Associations between accelerometer-measured circadian rest-activity rhythm, brain structural and genetic mechanisms, and dementia.

AIM: Knowledge of how circadian rhythm influences brain health remains limited. We aimed to investigate the associations of accelerometer-measured circadian rest-activity rhythm (CRAR) with incident dementia, cognitive dysfunction, and structural brain abnormalities in the general population and underlying biological mechanisms. METHODS: Fifty-seven thousand five hundred and two participants aged over 60 years with accelerometer data were included to investigate the association of CRAR with incidental dementia. Non-parametric CRAR parameters were utilized, including activity level during active periods of the day (M10), activity level during rest periods of the day (L5), and the relative difference between the M10 and L5 (relative amplitude, RA). Associations of CRAR with cognitive dysfunction and brain structure were studied in a subset of participants. Neuroimaging-transcriptomics analysis was utilized to identify the underlying molecular mechanisms. RESULTS: Over 6.86 (4.94-8.78) years of follow-up, 494 participants developed dementia. The risk of incident dementia was associated with decreasing M10 (hazard ratio [HR] 1.45; 95% conference interval [CI], 1.28-1.64) and RA (HR 1.37; 95% CI, 1.28-1.64), increasing L5 (HR 1.14, 95% CI 1.07-1.21) and advanced L5 onset time (HR 1.12; 95% CI, 1.02-1.23). The detrimental associations were exacerbated by APOE ε4 status and age (>65 years). Decreased RA was associated with lower processing speed (Beta -0.04; SE 0.011), predominantly mediated by abnormalities in subcortical regions and white matter microstructure. The genes underlying CRAR-related brain regional structure variation were enriched for synaptic function. CONCLUSIONS: Our study underscores the potential of intervention targeting at maintaining a healthy CRAR pattern to prevent dementia risk.

Evaluation of Changes in Social Isolation and Loneliness with Incident Cardiovascular Events and Mortality.

BACKGROUND: It remains unknown how the patterns of change of social isolation and loneliness are associated with the onset of cardiovascular disease (CVD) and mortality. We aimed to investigate the longitudinal association of changes in social isolation and loneliness with incident CVD, all-cause mortality, CVD mortality and subsequent cardiac function. METHODS: This prospective cohort study included 18,258 participants aged 38-73 years who participated in visit 0 (2006-2010) and visit 1 (2012-2013) using UK Biobank (mean age 57.1, standard deviation [SD] 7.4; 48.7% males). Social isolation or loneliness was categorized into four patterns: never, transient, incident, and persistent. Incident CVD, all-cause and CVD mortality were ascertained through linkage data. Cardiac function was assessed by cardiovascular magnetic resonance imaging in a subsample (N = 5188; visit 2, since 2014). RESULTS: Over a median follow-up of 8.3 (interquartile range [IQR] 8.1-8.6) years, compared with never social isolation, persistent social isolation was associated with the higher risk of incident CVD (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.03-1.33), all-cause (1.42, 1.12-1.81) and CVD (1.53, 1.05-2.23) mortality. Likewise, persistent loneliness was strongly associated with the greater risk of incident CVD (1.13, 1.00-1.27), all-cause (1.28, 1.02-1.61) and CVD mortality (1.52, 1.06-2.18). CONCLUSIONS: Persistent social isolation and loneliness posed a substantially higher risk for incident CVD, all-cause and CVD mortality, and cardiac dysfunction than other patterns. Persistent social isolation and loneliness, along with an increasing cumulative score, are associated with lower cardiac function.

Childhood maltreatment, genetic risk, and subsequent risk of arrhythmias: a prospective cohort study.

Background: Emerging evidence has linked childhood maltreatment with cardiovascular disease risk; however, the association between childhood maltreatment and cardiac arrhythmias remains unclear. Moreover, any genetic predispositions to atrial fibrillation (AF), a common cardiac arrhythmia associated with an elevated risk of stroke, heart failure, and mortality, that modify such associations have been undocumented.Purpose: To examine the associations between childhood maltreatment and incident arrhythmias, and whether a genetic predisposition to arrhythmias modifies these associations.Methods: This prospective analysis included 151,741 participants from the UK Biobank (mean age 55.8 years, 43.4% male). Childhood maltreatment, including five types, was measured using the Childhood Trauma Screener (CTS). Incident arrhythmias (AF, ventricular arrhythmias [VA], and bradyarrhythmia [BA]) were documented through linked hospital admission and death registry. Weighted AF genetic risk score was calculated. Cox proportional hazard models were conducted to test for associations between childhood maltreatment and incident arrhythmias.Results: During a median follow-up of 12.21 years (interquartile range, 11.49-12.90 years), 6,588 AF, 2,093 BA, and 742 VA events occurred. Compared with the absence of childhood maltreatment, having 3-5 types of childhood maltreatment was associated with an increased risk of incident AF (HR, 1.23; 95%CI 1.09-1.37), VA (HR, 1.39; 95%CI 1.03-1.89), and BA (HR, 1.32; 95%CI 1.09-1.61) after adjusting demographic, socioeconomic and lifestyle factors. The associations between cumulative type of childhood maltreatment and the risk of AF (Poverall < .001; Pnonlinear = .674) and BA (Poverall = .007; Pnonlinear = .377) demonstrated a linear pattern. There was a gradient association between childhood maltreatment and AF risks across the intermediate and high genetic risk groups (both Ptrend < .05) but not within the low genetic risk group (Ptrend = .378), irrespective of non-significant interaction effect (Pinteraction = .204).Conclusion: Childhood maltreatment was associated with higher risks of incident arrhythmias, especially AF and BA. Genetic risk of AF did not modify these associations.

Previous studies indicate that childhood maltreatment is associated with cardiovascular disease risk.Childhood maltreatment was associated with an increased risk of incident arrhythmias, particularly atrial fibrillation and bradyarrhythmia. Genetic predisposition to atrial fibrillation did not significantly modify these associations.Childhood maltreatment could be a new psychological risk factor for cardiac arrhythmias in later life. Inquiries into childhood maltreatment and subsequent referral to psychological services may be helpful.

Trajectories of social isolation and loneliness and the risk of incident type 2 diabetes mellitus across genetic risk score.

AIM: This study aimed to investigate the association of social isolation, loneliness, and their trajectory with the risk of developing type 2 diabetes mellitus (T2DM) across genetic risk. METHODS: We included 439,337 participants (mean age 56.3 ± 8.1 years) enrolled in the UK Biobank study who were followed up until May 31, 2021. Social isolation and loneliness were self-reported and were further categorized into never, transient, incident, and persistent patterns. RESULTS: During a median follow-up of 12.7 years, 15,258 incident T2DM cases were documented. Social isolation (versus no social isolation: hazard ratio (HR) 95 % confidence interval (CI) 1.04 [1.00;1.09]) and loneliness (versus no loneliness: 1.26 [1.19;1.34]) were associated with an increased T2DM risk, independent of the genetic risk for T2DM. The interactions existed between social isolation and loneliness (Pinteraction < 0.05); the increased T2DM risk associated with social isolation was only significant among participants without loneliness. In the longitudinal analysis, only persistent social isolation (versus never social isolation: 1.22 [1.02;1.45]) was associated with an increased T2DM risk, whereas incident loneliness (versus never loneliness: 1.95 [1.40;2.71]) and persistent loneliness (2.00 [1.31;3.04]) were associated with higher T2DM risks. CONCLUSION: Social isolation and loneliness, especially their persistent pattern, were independently associated with an increased incident T2DM risk, irrespective of an individual's genetic risk. Loneliness modified the association between social isolation and incident T2DM.

Joint association of physical activity and sleep duration with risk of all-cause and cause-specific mortality: a population-based cohort study using accelerometry.

AIMS: To investigate the joint association of accelerometer-measured physical activity (PA) and sleep duration with mortality risk. METHODS AND RESULTS: A 7-day accelerometer recording was performed on 92 221 participants (age 62.4 ± 7.8 years; 56.4% women) from the UK Biobank between February 2013 and December 2015. We divided sleep duration into three groups (short, normal, and long), total volume of PA into three levels according to tertiles (high, intermediate, low), and moderate-to-vigorous PA (MVPA) into two groups based on the World Health Organization guidelines. The mortality outcomes were prospectively collected through the death registry. Over a median follow-up of 7.0 years, 3080 adults died, of which 1074 died from cardiovascular disease (CVD) and 1871 from cancer. The associations of PA and sleep duration with mortality risk were all in a curvilinear dose-response pattern (Pnonlinearity <0.001). PA and sleep duration had additive and multiplicative interactions on mortality risk (Pinteraction <0.05). Compared with the participants with guideline-recommended MVPA and normal sleep duration, those without recommended MVPA but having short or long sleep duration were at a higher risk for all-cause mortality [short sleep: hazard ratio (HR) = 1.88; 95% confidence interval (CI), 1.61-2.20; long sleep: HR = 1.69; 95% CI, 1.49-1.90]. A higher volume of PA or recommended MVPA attenuated the detrimental effects of short or long sleep duration on all-cause and CVD mortality risks. CONCLUSION: MVPA meeting recommendations or a higher volume of PA at any intensity potentially diminished the adverse effects on all-cause and cause-specific mortality associated with short and long sleep duration.

All-cause and cause-specific mortality risks associated with accelerometer-measured short or long sleep duration were attenuated by physical activity (PA).Both accelerometer-measured short and long sleep duration were associated with higher risk for all-cause and CVD mortality.Either a higher volume of PA or moderate-to-vigorous PA reaching the WHO-recommended level, as was also measured with accelerometer, attenuated the excessive mortality risks associated with short or long sleep duration.

Social isolation, loneliness and subsequent risk of major adverse cardiovascular events among individuals with type 2 diabetes mellitus.

Background: Individuals with type 2 diabetes mellitus (T2DM) are more vulnerable to social disconnection compared with the general population; however, there are few relevant studies investigating this issue. Aims: To investigate whether social isolation or loneliness may be associated with subsequent risk of developing major adverse cardiovascular events, whether these associations vary according to fatal and non-fatal outcomes and how behavioural, psychological and physiological factors mediate these associations. Methods: This longitudinal analysis included data from 19 360 individuals with T2DM at baseline (2006-2010) from the UK Biobank. Social isolation and loneliness were measured using self-report questionnaires. The study outcomes included the first events of myocardial infarction (MI) or stroke (n=2273) and all-cause (n=2820) or cardiovascular disease-related mortality through linked hospital data or death registries. Results: Over a median follow-up of 12.4 years (interquartile range (IQR): 11.6-13.3 years), participants who were more socially isolated (most social isolation vs least social isolation) experienced increased risks for all-cause (hazard ratio (HR) : 1.33, 95% confidence interval (CI): 1.19 to 1.47) and cardiovascular disease (HR: 1.36, 95% CI: 1.17 to 1.59) mortality but not first MI or stroke. Loneliness (yes vs no) was associated with a greater risk for a composite of incident MI or stroke (HR: 1.37, 95% CI: 1.19 to 1.57) but not mortality. Social isolation was associated with fatal MI and stroke, whereas loneliness was associated with non-fatal MI and stroke. The significant associations of social isolation and loneliness with outcomes were mainly mediated by behavioural factors (mediating proportion: 17.8%-28.2% and 17.6%-17.8%, respectively). Conclusions: Among individuals with T2DM, social isolation and loneliness are associated with a greater risk of developing major adverse cardiovascular events, with differences in both risks stratified according to fatal and non-fatal events and underlying mediating factors.

Association of Social Isolation and Loneliness With Incident Heart Failure in a Population-Based Cohort Study.

BACKGROUND: Social isolation and loneliness have emerged as important risk factors for cardiovascular diseases, particularly during the coronavirus disease pandemic. However, it is unclear whether social isolation and loneliness had independent and joint associations with incident heart failure (HF). OBJECTIVES: This study sought to examine the association of social isolation, loneliness, and their combination with incident HF. METHODS: The UK Biobank study is a population-based cohort study. Social isolation and loneliness were assessed using self-reported questionnaires. HF cases were identified by linking hospital records and death registries. The weighted polygenic risk score associated with HF was calculated. RESULTS: Among the 464,773 participants (mean age: 56.5 ± 8.1 years, 45.3% male), 12,898 incident HF cases were documented during a median follow-up of 12.3 years. Social isolation (most vs least: adjusted HR: 1.17; 95% CI:1.11-1.23) and loneliness (yes vs no: adjusted HR: 1.19; 95% CI: 1.11-1.27) were significantly associated with an increased risk of incident HF. The association between an elevated risk of HF and social isolation was modified by loneliness (Pinteraction = 0.034). A gradient of association between social isolation and the risk of incident HF was found only among individuals without loneliness (Ptrend < 0.001), but not among those with loneliness (Ptrend = 0.829). These associations were independent of the genetic risk of HF. CONCLUSIONS: Social isolation and loneliness were independently associated with a higher likelihood of incident HF regardless of genetic risk. The association between social isolation and incident HF was potentially modified by loneliness status.

Joint Associations of Device-Measured Sleep Duration and Efficiency With All-Cause and Cause-Specific Mortality: A Prospective Cohort Study of 90 398 UK Biobank Participants.

BACKGROUND: Both sleep duration and efficiency are essential for health outcomes. However, few studies have considered the effects of both sleep duration and efficiency on predicting the risks of mortality. This study investigated the independent and joint associations of accelerometer-measured sleep duration and efficiency with all-cause and cause-specific mortality. METHODS: The UK Biobank is a cohort study of over 500 000 individuals recruited between 2006 and 2010. This study included participants wearing wrist accelerometers for 7 consecutive days between February 2013 and December 2015. Mortality was ascertained by the national death registries. RESULTS: Of the 90 398 participants (age, 62.4 [7.8] years, 43.5% male) who were included, 2 685 deaths were reported within a median follow-up duration of 6.4 years. Both accelerometer-measured short (adjusted hazard ratios, 1.27; 95% confidence interval [CI]: 1.11-1.45) and long sleep duration (adjusted hazard ratios, 1.16; 95% CI: 1.06-1.28) were positively associated with the risks of all-cause mortality. Lower sleep efficiency was associated with an increased risk of all-cause and cause-specific mortality. Significant interaction existed between accelerometer-measured sleep duration and efficiency for the risk of all-cause mortality (Pinteraction = .001), participants with long sleep duration and lower sleep efficiency had a double mortality risk compared with those with higher sleep efficiency and normal sleep duration (adjusted hazard ratios = 2.11; 95% CI: 1.44-3.09). CONCLUSIONS: Accelerometer-measured short/long sleep duration and lower sleep efficiency were associated with increased risks of mortality. Sleep efficiency modified the effects of long sleep duration on survival.

Interaction of night shift work with polymorphism in melatonin receptor 1B gene on incident stroke.

OBJECTIVES: The aim of this study was to investigate whether melatonin receptor type 1B (MTNR1B) rs10830963 polymorphism interacts with night shift work on the risk of incident stroke. METHODS: This study included individuals free of stroke at baseline from the UK Biobank. Night-shift work was assessed by the self-reported questions. MTNR1B rs10830963 was directly genotyped (CC, GC, and GG). Incident stroke was ascertained through hospital records and death registries. Cox proportional hazards models were employed to examine the associations of night shift work and MTNR1B rs10830963 with the risk of incident stroke. RESULTS: A total of 242 194 participants were finally included (mean age: 52.95 years; 51.63% women). Over 12-year follow-up, 3287 incident stroke events occurred. Night shift work increased the risk of incident stroke [hazard ratio (HR) 1.13, 95% confidence interval (CI) 1.00-1.28] after adjusting for socio-demographics, and this association attenuated after additional adjustment for lifestyle factors (HR 1.06, 95% CI 0.94-1.20). MTNR1B rs10830963 polymorphism modified the association between night shift work and incident stroke (Pfor interaction =0.010). In the Cox models adjusted for socio-demographics and lifestyle factors, among night-shift workers, minor allele G was associated with a reduced risk of incident stroke (GC versus CC, HR 0.74, 95% CI 0.58-0.95; GG versus CC, HR 0.65, 95% CI 0.40-1.06; P for trend=0.010); while night shift work was associated with a higher stroke risk only among MTNR1B rs10830963 CC carriers (HR 1.23, 95% CI 1.05-1.44) but not GC/GG carriers. CONCLUSIONS: These results suggest that MTNR1B rs10830963 may potentially modify the associations between night shift work and incident stroke.

Associations of Childhood Maltreatment and Genetic Risks With Incident Heart Failure in Later Life.

Background We aimed to determine the associations of childhood maltreatment with incident heart failure in later life and explore the potentially modifying effects of genetic risk for heart failure on the associations. Methods and Results This cohort study included adults free of heart failure at baseline enrolled between 2006 and 2010 in the UK Biobank. Childhood maltreatment was retrospectively assessed with the online Childhood Trauma Screener in 2016. Five types of childhood maltreatment (range, 0-5), including physical abuse, physical neglect, emotional abuse, emotional neglect, and sexual abuse, were combined into a total score. A weighted polygenic risk score for heart failure was constructed. Incident all-cause heart failure was prospectively ascertained via hospital inpatient and death records, followed up to May 31, 2021. A total of 153 287 adults (mean [SD] age, 55.9 [7.7] years; 43.6% male) were included. Over a median of 12.2 years (interquartile range, 11.5-12.9 years) of follow-up, 2352 participants had incident heart failure. Childhood maltreatment was associated with a greater risk of incident heart failure in a dose-response manner. One additional type of childhood maltreatment was associated with a 15% increase in the risk of developing heart failure (hazard ratio [HR], 1.15 [95% CI, 1.07-1.23]). There was no statistically significant interaction between genetic risk and childhood maltreatment (Pinteraction=0.218). Among participants with high genetic risk, those with 3 to 5 types of childhood maltreatment had a double hazard (HR, 2.00 [95% CI, 1.43-2.80]) of developing heart failure when taking those without any childhood maltreatment as the reference. Conclusions Irrespective of genetic risk for heart failure, childhood maltreatment was associated with an increased risk of incident heart failure in a dose-dependent manner.