic dysfunction may contribute to beta cell dysfunction and, ultimately, to the alteration of glucose metabolism status from normal glucose metabolism to prediabetes and type 2 diabetes.

The association of white matter connectivity with prevalence, incidence and course of depressive symptoms: The Maastricht Study.

BACKGROUND: Altered white matter brain connectivity has been linked to depression. The aim of this study was to investigate the association of markers of white matter connectivity with prevalence, incidence and course of depressive symptoms. METHODS: Markers of white matter connectivity (node degree, clustering coefficient, local efficiency, characteristic path length, and global efficiency) were assessed at baseline by 3 T MRI in the population-based Maastricht Study (n = 4866; mean ± standard deviation age 59.6 ± 8.5 years, 49.0% women; 17 406 person-years of follow-up). Depressive symptoms (9-item Patient Health Questionnaire; PHQ-9) were assessed at baseline and annually over seven years of follow-up. Major depressive disorder (MDD) was assessed with the Mini-International Neuropsychiatric Interview at baseline only. We used negative binominal, logistic and Cox regression analyses, and adjusted for demographic, cardiovascular, and lifestyle risk factors. RESULTS: A lower global average node degree at baseline was associated with the prevalence and persistence of clinically relevant depressive symptoms [PHQ-9 ⩾ 10; OR (95% confidence interval) per standard deviation = 1.21 (1.05-1.39) and OR = 1.21 (1.02-1.44), respectively], after full adjustment. On the contrary, no associations were found of global average node degree with the MDD at baseline [OR 1.12 (0.94-1.32) nor incidence or remission of clinically relevant depressive symptoms [HR = 1.05 (0.95-1.17) and OR 1.08 (0.83-1.41), respectively]. Other connectivity measures of white matter organization were not associated with depression. CONCLUSIONS: Our findings suggest that fewer white matter connections may contribute to prevalent depressive symptoms and its persistence but not to incident depression. Future studies are needed to replicate our findings.

Sex comparisons in the association of prediabetes and type 2 diabetes with cognitive function, depression, and quality of life: The Maastricht study.

AIMS: There are sex differences in the excess risk of diabetes-associated cardiovascular disease. However, it is not clear whether these sex differences exist with regard to other complications like mental health aspects. Therefore, we investigated sex differences in the association of prediabetes and type 2 diabetes (T2D) with cognitive function, depression, and quality of life (QoL). MATERIALS AND METHODS: In a population-based cross-sectional cohort study (n = 7639; age 40-75 years, 50% women, 25% T2D), we estimated sex-specific associations, and differences therein, of prediabetes and T2D (reference: normal glucose metabolism) with measures of cognitive function, depression, and physical and mental QoL. Sex differences were analysed using multiple regression models with interaction terms. RESULTS: In general, T2D, but not prediabetes, was associated with higher odds of cognitive impairment, major depressive disorder, and poorer QoL. The odds ratio (OR) of cognitive impairment associated with T2D was 1.29 (95% CI: 0.96-1.72) for women and 1.39 (1.10-1.75) for men. The OR of major depressive disorder associated with T2D was 1.19 (0.69-2.04) for women and 1.68 (1.02-2.75) for men. The mean difference of the physical QoL score (ranging from 0 to 100, with 100 indicating the best possible QoL) associated with T2D was -2.09 (-2.92 to -1.25) for women and -1.81 (-2.48 to -1.13) for men. The mean difference of the mental QoL score associated with T2D was -0.90 (-1.79 to -0.02) for women and -0.52 (-1.23 to 0.20) for men. There was no clear pattern of sex differences in the associations of either prediabetes or T2D with measures of cognitive function, depression, or QoL. CONCLUSIONS: In general, T2D was associated with worse cognitive function, depression, and poorer QoL. The strength of these associations was similar among women and men.

Association of perceived and objective neighborhood walkability with accelerometer-measured physical activity and sedentary time in the Maastricht Study.

BACKGROUND: We investigated the association of neighborhood walkability with accelerometer-measured physical activity (PA) and sedentary behavior (SB) and examined whether objective and subjective measures of walkability resulted in similar findings. METHODS: PA and SB from the first 7689 Maastricht Study participants ages 40-75 from 2010 to 2017 were measured using accelerometers for 7 days. Mean daily step count, light-intensity PA, moderate- to vigorous- intensity PA (MVPA), and SB were calculated. Objective walkability was measured by the 7-component Dutch Walkability Index within 500 m Euclidean buffers around residential addresses of participants. Subjective walkability was obtained from the Abbreviated Neighborhood Environment Walkability Scale. Linear regression models analyzed the associations of walkability with PA and SB, controlling for potential confounders. RESULTS: Objective walkability was negatively associated with light intensity PA in the most walkable quartile (b = -14.58, 95% CI = -20.94, -8.23). Compared to participants living in the least walkable neighborhoods, those in the most walkable quartile had statistically significantly higher SB levels (b = 11.64, 95% CI = 4.95, 18.32). For subjective walkability, mean daily step count was significantly higher in the most walkable quartile (b = 509.60, 95% CI = 243.38, 775.81). Higher subjective walkability was positively associated with MVPA (b = 4.40, 95% CI = 2.56, 6.23). CONCLUSION: Living in a neighborhood with higher objective walkability was associated with lower levels of PA and higher SB levels while higher subjective walkability was associated with higher levels of PA. These results show discordant findings and thus, the effect of walkability on participant PA and SB within our sample is to be determined.

Cognitive resilience depends on white matter connectivity: The Maastricht Study.

INTRODUCTION: Differences in brain network connectivity may reflect the capability of the neurological substrate to compensate for brain damage and preserve cognitive function (cognitive reserve). We examined the associations between white matter connectivity, brain damage markers, and cognition in a population sample of middle-aged individuals. METHODS: A total of 4759 participants from The Maastricht Study (mean age = 59.2, SD = 8.7, 50.2% male) underwent cognitive testing and diffusion magnetic resonance imaging (dMRI), from which brain volume, structural connectivity, and vascular damage were quantified. Multivariable linear regression was used to investigate whether connectivity modified the association between brain damage and cognition, adjusted for demographic and cardiometabolic risk factors. RESULTS: More atrophic and vascular brain damage was associated with worse cognition scores. Increasing connectivity moderated the negative association between damage and cognition (χ2 = 8.64, df = 3, p ≤ 0.001); individuals with high damage but strong connectivity showed normal cognition. DISCUSSION: Findings support the reserve hypothesis by showing that brain connectivity is associated with cognitive resilience.

Sedentary behaviour and physical activity are associated with biomarkers of endothelial dysfunction and low-grade inflammation-relevance for (pre)diabetes: The Maastricht Study.

AIMS/HYPOTHESIS: Biomarkers of endothelial dysfunction and low-grade inflammation are important in the pathogenesis of CVD and can potentially be modified by physical activity and sedentary behaviour. Effects of physical activity on biomarkers of endothelial dysfunction may be especially prominent in type 2 diabetes. METHODS: In the population-based Maastricht Study (n = 2363, 51.5% male, 28.3% type 2 diabetes, 15.1% prediabetes [defined as impaired glucose tolerance and impaired fasting glucose]), we determined biomarkers of endothelial dysfunction and low-grade inflammation, and combined z scores were calculated. Physical activity and sedentary behaviour were measured by activPAL. Linear regression analyses were used with adjustment for demographic, lifestyle and cardiovascular risk factors. RESULTS: The association between total, light, moderate-to-vigorous and vigorous intensity physical activity and sedentary time on the one hand and biomarkers of endothelial dysfunction on the other were generally significant and were consistently stronger in prediabetes and type 2 diabetes as compared with normal glucose metabolism status (p for interaction <0.05). Associations between physical activity and sedentary behaviour on the one hand and low-grade inflammation on the other were also significant and were similar in individuals with and without (pre)diabetes (p for interaction >0.05). CONCLUSIONS/INTERPRETATION: Physical activity and sedentary behaviour are associated with biomarkers of endothelial dysfunction and low-grade inflammation. For biomarkers of endothelial dysfunction, associations between physical activity and sedentary behaviour were consistently stronger in (pre)diabetes than in normal glucose metabolism. Whether increasing physical activity or decreasing sedentary time can positively influence biomarkers of endothelial dysfunction in individuals with prediabetes and type 2 diabetes requires further study.

The bidirectional longitudinal association between depressive symptoms and HbA1c : A systematic review and meta-analysis.

AIM: To investigate whether there is a bidirectional longitudinal association of depression with HbA1c . METHODS: We conducted a systematic literature search in PubMed, PsycINFO, CINAHL and EMBASE for observational, longitudinal studies published from January 2000 to September 2020, assessing the association between depression and HbA1c in adults. We assessed study quality with the Newcastle-Ottawa-Scale. Pooled effect estimates were reported as partial correlation coefficients (rp ) or odds ratios (OR). RESULTS: We retrieved 1642 studies; 26 studies were included in the systematic review and eleven in the meta-analysis. Most studies (16/26) focused on type 2 diabetes. Study quality was rated as good (n = 19), fair (n = 2) and poor (n = 5). Of the meta-analysed studies, six investigated the longitudinal association between self-reported depressive symptoms and HbA1c and five the reverse longitudinal association, with a combined sample size of n = 48,793 and a mean follow-up of 2 years. Higher levels of baseline depressive symptoms were associated with subsequent higher levels of HbA1c (partial r = 0.07; [95% CI 0.03, 0.12]; I2 38%). Higher baseline HbA1c values were also associated with 18% increased risk of (probable) depression (OR = 1.18; [95% CI 1.12,1.25]; I2 0.0%). CONCLUSIONS: Our findings support a bidirectional longitudinal association between depressive symptoms and HbA1c . However, the observed effect sizes were small and future research in large-scale longitudinal studies is needed to confirm this association. Future studies should investigate the role of type of diabetes and depression, diabetes distress and diabetes self-management behaviours. Our results may have clinical implications, as depressive symptoms and HbA1c levels could be targeted concurrently in the prevention and treatment of diabetes and depression. REGISTRATION: PROSPERO ID CRD42019147551.

Studying the association of diabetes and healthcare cost on distributed data from the Maastricht Study and Statistics Netherlands using a privacy-preserving federated learning infrastructure.

The mining of personal data collected by multiple organizations remains challenging in the presence of technical barriers, privacy concerns, and legal and/or organizational restrictions. While a number of privacy-preserving and data mining frameworks have recently emerged, much remains to show their practical utility. In this study, we implement and utilize a secure infrastructure using data from Statistics Netherlands and the Maastricht Study to learn the association between Type 2 Diabetes Mellitus (T2DM) and healthcare expenses considering the impact of lifestyle, physical activities, and complications of T2DM. Through experiments using real-world distributed personal data, we present the feasibility and effectiveness of the secure infrastructure for practical use cases of linking and analyzing vertically partitioned data across multiple organizations. We discovered that individuals diagnosed with T2DM had significantly higher expenses than those with prediabetes, while participants with prediabetes spent more than those without T2DM in all the included healthcare categories to different degrees. We further discuss a joint effort from technical, ethical-legal, and domain-specific experts that is highly valued for applying such a secure infrastructure to real-life use cases to protect data privacy.

Daily patterns of physical activity, sedentary behavior, and prevalent and incident depression-The Maastricht Study.

This study aims to compare the accelerometer-measured daily patterns of PA and sedentary behavior among participants with and without prevalent/incident depressive symptoms. We used data from 5582 individuals in The Maastricht Study (59.9 ± 8.6 years, 50.3% women). Daily patterns of sedentary time, light-intensity physical activity (LiPA), moderate-to-vigorous physical activity (MVPA), and sit-to-stand transitions were objectively measured at baseline with the activPAL3 activity monitor. Depressive symptoms were assessed using the 9-item Patient Health Questionnaire, both at baseline and annually (median follow-up: 5.1 years). General linear models were used to compare patterns of physical activity and sedentary behavior between those with and without prevalent/incident depressive symptoms. Participants with prevalent depressive symptoms had significantly more sedentary time (18.6 min/day) and lower LiPA (26.8 min/day) and MVPA (4.8 min/day) than participants without depressive symptoms. Considering the daily patterns, participants with prevalent depressive symptoms had significantly more sedentary time early in the afternoon (12:00-18:00), early evening (18:00-21:00), and during the night (00:00-03:00), less time in LiPA in all periods between 09:00-21.00 and less MVPA in the morning (09:00:12:00), early afternoon (12:00-15:00), and evening (18:00-21:00), than those without. Similar differences in activity and sedentary behavior patterns between those and without incident depressive symptoms were observed albeit the differences were smaller. Overall, we did not find specific time slots particularly associated with both prevalent and incident depressive symptoms. These findings may indicate that less sedentary time and more intense PA can be important targets for the prevention of depression irrespective of the timing of the day.

Social networks and type 2 diabetes: a narrative review.

It has been known for decades that social networks are causally related to disease and mortality risk. However, this field of research and its potential for implementation into diabetes care is still in its infancy. In this narrative review, we aim to address the state-of-the-art of social network research in type 2 diabetes prevention and care. Despite the diverse nature and heterogeneity of social network assessments, we can draw valuable lessons from the available studies. First, the structural network variable 'living alone' and the functional network variable 'lack of social support' have been associated with increased type 2 diabetes risk. The latter association may be modified by lifestyle risk factors, such as obesity, low level of physical activity and unhealthy diet. Second, smaller network size and less social support is associated with increased risk of diabetes complications, particularly chronic kidney disease and CHD. Third, current evidence shows a beneficial impact of social support on diabetes self-management. In addition, social support interventions were found to have a small, favourable effect on HbA1c values in the short-term. However, harmonisation and more detailed assessment of social network measurements are needed to utilise social network characteristics for more effective prevention and disease management in type 2 diabetes.

Associations between plasma kynurenines and cognitive function in individuals with normal glucose metabolism, prediabetes and type 2 diabetes: the Maastricht Study.

AIMS/HYPOTHESIS: Studies investigating associations between kynurenines and cognitive function have generally been small, restricted to clinical samples or have found inconsistent results, and associations in the general adult population, and in individuals with type 2 diabetes in particular, are not clear. Therefore, the aim of the present study was to investigate cross-sectional associations between plasma kynurenines and cognitive function in a cohort of middle-aged participants with normal glucose metabolism, prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes. METHODS: Plasma kynurenines were quantified in 2358 participants aged 61 ± 8 years. Cross-sectional associations of kynurenines with cognitive impairment and cognitive domain scores were investigated using logistic, multiple linear and restricted cubic spline regression analyses adjusted for several confounders. RESULTS: Effect modification by glucose metabolism status was found for several associations with cognitive impairment, hence analyses were stratified. In individuals with prediabetes, 3-hydroxykynurenine (OR per SD 0.59 [95% CI 0.37, 0.94]) and 3-hydroxyanthranilic acid (0.67 [0.47, 0.96]) were associated with lower odds of cognitive impairment after full adjustment. In individuals with type 2 diabetes, kynurenine (0.80 [0.66, 0.98]), 3-hydroxykynurenine (0.82 [0.68, 0.99]), kynurenic acid (0.81 [0.68, 0.96]), xanthurenic acid (0.73 [0.61, 0.87]) and 3-hydroxyanthranilic acid (0.73 [0.60, 0.87]) were all associated with lower odds of cognitive impairment. Kynurenic acid (ß per SD 0.07 [95% CI 0.02, 0.13]) and xanthurenic acid (0.06 [0.01, 0.11]) were also associated with better executive function/attention. No associations were observed in individuals with normal glucose metabolism. CONCLUSIONS/INTERPRETATION: Several kynurenines were cross-sectionally associated with lower odds of cognitive impairment and better cognitive functioning in type 2 diabetes, while less widespread associations were seen in prediabetes. Low levels of kynurenines might be involved in the pathway of type 2 diabetes and cognitive decline but this needs further studies.