Longitudinal associations between diurnal cortisol variation and later-life cognitive impairment

Objective: To determine whether HPAA dysfunction is prospectively associated with global cognitive impairment in later life Methods: This cross-cohort study integrates two large longitudinal datasets: Whitehall II and the National Survey for Health and Development (NSHD), on data collected in the Whitehall II study in 2002/2004, 2007/2009 and 2012/2013; and for NSHD in 2006/2010 and 2015. Serial salivary cortisol samples were collected multiple times within a 24-hour period at mean ages 61.2 and 65.9 years in Whitehall II and at age 60-64 from NSHD participants. Cortisol profile is defined using cortisol awakening response (CAR) and am:pm ratio. Cognitive function was measured using the MMSE in Whitehall II and ACE-III in NSHD, harmonised into a thirty-point score. Models were adjusted for age, sex, diagnoses of hypertension, diabetes, BMI, educational attainment and interval between HPAA and cognitive assessments. Results: In fully adjusted models, increased am:pm cortisol ratio was prospectively associated with better later-life cognitive function years later (0.02 fewer errors per SD increase in am:pm cortisol ratio, p<0.01) and verbal fluency (0.03 SD increase in verbal fluency per SD increase in am:pm ratio, p<0.01). Increasing age, lower educational attainment, diagnosis of hypertension, diagnosis of diabetes and increased BMI were associated with worse cognitive function and poorer verbal fluency. There were no associations between depression and later-life cognition or reverse associations between cognition and later-life cortisol profiles. Conclusions: Loss of diurnal HPAA variation is evident in individuals subsequently experiencing more cognitive impairment. It may serve as an early pre-clinical marker of cognitive decline

No evidence of a longitudinal association between diurnal cortisol patterns and cognition

We examined the effect of salivary cortisol on cognitive performance and decline in 3229 adults (79% men), mean age 61years. Six saliva samples over the day along with a cognition test battery were administered twice in 5years. In fully-adjusted cross-sectional analyses from 2002 to 2004, higher waking cortisol was associated with higher reasoning score (β= 0.08, 95% confidence interval: 0.01, 0.15) but this finding was not replicated using data from 2007 to 2009. Over the mean 5years follow-up there was decline in all cognitive tests but this decline did not vary as a function of cortisol levels; the exception was among APOE e4 carriers where a flatter diurnal slope and higher bedtime cortisol were associated with faster decline in verbal fluency. Changes in cortisol measures between 2002/2004 and 2007/2009 or chronically elevated levels were not associated with cognitive performance in 2007/2009. These results, based on a large sample of community-dwelling adults suggest that variability in hypothalamic-pituitary-adrenal function is not a strong contributor to cognitive aging. © 2014 The Authors

Comparison of sex differences in cognitive function in older adults between high- and middle-income countries and the role of education: a population-based multicohort study

BACKGROUND: The extent to which education explains variations in sex differences in cognitive function between countries at different levels of economic development is unknown. We examined the role of education in sex differences in four cognitive domains in high- and middle-income countries. METHODS: Analyses were based on 70,846 participants, aged 60 years and older, in cohort studies from a high-income (United States) and four middle-income countries (Mexico, Brazil, China, and India). We used weighted linear models to allow nationally-representative comparisons of sex differences in orientation, memory, attention, and fluency using the United States as the reference, before and after adjustment for education, and after stratification by education. RESULTS: Females had lower levels of education than males in all countries, particularly in India. Before adjustment for education, sex differences in orientation and attention in all middle-income countries, memory in Brazil, China, and India, and fluency in India were less favourable to females than in the United States (P < 0.010). For example, females outperformed males in memory in the United States (mean difference [male-female scores] = -0.26 standard deviations [95% CI -0.30, -0.22]) but not in China (0.15 [0.09, 0.21]) or India (0.16 [0.13, 0.19]). Adjustment for education attenuated these sex differences. In analyses stratified by education, there were minimal sex differences in the high education group in all countries. CONCLUSION: Education contributes to larger female disadvantages in cognitive function at older ages in middle-income countries compared with the United States. Gender equity in education is an important target to reduce sex disparities in cognitive function globally

Coronary heart disease and risk factors as predictors of trajectories of psychological distress from midlife to old age

Objective To examine coronary heart disease (CHD) and its risk factors as predictors of long-term trajectories of psychological distress from midlife to old age. Methods In the Whitehall II cohort study, 6890 participants (4814 men, 2076 women; mean age 49.5 years) had up to seven repeat assessments of psychological distress over 21 years (mean follow-up 19 years). CHD and its risk factors (lifestyle-related risk factors, diabetes, hypertension and cholesterol) were assessed at baseline. Group-based trajectory modelling was used to identify clusters of individuals with a similar pattern of psychological distress over time. Results We identified four trajectories of psychological distress over the follow-up: 'persistently low (69% of the participants), 'persistently intermediate' (13%), 'intermediate to low' (12%) and 'persistently high' (7%). The corresponding proportions were 60%, 16%, 13% and 11% among participants with CHD; 63%, 15%, 12% and 10% among smokers and 63%, 16%, 12% and 10% among obese participants. In multivariable adjusted multinomial regression analyses comparing other trajectories to persistently low trajectory, prevalent CHD was associated with intermediate to low (OR 1.70, 95% CI 1.08 to 2.68) and persistently high (OR 1.92, 95% CI 1.16 to 3.19) trajectories. Smoking (OR 1.33, 95% CI 1.07 to 1.64; OR 1.55, 95% CI 1.19 to 2.04) and obesity (OR 1.33, 95% CI 1.04 to 1.70; OR 1.47, 95% CI 1.07 to 2.01) were associated with persistently intermediate and persistently high trajectories, respectively. Conclusion CHD, smoking and obesity may have a role in the development of long-lasting psychological distress from midlife to old age.Peer reviewe

Association of sleep duration at age 50, 60, and 70 years with risk of multimorbidity in the UK : 25-year follow-up of the Whitehall II cohort study

Publisher Copyright: © 2022 Sabia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background Sleep duration has been shown to be associated with individual chronic diseases but its association with multimorbidity, common in older adults, remains poorly understood. We examined whether sleep duration is associated with incidence of a first chronic disease, subsequent multimorbidity and mortality using data spanning 25 years. Methods and findings Data were drawn from the prospective Whitehall II cohort study, established in 1985 on 10,308 persons employed in the London offices of the British civil service. Self-reported sleep duration was measured 6 times between 1985 and 2016, and data on sleep duration was extracted at age 50 (mean age (standard deviation) = 50.6 (2.6)), 60 (60.3 (2.2)), and 70 (69.2 (1.9)). Incidence of multimorbidity was defined as having 2 or more of 13 chronic diseases, follow-up up to March 2019. Cox regression, separate analyses at each age, was used to examine associations of sleep duration at age 50, 60, and 70 with incident multimorbidity. Multistate models were used to examine the association of sleep duration at age 50 with onset of a first chronic disease, progression to incident multimorbidity, and death. Analyses were adjusted for sociodemographic, behavioral, and health-related factors. A total of 7,864 (32.5% women) participants free of multimorbidity had data on sleep duration at age 50; 544 (6.9%) reported sleeping ≤5 hours, 2,562 (32.6%) 6 hours, 3,589 (45.6%) 7 hours, 1,092 (13.9%) 8 hours, and 77 (1.0%) ≥9 hours. Compared to 7-hour sleep, sleep duration ≤5 hours was associated with higher multimorbidity risk (hazard ratio: 1.30, 95% confidence interval = 1.12 to 1.50; p < 0.001). This was also the case for short sleep duration at age 60 (1.32, 1.13 to 1.55; p < 0.001) and 70 (1.40, 1.16 to 1.68; p < 0.001). Sleep duration ≥9 hours at age 60 (1.54, 1.15 to 2.06; p = 0.003) and 70 (1.51, 1.10 to 2.08; p = 0.01) but not 50 (1.39, 0.98 to 1.96; p = 0.07) was associated with incident multimorbidity. Among 7,217 participants free of chronic disease at age 50 (mean follow-up = 25.2 years), 4,446 developed a first chronic disease, 2,297 progressed to multimorbidity, and 787 subsequently died. Compared to 7-hour sleep, sleeping ≤5 hours at age 50 was associated with an increased risk of a first chronic disease (1.20, 1.06 to 1.35; p = 0.003) and, among those who developed a first disease, with subsequent multimorbidity (1.21, 1.03 to 1.42; p = 0.02). Sleep duration ≥9 hours was not associated with these transitions. No association was found between sleep duration and mortality among those with existing chronic diseases. The study limitations include the small number of cases in the long sleep category, not allowing conclusions to be drawn for this category, the self-reported nature of sleep data, the potential for reverse causality that could arise from undiagnosed conditions at sleep measures, and the small proportion of non-white participants, limiting generalization of findings. Conclusions In this study, we observed short sleep duration to be associated with risk of chronic disease and subsequent multimorbidity but not with progression to death. There was no robust evidence of an increased risk of chronic disease among those with long sleep duration at age 50. Our findings suggest an association between short sleep duration and multimorbidity.Peer reviewe

Association of body mass index and waist circumference with successful ageing: 16 year follow-up of the Whitehall II study

Objective: We examined whether midlife body mass index (BMI) and waist circumference (WC) predict successful ageing. Design and Methods BMI/WC were assessed in 4869 persons (mean age 51.2, range 42–63 in 1991/93) and survival and successful ageing (alive, no chronic disease at age >60 years, not in the worst age- and sex-standardized quintile of cognitive, physical, respiratory, and cardiovascular, and mental health) ascertained over a 16-year follow-up, analysed using logistic regression adjusted for socio-demographic factors and health behaviours. Results: 507 participants died, 1008 met the criteria for successful ageing. Those with BMI≥30 kg/m2 had lower odds of successful ageing (Odds Ratio (OR)=0.37; 95% Confidence Interval (CI): 0.27, 0.50) and survival (OR=0.55; 95% CI: 0.41, 0.74) compared to BMI between 18.5–25 kg/m2. Those with a large waist circumference (≥102/88 cm in men/women) had lower odds of successful ageing (OR=0.41; 95% CI: 0.31, 0.54) and survival (OR=0.57; 95% CI: 0.44, 0.73) compared to those with a small waist (<94/80 cm in men/women). Analysis with finer categories showed lower odds of successful ageing starting at BMI ≥23.5 kg/m2 and waist circumference 82/68 cm in men/women. Conclusions: Optimal midlife BMI and waist circumference for successful ageing might be substantially below the current thresholds used to define obesity

Structural social relations and cognitive ageing trajectories : evidence from the Whitehall II cohort study

Background: Social relations are important for health, particularly at older ages. We examined the salience of frequency of social contacts and marital status for cognitive ageing trajectories over 21 years, from midlife to early old age. Methods: Data are from the Whitehall II cohort study, including 4290 men and 1776 women aged 35-55 years at baseline (1985-88). Frequency of social contacts and marital status were measured in 1985-88 and 1989-90. Assessment of cognitive function on five occasions (1991-94, 1997-99, 2003-04, 2007-09 and 2012-13) included the following tests: short-term memory, inductive reasoning, verbal fluency (phonemic and semantic) and a combined global score. Cognitive trajectories over the study period were analysed using longitudinal latent growth class analyses, and the associations of these latent classes (trajectory memberships) with social relations were analysed using multinominal logistic regression. Results: More frequent social contacts [relative risk (RRR) 0.96, 95% confidence interval (CI) 0.94 - 0.98] and being married (RRR 0.70, 95% CI 0.58 - 0.84) were associated with lower probability of being on a low rather than high cognitive performance trajectory over the subsequent 21 years. These associations persisted after adjustment for covariates. Of the subtests, social relations variables had the strongest association with phonemic fluency (RRR 0.95, 95% CI 0.94 - 0.97 for frequent contact; RRR 0.59, 95% CI 0.48 - 0.71 for being married). Conclusions: More frequent social contacts and having a spouse were associated with more favourable cognitive ageing trajectories. Further studies are needed to examine whether interventions designed to improve social connections affect cognitive ageing.Peer reviewe

Predictive utility of the Framingham general cardiovascular disease risk profile for cognitive function: evidence from the Whitehall II study

Aims Vascular risk factors are associated with cognitive impairment and dementia, although most of the research in this domain focuses on cerebrovascular factors. We examined the relationship between the recently developed Framingham general cardiovascular risk profile and cognitive function and 10-year decline in late midlife.Methods and results Study sample comprised of 3486 men and 1341 women, mean age 55 years [standard deviation (SD)=6], from the Whitehall II study, a longitudinal British cohort study. The Framingham General Cardiovascular Risk profile, assessed between 1997 and 1999, included age, sex, HDL cholesterol, total cholesterol, systolic blood pressure, smoking status, and diabetes status. Measures of cognitive function consisted of tests of reasoning (Alice Heim 4-I), memory, phonemic and semantic fluency, and vocabulary (Mill-Hill), assessed three times (1997-1999, 20022004, 2007-2009) over 10 years. In cross-sectional age-adjusted models, 10% point increments in cardiovascular risk were associated with poor performance in all cognitive domains in both men and women (all P-values <0.001). In models adjusted for age, ethnicity, marital status, and education, 10% higher cardiovascular risk was associated with greater overall 10-year cognitive decline in men, reasoning in particular (-0.47; 95% CI: -0.81, -0.11).Conclusion In middle-aged individuals free of cardiovascular disease, an adverse cardiovascular risk profile is associated with poor cognitive function, and decline in at least one cognitive domain in men

Association between age at onset of multimorbidity and incidence of dementia: 30 year follow-up in Whitehall II prospective cohort study

OBJECTIVE: To examine the association of midlife and late life multimorbidity, including severity of multimorbidity, with incident dementia. DESIGN: Prospective cohort study. SETTING: Civil service departments in London (Whitehall II study, study inception in 1985-88). PARTICIPANTS: 10 095 participants, aged 35 to 55 at baseline. MAIN OUTCOME MEASURE: Incident dementia at follow-up between 1985 and 2019. Cause specific Cox proportional hazards regression was used to examine the association of multimorbidity overall and at age 55, 60, 65, and 70 with subsequent dementia, taking into account the competing risk of death. RESULTS: The prevalence of multimorbidity (≥2 chronic diseases) was 6.6% (655/9937) at age 55 and 31.7% (2464/7783) at age 70; 639 cases of incident dementia occurred over a median follow-up of 31.7 years. After adjustment for sociodemographic factors and health behaviours, multimorbidity at age 55 was associated with subsequent risk of dementia (difference in incidence rate per 1000 person years 1.56, 95% confidence interval 0.62 to 2.77; hazard ratio 2.44, 95% confidence interval 1.82 to 3.26). The association weakened progressively with older age at onset of multimorbidity. At age 65, onset of multimorbidity before age 55 was associated with 3.86 (1.80 to 6.52) per 1000 person years higher incidence of dementia (hazard ratio 2.46, 1.80 to 2.26) and onset between 60 and 65 was associated with 1.85 (0.64 to 3.39) per 1000 person years higher incidence (1.51, 1.16 to 1.97). Severity of multimorbidity (≥3 chronic diseases) at age 55 was associated with a 5.22 (1.14 to 11.95) per 1000 person years higher incidence of dementia (hazard ratio 4.96, 2.54 to 9.67); the same analyses at age 70 showed 4.49 (2.33 to 7.19) per 1000 person years higher incidence (1.65, 1.25 to 2.18). CONCLUSION: Multimorbidity, particularly when onset is in midlife rather than late life, has a robust association with subsequent dementia. The increasingly younger age at onset of multimorbidity makes prevention of multimorbidity in people with a first chronic disease important