Associations between circadian alignment and cognitive functioning in a nationally representative sample of older adults.

Proper alignment of activity-rest and light-dark patterns allows for healthy bodily functions to occur at optimal times of the day. Disruptions to this alignment may cause poor sleep as well as physical, mental, and cognitive problems. The purpose of this cross-sectional study was to determine if poorer circadian alignment was associated with decreased cognitive functioning among older (> 60 years) participants in the National Health and Nutrition Examination Survey. We utilized actigraphy-based rest-activity and dark-light measurements to calculate phasor magnitude (strength of circadian alignment coupling) and phasor angle (phase difference between activity-rest and light-dark cycles). Multiple linear regression models were used to determine associations of phasor magnitude and angle with performance in various cognitive tests, including Digit Symbol Substitution Test score (DSSS), CERAD Savings Percentage (CSP), and Animal Fluency Test (AFT) score. The results showed that a lower phasor magnitude (which indicates decreased strength of alignment coupling between rest-activity and dark-light cycles) was significantly associated with decreased DSSS (indicating slower processing speed and poorer working memory) when controlling for many important sociodemographic factors. However, this association became non-significant when accounting for sleep duration and total physical activity. Phasor angle did not have a significant association with any of the cognitive scores. Overall, we provided evidence indicating that circadian alignment may be a predictor of cognitive performance. Future studies should investigate whether improving circadian alignment may improve cognitive function and prevent cognitive decline.

Associations between Rest-Activity Rhythms and Liver Function Tests: The US National Health and Nutrition Examination Survey, 2011-2014.

Liver functions are regulated by the circadian rhythm; however, whether a weakened circadian rhythm is associated with impaired liver function is unclear. This study aims to investigate the association of characteristics of rest-activity rhythms with abnormal levels of biomarkers of liver function. Data were obtained from the National Health and Nutrition Examination Survey 2011-2014. Seven rest-activity rhythm parameters were derived from 24 h actigraphy data using the extended cosine model and non-parametric methods. Multiple logistic regression and multiple linear regression models were used to assess the associations between rest-activity rhythm parameters and alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transaminase (GGT), albumin and bilirubin. Weakened overall rhythmicity characterized by a lower F statistic was associated with higher odds of abnormally elevated ALP (ORQ1vs.Q5: 2.16; 95% CI 1.19, 3.90) and GGT (ORQ1vs.Q5: 2.04; 95% CI 1.30, 3.20) and abnormally lowered albumin (ORQ1vs.Q5: 5.15; 95% CI 2.14, 12.38). Similar results were found for a lower amplitude, amplitude:mesor ratio, interdaily stability and intradaily variability. Results were robust to the adjustment of confounders and cannot be fully explained by individual rest-activity behaviors, including sleep and physical activity. Weakened rest-activity rhythms were associated with worse liver function as measured by multiple biomarkers, supporting a potential role of circadian rhythms in liver health.

U.S. Adolescent Rest-Activity patterns: insights from functional principal component analysis (NHANES 2011-2014).

BACKGROUND: Suboptimal rest-activity patterns in adolescence are associated with worse health outcomes in adulthood. Understanding sociodemographic factors associated with rest-activity rhythms may help identify subgroups who may benefit from interventions. This study aimed to investigate the association of rest-activity rhythm with demographic and socioeconomic characteristics in adolescents. METHODS: Using cross-sectional data from the nationally representative National Health and Nutrition Examination Survey (NHANES) 2011-2014 adolescents (N = 1814), this study derived rest-activity profiles from 7-day 24-hour accelerometer data using functional principal component analysis. Multiple linear regression was used to assess the association between participant characteristics and rest-activity profiles. Weekday and weekend specific analyses were performed in addition to the overall analysis. RESULTS: Four rest-activity rhythm profiles were identified, which explained a total of 82.7% of variance in the study sample, including (1) High amplitude profile; (2) Early activity window profile; (3) Early activity peak profile; and (4) Prolonged activity/reduced rest window profile. The rest-activity profiles were associated with subgroups of age, sex, race/ethnicity, and household income. On average, older age was associated with a lower value for the high amplitude and early activity window profiles, but a higher value for the early activity peak and prolonged activity/reduced rest window profiles. Compared to boys, girls had a higher value for the prolonged activity/reduced rest window profiles. When compared to Non-Hispanic White adolescents, Asian showed a lower value for the high amplitude profile, Mexican American group showed a higher value for the early activity window profile, and the Non-Hispanic Black group showed a higher value for the prolonged activity/reduced rest window profiles. Adolescents reported the lowest household income had the lowest average value for the early activity window profile. CONCLUSIONS: This study characterized main rest-activity profiles among the US adolescents, and demonstrated that demographic and socioeconomic status factors may shape rest-activity behaviors in this population.

Alignment Between 24-h Light-Dark and Activity-Rest Rhythms Is Associated With Diabetes and Glucose Metabolism in a Nationally Representative Sample of American Adults.

OBJECTIVE: The alignment between environmental stimuli (e.g., dark, light) and behavior cycles (e.g., rest, activity) is an essential feature of the circadian timing system, a key contributor to metabolic health. However, no previous studies have investigated light-activity alignment in relation to glycemic control in human populations. RESEARCH DESIGN AND METHODS: The analysis included ∼7,000 adults (aged 20-80 years) from the National Health and Nutrition Examination Survey (NHANES) (2011-2014) with actigraphy-measured, multiday, 24-h activity and light data. We used phasor analysis to derive phasor magnitude and phasor angle, which measures coupling strength and phase difference between the activity-rest and light-dark cycles, respectively. We used multinomial logistic regression and multiple linear regression to study phasor magnitude and phasor angle in relation to diabetes (primary outcome) and multiple secondary biomarkers of glycemic control. RESULTS: Lower alignment strength (i.e., a shorter phasor magnitude) and more delayed activity relative to the light cycle (i.e., a larger phasor angle) were both associated with diabetes. Specifically, compared with individuals in the quintiles indicating the most proper alignment (Q5 for phasor magnitude and Q1 for phasor angle), those in the quintiles with the most impaired alignment had a >70% increase in the odds of diabetes for phasor magnitude (odds ratio 1.76 [95% CI 1.39, 2.24]) and for phasor angle (1.73 [1.34, 2.25]). Similar associations were observed for biomarkers for glucose metabolism. The results were generally consistent across diverse sociodemographic and obesity groups. CONCLUSIONS: The alignment pattern between 24-h activity-rest and light-dark cycles may be a critical factor in metabolic health.

The influence of growth and sex hormones on risk of alzheimer's disease: a mendelian randomization study.

Alzheimer's disease is more prevalent in women, possibly due to sex or growth hormones but existing evidence is inconclusive. We investigated whether genetically predicted sex and growth hormones are associated with risk of Alzheimer's disease. Genetic variants strongly and independently predicting insulin-like growth factor 1 (IGF-1), testosterone and sex hormone-binding globulin (SHBG) were obtained from large, published genome wide associations studies (GWAS) and applied to GWAS of Alzheimer's disease based on clinical diagnosis (cases = 21,982, control = 41,944) from the International Genomics of Alzheimer's Project and the UK Biobank parental (maternal cases = 27,696; paternal cases = 14,338) and siblings' diagnosis (cases = 2,171) as proxy cases. Published GWAS summary statistics were used in our analyses. Estimates were obtained from inverse variance weighting with sensitivity analysis (i.e., MR-Egger, weighted median and MR-PRESSO). Multivariable analyses adjusted for pleiotropic effects and possible sources of selection bias were also performed. Genetically predicted higher total testosterone may reduce the risk of paternal Alzheimer's disease (odds ratio (OR) 0.86, 95% confidence interval (CI) 0.76 to 0.97, per SD increase in testosterone) and in meta-analysis for women (OR 0.92, 95% CI 0.87, 0.98) with directionally similar results from other analyses. SHBG were not associated with Alzheimer's disease. IGF-1 in women was inversely associated with risk of clinical Alzheimer's disease in sensitivity analysis but not in the main analysis. These results suggest genetically predicted higher total testosterone may lower risk of Alzheimer's disease. The role of testosterone and the immune system in Alzheimer's disease could be further investigated.

Associations between actigraphy-derived rest-activity rhythm characteristics and hypertension in United States adults.

People with disrupted circadian rhythms, such as shift workers, have shown a higher risk of hypertension. However, it is unclear whether more subtle differences in diurnal rest-activity rhythms in the population are associated with hypertension. Clarifying the association between the rest-activity rhythm, a modifiable behavioural factor, and hypertension could provide insight into preventing hypertension and possibly cardiovascular diseases. In this study, we investigated the association between rest-activity rhythm characteristics and hypertension in a large representative sample of United States adults. Cross-sectional data were obtained from the National Health and Nutrition Examination Survey 2011-2014 (N = 6726; mean [range] age 49 [20-79] years; 52% women). Five rest-activity rhythm parameters (i.e., pseudo F statistic, amplitude, mesor, amplitude:mesor ratio, and acrophase) were derived from 24-h actigraphy data using the extended cosine model. We performed multiple logistic regression to assess the associations between the rest-activity rhythm parameters and hypertension. Subgroup analysis stratified by age, gender, race/ethnicity, body mass index and diabetes status was also conducted. A weakened overall rest-activity rhythm, characterised by a lower F statistic, was associated with higher odds of hypertension (odds ratio quintile 1 versus quintile 5 [OR Q1vs.Q5 ] 1.61, 95% confidence interval [CI] 1.26-2.05; p trend < 0.001). Similar results were found for lower amplitude (OR Q1vs.Q5 1.51, 95% CI 1.13-2.03; p trend = 0.01) and amplitude:mesor ratio (OR Q1vs.Q5 1.34, 95% CI 1.01-1.78; p trend = 0.03). The results were robust to the adjustment of confounders, individual behaviours including physical activity levels and sleep duration and appeared consistent across subgroups. Possible interaction between the rest-activity rhythm and body mass index was found. Our results support an association between weakened rest-activity rhythms and higher odds of hypertension.

Association of autoimmune diseases with Alzheimer's disease: A mendelian randomization study.

BACKGROUND: Alzheimer's disease may have an autoimmune component, but the association is unclear. OBJECTIVE: The objective of this Mendelian randomization (MR) study was to evaluate the association of liability to autoimmune diseases with Alzheimer's disease. METHODS: A systematic search was done using PubMed to identify autoimmune diseases that have been suggested as associated with Alzheimer's disease. Genetic predictors of these autoimmune diseases were obtained from the largest and most recent genome-wide association studies (GWAS). Genetic associations with clinically-diagnosed Alzheimer's disease were obtained from the International Genomics of Alzheimer's Project GWAS (21982 cases; 41944 controls); and with parental and sibling history of Alzheimer's disease from the UK Biobank GWAS (27696 maternal, 14338 paternal and 2171 sibling cases). MR estimates were obtained using inverse variance weighting, MR-Egger and weighted median. To address possible selection bias due to inevitably recruiting only survivors, the analysis was repeated in younger people, i.e., UK Biobank siblings and adjusting for competing risk of Alzheimer's disease. RESULTS: Of the 7 autoimmune diseases considered, liability to psoriasis and sarcoidosis were not associated with Alzheimer's disease. Some evidence was found for liability to multiple sclerosis being associated with higher risk and liability to Sjogren's syndrome with lower risk of Alzheimer's disease. Associations found for liability to giant cell arteritis, type 1 diabetes and rheumatoid arthritis were inconsistent in sensitivity analyses. CONCLUSION: Liability to multiple sclerosis and Sjogren's syndrome could be associated with Alzheimer's disease. The underlying mechanisms, such as the role of myelin and neuroinflammation, should be further investigated.

Circulating Cytokines and Coronavirus Disease: A Bi-Directional Mendelian Randomization Study.

BACKGROUND: Immune system functioning is relevant to vulnerability to coronavirus disease (COVID-19). Cytokines are important to immunity. To further elucidate the role of the immune system in COVID-19, we used Mendelian randomization (MR) to assess comprehensively and bi-directionally the role of cytokines in COVID-19. METHODS: We assessed primarily whether genetically different levels of 41 cytokines affected risk of any COVID-19 (laboratory confirmed, physician confirmed or self-reported, 36,590 cases, 1,668,938 controls), and conversely if genetic risk of liability to any COVID-19 affected these cytokines (n ≤ 8293) using the most recent genome-wide association studies. We obtained inverse variance weighting (IVW) estimates, conducted sensitivity analyses and used a Benjamini-Hochberg correction to account for multiple comparisons. We also assessed whether any findings were evident for hospitalized COVID-19 (hospitalized laboratory confirmed, 12,888 cases, 1,295,966 controls). RESULTS: Macrophage inflammatory protein-1ß (MIP1b; more commonly known as Chemokine (C-C motif) ligands 4 (CCL4) was inversely associated with COVID-19 [odds ratio (OR) 0.97 per SD, 95% confidence interval (CI) 0.96-0.99] but not after adjustment for multiple comparisons. This finding replicated for hospitalized COVID-19 (OR 0.93, 95% CI 0.89-0.98). Liability to any COVID-19 was nominally associated with several cytokines, such as granulocyte colony-stimulating factor (GCSF) and hepatocyte growth factor (HGF) but not after correction. CONCLUSION: A crucial element of immune response to infection (CCL4) was related to COVID-19, whether it is a target of intervention to prevent COVID-19 warrants further investigation.

Systemic inflammatory regulators and risk of Alzheimer's disease: a bidirectional Mendelian-randomization study.

BACKGROUND: Systemic inflammation has been suggested to be associated with Alzheimer's-disease progression, although whether it is a cause or a downstream effect is still controversial. This study aims to assess the effect of systemic inflammatory regulators on Alzheimer's disease within a bidirectional Mendelian-randomization design. METHODS: Genetic associations with Alzheimer's disease were obtained from the largest and most up-to-date genome-wide association study (GWAS) (cases and proxy cases: 71 880; controls: 383 378) and with inflammatory regulators from two recent GWASs on the human proteome and cytokines. Estimates were obtained by inverse-variance weighting with sensitivity analyses using MR-Egger, weighted median and MR-PRESSO. Possible bias due to selective survival and competing risk was also considered. RESULTS: None of 41 systemic inflammatory regulators was associated with risk of Alzheimer's disease with consistent results in validation analysis. Conversely, Alzheimer's disease was suggestively associated with five systemic inflammatory regulators, i.e. basic fibroblast growth factor, granulocyte-colony-stimulating factor, interferon gamma, interleukin-13 and interleukin-7. CONCLUSION: The systemic inflammatory regulators considered did not appear to be associated with the risk of Alzheimer's disease. Conversely, specific systemic inflammatory regulators may be downstream effects of Alzheimer's disease or consequences of common factors causing both inflammation and Alzheimer's disease.

Amyloid, tau and risk of Alzheimer's disease: a Mendelian randomization study.

This study was carried out to assess the effect of amyloid and tau on Alzheimer's disease using two-sample Mendelian randomization design. Genetic associations with plasma amyloid species (amyloid precursor protein, amyloid-like protein 2, serum amyloid P-component, amyloid beta peptide), cerebrospinal fluid (CSF) amyloid beta, total tau, and phosphorylated tau181 were extracted from the largest genome-wide association study (GWAS) available. Genetic associations with Alzheimer's disease were obtained from a GWAS of proxy-cases based on family history of Alzheimer's disease with 314,278 participants from the UK Biobank and a GWAS with clinically diagnosed Alzheimer's disease from the International Genomics of Alzheimer's Project (IGAP) with 21,982 cases and 41,944 controls. Estimates were obtained using inverse variance weighting with sensitivity analyses including MR-Egger, weighted median and MR-PRESSO. Presence of bias due to selective survival and competing risk was also considered. Plasma amyloid species, CSF total tau and phosphorylated tau181 were not associated with Alzheimer's disease. For CSF Aß42, no association was found using the proxy-cases but an inverse association was found after removing outliers with MR-PRESSO using IGAP. Higher genetically predicted (p < 1 × 10-5) plasma amyloid species, CSF total tau and phosphorylated tau181 (based on sample sizes ~ 3300) were not associated with Alzheimer's disease using family history or clinically diagnosed cases while effects of CSF Aß42 were inconsistent between the family history and IGAP GWAS.

Targeting bile acid metabolism in obesity reduction: A systematic review and meta-analysis.

A systematic review and meta-analysis was conducted of studies that address the association of bile acid (BA) with obesity and of studies on the effects of treatment in patients with obesity on BA metabolism, assessed from systemic BA, fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4) level, and faecal BA. We searched PubMed, Embase, and the Cochrane Library from inception to 1 August 2019 using the keywords obesity, obese, body mass index, and overweight with bile acid, FGF19, FXR, and TGR5. Two reviewers independently searched, selected, and assessed the quality of studies. Data were analysed using either fixed or random effect models with inverse variance weighting. Of 3771 articles, 33 papers were relevant for the association of BA with obesity of which 22 were included in the meta-analysis, and 50 papers were relevant for the effect of obesity interventions on BA of which 20 were included in the meta-analysis. Circulating fasting total BA was not associated with obesity. FGF19 was inversely and faecal BA excretion was positively associated with obesity. Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) modulated BA metabolism, ie, increased BA and FGF19. Our results indicate that BA metabolism is altered in obesity. Certain bariatric surgeries including RYGB and SG modulate BA, whether these underlie the beneficial effect of the treatment should be investigated.

Lean mass, grip strength and risk of type 2 diabetes: a bi-directional Mendelian randomisation study.

AIMS/HYPOTHESIS: Muscle mass and strength may protect against type 2 diabetes as a sink for glucose disposal. In randomised controlled trials, resistance training improves glucose metabolism in people with the metabolic syndrome. Whether increasing muscle mass and strength protects against diabetes in the general population is unknown. We assessed the effect of markers of muscle mass and strength on diabetes and glycaemic traits using bi-directional Mendelian randomisation. METHODS: Inverse variance weighting estimates were obtained by applying genetic variants that predict male lean mass, female lean mass and grip strength, obtained from the UK Biobank GWAS, to the largest available case-control study of diabetes (DIAbetes Genetics Replication And Meta-analysis [DIAGRAM]; n = 74,124 cases and 824,006 controls) and to a study of glycaemic traits (Meta-Analyses of Glucose and Insulin-related traits Consortium [MAGIC]). Conversely, we also applied genetic variants that predict diabetes, HbA1c, fasting glucose, fasting insulin and HOMA-B to UK Biobank summary statistics for genetic association with lean mass and grip strength. As sensitivity analyses we used weighted median, Mendelian randomisation (MR)-Egger and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) and removed pleiotropic SNPs. RESULTS: Grip strength was not significantly associated with diabetes using inverse variance weighting (OR 0.72 per SD increase in grip strength, 95% CI 0.51, 1.01, p = 0.06) and including pleiotropic SNPs but was significantly associated with diabetes using MR-PRESSO (OR 0.77, 95% CI 0.62, 0.95, p = 0.02) after removing pleiotropic SNPs. Female lean mass was significantly associated with diabetes (OR 0.91, 95% CI 0.84, 0.99, p = 0.02) while male lean mass was not significant but directionally similar (OR 0.94, 95% CI 0.88, 1.01, p = 0.09). Conversely, diabetes was inversely and significantly associated with male lean mass (ß -0.02 SD change in lean mass, 95% CI -0.04, -0.00, p = 0.04) and grip strength (ß -0.01, 95% CI -0.02, -0.00, p = 0.01). CONCLUSIONS/INTERPRETATION: Increased muscle mass and strength may be related to lower diabetes risk. Diabetes may also be associated with grip strength and lean mass. Muscle strength could warrant further investigation as a possible target of intervention for diabetes prevention.

The Decreasing Trend in Dietary Glycaemic Index and Glycaemic Load in Australian Children and Adolescents between 1995 and 2012.

This study aims to examine whether there were changes between 1995⁻2012 in the dietary glycaemic index (dGI) and glycaemic load (dGL) in Australian children (<16 years) according to three national surveys in 1995 (1995NS), 2007 (2007NS), and 2011⁻2012 (2012NS). Glycaemic index (GI) values of foods were assigned using published methodology. Plausible 24-h recall data from the 1995NS, 2007NS and 2012NS (weighted n = 2475, 4373 and 1691 respectively) were compared for differences in dGI and dGL, and the contribution to dGL from different foods using one-way ANOVA with Bonferroni post hoc comparisons and linear regression. Decreasing trends across surveys were found in dGI and dGL (p < 0.001). Between 1995 and 2012, dGI and dGL per Megajoule (MJ) dropped by 2% and 6% respectively. The per capita dGL contribution from breads and bread rolls, fruit and vegetable juices, sweetened beverages and potatoes showed strong decreasing trends (R² > 0.7). Our findings suggest that dGI and dGL of Australian youths declined between 1995 to 2012, which may be due to increased awareness of the GI concept and healthy diet, widened food choices and immigrants with diverse dietary habits. This may lower the future risks of chronic degenerative diseases in Australian youths.

Modelling of the impact of universal added sugar reduction through food reformulation.

Food reformulation has been suggested to be one of the strategies to reduce population added sugar (AS) intake. This study aims to investigate the untested assumption that a reduction in AS through reformulation will result in a reduction in population intakes of AS and energy. Plausible dietary data from 4,140 respondents of an Australian national nutrition survey were used. Dietary modelling was performed at AS reductions of 10%, 15%, and 25% using four strategies: simple removal of AS or replacement with non-nutritive sweeteners (NNS), and replacement of AS with NNS and either: polyols, 50% fibres or 50% maltodextrin. Paired t-tests were conducted to compare the intake of energy, fat, and AS pre- and post-reformulation. The chosen reformulation strategies resulted in a projected reduction in AS and energy, with the greatest reduction found in 25% reformulation which was the highest level modelled. The overall projected mean (SD) reduction in energy and AS after 25% reformulation was 114 (92) kJ/day and 11.73 (7.52) g/day, p < 0.001. To conclude, product reformulation may be a potentially useful strategy for reducing AS intake. Although the magnitude of projected reduction was small at the individual level, the impact may be meaningful at a population level.