Lisette A. Zuurbier

Stability and Fragmentation of the Activity Rhythm Across the Sleep-Wake Cycle: The Importance of Age, Lifestyle, and Mental Health

The rhythms of activity across the 24-h sleep-wake cycle, determined in part by the circadian clock, change with aging. Few large-scale studies measured the activity rhythm objectively in the general population. The present population-based study in middle-aged and elderly persons evaluated how activity rhythms change with age, and additionally investigated sociodemographics, mental health, lifestyle, and sleep characteristics as determinants of rhythms of activity. Activity rhythms were measured objectively with actigraphy. Recordings of at least 96 h (138 ± 14 h, mean ± SD) were collected from 1734 people (age: 62 ± 9.4 yrs) participating in the Rotterdam Study. Activity rhythms were quantified by calculating interdaily stability, i.e., the stability of the rhythm over days, and intradaily variability, i.e., the fragmentation of the rhythm relative to its 24-h amplitude. We assessed age, gender, presence of a partner, employment, cognitive functioning, depressive symptoms, body mass index (BMI), coffee use, alcohol use, and smoking as determinants. The results indicate that older age is associated with a more stable 24-h activity profile (β = 0.07, p = 0.02), but also with a more fragmented distribution of periods of activity and inactivity (β = 0.20, p < 0.001). Having more depressive symptoms was related to less stable (β = −0.07, p = 0.005) and more fragmented (β = 0.10, p < 0.001) rhythms. A high BMI and smoking were also associated with less stable rhythms (BMI: β = −0.11, p < 0.001; smoking: β = −0.11, p < 0.001) and more fragmented rhythms (BMI: β = 0.09, p < 0.001; smoking: β = 0.11, p < 0.001). We conclude that with older age the 24-h activity rhythm becomes more rigid, whereas the ability to maintain either an active or inactive state for a longer period of time is compromised. Both characteristics appear to be important for major health issues in old age.

Fragmentation and Stability of Circadian Activity Rhythms Predict Mortality The Rotterdam Study

Circadian rhythms and sleep patterns change as people age. Little is known about the associations between circadian rhythms and mortality rates. We investigated whether 24-hour activity rhythms and sleep characteristics independently predicted mortality. Actigraphy was used to determine the stability and fragmentation of the 24-hour activity rhythm in 1,734 persons (aged 45-98 years) from the Rotterdam Study (2004-2013). Sleep was assessed objectively using actigraphy and subjectively using sleep diaries to estimate sleep duration, sleep onset latency, and waking after sleep onset. The mean follow-up time was 7.3 years; 154 participants (8.9%) died. Sleep measures were not related to mortality after adjustment for health parameters. In contrast, a more stable 24-hour activity rhythm was associated with a lower mortality risk (per 1 standard deviation, hazard ratio = 0.83, 95% confidence interval: 0.71, 0.96), and a more fragmented rhythm was associated with a higher mortality risk (per 1 standard deviation, hazard ratio = 1.22, 95% confidence interval: 1.04, 1.44). Low stability and high fragmentation of the 24-hour activity rhythm predicted all-cause mortality, whereas estimates from actigraphy and sleep diaries did not. Disturbed circadian activity rhythms reflect age-related alterations in the biological clock and could be an indicator of disease.

24-hour activity rhythm and sleep disturbances in depression and anxiety: a population-based study of middle-aged and older persons

Disturbed circadian rhythms have been associated with depression and anxiety, but it is unclear if disturbances in the 24‐hr activity rhythm and sleep are independently and specifically related to these disorders.

Associations of the 24-h activity rhythm and sleep with cognition: a population-based study of middle-aged and elderly persons

BACKGROUND Cognitive functioning changes with age, sleep, and the circadian rhythm. We investigated whether these factors are independently associated with different cognitive domains assessed in middle-aged and elderly persons. METHODS In 1723 middle-aged and elderly persons (age 62 ± 9.4 years, mean ± standard deviation, SD) of the Rotterdam Study, we collected actigraphy recordings of on average 138 h. Actigraphy was used to quantify 24-h rhythms by calculating the stability of the rhythm over days and the fragmentation of the rhythm. Sleep parameters including total sleep time, sleep-onset latency, and wake after sleep onset were also estimated from actigraphy. Cognitive functioning was assessed with the word learning test (WLT), word fluency test (WFT), letter digit substitution task (LDST), and Stroop color word test (Stroop). RESULTS Persons with less stable 24-h rhythms performed worse on the LDST (B = 0.42 per SD increase, p = 0.004) and the Stroop interference trial (B = -1.04 per SD increase, p = 0.003) after full adjustment. Similarly, persons with more fragmented rhythms performed worse on the LDST (B = -0.47 per SD increase, p = 0.002) and the Stroop (B = 1.47 per SD increase, p <0.001). By contrast, longer observed sleep-onset latencies were related to worse performance on the WLT delayed recall (B = -0.19 per SD increase, p = 0.027) and the WFT (B = -0.45 per SD increase, p = 0.007). CONCLUSIONS Disturbances of sleep and the 24-h activity rhythm were independently related to cognition; while persons with longer sleep-onset latencies had worse performance on memory and verbal tasks, persons with 24-h rhythm disturbances performed less on executive functioning and perceptual speed tasks.

Associations of heart failure with sleep quality: the Rotterdam Study.

STUDY OBJECTIVES The prevalence of sleep disturbances and heart failure increases with age. We aimed to evaluate the associations of incident heart failure and cardiac dysfunction with changes in sleep quality. METHODS This prospective population-based study was conducted in the Rotterdam Study. Of the 3445 eligible persons (mean age 72.0±7.1 years) available for cross-sectional analyses, 8.9% (n = 307) had prevalent clinical heart failure. In longitudinal analyses, 1989 eligible persons (mean age 70.0±5.8 years) were followed for an average of 6.5±0.4 years, of which 4.6% (n = 91) had prevalent or incident clinical heart failure. Heart failure was assessed according to European Society of Cardiology criteria. To estimate cardiac function, we measured left ventricular fractional shortening, left ventricular systolic function, and E/A ratio by echocardiography. Heart failure and cardiac dysfunction were studied with linear regression in relation to sleep quality, assessed by the Pittsburgh Sleep Quality Index. RESULTS No associations between clinical heart failure and sleep quality were observed in cross-sectional analyses. Clinical heart failure predicted a reduction of sleep quality (B = 1.00 points on the Pittsburgh Sleep Quality Index; 95% CI 0.40, 1.60) in longitudinal assessment. This association was driven by the sleep onset latency and sleep quality components of the Pittsburgh Sleep Quality Index. Cardiac dysfunction was not related to sleep quality in cross-sectional or longitudinal analyses. CONCLUSIONS Clinical heart failure, but not cardiac dysfunction measured by echocardiography, increases the risk of poor sleep quality in the general population over time. These findings suggest that clinical manifestations of heart failure negatively affect sleep.

Sleep and 24-h activity rhythms in relation to cortisol change after a very low-dose of dexamethasone.

The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in sleep. Nevertheless, the association of sleep and its 24-h organization with negative feedback control of the HPA axis has received limited attention in population-based studies. We explored this association in 493 middle-aged persons of the Rotterdam Study, a large population-based study (mean age 56 years, standard deviation: 5.3 years; 57% female). The negative feedback of the HPA axis was measured as the change in morning saliva cortisol after the intake of 0.25mg dexamethasone the night before. Actigraphy allowed us to measure the stability and fragmentation of the activity rhythm and to estimate total sleep time, sleep onset latency and wake after sleep onset. A sleep diary kept during the week of actigraphy was used to assess self-reported total sleep time, sleep onset latency, number of awakenings and perceived sleep quality. In our study, enhanced negative feedback of the HPA axis was found in association with unstable activity rhythms (B=0.106, 95% confidence interval (CI): 0.002; 0.210), total sleep time (B=0.108, 95%CI: 0.001; 0.215) and poor subjective sleep quality (B=0.107, 95%CI: 0.009; 0.206) after multivariate adjustment. These results indicated that the 24-h organization, duration and experience of sleep are all associated with the negative feedback control of the HPA axis.

REM sleep and depressive symptoms in a population-based study of middle-aged and elderly persons

Alterations in rapid eye movement sleep have been consistently related to depression in clinical studies. So far, there is limited evidence from population‐based studies for this association of rapid eye movement sleep alterations with depressive symptoms. In 489 participants of the Rotterdam Study, we assessed rapid eye movement sleep latency, rapid eye movement sleep duration and rapid eye movement density with ambulant polysomnography, and depressive symptoms with the Center of Epidemiologic Studies‐Depression Scale. A longer rapid eye movement sleep latency (B = 0.002, P = 0.025) and higher rapid eye movement density (B = 0.015, P = 0.046) were related to depressive symptoms after age–sex adjustment. When we excluded persons who used sleep medication or medication for the nervous system (n = 124), only rapid eye movement density remained related to depressive symptoms (B = 0.018, P = 0.027). Our results suggest that rapid eye movement density is a marker of depressive symptoms in the general population, and that associations of rapid eye movement sleep with depressive symptoms are modified by the use of medication.

Cerebral small vessel disease is related to disturbed 24-h activity rhythms: A population-based study

Cerebral small vessel disease is common in elderly persons. Patients with dementia or stroke frequently have cerebral small vessel disease and often experience disturbances in the sleep−wake rhythm. It is unknown whether cerebral small vessel disease is related to disturbances in sleep and 24‐h activity rhythms.

Actigraphic sleep fragmentation, efficiency and duration associate with dietary intake in the Rotterdam Study.

Short self‐reported sleep duration is associated with dietary intake and this association may partly mediate the link between short sleep and metabolic abnormalities. Subjective sleep measures, however, may be inaccurate and biased. The objective of this study was to evaluate the associations between actigraphic measures of sleep fragmentation, efficiency and duration and energy and macronutrient intakes. We used data from a subgroup of 439 participants of the population‐based cohort, Rotterdam Study. Sleep was assessed using 7‐day actigraphy and sleep diaries, and dietary data with a validated food frequency questionnaire. We assessed the associations of actigraphic sleep parameters with dietary intake using multivariable linear regression models. Higher sleep fragmentation was associated with 4.19 g lower carbohydrate intake per standard deviation of fragmentation {β [95% confidence interval (CI) = −4.19 (−8.0, −0.3)]; P = 0.03}. Each additional percentage increase in sleep efficiency was associated with 11.1 kcal lower energy intake [β (95% CI) = −11.1 (−20.6, −1.7); P = 0.02]. Furthermore, very short sleep duration (<5.5 h) was associated with 218.1 kcal higher energy intake [β (95% CI = 218.06 (33.3, 402.8), P = 0.02], relative to the reference group (≥6.5 to <7.5 h). We observed associations between higher sleep fragmentation with lower carbohydrate intake, and both lower sleep efficiency and very short sleep duration (<5 h) with higher energy intake. The association between sleep and higher energy intake could mediate, in part, the link between short sleep or sleep fragmentation index and metabolic abnormalities.

Use of selective serotonin reuptake inhibitors and sleep quality: A population-based study

STUDY OBJECTIVES Poor sleep is a risk factor for the development and recurrence of depression. Selective serotonin reuptake inhibitor (SSRI) use is consistently associated with good subjective sleep in clinically depressed patient populations. However, studies in the general population are lacking. Our objective was to investigate the association between SSRIs and subjective sleep in a middle-aged and elderly population in a daily practice setting. METHODS We included participants from the prospective Rotterdam Study cohort. Participants had up to two subjective sleep measurements assessed with Pittsburgh Sleep Quality Index ([PSQI], number of measurements = 14,770). SSRI use was based on pharmacy records. We assessed the association between SSRIs and PSQI score and its sub-components, with nonusers of any antidepressant as reference. Analyses were, among others, adjusted for presence of depressive symptoms and concurrent psycholeptic drug use. RESULTS We included 9,267 participants, average baseline age 66.3 y (standard deviation 10.6), and 57.6% women. SSRI use was significantly associated with a 0.78-point lower PSQI score (95% confidence interval [CI] -1.11; -0.44) which reflects better sleep, compared with non-use. The association was more prominent in continuous SSRI users (-0.71 points, 95% CI -1.18; -0.24). Of the sub-components, SSRIs were associated with 0.70-h longer sleep duration (95% CI 0.56; 0.85), higher sleep quality, higher sleep efficiency, and in contrast more daytime dysfunction. CONCLUSIONS SSRI use was associated with better subjective sleep, after adjustment for depressive symptoms and concurrent psycholeptic drug use. This suggests that, in clinical practice in the middle-aged and elderly population, the sleep quality of some persons may benefit from, continued, SSRI use.