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1.  Socioeconomic and Psychosocial Adversity in Midlife and Depressive Symptoms Post Retirement: A 21-year Follow-up of the Whitehall II Study 
We examined whether socioeconomic and psychosocial adversity in midlife predicts post-retirement depressive symptoms.
Design and Setting
A prospective cohort study of British civil servants who responded to a self-administered questionnaire in middle-age and at older ages, 21 years later.
The study sample consisted of 3,939 Whitehall II Study participants (2,789 men, 1,150 women; mean age 67.6 years at follow-up) who were employed at baseline and retired at follow-up.
Midlife adversity was assessed by self-reported socioeconomic adversity (low occupational position; poor standard of living) and psychosocial adversity (high job strain; few close relationships). Symptoms of depression post-retirement were measured by the Center for Epidemiologic Studies Depression scale.
After adjustment for sociodemographic and health-related covariates at baseline and follow-up, there were strong associations between midlife adversities and post-retirement depressive symptoms: low occupational position (odds ratio [OR]: 1.70, 95% confidence interval [CI]: 1.15–2.51), poor standard of living (OR: 2.37, 95% CI: 1.66–3.39), high job strain (OR: 1.52, 95% CI: 1.09–2.14), and few close relationships (OR: 1.51, 95% CI: 1.12–2.03). The strength of the associations between socioeconomic, psychosocial, work-related, or non-work related exposures and depressive symptoms was similar.
Robust associations from observational data suggest that several socioeconomic and psychosocial risk factors for symptoms of depression post-retirement can be detected already in midlife.
PMCID: PMC4270962  PMID: 24816123
Depression; elderly; inequalities; life course; mood disorders; old age; prospective; stress
2.  Long working hours, socioeconomic status, and the risk of incident type 2 diabetes: a meta-analysis of published and unpublished data from 222 120 individuals 
Working long hours might have adverse health effects, but whether this is true for all socioeconomic status groups is unclear. In this meta-analysis stratified by socioeconomic status, we investigated the role of long working hours as a risk factor for type 2 diabetes.
We identified four published studies through a systematic literature search of PubMed and Embase up to April 30, 2014. Study inclusion criteria were English-language publication; prospective design (cohort study); investigation of the effect of working hours or overtime work; incident diabetes as an outcome; and relative risks, odds ratios, or hazard ratios (HRs) with 95% CIs, or sufficient information to calculate these estimates. Additionally, we used unpublished individual-level data from 19 cohort studies from the Individual-Participant-Data Meta-analysis in Working-Populations Consortium and international open-access data archives. Effect estimates from published and unpublished data from 222 120 men and women from the USA, Europe, Japan, and Australia were pooled with random-effects meta-analysis.
During 1·7 million person-years at risk, 4963 individuals developed diabetes (incidence 29 per 10 000 person-years). The minimally adjusted summary risk ratio for long (≥55 h per week) compared with standard working hours (35–40 h) was 1·07 (95% CI 0·89–1·27, difference in incidence three cases per 10 000 person-years) with significant heterogeneity in study-specific estimates (I2=53%, p=0·0016). In an analysis stratified by socioeconomic status, the association between long working hours and diabetes was evident in the low socioeconomic status group (risk ratio 1·29, 95% CI 1·06–1·57, difference in incidence 13 per 10 000 person-years, I2=0%, p=0·4662), but was null in the high socioeconomic status group (1·00, 95% CI 0·80–1·25, incidence difference zero per 10 000 person-years, I2=15%, p=0·2464). The association in the low socioeconomic status group was robust to adjustment for age, sex, obesity, and physical activity, and remained after exclusion of shift workers.
In this meta-analysis, the link between longer working hours and type 2 diabetes was apparent only in individuals in the low socioeconomic status groups.
Medical Research Council, European Union New and Emerging Risks in Occupational Safety and Health research programme, Finnish Work Environment Fund, Swedish Research Council for Working Life and Social Research, German Social Accident Insurance, Danish National Research Centre for the Working Environment, Academy of Finland, Ministry of Social Affairs and Employment (Netherlands), Economic and Social Research Council, US National Institutes of Health, and British Heart Foundation.
PMCID: PMC4286814  PMID: 25262544
3.  Time may not fully attenuate solvent-associated cognitive deficits in highly exposed workers 
Neurology  2014;82(19):1716-1723.
To test the effects of lifetime occupational solvent exposure, as measured by dose and timing, on performance on multiple cognitive tests among retired French utility workers.
A total of 2,143 retirees in the GAZEL cohort underwent cognitive testing in 2010. Lifetime exposure to chlorinated solvents, petroleum solvents, and benzene was assessed using a job exposure matrix. We modeled effects of lifetime solvent dose, timing of last exposure, and a combination of these metrics on risk for cognitive impairment.
Thirty-three percent of participants were exposed to chlorinated solvents, 26% to benzene, and 25% to petroleum solvents. High exposure to solvents was significantly associated with poor cognition; for example, those highly exposed to chlorinated solvents were at risk of impairment on the Mini-Mental State Examination (risk ratio 1.18; 95% confidence interval 1.06, 1.31), the Digit Symbol Substitution Test (1.54; 1.31, 1.82), semantic fluency test (1.33; 1.14, 1.55), and the Trail Making Test B (1.49; 1.25, 1.77). Retirees at greatest risk for deficits had both high lifetime exposure to solvents and were last exposed 12 to 30 years before testing. Risk was somewhat elevated among those with high lifetime exposure who were last exposed 31 to 50 years before testing. Those with high, recent exposure exhibited impairment in almost all domains, including those not typically associated with solvent exposure.
While risk of cognitive impairment among moderately exposed workers may attenuate with time, this may not be fully true for those with higher exposure. This has implications for physicians working with formerly solvent-exposed patients as well as for workplace exposure limit policies.
PMCID: PMC4032208  PMID: 24821933
4.  Non-Consent to a Wrist-Worn Accelerometer in Older Adults: The Role of Socio-Demographic, Behavioural and Health Factors 
PLoS ONE  2014;9(10):e110816.
Accelerometers, initially waist-worn but increasingly wrist-worn, are used to assess physical activity free from reporting-bias. However, its acceptability by study participants is unclear. Our objective is to assess factors associated with non-consent to a wrist-mounted accelerometer in older adults.
Data are from 4880 Whitehall II study participants (1328 women, age range = 60–83), requested to wear a wrist-worn accelerometer 24 h every day for 9 days in 2012/13. Sociodemographic, behavioral, and health-related factors were assessed by questionnaire and weight, height, blood pressure, cognitive and motor function were measured during a clinical examination.
210 participants had contraindications and 388 (8.3%) of the remaining 4670 participants did not consent. Women, participants reporting less physical activity and less favorable general health were more likely not to consent. Among the clinical measures, cognitive impairment (Odds Ratio = 2.21, 95% confidence interval: 1.22–4.00) and slow walking speed (Odds Ratio = 1.38, 95% confidence interval: 1.02–1.86) were associated with higher odds of non-consent.
The rate of non-consent in our study of older adults was low. However, key markers of poor health at older ages were associated with non-consent, suggesting some selection bias in the accelerometer data.
PMCID: PMC4208789  PMID: 25343453
5.  Negative Aspects of Close Relationships as Risk Factors for Cognitive Aging 
American Journal of Epidemiology  2014;180(11):1118-1125.
The extent to which social relationships influence cognitive aging is unclear. In this study, we investigated the association of midlife quality of close relationships with subsequent cognitive decline. Participants in the Whitehall II Study (n = 5,873; ages 45–69 years at first cognitive assessment) underwent executive function and memory tests 3 times over a period of 10 years (1997–1999 to 2007–2009). Midlife negative and positive aspects of close relationships were assessed twice using the Close Persons Questionnaire during the 8 years preceding cognitive assessment. Negative aspects of close relationships, but not positive aspects, were associated with accelerated cognitive aging. Participants in the top third of reported negative aspects of close relationships experienced a faster 10-year change in executive function (−0.04 standard deviation, 95% confidence interval: −0.08, −0.01) than those in the bottom third, which was comparable with 1 extra year of cognitive decline for participants aged 60 years after adjustment for sociodemographic and health status. Longitudinal analysis found no evidence of reverse causality. This study highlights the importance of differentiating aspects of social relationships to evaluate their unique associations with cognitive aging.
PMCID: PMC4239796  PMID: 25342204
aging; cognitive decline; longitudinal studies; social relationships
6.  Informal Caregiving and the Risk for Coronary Heart Disease: The Whitehall II Study 
The stress associated with informal caregiving has been shown to be associated with poor health, including coronary heart disease (CHD). However, it is unclear if the risk of CHD is attributable to caregiving or prior poor health of the caregiver.
We used data from the Whitehall II cohort study. Caregiving and caregiver’s health (using 3 measures: self-rated health, mental health using the General Health Questionnaire, and physical component score of the SF-36) were assessed in 1991–1993 among 5,468 men and 2,457 women aged 39–63 years. CHD (fatal CHD, clinically verified nonfatal myocardial infarction, and definite angina) incidence was recorded for a mean 17 years; sociodemographic variables, health behaviors, and cardiovascular risk factors were included as covariates.
Cox regression showed the risk of CHD in caregivers not to be higher (hazard ratio = 1.18; 95% CI: 0.96, 1.45) compared with noncaregivers. Analyses stratified by health status showed that compared with noncaregivers in good health, caregivers with poor self-rated (hazard ratio = 2.00; 95% CI: 1.44, 2.78), mental (hazard ratio = 1.63; 95% CI: 1.16, 2.30), or physical (hazard ratio =1.87; 95% CI: 1.34, 2.62) health had greater risk of CHD. A similar elevated risk was observed in noncaregivers with poor health; no excess risk was observed among caregivers reporting good health, and the combined effect of poor health and caregiving did not exceed their independent effects.
Caregiving in midlife is not in itself associated with greater risk of CHD, but it is associated with increased risk for CHD among caregivers who report being in poor health.
PMCID: PMC3779628  PMID: 23525476
Coronary heart disease; Stress; Caregiver.
7.  Association of body mass index and waist circumference with successful ageing: 16 year follow-up of the Whitehall II study 
Obesity (Silver Spring, Md.)  2013;22(4):1172-1178.
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.
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.
Optimal midlife BMI and waist circumference for successful ageing might be substantially below the current thresholds used to define obesity.
PMCID: PMC3968224  PMID: 24167036
obesity; body mass index; waist circumference; ageing
8.  No evidence of a longitudinal association between diurnal cortisol patterns and cognition☆ 
Neurobiology of Aging  2014;35(10):2239-2245.
We examined the effect of salivary cortisol on cognitive performance and decline in 3229 adults (79% men), mean age 61 years. Six saliva samples over the day along with a cognition test battery were administered twice in 5 years. 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 5 years 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.
PMCID: PMC4099515  PMID: 24735831
Cortisol; Glucocorticoid; Cognitive decline
9.  Bidirectional association between physical activity and symptoms of anxiety and depression: the Whitehall II study 
European journal of epidemiology  2012;27(7):537-546.
Although it has been hypothesized that the association of physical activity with depressive and anxiety symptoms is bidirectional, few studies have examined this issue in a prospective setting. We studied this bidirectional association using data on physical activity and symptoms of anxiety and depression at three points in time over 8 years. A total of 9,309 participants of the British Whitehall II prospective cohort study provided data on physical activity, anxiety and depression symptoms and 10 covariates at baseline in 1985. We analysed the associations of physical activity with anxiety and/or depression symptoms using multinomial logistic regression (with anxiety and depression symptoms as dependent variables) and binary logistic regression (with physical activity as the dependent variable). There was a cross-sectional inverse association between physical activity and anxiety and/or depressive symptoms at baseline (ORs between 0.63 and 0.72). In cumulative analyses, regular physical activity across all three data waves, but not irregular physical activity, was associated with reduced likelihood of depressive symptoms at follow-up (OR = 0.71, 95 % CI 0.54, 0.99). In a converse analysis, participants with anxiety and depression symptoms at baseline had higher odds of not meeting the recommended levels of physical activity at follow-up (OR = 1.79, 95 % CI 1.17, 2.74). This was also the case in individuals with anxiety and/or depression symptoms at both baseline and follow-up (OR = 1.70, 95 % CI 1.10, 2.63). The association between physical activity and symptoms of anxiety and/or depression appears to be bidirectional.
PMCID: PMC4180054  PMID: 22623145
Common mental disorders; Physical activity; Bidirectional association; Longitudinal studies
10.  Associations Between Change in Sleep Duration and Inflammation: Findings on C-reactive Protein and Interleukin 6 in the Whitehall II Study 
American Journal of Epidemiology  2013;178(6):956-961.
Cross-sectional evidence suggests associations between sleep duration and levels of the inflammatory markers, C-reactive protein and interleukin-6. This longitudinal study uses data from the London-based Whitehall II study to examine whether changes in sleep duration are associated with average levels of inflammation from 2 measures 5 years apart. Sleep duration (≤5, 6, 7, 8, ≥9 hours on an average week night) was assessed in 5,003 middle-aged women and men in 1991/1994 and 1997/1999. Fasting levels of C-reactive protein and interleukin-6 were measured in 1997/1999 and 2002/2004. Cross-sectional analyses indicated that shorter sleep is associated with higher levels of inflammatory markers. Longitudinal analyses showed that each hour per night decrease in sleep duration between 1991/1994 and 1997/1999 was associated with higher levels of C-reactive protein (8.1%) and interleukin-6 (4.5%) averaged across measures in 1997/1999 and 2002/2004. Adjustment for longstanding illness and major cardiometabolic risk factors indicated that disease processes may partially underlie these associations. An increase in sleep duration was not associated with average levels of inflammatory markers. These results suggest that both short sleep and reductions in sleep are associated with average levels of inflammation over a 5-year period.
PMCID: PMC3817449  PMID: 23801012
change in sleep duration; C-reactive protein; inflammatory markers; interleukin-6; sleep duration
11.  Increased risk of coronary heart disease among individuals reporting adverse impact of stress on their health: the Whitehall II prospective cohort study 
European Heart Journal  2013;34(34):2697-2705.
Response to stress can vary greatly between individuals. However, it remains unknown whether perceived impact of stress on health is associated with adverse health outcomes. We examined whether individuals who report that stress adversely affects their health are at increased risk of coronary heart disease (CHD) compared with those who report that stress has no adverse health impact.
Methods and results
Analyses are based on 7268 men and women (mean age: 49.5 years, interquartile range: 11 years) from the British Whitehall II cohort study. Over 18 years of follow-up, there were 352 coronary deaths or first non-fatal myocardial infarction (MI) events. After adjustment for sociodemographic characteristics, participants who reported at baseline that stress has affected their health ‘a lot or extremely’ had a 2.12 times higher (95% CI 1.52–2.98) risk of coronary death or incident non-fatal MI when compared with those who reported no effect of stress on their health. This association was attenuated but remained statistically significant after adjustment for biological, behavioural, and other psychological risk factors including perceived stress levels, and measures of social support; fully adjusted hazard ratio: 1.49 (95% CI 1.01–2.22).
In this prospective cohort study, the perception that stress affects health, different from perceived stress levels, was associated with an increased risk of coronary heart disease. Randomized controlled trials are needed to determine whether disease risk can be reduced by increasing clinical attention to those who complain that stress greatly affects their health.
PMCID: PMC3766148  PMID: 23804585
Epidemiology; Stress; Coronary heart disease; Prospective studies
12.  Midlife stroke risk and cognitive decline: A 10-year follow-up of the Whitehall II cohort study 
Stroke is associated with an increased risk of dementia. However, it is unclear if risk of stroke in those free of stroke, particularly in non-elderly populations, leads to differential rates of cognitive decline. Our aim was to assess whether risk of stroke in midlife was associated with cognitive decline over 10 years of follow-up.
We studied 4,153 men and 1,657 women, mean age 55.6 years at baseline, from the Whitehall II study, a longitudinal British cohort study. We used the Framingham Stroke Risk Profile (FSRP) that incorporates age, systolic blood pressure, diabetes mellitus, smoking, prior cardiovascular disease, atrial fibrillation, left ventricular hypertrophy, and use of antihypertensive medication. Cognitive tests included reasoning, memory, verbal fluency, and vocabulary assessed three times over ten years. Longitudinal associations between FSRP and its components were tested using mixed effects models and rates of cognitive change over 10 years were estimated.
Higher stroke risk was associated with faster decline in verbal fluency, vocabulary and global cognition. For example, for global cognition there was greater decline in the highest FSRP quartile (−0.25 of a standard deviation; 95% CI: −0.28 to −0.21) compared to the lowest risk quartile (P=0.03). No association was observed for memory and reasoning. Of the individual components of FSRP only diabetes was independently associated with faster cognitive decline (β=−0.06; 95% CI:−0.01, −0.003, P=0.03).
Elevated stroke risk is associated with accelerated cognitive decline over 10 years. Aggregation of risk factors may be especially important in this association.
PMCID: PMC3918666  PMID: 23199495
vascular risk factors; cognitive decline; Framingham Stroke Risk Profile; aging; midlife
13.  Personality and All-Cause Mortality: Individual-Participant Meta-Analysis of 3,947 Deaths in 76,150 Adults 
American Journal of Epidemiology  2013;178(5):667-675.
Personality may influence the risk of death, but the evidence remains inconsistent. We examined associations between personality traits of the five-factor model (extraversion, neuroticism, agreeableness, conscientiousness, and openness to experience) and the risk of death from all causes through individual-participant meta-analysis of 76,150 participants from 7 cohorts (the British Household Panel Survey, 2006–2009; the German Socio-Economic Panel Study, 2005–2010; the Household, Income and Labour Dynamics in Australia Survey, 2006–2010; the US Health and Retirement Study, 2006–2010; the Midlife in the United States Study, 1995–2004; and the Wisconsin Longitudinal Study's graduate and sibling samples, 1993–2009). During 444,770 person-years at risk, 3,947 participants (54.4% women) died (mean age at baseline = 50.9 years; mean follow-up = 5.9 years). Only low conscientiousness—reflecting low persistence, poor self-control, and lack of long-term planning—was associated with elevated mortality risk when taking into account age, sex, ethnicity/nationality, and all 5 personality traits. Individuals in the lowest tertile of conscientiousness had a 1.4 times higher risk of death (hazard ratio = 1.37, 95% confidence interval: 1.18, 1.58) compared with individuals in the top 2 tertiles. This association remained after further adjustment for health behaviors, marital status, and education. In conclusion, of the higher-order personality traits measured by the five-factor model, only conscientiousness appears to be related to mortality risk across populations.
PMCID: PMC3755650  PMID: 23911610
meta-analysis; mortality; personality; psychology; survival analysis
14.  Interleukin-6 and C-reactive protein as predictors of cognitive decline in late midlife 
Neurology  2014;83(6):486-493.
Peripheral inflammatory markers are elevated in patients with dementia. In order to assess their etiologic role, we examined whether interleukin-6 (IL-6) and C-reactive protein (CRP) measured in midlife predict concurrently assessed cognition and subsequent cognitive decline.
Mean value of IL-6 and CRP, assessed on 5,217 persons (27.9% women) in 1991–1993 and 1997–1999 in the Whitehall II longitudinal cohort study, were categorized into tertiles to examine 10-year decline (assessments in 1997–1999, 2002–2004, and 2007–2009) in standardized scores (mean = 0, SD = 1) of memory, reasoning, and verbal fluency using mixed models. Mini-Mental State Examination (MMSE) was administered in 2002–2004 and 2007–2009; decline ≥3 points was modeled with logistic regression. Analyses were adjusted for baseline age, sex, education, and ethnicity; further analyses were also adjusted for smoking, obesity, Framingham cardiovascular risk score, and chronic diseases (cancer, coronary heart disease, stroke, diabetes, and depression).
In cross-sectional analysis, reasoning was 0.08 SD (95% confidence interval [CI] −0.14, −0.03) lower in participants with high compared to low IL-6. In longitudinal analysis, 10-year decline in reasoning was greater (ptrend = 0.01) among participants with high IL-6 (−0.35; 95% CI −0.37, −0.33) than those with low IL-6 (−0.29; 95% CI −0.31, −0.27). In addition, participants with high IL-6 had 1.81 times greater odds ratio of decline in MMSE (95% CI 1.20, 2.71). CRP was not associated with decline in any test.
Elevated IL-6 but not CRP in midlife predicts cognitive decline; the combined cross-sectional and longitudinal effects over the 10-year observation period corresponded to an age effect of 3.9 years.
PMCID: PMC4141998  PMID: 24991031
15.  Metabolically Healthy Obesity and Risk of Mortality 
Diabetes Care  2013;36(8):2294-2300.
To assess the association of a “metabolically healthy obese” phenotype with mortality using five definitions of metabolic health.
Adults (n = 5,269; 71.7% men) aged 39–62 years in 1991 through 1993 provided data on BMI and metabolic health, defined using data from the Adult Treatment Panel-III (ATP-III); criteria from two studies; and the Matsuda and homeostasis model assessment (HOMA) indices. Cross-classification of BMI categories and metabolic status (healthy/unhealthy) created six groups. Cox proportional hazards regression models were used to analyze associations with all-cause and cardiovascular disease (CVD) mortality during a median follow-up of 17.7 years.
A total of 638 individuals (12.1% of the cohort) were obese, of whom 9–41% were metabolically healthy, depending on the definition. Regardless of the definition, compared with metabolically healthy, normal-weight individuals, both the metabolically healthy obese (hazard ratios [HRs] ranged from 1.81 [95% CI 1.16–2.84] for ATP-III to 2.30 [1.13–4.70] for the Matsuda index) and the metabolically abnormal obese (HRs ranged from 1.57 [1.08–2.28] for the Matsuda index to 2.05 [1.44–2.92] for criteria defined in a separate study) had an increased risk of mortality. The only exception was the lack of excess risk using the HOMA criterion for the metabolically healthy obese (1.08; 0.67–1.74). Among the obese, the risk of mortality did not vary as a function of metabolic health apart from when using the HOMA criterion (1.93; 1.15–3.22). Similar results were obtained for cardiovascular mortality.
For most definitions of metabolic health, both metabolically healthy and unhealthy obese patients carry an elevated risk of mortality.
PMCID: PMC3714476  PMID: 23637352
16.  Combined impact of smoking and heavy alcohol use on cognitive decline in early old age: Whitehall II prospective cohort study 
The British Journal of Psychiatry  2013;203(2):120-125.
Identifying modifiable risk factors for cognitive decline may inform prevention of dementia.
To examine the combined impact of cigarette smoking and heavy alcohol consumption on cognitive decline from midlife.
Prospective cohort study (Whitehall II cohort) with three clinical examinations in 1997/99, 2002/04 and 2007/09. Participants were 6473 adults (72% men), mean age 55.76 years (s.d. = 6.02) in 1997/99. Four cognitive tests, assessed three times over 10 years, combined into a global z-score (mean 0, s.d. = 1).
Age-related decline in the global cognitive score was faster in individuals who were smoking heavy drinkers than in non-smoking moderate alcohol drinkers (reference group). The interaction term (P = 0.04) suggested that the combined effects of smoking and alcohol consumption were greater than their individual effects. Adjusting for age, gender, education and chronic diseases, 10-year decline in global cognition was –0.42 z-scores (95% CI –0.45 to –0.39) for the reference group. In individuals who were heavy alcohol drinkers who also smoked the decline was –0.57 z-scores (95% CI –0.67 to –0.48); 36% faster than the reference group.
Individuals who were smokers who drank alcohol heavily had a 36% faster cognitive decline, equivalent to an age-effect of 2 extra years over 10-year follow-up, compared with individuals who were non-smoking moderate drinkers.
PMCID: PMC3730115  PMID: 23846998
17.  Combined effect of physical activity and leisure time sitting on long-term risk of incident obesity and metabolic risk factor clustering 
Diabetologia  2014;57(10):2048-2056.
Our study aimed to investigate the combined effects of moderate-to-vigorous physical activity and leisure time sitting on the long-term risk of obesity and clustering of metabolic risk factors.
The duration of moderate and vigorous physical activity and of leisure time sitting was assessed by questionnaire between 1997 and 1999 among 3,670 participants from the Whitehall II cohort study (73% male; mean age 56 years). Multivariable-adjusted logistic regression models examined associations of physical activity and leisure time sitting tertiles with odds of incident obesity (BMI ≥ 30 kg/m2) and incident metabolic risk factor clustering (two or more of the following: low HDL-cholesterol, high triacylglycerol, hypertension, hyperglycaemia, insulin resistance) at 5 and 10 year follow-ups.
Physical activity, but not leisure time sitting, was associated with incident obesity. The lowest odds of incident obesity after 5 years were observed for individuals reporting both high physical activity and low leisure time sitting (OR = 0.26; 95% CI 0.11, 0.64), with weaker effects after 10 years. Compared with individuals in the low physical activity/high leisure time sitting group, those with intermediate levels of both physical activity and leisure time sitting had lower odds of incident metabolic risk factor clustering after 5 years (OR 0.53; 95% CI 0.36, 0.78), with similar odds after 10 years.
Both high levels of physical activity and low levels of leisure time sitting may be required to substantially reduce the risk of obesity. Associations with developing metabolic risk factor clustering were less clear.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-014-3323-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC4153972  PMID: 25078481
Epidemiology; Exercise; Metabolic syndrome; Obesity; Weight regulation
19.  Study protocol: the Whitehall II imaging sub-study 
BMC Psychiatry  2014;14:159.
The Whitehall II (WHII) study of British civil servants provides a unique source of longitudinal data to investigate key factors hypothesized to affect brain health and cognitive ageing. This paper introduces the multi-modal magnetic resonance imaging (MRI) protocol and cognitive assessment designed to investigate brain health in a random sample of 800 members of the WHII study.
A total of 6035 civil servants participated in the WHII Phase 11 clinical examination in 2012–2013. A random sample of these participants was included in a sub-study comprising an MRI brain scan, a detailed clinical and cognitive assessment, and collection of blood and buccal mucosal samples for the characterisation of immune function and associated measures. Data collection for this sub-study started in 2012 and will be completed by 2016. The participants, for whom social and health records have been collected since 1985, were between 60–85 years of age at the time the MRI study started. Here, we describe the pre-specified clinical and cognitive assessment protocols, the state-of-the-art MRI sequences and latest pipelines for analyses of this sub-study.
The integration of cutting-edge MRI techniques, clinical and cognitive tests in combination with retrospective data on social, behavioural and biological variables during the preceding 25 years from a well-established longitudinal epidemiological study (WHII cohort) will provide a unique opportunity to examine brain structure and function in relation to age-related diseases and the modifiable and non-modifiable factors affecting resilience against and vulnerability to adverse brain changes.
PMCID: PMC4048583  PMID: 24885374
Epidemiology; Magnetic resonance imaging; Diffusion tensor imaging; White matter; Functional MRI; Connectome; Resting state brain networks; Neuropsychology; Dementia; Affective disorders
20.  Predicting cognitive decline 
Neurology  2013;80(14):1300-1306.
Our aim was to compare 2 Framingham vascular risk scores with a dementia risk score in relation to 10-year cognitive decline in late middle age.
Participants were men and women with mean age of 55.6 years at baseline, from the Whitehall II study, a longitudinal British cohort study. We compared the Framingham general cardiovascular disease risk score and the Framingham stroke risk score with the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score that uses risk factors in midlife to estimate risk of late-life dementia. Cognitive tests included reasoning, memory, verbal fluency, vocabulary, and global cognition, assessed 3 times over 10 years.
Higher cardiovascular disease risk and higher stroke risk were associated with greater cognitive decline in all tests except memory; higher dementia risk was associated with greater decline in reasoning, vocabulary, and global cognitive scores. Compared with the dementia risk score, cardiovascular and stroke risk scores showed slightly stronger associations with 10-year cognitive decline; these differences were statistically significant for semantic fluency and global cognitive scores. For example, cardiovascular disease risk was associated with −0.06 SD (95% confidence interval [CI] = −0.08, −0.05) decline in the global cognitive scores over 10 years whereas dementia risk was associated with −0.03 SD (95% CI = −0.04, −0.01) decline (difference in β coefficients = 0.03; 95% CI = 0.01, 0.05).
The CAIDE dementia and Framingham risk scores predict cognitive decline in late middle age but the Framingham risk scores may have an advantage over the dementia risk score for use in primary prevention for assessing risk of cognitive decline and targeting of modifiable risk factors.
PMCID: PMC3656460  PMID: 23547265
22.  Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a post-hoc analysis of the Whitehall II cohort study 
Type 2 diabetes increases the risk for dementia, but whether it affects cognition before old age is unclear. We investigated whether duration of diabetes in late midlife and poor glycaemic control were associated with accelerated cognitive decline.
5653 participants from the Whitehall II cohort study (median age 54·4 years [IQR 50·3–60·3] at first cognitive assessment), were classified into four groups: normoglycaemia, prediabetes, newly diagnosed diabetes, and known diabetes. Tests of memory, reasoning, phonemic and semantic fluency, and a global score that combined all cognitive tests, were assessed three times over 10 years (1997–99, 2002–04, and 2007–09). Mean HbA1c was used to assess glycaemic control during follow-up. Analyses were adjusted for sociodemographic characteristics, health-related behaviours, and chronic diseases.
Compared with normoglycaemic participants, those with known diabetes had a 45% faster decline in memory (10 year difference in decline −0·13 SD, 95% CI −0·26 to −0·00; p=0·046), a 29% faster decline in reasoning (−0·10 SD, −0·19 to −0·01; p=0·026), and a 24% faster decline in the global cognitive score (−0·11 SD, −0·21 to −0·02; p=0·014). Participants with prediabetes or newly diagnosed diabetes had similar rates of decline to those with normoglycaemia. Poorer glycaemic control in participants with known diabetes was associated with a significantly faster decline in memory (−0·12 [–0·22 to −0·01]; p=0·034) and a decline in reasoning that approached significance (−0·07 [–0·15 to 0·00]; p=0·052).
The risk of accelerated cognitive decline in middle-aged patients with type 2 diabetes is dependent on both disease duration and glycaemic control.
US National Institutes of Health, UK Medical Research Council.
PMCID: PMC4274502  PMID: 24622753
23.  Trajectories of the Framingham general cardiovascular risk profile in midlife and poor motor function later in life: The Whitehall II study☆☆☆ 
Vascular risk factors are associated with increased risk of cognitive impairment and dementia, but their association with motor function, another key feature of aging, has received little research attention. We examined the association between trajectories of the Framingham general cardiovascular disease risk score (FRS) over midlife and motor function later in life.
A total of 5376 participants of the Whitehall II cohort study (29% women) who had up to four repeat measures of FRS between 1991–1993 (mean age = 48.6 years) and 2007–2009 (mean age = 65.4 years) and without history of stroke or coronary heart disease in 2007–2009 were included. Motor function was assessed in 2007–2009 through objective tests (walking speed, chair rises, balance, finger tapping, grip strength). We used age- and sex-adjusted linear mixed models.
Participants with poorer performances for walking speed, chair rises, and balance in 2007–2009 had higher FRS concurrently and also in 1991–1993, on average 16 years earlier. These associations were robust to adjustment for cognition, socio-economic status, height, and BMI, and not explained by incident mobility limitation prior to motor assessment. No association was found with finger tapping and grip strength.
Cardiovascular risk early in midlife is associated with poor motor performances later in life. Vascular risk factors play an important and under-recognized role in motor function, independently of their impact on cognition, and suggest that better control of vascular risk factors in midlife may prevent physical impairment and disability in the elderly.
PMCID: PMC3991855  PMID: 24461963
CVD, cardiovascular disease; FRS, Framingham general cardiovascular disease risk score; SES, socioeconomic status; BMI, body mass index; SD, standard deviation; Cardiovascular risk score; Motor function; Aging; Stroke; Cohort study
24.  Low Conscientiousness and Risk of All-Cause, Cardiovascular and Cancer Mortality over 17 Years: Whitehall II Cohort Study 
To examine the personality trait conscientiousness as a risk factor for mortality and to identify candidate explanatory mechanisms.
Participants in the Whitehall II cohort study (N = 6800, aged 34 to 55 at recruitment in 1985) completed two self-reported items measuring conscientiousness in 1991–1993 (‘I am overly conscientious’ and ‘I am overly perfectionistic’, Cronbach's α = .72), the baseline for this study. Age, socio-economic status (SES), social support, health behaviours, physiological variables and minor psychiatric morbidity were also recorded at baseline. The vital status of participants was then monitored for a mean of 17 years. All-cause and cause-specific mortality was ascertained through linkage to a national mortality register until January 2010.
Each 1 standard deviation decrease in conscientiousness was associated with a 10% increase in all-cause (hazard ratio [HR] = 1.10, 95% CI 1.003, 1.20) mortality. Patterns were similar for cardiovascular (HR = 1.17, 95% CI 0.98, 1.39) and cancer mortality (HR = 1.10, 95% CI 0.96, 1.25), not reaching statistical significance. The association with all-cause mortality was attenuated by 5% after adjustment for SES, 13% for health behaviours, 14% for cardiovascular risk factors, 5% for minor psychiatric morbidity, 29% for all variables. Repeating analyses with each item separately and excluding participants who died within five years of personality assessment did not change the results materially.
Low conscientiousness in midlife is a risk factor for all-cause mortality. This association is only partly explained by health behaviours, SES, cardiovascular disease risk factors and minor psychiatric morbidity in midlife.
PMCID: PMC3936113  PMID: 22789411
cohort study; conscientiousness; mortality; perfectionism; personality traits; socio-economic status
25.  Study protocol for examining job strain as a risk factor for severe unipolar depression in an individual participant meta-analysis of 14 European cohorts 
F1000Research  2014;2:233.
Background: Previous studies have shown that gainfully employed individuals with high work demands and low control at work (denoted “job strain”) are at increased risk of common mental disorders, including depression. Most existing studies have, however, measured depression using self-rated symptom scales that do not necessarily correspond to clinically diagnosed depression. In addition, a meta-analysis from 2008 indicated publication bias in the field.
Methods: This study protocol describes the planned design and analyses of an individual participant data meta-analysis, to examine whether job strain is associated with an increased risk of clinically diagnosed unipolar depression based on hospital treatment registers.  The study will be based on data from approximately 120,000 individuals who participated in 14 studies on work environment and health in 4 European countries. The self-reported working conditions data will be merged with national registers on psychiatric hospital treatment, primarily hospital admissions. Study-specific risk estimates for the association between job strain and depression will be calculated using Cox regressions. The study-specific risk estimates will be pooled using random effects meta-analysis.
Discussion: The planned analyses will help clarify whether job strain is associated with an increased risk of clinically diagnosed unipolar depression. As the analysis is based on pre-planned study protocols and an individual participant data meta-analysis, the pooled risk estimates will not be influenced by selective reporting and publication bias. However, the results of the planned study may only pertain to severe cases of unipolar depression, because of the outcome measure applied.
PMCID: PMC3938244  PMID: 24627793

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