Clinical, socioeconomic, and behavioural factors at age 50 years and risk of cardiometabolic multimorbidity and mortality: A cohort study

BACKGROUND: Multimorbidity is increasingly common and is associated with adverse health outcomes, highlighting the need to broaden the single-disease framework that dominates medical research. We examined the role of midlife clinical characteristics, socioeconomic position, and behavioural factors in the development of cardiometabolic multimorbidity (at least 2 of diabetes, coronary heart disease, and stroke), along with how these factors modify risk of mortality. METHODS AND FINDINGS: Data on 8,270 men and women were drawn from the Whitehall II cohort study, with mean follow-up of 23.7 years (1985 to 2017). Three sets of risk factors were assessed at age 50 years, each on a 5-point scale: clinical profile (hypertension, hypercholesterolemia, overweight/obesity, family history of cardiometabolic disease), occupational position, and behavioural factors (smoking, alcohol consumption, diet, physical activity). The outcomes examined were cardiometabolic disease (diabetes, coronary heart disease, stroke), cardiometabolic multimorbidity, and mortality. We used multi-state models to examine the role of risk factors in 5 components of the cardiometabolic disease trajectory: from healthy state to first cardiometabolic disease, from first cardiometabolic disease to cardiometabolic multimorbidity, from healthy state to death, from first cardiometabolic disease to death, and from cardiometabolic multimorbidity to death. A total of 2,501 participants developed 1 of the 3 cardiometabolic diseases, 511 developed cardiometabolic multimorbidity, and 1,406 died. When behavioural and clinical risk factors were considered individually, only smoking was associated with all five transitions. In a model containing all 3 risk factor scales, midlife clinical profile was the strongest predictor of first cardiometabolic disease (hazard ratio for the least versus most favourable profile: 3.74; 95% CI: 3.14-4.45) among disease-free participants. Among participants with 1 cardiometabolic disease, adverse midlife socioeconomic (1.54; 95% CI: 1.10-2.15) and behavioural factors (2.00; 95% CI: 1.40-2.85), but not clinical characteristics, were associated with progression to cardiometabolic multimorbidity. Only midlife behavioural factors predicted mortality among participants with cardiometabolic disease (2.12; 95% CI: 1.41-3.18) or cardiometabolic multimorbidity (3.47; 95% CI: 1.81-6.66). A limitation is that the study was not large enough to estimate transitions between each disease and subsequent outcomes and between all possible pairs of diseases. CONCLUSIONS: The importance of specific midlife factors in disease progression, from disease-free state to single disease, multimorbidity, and death, varies depending on the disease stage. While clinical risk factors at age 50 determine the risk of incident cardiometabolic disease in a disease-free population, midlife socioeconomic and behavioural factors are stronger predictors of progression to multimorbidity and mortality in people with cardiometabolic disease

Capacités de discrimination des femelles de quatre souches de Callosobruchus maculatus Fab. (Coléoptera : Chrysomelidae, Bruchinae) pour la localisation de l’hôte et la ponte aux dépens d’hôtes secondaires

L’objectif de cette étude est de savoir comment les femelles de quatre souches de Callosobruchus maculatus F., localisent leur hôte, distribuent les oeufs sur des graines de taille différente dans des conditions de libre choix, de semi choix et de non choix. Ainsi, des couples de C. maculatus ont été transférés du niébé, Vigna unguiculata (L.) Walp. (Fabaceae), et maintenus sur les graines de deux variétés de voandzou, Vigna subterranea (L.) Verdc. (Fabaceae), et du pois d’angole, Cajanus cajan (L.) Millsp (Fabaceae), trois ans durant. La capacité des femelles à reconnaître les odeurs de ces quatre types de graines a été testée à l’aide d’un olfactomètre et dans un dispositif tridimensionnel. Elles ont été ensuite mises en contact avec les différentes graines pour la ponte. Dans l’olfatomètre, lorsqu’elles ont le choix entre l’air pur et l’air provenant de leurs hôtes d’origine, elles sont significativement attirées par l’air odorant. Quand les femelles issues des souches du voandzou ou du pois d’angole ont le choix entre le niébé et leur plante d’origine, elles préfèrent le niébé. Dans le dispositif tridimensionnel, quand les femelles issues du voandzou ou du pois d’angole ont un libre choix entre les quatre types de graines, elles (> 30%) préfèrent leurs plantes hôtes d’origine. Les odeurs dégagées par les graines semblent contribuer à l’orientation des femelles vers ces graines. C. maculatus utilisent des signaux chimiques dans la localisation de leurs hôtes. Ceci entraînerait ou stimulerait l’utilisation des répulsifs et attractants dans la gestion intégrée des insectes de stocks.Mots clés: Capacités de discrimination, localisation, ponte, C. maculatus, plantes hôtes secondaire

Interleukin-6 and C-reactive protein as predictors of cognitive decline in late midlife

Objective: 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. Methods: 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). Results: In cross-sectional analysis, reasoning was 0.08 SD (95%confidence interval [CI] -0.14, 20.03) 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. Conclusions: Elevated IL-6 but not CRP in midlife predicts cognitive decline; the combined crosssectional and longitudinal effects over the 10-year observation period corresponded to an age effect of 3.9 years. © 2014 American Academy of Neurology

Association of moderate and vigorous physical activity with incidence of type 2 diabetes and subsequent mortality: 27 year follow-up of the Whitehall II study

AIMS/HYPOTHESIS: This work examined the role of physical activity in the course of diabetes using data spanning nearly three decades. Our first aim was to examine the long-term association of moderate and vigorous physical activity with incidence of type 2 diabetes. Our second aim was to investigate the association of moderate-to-vigorous physical activity post-diabetes diagnosis with subsequent risk of all-cause and cardiovascular disease mortality. METHODS: A total of 9987 participants from the Whitehall II cohort study free of type 2 diabetes at baseline (1985-1988) were followed for incidence of type 2 diabetes, based on clinical assessments between 1985 and 2016 and linkage to electronic health records up to 31 March 2017. We first examined the association of moderate and vigorous physical activity measured by questionnaire in 1985-1988 (mean age 44.9 [SD 6.0] years; women, 32.7%) with incident type 2 diabetes, using the interval-censored, illness-death model, a competing risk analysis that takes into account both competing risk of death and intermittent ascertainment of diabetes due to reliance on data collection cycles (interval-censored). The second analysis was based on individuals with type 2 diabetes over the follow-up period where we used Cox regression with inverse probability weighting to examine the association of moderate-to-vigorous physical activity after diagnosis of type 2 diabetes with risk of all-cause and cardiovascular disease mortality. RESULTS: Of the 9987 participants, 1553 developed type 2 diabetes during a mean follow-up of 27.1 (SD 6.3) years. Compared with participants who were inactive in 1985-1988, those who undertook any duration of moderate-to-vigorous physical activity had a lower risk of type 2 diabetes (HR 0.85 [95% CI 0.75, 0.97], p = 0.02; analysis adjusted for sociodemographic, behavioural and health-related factors). In 1026 participants with a diagnosis of type 2 diabetes over the follow-up period, data on moderate-to-vigorous physical activity after diabetes diagnosis were available; 165 all-cause deaths and 55 cardiovascular disease-related deaths were recorded during a mean follow-up of 8.8 (SD 6.1) years. In these participants with diabetes, any duration of moderate-to-vigorous physical activity was associated with lower all-cause mortality (HR 0.61 [95% CI 0.41, 0.93], p = 0.02) while the association with cardiovascular mortality was evident only for physical activity undertaken at or above recommendations (≥2.5 h per week of moderate-to-vigorous physical activity or ≥1.25 h per week of vigorous physical activity; HR 0.40 [95% CI 0.16, 0.96], p = 0.04) in fully adjusted models. CONCLUSIONS/INTERPRETATION: Moderate-to-vigorous physical activity plays an important role in diabetes, influencing both its incidence and prognosis. A protective effect on incidence was seen for durations of activity below recommendations and a marginal additional benefit was observed at higher durations. Among individuals with type 2 diabetes, any duration of moderate-to-vigorous physical activity was associated with reduced all-cause mortality while recommended durations of physical activity were required for protection against cardiovascular disease-related mortality. DATA AVAILABILITY: Whitehall II data, protocols and other metadata are available to the scientific community. Please refer to the Whitehall II data sharing policy at https://www.ucl.ac.uk/epidemiology-health-care/research/epidemiology-and-public-health/research/whitehall-ii/data-sharing

Association of big-5 personality traits with cognitive impairment and dementia: a longitudinal study

BACKGROUND: Personality traits have been linked to cognitive outcomes such as dementia, but whether these associations are robust to the effects of third variables remains the subject of debate. We examined the role of socioeconomic status, depression (history and depressive symptoms), health behaviours and chronic conditions in the association of the big-5 personality traits with cognitive performance, cognitive impairment and incidence of dementia. METHODS: Data on 6135 persons (30% women), aged 60-83 years in 2012/13, are drawn from the Whitehall II Study. Participants responded to the 26-item Midlife Development Inventory to assess personality traits (openness, conscientiousness, extraversion, agreeableness and neuroticism), underwent cognitive testing in 2012/13 and 2015/16 and were followed for incidence of dementia (N=231) until 2019. RESULTS: Logistic regression, adjusted for sociodemographic factors, suggested a cross-sectional association with cognitive impairment for four of the five traits but only neuroticism was associated with incident cognitive impairment. All associations were completely attenuated when the analyses were adjusted for depression. Cox regression (mean follow-up: 6.18 years) adjusted for sociodemographic variables showed higher conscientiousness (HR per SD increment=0.72; 95% CI 0.65 to 0.81) and extraversion (HR=0.85; 95% CI 0.75 to 0.97) to be associated with lower dementia risk; higher neuroticism (HR=1.32; 95% CI 1.17 to 1.49) was associated with increased risk. Further adjustment for depression led to only conscientiousness retaining an association with dementia (HR=0.81; 95% CI 0.69 to 0.96), which was robust to adjustment for all covariates (HR=0.84; 95% CI 0.71 to 0.91; P=0.001). CONCLUSION: Our results show that only conscientiousness has an association with incidence of dementia that is not attributable to socioeconomic status or depression. The association of neuroticism with dementia was explained by depression

Sex differences in functional limitations and the role of socioeconomic factors: a multi-cohort analysis

Background: Women are more likely to have functional limitations than are men, partly because of greater socioeconomic disadvantage. However, how sex differences vary by severity of functional limitations remains unclear. We examined sex differences in functional limitations, with attention to socioeconomic factors and severity of limitations. Methods: Longitudinal data on limitations in basic activities of daily living (ADL) and instrumental activities of daily living (IADL) and mobility activities were drawn from 62 375 participants from 14 countries. For ADL, IADL, and mobility, participants were categorised based on number of limited activities (0, 1, 2, or ≥3). Sex differences in limitations in four birth cohorts (1895–1929, 1930–38, 1939–45, and 1946–60) were analysed before and after adjustment for socioeconomic factors (education and labour force status). Findings: The prevalence of IADL and ADL limitations was higher in women than in men. After adjustment for socioeconomic factors, this sex difference was attenuated. The sex difference in IADL limitations at age 75 years (in the 1895–1929 cohort) was 3·7% before adjustment for socioeconomic factors (95% CI 2·6–4·7) and 1·7% (1·1–2·2) after adjustment. For ADL, the sex difference in limitations at age 75 years (in the 1895–1929 cohort) was 3·2% (2·3–4·1) before adjustment for socioeconomic factors and 1·4% (0·9–1·8) after adjustment. Sex differences in mobility limitations (16·1%, 95% CI 14·4–17·7) remained after adjustment for socioeconomic factors (14·3%, 12·7–15·9). After age 85 years, women were more likely to have three or more IADL or mobility limitations and men were more likely to have one or two limitations. Interpretation: Socioeconomic factors largely explain sex differences in IADL and ADL limitations but not mobility. Sex differences in mobility limitations in midlife are important targets for future research and interventions. Funding: National Institute on Aging, UK National Institute for Health Research, European Commission, and US Social Security Administration

Sex differences and the role of education in cognitive ageing: analysis of two UK-based prospective cohort studies

BACKGROUND: Previous studies have shown an excess risk of Alzheimer's disease and related dementias among women. Education is thought to have a causal association with dementia onset. We aimed to investigate the role of education in influencing sex differences in cognitive ageing. METHODS: We analysed data from two prospective cohort studies in the UK; the English Longitudinal Study of Ageing (ELSA) and the Whitehall II study, to assess sex differences in cognitive performance and cognitive decline by birth cohort (birth year 1930-38, 1939-45, or 1946-55), before and after adjustment for education, and by high and low education level. Memory was assessed using immediate recall, for which data were available from all waves of the ELSA (2002-14) and Whitehall II (1997-2015) studies. Fluency was assessed using a semantic fluency test based on an animal naming task, with data available from all waves of the Whitehall II study and waves one to five (2002-10) and wave seven (2014) of the ELSA study. Cognitive scores were standardised separately in each study based on the mean and SD of the corresponding test among participants aged 50-59 years with secondary education. FINDINGS: 15 924 participants were included from the two studies. In pooled analyses, women had better memory scores than men in all birth cohorts, irrespective of adjustment for education (eg, at age 60 years, birth cohort 1930-38, mean difference between sexes [male scores minus female scores] -0·25 SDs [95% CI -0·32 to -0·19] after adjustment for education), and in both education level groups. Memory decline was faster in men than in women (at age 60 years, birth cohort 1946-55, mean difference in 13-year change -0·15 SDs [-0·20 to -0·09]; after adjustment for education -0·14 SDs [-0·20 to -0·08]). Men had better fluency scores than women in earlier birth cohorts and in the low education group (at age 60 years, birth cohort 1930-38, mean difference 0·20 SDs [95% CI 0·05 to 0·36]); but women had better fluency scores than men in later birth cohorts and in the high education group (at age 60 years, birth cohort 1946-55, mean difference -0·17 SDs [-0·24 to -0·10]). No sex differences were observed for fluency decline. INTERPRETATION: Our findings suggest that decreasing disparities between sexes in education, due to secular increases in educational opportunities, could attenuate sex differences in dementia risk and cognitive decline in the future. FUNDING: National Institute on Aging, National Institutes of Health; UK Medical Research Council; British Heart Foundation; and National Institute for Health Research

The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study

Background: Approximately 25% of the general population carries at least one ε4 allele of the Apolipoprotein E (APOE ε4), the strongest genetic risk factor for late onset Alzheimer’s disease. Beyond its association with late-onset dementia, the association between APOE ε4 and change in cognition over the adult life course remains uncertain. This study aims to examine whether the association between Apolipoprotein E (APOE) ε4 zygosity and cognition function is modified between midlife and old age. Methods: A cohort study of 5561 participants (mean age 55.5 (SD = 5.9) years, 27.1% women) with APOE genotyping and repeated cognitive tests for reasoning, memory, and semantic and phonemic fluency, during a mean (SD) follow-up of 20.2 (2.8) years (the Whitehall II study). We used joint models to examine the association of APOE genotype with cognitive function trajectories between 45 and 85 years taking drop-out, dementia, and death into account and Fine and Gray models to examine associations with dementia. Results: Compared to non-carriers, heterozygote (prevalence 25%) and homozygote (prevalence 2%) APOE ε4 carriers had increased risk of dementia, sub-distribution hazard ratios 2.19 (95% CI 1.73, 2.77) and 5.97 (95% CI 3.85, 9.28) respectively. Using data spanning 45–85 years with non-ε4 carriers as the reference, ε4 homozygotes had poorer global cognitive score starting from 65 years; ε4 heterozygotes had better scores between 45 and 55 years, then no difference until poorer cognitive scores from 75 years onwards. In analysis of individual cognitive tests, better cognitive performance in the younger ε4 heterozygotes was primarily attributable to executive function. Conclusions: Both heterozygous and homozygous ε4 carriers had poorer cognition and greater risk of dementia at older ages. Our findings show some support for a complex antagonist pleiotropic effect of APOE ε4 heterozygosity over the adult life course, characterized by cognitive advantage in midlife

Association between ATN profiles and mortality in a clinical cohort of patients with cognitive disorders

BACKGROUND: Alzheimer's disease (AD) is the 5th leading cause of death in people 65 years and older. The ATN classification reflects a biological definition of AD pathology with markers of Aβ deposition (A), pathologic tau (T), and neurodegeneration (N). Little is known about the relationship between ATN status and the risk of mortality, leading us to examine this association in a relatively large population of patients seen at a memory clinic for cognitive disorders. METHODS: Data were drawn from the BioCogBank Study, including patients seen for cognitive disorders in Lariboisiere Hospital (Paris, France), followed up to 15 years. All participants underwent a lumbar puncture for an assessment of the levels of CSF tau (tau), phosphorylated tau (p-tau181), and β-amyloid 42 peptide (Aβ42). Vital status on July 1, 2020, was recorded for each participant using the national mortality register. Individuals were categorized according to their ATN profiles based on CSF Aβ42 or Aβ42/40 ratio, p-tau181, and tau. Kaplan-Meier and multivariate Cox analyses were performed with A-T-N - participants as the reference using a short (5 years) and long follow-up (15 years). RESULTS: Of the 1353 patients in the study (mean age: 68 years old, 53% of women, mean MMSE score: 22.6), 262 died during the follow-up. At 5 years of follow-up, A-T-N + individuals had the highest risk of mortality in Kaplan-Meier and adjusted Cox analyses [HR (95% CI) = 2.93 (1.31-6.56)]. At 15 years of follow-up, patients in the AD spectrum had a higher mortality risk with a gradient effect for biomarker positivity: A-T + [HR = 1.63 (1.04-2.55)], A + T - [HR = 2.17 (1.44-3.26)], and A + T + individuals [HR = 2.38 (1.66-3.39)], compared to A-T-N - patients. Adjustments on potential confounders had little impact on these associations. CONCLUSION: This study shows ATN profiles to be associated with mortality in a relatively large patient cohort based on a memory clinic. Patients with isolated evidence of neurodegeneration had a higher mortality rate in the short follow-up, and patients with the AD profile had the highest mortality rate in the long follow-up

Association of daily composition of physical activity and sedentary behaviour with incidence of cardiovascular disease in older adults.

BACKGROUND: Moderate-to-vigorous physical activity (MVPA) is proposed as key for cardiovascular diseases (CVD) prevention. At older ages, the role of sedentary behaviour (SB) and light intensity physical activity (LIPA) remains unclear. Evidence so far is based on studies examining movement behaviours as independent entities ignoring their co-dependency. This study examines the association between daily composition of objectively-assessed movement behaviours (MVPA, LIPA, SB) and incident CVD in older adults. METHODS: Whitehall II accelerometer sub-study participants free of CVD at baseline (N = 3319, 26.7% women, mean age = 68.9 years in 2012-2013) wore a wrist-accelerometer from which times in SB, LIPA, and MVPA during waking period were extracted over 7 days. Compositional Cox regression was used to estimate the hazard ratio (HR) for incident CVD for daily compositions of movement behaviours characterized by 10 (20 or 30) minutes greater duration in one movement behaviour accompanied by decrease in another behaviour, while keeping the third behaviour constant, compared to reference composition. Analyses were adjusted for sociodemographic, lifestyle, cardiometabolic risk factors and multimorbidity index. RESULTS: Of the 3319 participants, 299 had an incident CVD over a mean (SD) follow-up of 6.2 (1.3) years. Compared to daily movement behaviour composition with MVPA at recommended 21 min per day (150 min/week), composition with additional 10 min of MVPA and 10 min less SB was associated with smaller risk reduction - 8% (HR, 0.92; 95% CI, 0.87-0.99) - than the 14% increase in risk associated with a composition of similarly reduced time in MVPA and more time in SB (HR, 1.14; 95% CI, 1.02-1.27). For a given MVPA duration, the CVD risk did not differ as a function of LIPA and SB durations. CONCLUSIONS: Among older adults, an increase in MVPA duration at the expense of time in either SB or LIPA was found associated with lower incidence of CVD. This study lends support to public health guidelines encouraging increase in MVPA or at least maintain MVPA at current duration