Sex Differences in Cardiac Troponin Trajectories Over the Life Course.

BACKGROUND: Cardiac troponin concentrations are lower in women than men. We examined whether age- and risk factor-related changes in cardiac troponin over the life course differ by sex and if the trajectory of cardiac troponin was informative in respect of cardiovascular outcomes in women and men in the general population. METHODS: In the Whitehall II cohort, high-sensitivity cardiac troponin I concentrations were measured on 3 occasions over a 15-year period. Using linear mixed-effects models, the sex-specific trajectories of cardiac troponin were evaluated, and the relationship with conventional cardiovascular risk factors determined. Using multistate joint models, the association between sex-specific trajectories of cardiac troponin and a composite outcome of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death was evaluated. RESULTS: In 2142 women and 5151 men (mean, 58±7 and 57±7 years of age, respectively), there were 177 (8.3%) and 520 (10.1%) outcome events, respectively, during a median follow-up of 20.9 (25th to 75th percentile, 15.8-21.3) years. Cardiac troponin concentrations were persistently lower in women than in men (median baseline concentration: 2.4 [25th to 75th percentile, 1.7-3.6] ng/L versus 3.7 [25th to 75th percentile, 2.6-5.8] ng/L, respectively, P<0.001), with women exhibiting a relatively larger increase with advancing age as compared with men (Pinteraction<0.001). Apart from age, a significant and divergent interaction with sex was found for the association between cardiac troponin and body mass index (BMI) (Pinteraction=0.008) and diabetes (Pinteraction=0.003). During follow-up, cardiac troponin concentrations were associated to the outcome in both women and men (adjusted hazard ratio per 2-fold difference [95% CI, 1.34 (1.17-1.52) and 1.30 (1.21-1.40), respectively], Pinteraction=0.752). The slope of cardiac troponin was significantly associated with the outcome in women, but not in men (adjusted hazard ratio [95% CI, 2.70 (1.01-7.33) and 1.31 (0.62-2.75), respectively], Pinteraction=0.250). CONCLUSIONS: Trajectories of cardiac troponin differ between women and men in the general population, with differing associations to conventional risk factors and cardiovascular outcomes. Our findings highlight the importance of a sex-specific approach when serial cardiac troponin testing is applied for cardiovascular risk prediction.

Risk of Macrovascular and Microvascular Disease in Diabetes Diagnosed Using Oral Glucose Tolerance Test With and Without Confirmation by Hemoglobin A1c: The Whitehall II Cohort Study.

BACKGROUND: It is unclear whether replacing oral glucose tolerance test (OGTT) with hemoglobin A1c (HbA1c) measurement for diagnosing diabetes is justified. We aimed to assess the proportion of OGTT-diagnosed diabetes cases that can be confirmed by HbA1c and to examine whether individuals with OGTT diagnosis but nondiagnostic HbA1c are at higher risk of macrovascular and microvascular disease. METHODS: Participants were 5773 men and women from the population-based Whitehall II prospective cohort study in the United Kingdom. New OGTT diabetes cases diagnosed in clinical examinations in 2002 to 2004 and 2007 to 2009 were assessed for HbA1c confirmation (≥6.5%) in these and subsequent clinical examinations in 2012 to 2013 and 2015 to 2016. All participants were followed up for major cardiovascular events through linkage to electronic health records until 2017 and for incident chronic kidney disease (estimated glomerular filtration rate <60 mL·min-1·1.73 m-2) until the last clinical examination. In analysis of vascular disease risk, new OGTT-diagnosed diabetes cases with and without diagnostic HbA1c and preexisting diabetes cases were compared with diabetes-free participants. RESULTS: Of the 378 (59.3%) participants with OGTT-diagnosed diabetes, 224 were confirmed by HbA1c during 4.1 years (SD, 4.1 years) of follow-up. We recorded 942 cardiovascular events over 12.1 years. After adjustment for nonmodifiable risk factors and compared with the 4997 diabetes-free participants, 371 participants with new HbA1c-confirmed diabetes and 405 participants with preexisting diabetes had increased risk of cardiovascular disease (hazard ratio, 1.53 [95% CI, 1.12-2.10] and 1.85 [95% CI, 1.50-2.28], respectively). The corresponding hazard ratios in the analysis of incident chronic kidney disease (487 cases; follow-up, 6.6 years) were 1.69 (95% CI, 1.09-2.62) for 282 participants with new HbA1c-confirmed diabetes and 1.67 (95% CI, 1.22-2.28) for 276 participants with preexisting diabetes. In both analyses, OGTT cases with nondiagnostic HbA1c (n=149 and 107) had a risk (hazard ratio, 0.99-1.07) similar to that of the diabetes-free population. CONCLUSIONS: More than 40% of OGTT-diagnosed diabetes cases were not confirmed by HbA1c during an extended follow-up. However, because these individuals have a risk of cardiovascular disease and chronic kidney disease similar to that of the diabetes-free population, replacement of OGTT with HbA1c-based diagnosis appears justified.

Trajectories of cardiac troponin in the decades before cardiovascular death: a longitudinal cohort study.

BACKGROUND: High-sensitivity cardiac troponin testing is a promising tool for cardiovascular risk prediction, but whether serial testing can dynamically predict risk is uncertain. We evaluated the trajectory of cardiac troponin I in the years prior to a cardiovascular event in the general population, and determine whether serial measurements could track risk within individuals. METHODS: In the Whitehall II cohort, high-sensitivity cardiac troponin I concentrations were measured on three occasions over a 15-year period. Time trajectories of troponin were constructed in those who died from cardiovascular disease compared to those who survived or died from other causes during follow up and these were externally validated in the HUNT Study. A joint model that adjusts for cardiovascular risk factors was used to estimate risk of cardiovascular death using serial troponin measurements. RESULTS: In 7,293 individuals (mean 58 ± 7 years, 29.4% women) cardiovascular and non-cardiovascular death occurred in 281 (3.9%) and 914 (12.5%) individuals (median follow-up 21.4 years), respectively. Troponin concentrations increased in those dying from cardiovascular disease with a steeper trajectory compared to those surviving or dying from other causes in Whitehall and HUNT (Pinteraction < 0.05 for both). The joint model demonstrated an independent association between temporal evolution of troponin and risk of cardiovascular death (HR per doubling, 1.45, 95% CI,1.33-1.75). CONCLUSIONS: Cardiac troponin I concentrations increased in those dying from cardiovascular disease compared to those surviving or dying from other causes over the preceding decades. Serial cardiac troponin testing in the general population has potential to track future cardiovascular risk.

Association of air pollution with dementia: a systematic review with meta-analysis including new cohort data from China.

It remains unclear whether a total exposure to air pollution (AP) is associated with an increased risk of dementia. Little is known on the association in low- and middle-income countries. Two cohort studies in China (in Anhui cohort 1402 older adults aged ≥ 60 followed up for 10 years; in Zhejiang cohort 6115 older adults followed up for 5 years) were conducted to examine particulate matter - PM2.5 associated with all dementia and air quality index (AQI) with Alzheimer's disease, respectively. A systematic literature review and meta-analysis was performed following worldwide literature searched until May 20, 2020 to identify 15 population-based cohort studies examining the association of AP with dementia (or any specific type of dementia) through PubMed, MEDLINE, PsycINFO, SocINDEX, CINHAL, and CNKI. The cohort studies in China showed a significantly increased relative risk (RR) of dementia in relation to AP exposure; in Anhui cohort the adjusted RR was 2.14 (95% CI 1.00-4.56) in people with PM2.5 exposure at ≥ 64.5 µg/m3 versus <63.5 µg/m3 and in Zhejiang cohort the adjusted RR was 2.28 (1.07-4.87) in AQI>90 versus ≤ 80. The systematic review revealed that all 15 studies were undertaken in high income countries/regions, with inconsistent findings. While they had reasonably good overall quality of studies, seven studies did not adjust smoking in analysis and 13 did not account for depression. Pooling all eligible data demonstrated that dementia risk increased with the total AP exposure (1.13, 1.08-1.19). Data analysis of air pollutants showed that the RR significantly increased with PM2.5 (1.06, 1.03-1.10 in 2nd tertile exposure; 1.13, 1.07-1.19 in 3rd tertile versus 1st tertile), PM10 (1.05, 0.86-1.29; 1.62, 0.60-4.36), carbon monoxide (1.69, 0.72-3.93; 1.52, 1.35-1.71), nitrogen dioxide (1.06, 1.03-1.09; 1.18, 1.10-1.28) and nitrogen oxides (1.09, 1.04-1.15; 1.26, 1.13-1.41), but not ozone. Controlling air pollution and targeting on specific pollutants would reduce dementia globally.

QRS micro-fragmentation as a mortality predictor.

AIMS: Fragmented QRS complex with visible notching on standard 12-lead electrocardiogram (ECG) is understood to represent depolarization abnormalities and to signify risk of cardiac events. Depolarization abnormalities with similar prognostic implications likely exist beyond visual recognition but no technology is presently suitable for quantification of such invisible ECG abnormalities. We present such a technology. METHODS AND RESULTS: A signal processing method projects all ECG leads of the QRS complex into optimized three perpendicular dimensions, reconstructs the ECG back from this three-dimensional projection, and quantifies the difference (QRS 'micro'-fragmentation, QRS-µf) between the original and reconstructed signals. QRS 'micro'-fragmentation was assessed in three different populations: cardiac patients with automatic implantable cardioverter-defibrillators, cardiac patients with severe abnormalities, and general public. The predictive value of QRS-µf for mortality was investigated both univariably and in multivariable comparisons with other risk factors including visible QRS 'macro'-fragmentation, QRS-Mf. The analysis was made in a total of 7779 subjects of whom 504 have not survived the first 5 years of follow-up. In all three populations, QRS-µf was strongly predictive of survival (P < 0.001 univariably, and P < 0.001 to P = 0.024 in multivariable regression analyses). A similar strong association with outcome was found when dichotomizing QRS-µf prospectively at 3.5%. When QRS-µf was used in multivariable analyses, QRS-Mf and QRS duration lost their predictive value. CONCLUSION: In three populations with different clinical characteristics, QRS-µf was a powerful mortality risk factor independent of several previously established risk indices. Electrophysiologic abnormalities that contribute to increased QRS-µf values are likely responsible for the predictive power of visible QRS-Mf.

Appetite disinhibition rather than hunger explains genetic effects on adult BMI trajectory.

BACKGROUND/OBJECTIVES: The mediating role of eating behaviors in genetic susceptibility to weight gain during mid-adult life is not fully understood. This longitudinal study aims to help us understand contributions of genetic susceptibility and appetite to weight gain. SUBJECTS/METHODS: We followed the body-mass index (BMI) trajectories of 2464 adults from 45 to 65 years of age by measuring weight and height on four occasions at 5-year intervals. Genetic risk of obesity (gene risk score: GRS) was ascertained, comprising 92 BMI-associated single-nucleotide polymorphisms and split at a median (=high and low risk). At the baseline, the Eating Inventory was used to assess appetite-related traits of 'disinhibition', indicative of opportunistic eating or overeating and 'hunger' which is susceptibility to/ability to cope with the sensation of hunger. Roles of the GRS and two appetite-related scores for BMI trajectories were examined using a mixed model adjusted for the cohort effect and sex. RESULTS: Disinhibition was associated with higher BMI (ß = 2.96; 95% CI: 2.66-3.25 kg/m2), and accounted for 34% of the genetically-linked BMI difference at age 45. Hunger was also associated with higher BMI (ß = 1.20; 0.82-1.59 kg/m2) during mid-life and slightly steeper weight gain, but did not attenuate the effect of disinhibition. CONCLUSIONS: Appetite disinhibition is most likely to be a defining characteristic of genetic susceptibility to obesity. High levels of appetite disinhibition, rather than hunger, may underlie genetic vulnerability to obesogenic environments in two-thirds of the population of European ancestry.

Serum transthyretin and risk of cognitive decline and dementia: 22-year longitudinal study.

Serum transthyretin (TTR) may be an early biomarker for Alzheimer's disease and related disorders (ADRD). We investigated associations of TTR measured at baseline with cognitive decline and incident ADRD and whether TTR trajectories differ between ADRD cases and non-cases, over 22 years before diagnosis. A total of 6024 adults aged 45-69 in 1997-1999 were followed up until 2019. TTR was assessed three times, and 297 cases of dementia were recorded. Higher TTR was associated with higher cognitive function at baseline; however, TTR was unrelated to subsequent change in cognitive function. TTR at baseline did not predict ADRD risk (hazard ratio per SD TTR (4.8 mg/dL) = 0.97; 95% confidence interval: 0.94-1.00). Among those later diagnosed with ADRD, there was a marginally steeper downward TTR trajectory than those free of ADRD over follow-up (P=0.050). Our findings suggest TTR is not neuroprotective. The relative decline in TTR level in the preclinical stage of ADRD is likely to be a consequence of disease processes.

Potential impact of diabetes prevention on mortality and future burden of dementia and disability: a modelling study.

AIMS/HYPOTHESIS: Diabetes is associated with an increased risk of dementia. We estimated the potential impact of trends in diabetes prevalence upon mortality and the future burden of dementia and disability in England and Wales. METHODS: We used a probabilistic multi-state, open cohort Markov model to integrate observed trends in diabetes, cardiovascular disease and dementia to forecast the occurrence of disability and dementia up to the year 2060. Model input data were taken from the English Longitudinal Study of Ageing, Office for National Statistics vital data and published effect estimates for health-state transition probabilities. The baseline scenario corresponded to recent trends in obesity: a 26% increase in the number of people with diabetes by 2060. This scenario was evaluated against three alternative projected trends in diabetes: increases of 49%, 20% and 7%. RESULTS: Our results suggest that changes in the trend in diabetes prevalence will lead to changes in mortality and incidence of dementia and disability, which will become visible after 10-15 years. If the relative prevalence of diabetes increases 49% by 2060, expected additional deaths would be approximately 255,000 (95% uncertainty interval [UI] 236,000-272,200), with 85,900 (71,500-101,600) cumulative additional cases of dementia and 104,900 (85,900-125,400) additional cases of disability. With a smaller relative increase in diabetes prevalence (7% increase by 2060), we estimated 222,200 (205,700-237,300) fewer deaths, and 77,000 (64,300-90,800) and 93,300 (76,700-111,400) fewer additional cases of dementia and disability, respectively, than the baseline case of a 26% increase in diabetes. CONCLUSIONS/INTERPRETATION: Reducing the burden of diabetes could result in substantial reductions in the incidence of dementia and disability over the medium to long term.

Associations between arterial stiffening and brain structure, perfusion, and cognition in the Whitehall II Imaging Sub-study: A retrospective cohort study.

BACKGROUND: Aortic stiffness is closely linked with cardiovascular diseases (CVDs), but recent studies suggest that it is also a risk factor for cognitive decline and dementia. However, the brain changes underlying this risk are unclear. We examined whether aortic stiffening during a 4-year follow-up in mid-to-late life was associated with brain structure and cognition in the Whitehall II Imaging Sub-study. METHODS AND FINDINGS: The Whitehall II Imaging cohort is a randomly selected subset of the ongoing Whitehall II Study, for which participants have received clinical follow-ups for 30 years, across 12 phases. Aortic pulse wave velocity (PWV) was measured in 2007-2009 (Phase 9) and at a 4-year follow-up in 2012-2013 (Phase 11). Between 2012 and 2016 (Imaging Phase), participants received a multimodal 3T brain magnetic resonance imaging (MRI) scan and cognitive tests. Participants were selected if they had no clinical diagnosis of dementia and no gross brain structural abnormalities. Voxel-based analyses were used to assess grey matter (GM) volume, white matter (WM) microstructure (fractional anisotropy (FA) and diffusivity), white matter lesions (WMLs), and cerebral blood flow (CBF). Cognitive outcomes were performance on verbal memory, semantic fluency, working memory, and executive function tests. Of 542 participants, 444 (81.9%) were men. The mean (SD) age was 63.9 (5.2) years at the baseline Phase 9 examination, 68.0 (5.2) at Phase 11, and 69.8 (5.2) at the Imaging Phase. Voxel-based analysis revealed that faster rates of aortic stiffening in mid-to-late life were associated with poor WM microstructure, viz. lower FA, higher mean, and radial diffusivity (RD) in 23.9%, 11.8%, and 22.2% of WM tracts, respectively, including the corpus callosum, corona radiata, superior longitudinal fasciculus, and corticospinal tracts. Similar voxel-wise associations were also observed with follow-up aortic stiffness. Moreover, lower mean global FA was associated with faster rates of aortic stiffening (B = -5.65, 95% CI -9.75, -1.54, Bonferroni-corrected p < 0.0125) and higher follow-up aortic stiffness (B = -1.12, 95% CI -1.95, -0.29, Bonferroni-corrected p < 0.0125). In a subset of 112 participants who received arterial spin labelling scans, faster aortic stiffening was also related to lower cerebral perfusion in 18.4% of GM, with associations surviving Bonferroni corrections in the frontal (B = -10.85, 95% CI -17.91, -3.79, p < 0.0125) and parietal lobes (B = -12.75, 95% CI -21.58, -3.91, p < 0.0125). No associations with GM volume or WMLs were observed. Further, higher baseline aortic stiffness was associated with poor semantic fluency (B = -0.47, 95% CI -0.76 to -0.18, Bonferroni-corrected p < 0.007) and verbal learning outcomes (B = -0.36, 95% CI -0.60 to -0.12, Bonferroni-corrected p < 0.007). As with all observational studies, it was not possible to infer causal associations. The generalisability of the findings may be limited by the gender imbalance, high educational attainment, survival bias, and lack of ethnic and socioeconomic diversity in this cohort. CONCLUSIONS: Our findings indicate that faster rates of aortic stiffening in mid-to-late life were associated with poor brain WM microstructural integrity and reduced cerebral perfusion, likely due to increased transmission of pulsatile energy to the delicate cerebral microvasculature. Strategies to prevent arterial stiffening prior to this point may be required to offer cognitive benefit in older age. TRIAL REGISTRATION: ClinicalTrials.gov NCT03335696.

Educational Inequalities in Hospital Use Among Older Adults in England, 2004-2015.

Policy Points US policymakers considering proposals to expand public health care (such as "Medicare for all") as a means of reducing inequalities in health care access and use could learn from the experiences of nations where well-funded universal health care systems are already in place. In England, which has a publicly funded universal health care system, the use of core inpatient services by adults 65 years and older is equal across groups defined by education level, after controlling for health status. However, variation among these groups in the use of outpatient and emergency department care developed between 2010 and 2015, a period of relative financial austerity. Based on England's experience, introducing universal health care in the United States seems likely to reduce, but not entirely eliminate, inequalities in health care use across different population groups. CONTEXT: Expanding access to health care is once again high on the US political agenda, as is concern about those who are being "left behind." But is universal health care that is largely free at the point of use sufficient to eliminate inequalities in health care use? To explore this question, we studied variation in the use of hospital care among education-level-defined groups of older adults in England, before and after controlling for differences in health status. In England, the National Health Service (NHS) provides health care free to all, but the growth rate for NHS funding has slowed markedly since 2010 during a widespread austerity program, potentially increasing inequalities in access and use. METHODS: Novel linkage of data from six waves (2004-2015) of the English Longitudinal Study of Ageing (ELSA) with participants' hospital records (Hospital Episode Statistics [HES]) produced longitudinal data for 7,713 older adults (65 years and older) and 25,864 observations. We divided the sample into three groups by education level: low (no formal qualifications), mid (completed compulsory education), and high (at least some higher education). Four outcomes were examined: annual outpatient appointments, elective inpatient admissions, emergency inpatient admissions, and emergency department (ED) visits. We estimated regressions for the periods 2004-2005 to 2008-2009 and 2010-2011 to 2014-2015 to examine whether potential education-related inequalities in hospital use increased after the growth rate for NHS funding slowed in 2010. FINDINGS: For the study period, our sample of ELSA respondents in the low-education group made 2.44 annual outpatient visits. In comparison, after controlling for health status, we found that participants in the high-education group made an additional 0.29 outpatient visits annually (95% confidence interval [CI], 0.11-0.47). Additional outpatient health care use in the high-education group was driven by follow-up and routine appointments. This inequality widened after 2010. Between 2010 and 2015, individuals in the high-education group made 0.48 (95% CI, 0.21-0.74) more annual outpatient visits than those in the low-education (16.9% [7.5% to 26.2%] of annual average 2.82 visits). In contrast, after 2010, the high-education group made 0.04 (95% CI, -0.075 to 0.001) fewer annual ED visits than the low-education group, which had a mean of 0.30 annual ED visits. No significant differences by education level were found for elective or emergency inpatient admissions in either period. CONCLUSIONS: After controlling for demographics and health status, there was no evidence of inequality in elective and emergency inpatient admissions among the education groups in our sample. However, a period of financial budget tightening for the NHS after 2010 was associated with the emergence of education gradients in other forms of hospital care, with respondents in the high-education group using more outpatient care and less ED care than peers in the low-education group. These estimates point to rising inequalities in the use of hospital care that, if not reversed, could exacerbate existing health inequalities in England. Although the US and UK settings differ in many ways, our results also suggest that a universal health care system would likely reduce inequality in US health care use.

Association of aortic stiffness with cognitive decline: Whitehall II longitudinal cohort study.

Aortic stiffness is associated with an increased risk of cardio- and cerebrovascular disease and mortality and may increase risk of dementia. The aim of the present study is to examine the association between arterial stiffness and cognitive decline in a large prospective cohort study with three repeated cognitive assessment over 7 years of follow-up. Aortic pulse wave velocity (PWV) was measured among 4300 participants (mean ± standard deviation age 65.1 ± 5.2 years) in 2007-2009 and categorized based on the tertiles: (lowest third: < 7.41 m/s), (middle third: 7.41-8.91 m/s), and (highest third: > 8.91 m/s). A global cognitive score was calculated in 2007-2009, 2012-2013, and 2015-2016 based on responses to memory, reasoning and fluency tests. Standardized global cognitive score (mean = 0, SD = 1) in highest third versus lowest third of PWV category was lower at baseline (- 0.12, 95% CI - 0.18, - 0.06). Accelerated 7-year cognitive decline was observed among individuals with the highest PWV [difference in 7-year cognitive change for highest third versus lowest third PWV: - 0.06, 95% CI - 0.11, - 0.01, P < 0.01]. Higher aortic stiffness was associated with faster cognitive decline. Clinicians may be able to use arterial stiffness severity as an indicator to administer prompt treatments to prevent or delay the onset of cognitive decline or dementia. Future studies need to determine whether early intervention of vascular stiffness is effective in delaying these outcomes.

Carotid artery wave intensity in mid- to late-life predicts cognitive decline: the Whitehall II study.

AIMS: Excessive arterial pulsatility may contribute to cognitive decline and risk of dementia via damage to the fragile cerebral microcirculation. We hypothesized that the intensity of downstream-travelling pulsatile waves measured by wave intensity analysis in the common carotid artery during mid- to late-life would be associated with subsequent cognitive decline. METHODS AND RESULTS: Duplex Doppler ultrasound was used to calculate peak forward-travelling compression wave intensity (FCWI) within the common carotid artery in 3191 individuals [mean ± standard deviation (SD), age = 61 ± 6 years; 75% male] assessed as part of the Whitehall II study in 2003-05. Serial measures of cognitive function were taken between 2002-04 and 2015-16. The relationship between FCWI and cognitive decline was adjusted for sociodemographic variables, genetic and health-related risk factors, and health behaviours. Mean (SD) 10-year change in standardized global cognitive score was -0.39 (0.18). Higher FCWI at baseline was associated with accelerated cognitive decline during follow-up [difference in 10-year change of global cognitive score per 1 SD higher FCWI = -0.02 (95% confidence interval -0.04 to -0.00); P = 0.03]. This association was largely driven by cognitive changes in individuals with the highest FCWI [Q4 vs. Q1-Q3 = -0.05 (-0.09 to -0.01), P = 0.01], equivalent to an age effect of 1.9 years. Compared to other participants, this group was ∼50% more likely to exhibit cognitive decline (defined as the top 15% most rapid reductions in cognitive function during follow-up) even after adjustments for multiple potential confounding factors [odds ratio 1.49 (1.17-1.88)]. CONCLUSION: Elevated carotid artery wave intensity in mid- to late-life predicts faster cognitive decline in long-term follow-up independent of other cardiovascular risk factors.

Long-term risk of dementia following hospitalization due to physical diseases: A multicohort study.

INTRODUCTION: Conventional risk factors targeted by prevention (e.g., low education, smoking, and obesity) are associated with a 1.2- to 2-fold increased risk of dementia. It is unclear whether having a physical disease is an equally important risk factor for dementia. METHODS: In this exploratory multicohort study of 283,414 community-dwelling participants, we examined 22 common hospital-treated physical diseases as risk factors for dementia. RESULTS: During a median follow-up of 19 years, a total of 3416 participants developed dementia. Those who had erysipelas (hazard ratio = 1.82; 95% confidence interval = 1.53 to 2.17), hypothyroidism (1.94; 1.59 to 2.38), myocardial infarction (1.41; 1.20 to 1.64), ischemic heart disease (1.32; 1.18 to 1.49), cerebral infarction (2.44; 2.14 to 2.77), duodenal ulcers (1.88; 1.42 to 2.49), gastritis and duodenitis (1.82; 1.46 to 2.27), or osteoporosis (2.38; 1.75 to 3.23) were at a significantly increased risk of dementia. These associations were not explained by conventional risk factors or reverse causation. DISCUSSION: In addition to conventional risk factors, several physical diseases may increase the long-term risk of dementia.

Weight change increases the odds of psychological distress in middle age: bidirectional analyses from the Whitehall II Study.

BACKGROUND: Mood disorders and adiposity are major public health challenges. Few studies have investigated the bidirectional association of weight and waist circumference (WC) change with psychological distress in middle age, while taking into account the potential U-shape of the association. The aim of this study was to examine the bidirectional association between psychological distress and categorical change in objectively measured weight and WC. METHODS: We analysed repeated measures (up to 17 522 person-observations in adjusted analyses) of psychological distress, weight and WC from the Whitehall II cohort. Participants were recruited at age 35-55 and 67% male. Psychological distress was assessed using the General Health Questionnaire. We used random-effects regressions to model the association between weight and WC changes and psychological distress, with and without a 5-year lag period. RESULTS: Psychological distress was associated with weight and WC gain over the subsequent 5 years but not the second 5-year period. Weight gain and loss were associated with increased odds for incident psychological distress in models with and without time-lag [odds ratio (OR) for incident psychological distress after 5-year time-lag: loss 1.20, 95% confidence interval (CI) 1.00-1.43; gain>5% 1.20, 95% CI 1.02-1.40]. WC changes were only associated with psychological distress in models without time-lag (OR for incident psychological distress: loss 1.29, 95% CI 1.02-1.64; gain>5% 1.33, 95% CI 1.11-1.58). CONCLUSIONS: Weight gain and loss increase the odds for psychological distress compared with stable weight over subsequent 10 years. In contrast, the association between psychological distress and subsequent weight and WC changes was limited to the first 5 years of follow-up.

Adiposity in middle and old age and risk of death from dementia: 40-year follow-up of 19,000 men in the Whitehall study.

AIMS AND OBJECTIVES: to examine the hypothesis that obesity is protective for dementia, we compared the associations of death from dementia with body weight and body mass index (BMI) in both middle and old age. DESIGN: height and weight were measured in a prospective study of 19,019 middle-aged men in the Whitehall study in 1967-70 and in 6,158 surviving participants at resurvey in 1997. Cox regression was used to examine the associations of death from dementia over a 40-year period with weight or BMI measured by health professionals in middle and old age adjusting for age, smoking habits, employment grade and marital status. SETTING: central government employees in London, UK. MAIN OUTCOMES MEASURE: death due to dementia in 320 participants. RESULTS: body weight measured in middle age was weakly inversely associated with death from dementia (hazard ratio 0.98 [95%CI: 0.97-0.99] per kg), but neither height nor BMI were related to risk of dementia. In contrast, body weight in old age was more strongly inversely related to deaths from dementia (0.96; [0.95-0.98] per kg) as was BMI (0.92 [0.86-0.97] per kg/m2). Weight loss over the 30 years between baseline and resurvey was associated with a higher risk of death from dementia, with an adjusted HR per kg/30 years of 1.04 [95%CI: 1.02-1.08] and the association with loss of BMI was even stronger (adjusted HR of 1.10 [1.03-1.19]) per kg/m2 decrease. CONCLUSIONS: the stronger inverse associations of deaths from dementia with BMI in old age, compared with middle age, together with strong positive associations of loss of BMI or body weight between middle and old age casts doubt on previous suggestions that obesity protects against death from dementia.

Association between systolic blood pressure and dementia in the Whitehall II cohort study: role of age, duration, and threshold used to define hypertension.

Aims: To examine associations of diastolic and systolic blood pressure (SBP) at age 50, 60, and 70 years with incidence of dementia, and whether cardiovascular disease (CVD) over the follow-up mediates this association. Methods and results: Systolic and diastolic blood pressure were measured on 8639 persons (32.5% women) from the Whitehall II cohort study in 1985, 1991, 1997, and 2003. Incidence of dementia (n dementia/n total = 385/8639) was ascertained from electronic health records followed-up until 2017. Cubic splines using continuous blood pressure measures suggested SBP ≥130 mmHg at age 50 but not at age 60 or 70 was associated with increased risk of dementia, confirmed in Cox regression analyses adjusted for sociodemographic factors, health behaviours, and time varying chronic conditions [hazard ratio (HR) 1.38; 95% confidence interval (95% CI) 1.11, 1.70]. Diastolic blood pressure was not associated with dementia. Participants with longer exposure to hypertension (SBP ≥ 130 mmHg) between mean ages of 45 and 61 years had an increased risk of dementia compared to those with no or low exposure to hypertension (HR 1.29, 95% CI 1.00, 1.66). In multi-state models, SBP ≥ 130 mmHg at 50 years of age was associated with greater risk of dementia in those free of CVD over the follow-up (HR 1.47, 95% CI 1.15, 1.87). Conclusion: Systolic blood pressure ≥130 mmHg at age 50, below the conventional ≥140 mmHg threshold used to define hypertension, is associated with increased risk of dementia; in these persons this excess risk is independent of CVD.

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.

Socioeconomic status and the 25 × 25 risk factors as determinants of premature mortality: a multicohort study and meta-analysis of 1·7 million men and women.

BACKGROUND: In 2011, WHO member states signed up to the 25 × 25 initiative, a plan to cut mortality due to non-communicable diseases by 25% by 2025. However, socioeconomic factors influencing non-communicable diseases have not been included in the plan. In this study, we aimed to compare the contribution of socioeconomic status to mortality and years-of-life-lost with that of the 25 × 25 conventional risk factors. METHODS: We did a multicohort study and meta-analysis with individual-level data from 48 independent prospective cohort studies with information about socioeconomic status, indexed by occupational position, 25 × 25 risk factors (high alcohol intake, physical inactivity, current smoking, hypertension, diabetes, and obesity), and mortality, for a total population of 1 751 479 (54% women) from seven high-income WHO member countries. We estimated the association of socioeconomic status and the 25 × 25 risk factors with all-cause mortality and cause-specific mortality by calculating minimally adjusted and mutually adjusted hazard ratios [HR] and 95% CIs. We also estimated the population attributable fraction and the years of life lost due to suboptimal risk factors. FINDINGS: During 26·6 million person-years at risk (mean follow-up 13·3 years [SD 6·4 years]), 310 277 participants died. HR for the 25 × 25 risk factors and mortality varied between 1·04 (95% CI 0·98-1·11) for obesity in men and 2 ·17 (2·06-2·29) for current smoking in men. Participants with low socioeconomic status had greater mortality compared with those with high socioeconomic status (HR 1·42, 95% CI 1·38-1·45 for men; 1·34, 1·28-1·39 for women); this association remained significant in mutually adjusted models that included the 25 × 25 factors (HR 1·26, 1·21-1·32, men and women combined). The population attributable fraction was highest for smoking, followed by physical inactivity then socioeconomic status. Low socioeconomic status was associated with a 2·1-year reduction in life expectancy between ages 40 and 85 years, the corresponding years-of-life-lost were 0·5 years for high alcohol intake, 0·7 years for obesity, 3·9 years for diabetes, 1·6 years for hypertension, 2·4 years for physical inactivity, and 4·8 years for current smoking. INTERPRETATION: Socioeconomic circumstances, in addition to the 25 × 25 factors, should be targeted by local and global health strategies and health risk surveillance to reduce mortality. FUNDING: European Commission, Swiss State Secretariat for Education, Swiss National Science Foundation, the Medical Research Council, NordForsk, Portuguese Foundation for Science and Technology.

High-Sugar, High-Saturated-Fat Dietary Patterns Are Not Associated with Depressive Symptoms in Middle-Aged Adults in a Prospective Study.

Background: The consumption of unhealthy "Western" dietary patterns has been previously associated with depressive symptoms in different populations. Objective: We examined whether high-sugar and high-saturated-fat dietary patterns are associated with depressive symptoms over 5 y in a British cohort of men and women. Methods: We used data from the Whitehall II study in 5044 individuals (aged 35-55 y). Diet was assessed at phase 7 (2003-2004) using a validated food-frequency questionnaire. Dietary patterns were derived by using reduced rank regression with sugar, saturated fat, and total fat as response variables. The Center for Epidemiological Studies-Depression (CES-D) scale was used to assess depressive symptoms (CES-D sum score ≥16 and/or use of antidepressant medication) at phase 7 and at phase 9 (2008-2009). We applied logistic regression analyses to test the association between dietary patterns and depressive symptoms. All analyses were stratified by sex. Results: In total, 398 cases of recurrent and 295 cases of incident depressive symptoms were observed. We identified 2 dietary patterns: a combined high-sugar and high-saturated-fat (HSHF) and a high-sugar dietary pattern. No association was observed between the dietary patterns and either incidence of or recurrent depressive symptoms in men or women. For example, higher consumption of the HSHF dietary pattern was not associated with recurrent depressive symptoms in men (model 3, quartile 4: OR: 0.67; 95% CI: 0.36, 1.23; P-trend = 0.13) or in women (model 3, quartile 4: OR: 1.26; 95% CI: 0.58, 2.77; P-trend = 0.97). Conclusion: Among middle-aged men and women living in the United Kingdom, dietary patterns containing high amounts of sugar and saturated fat are not associated with new onset or recurrence of depressive symptoms.

Does pattern mixture modelling reduce bias due to informative attrition compared to fitting a mixed effects model to the available cases or data imputed using multiple imputation?: a simulation study.

BACKGROUND: Informative attrition occurs when the reason participants drop out from a study is associated with the study outcome. Analysing data with informative attrition can bias longitudinal study inferences. Approaches exist to reduce bias when analysing longitudinal data with monotone missingness (once participants drop out they do not return). However, findings may differ when using these approaches to analyse longitudinal data with non-monotone missingness. METHODS: Different approaches to reduce bias due to informative attrition in non-monotone longitudinal data were compared. To achieve this aim, we simulated data from a Whitehall II cohort epidemiological study, which used the slope coefficients from a linear mixed effects model to investigate the association between smoking status at baseline and subsequent decline in cognition scores. Participants with lower cognitive scores were thought to be more likely to drop out. By using a simulation study, a range of scenarios using distributions of variables which exist in real data were compared. Informative attrition that would introduce a known bias to the simulated data was specified and the estimates from a mixed effects model with random intercept and slopes when fitted to: available cases; data imputed using multiple imputation (MI); imputed data adjusted using pattern mixture modelling (PMM) were compared. The two-fold fully conditional specification MI approach, previously validated for non-monotone longitudinal data under ignorable missing data assumption, was used. However, MI may not reduce bias because informative attrition is non-ignorable missing. Therefore, PMM was applied to reduce the bias, usually unknown, by adjusting the values imputed with MI by a fixed value equal to the introduced bias. RESULTS: With highly correlated repeated outcome measures, the slope coefficients from a mixed effects model were found to have least bias when fitted to available cases. However, for moderately correlated outcome measurements, the slope coefficients from fitting a mixed effects model to data adjusted using PMM were least biased but still underestimated the true coefficients. CONCLUSIONS: PMM may potentially reduce bias in studies analysing longitudinal data with suspected informative attrition and moderately correlated repeated outcome measurements. Including additional auxiliary variables in the imputation model may also reduce any remaining bias.