Men Have a Stronger Monocyte-Derived Cytokine Production Response upon Stimulation with the Gram-Negative Stimulus Lipopolysaccharide than Women: A Pooled Analysis Including 15 Study Populations.

The incidence of bacterial infections and sepsis, as well as the mortality risk from sepsis, is sex specific. These clinical findings have been attributed to sex differences in immune responsiveness. The aim of the present study was to investigate sex differences in monocyte-derived cytokine production response upon stimulation with the gram-negative stimulus lipopolysaccharide (LPS) using cytokine data from 15 study populations. Individual data on ex vivo cytokine production response upon stimulation with LPS in whole blood were available for 4,020 subjects originating from these 15 study populations, either from the general population or from patient populations with specific diseases. Men had a stronger cytokine production response than women to LPS for tumour necrosis factor-α, interleukin (IL)-6, IL-12, IL-1ß, IL-1RA, and IL-10, but not for interferon-γ. The granulocyte-macrophage colony-stimulating factor production response was lower in men than in women. These sex differences were independent of chronological age. As men had higher monocyte concentrations, we normalized the cytokine production responses for monocyte concentration. After normalization, the sex differences in cytokine production response to LPS disappeared, except for IL-10, for which the production response was lower in men than in women. A sex-based approach to interpreting immune responsiveness is crucial.

Low thyroid function is not associated with an accelerated deterioration in renal function.

BACKGROUND: Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups. METHODS: Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models. RESULTS: A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function. CONCLUSIONS: Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.

Prediction of functional decline in community-dwelling older persons in general practice: a cohort study.

BACKGROUND: A first step to offer community-dwelling older persons proactive care is to identify those at risk of functional decline within a year. This study investigates the predictive value of registered information, questionnaire and GP-opinion on functional decline. METHODS: In this cohort study, embedded within the ISCOPE-trial, participants (≥75 years) completed the ISCOPE-screening questionnaire on four health domains. GPs gave their opinion on vulnerability of participants. Functional status was measured at baseline and 12 months (Groningen Activities Restriction Scale [GARS]). The outcome was functional decline (death, nursing home admission, 10% with greatest functional decline). The predictive value of pre-selected variables (age, sex, polypharmacy, multimorbidity, living situation; GPs' opinion on vulnerability, number of domains with problems [ISCOPE-score]) was compared with the area under the curves (AUC) for logistic regression models. RESULTS: 2018 of the 2211 participants (median age 82.1 years [IQR 78.8-86.5], 68.0% female, median GARS 31 [IQR 24-41]) were visited at 12 months (median GARS 34 [IQR 26-44]). 394 participants (17.8%) had functional decline (148 died, 45 nursing home admissions, 201 with greatest functional decline). The AUC for age and sex was 0.602, increasing to 0.620 (p = 0.029) with polypharmacy, multimorbidity and living situation. The GPs' opinion added more (AUC 0.672, p < 0.001) than the ISCOPE-score (AUC 0.649, p = 0.007). AUC with all variables was 0.686 (p = 0.016), and 0.643 for GPs' opinion alone. CONCLUSIONS: The GPs' opinion and ISCOPE-score improve this prediction model for functional decline based on readily available variables. GPs could identify older patients for further assessment with their clinical judgement. TRIAL REGISTRATION: Netherlands trial register, NTR1946 . Registered 10 August 2009.

Correction: Examining the construct and known-group validity of a composite endpoint for The Older Persons and Informal Caregivers Survey Minimum Data Set (TOPICS-MDS); A large-scale data sharing initiative.

[This corrects the article DOI: 10.1371/journal.pone.0173081.].

Longevity Around the Turn of the 20th Century: Life-Long Sustained Survival Advantage for Parents of Today's Nonagenarians.

Members of longevous families live longer than individuals from similar birth cohorts and delay/escape age-related diseases. Insight into this familial component of longevity can provide important knowledge about mechanisms protecting against age-related diseases. This familial component of longevity was studied in the Leiden Longevity Study which consists of 944 longevous siblings (participants), their parents (N = 842), siblings (N = 2,302), and spouses (N = 809). Family longevity scores were estimated to explore whether human longevity is transmitted preferentially through the maternal or paternal line. Standardized mortality ratios (SMRs) were estimated to investigate whether longevous siblings have a survival advantage compared with longevous singletons and we investigated whether parents of longevous siblings harbor a life-long sustained survival advantage compared with the general Dutch population by estimating lifetime SMRs (L-SMRs). We found that sibships with long-lived mothers and non-long-lived fathers had 0.41 (p = .024) less observed deaths than sibships with long-lived fathers and non-long-lived mothers and 0.48 (p = .008) less observed deaths than sibships with both parents non-long lived. Participants had 18.6 per cent less deaths compared with matched singletons and parents had a life-long sustained survival advantage (L-SMR = 0.510 and 0.688). In conclusion, genetic longevity studies may incorporate the maternal transmission pattern and genes influencing the entire life-course of individuals.

Early prediction of hospital admission for emergency department patients: a comparison between patients younger or older than 70 years.

OBJECTIVE: The aim of this study was to develop models that predict hospital admission to ED of patients younger and older than 70 and compare their performance. METHODS: Prediction models were derived in a retrospective observational study of all patients≥18 years old visiting the ED of a university hospital during the first 6 months of 2012. Patients were stratified into two age groups (<70 years old and ≥70 years old). Multivariable logistic regression analysis was used to identify predictors of hospital admission among factors available immediately after patient arrival to the ED. Validation of the prediction models was performed on patients presenting to the ED during the second half of the year 2012. RESULTS: 10 807 patients were included in the derivation and 10 480 in the validation cohorts. The strongest independent predictors of hospital admission among the 8728 patients <70 years old were age, sex, triage category, mode of arrival, performance of blood tests, chief complaint, ED revisit, type of specialist, phlebotomised blood sample and all vital signs. The area under the curve (AUC) of the validation cohort for those <70 years old was 0.86 (95% CI 0.85 to 0.87). Among the 2079 patients ≥70 years, the same factors were predictive, except for gender, type of specialist and heart rate; the AUC was 0.77 (95% CI 0.75 to 0.79). The prediction models could identify a group of 10% of patients with the highest risk in whom hospital admission was predicted at ED triage, with a positive predictive value (PPV) of 71% (95% CI 68% to 74%) in younger patients and PPV of 87% (95% CI 81% to 92%) in older patients. CONCLUSION: Demographic and clinical factors readily available early in the ED visit can be useful in identifying patients who are likely to be admitted to the hospital. While the model for the younger patients had a higher AUC, the model for older patients had a higher PPV in identifying the patients at highest risk for admission. Of note, heart rate was not a useful predictor in the older patients.

Association of diastolic blood pressure with cardiovascular events in older people varies upon cardiovascular history.

BACKGROUND: In older age, a low DBP has been associated with increased risk of cardiovascular events, especially in frail older people. We tested the hypothesis that low DBP is associated with a high risk of cardiovascular events in people with a previous history of cardiovascular disease, as a proxy of vascular impairment. METHODS: We included 5804 participants (mean age 75 years) from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) who as part of the trial were intensively monitored for an average period of 3.2 years. DBP was categorized in low (<70 mmHg), normal (70-90 mmHg) or high (>90 mmHg). Cox proportional hazards analyses were used to estimate hazard ratio with 95% confidence intervals (CI); analyses were stratified for cardiovascular history. RESULTS: Participants with low DBP had a 1.24-fold (1.04; 1.49) increased risk of cardiovascular events compared with those with normal DBP. After further adjusting for cardiovascular factors, this association attenuated to 1.05 (0.86; 1.28). A previous history of cardiovascular disease significantly modified the relation between DBP and risk of cardiovascular events (P-interaction 0.042). In participants without a history of cardiovascular disease, DBP was marginally significantly associated with an increased event risk (hazard ratio (95% CI) per 10 mmHg increase in DBP 1.08 (0.99; 1.18), P value = 0.07), whereas in participants with a history of cardiovascular disease, higher DBP was associated with a decreased risk of cardiovascular events (hazard ratio (95% CI) per 10 mmHg increase in DBP 0.92 (0.85; 0.99, P value = 0.018). These risk estimates were independent of potential confounders, including classical cardiovascular risk factors. CONCLUSION: The association of DBP with cardiovascular events in older people varies upon their previous history, showing that in participants with preexisting cardiovascular diseases, a higher DBP associates with a decreased risk of future cardiovascular events.

The Missing Link in the Pathophysiology of Vascular Cognitive Impairment: Design of the Heart-Brain Study.

BACKGROUND: Hemodynamic balance in the heart-brain axis is increasingly recognized as a crucial factor in maintaining functional and structural integrity of the brain and thereby cognitive functioning. Patients with heart failure (HF), carotid occlusive disease (COD), and vascular cognitive impairment (VCI) present themselves with complaints attributed to specific parts of the heart-brain axis, but hemodynamic changes often go beyond the part of the axis for which they primarily seek medical advice. The Heart-Brain Study hypothesizes that the hemodynamic status of the heart and the brain is an important but underestimated cause of VCI. We investigate this by studying to what extent hemodynamic changes contribute to VCI and what the mechanisms involved are. Here, we provide an overview of the design and protocol. METHODS: The Heart-Brain Study is a multicenter cohort study with a follow-up measurement after 2 years among 645 participants (175 VCI, 175 COD, 175 HF, and 120 controls). Enrollment criteria are the following: 1 of the 3 diseases diagnosed according to current guidelines, age ≥50 years, no magnetic resonance contraindications, ability to undergo cognitive testing, and independence in daily life. A core clinical dataset is collected including sociodemographic factors, cardiovascular risk factors, detailed neurologic, cardiac, and medical history, medication, and a physical examination. In addition, we perform standardized neuropsychological testing, cardiac, vascular and brain MRI, and blood sampling. In subsets of participants we assess Alz-heimer biomarkers in cerebrospinal fluid, and assess echocardiography and 24-hour blood pressure monitoring. Follow-up measurements after 2 years include neuropsychological testing, brain MRI, and blood samples for all participants. We use centralized state-of-the-art storage platforms for clinical and imaging data. Imaging data are processed centrally with automated standardized pipelines. RESULTS AND CONCLUSIONS: The Heart-Brain Study investigates relationships between (cardio-)vascular factors, the hemodynamic status of the heart and the brain, and cognitive impairment. By studying the complete heart-brain axis in patient groups that represent components of this axis, we have the opportunity to assess a combination of clinical and subclinical manifestations of disorders of the heart, vascular system and brain, with hemodynamic status as a possible binding factor.

High Sensitivity Cardiac Troponin T and Cognitive Function in the Oldest Old: The Leiden 85-Plus Study.

BACKGROUND: Impaired cardiac function has been related to accelerated cognitive decline in late-life. OBJECTIVE: To investigate whether higher levels of high sensitivity cardiac troponin T (hs-cTnT), a sensitive marker for myocardial injury, are associated with worse cognitive function in the oldest old. METHODS: In 455 participants of the population-based Leiden 85-plus Study, hs-cTnT was measured at 86 years. Cognitive function was measured annually during four years with the Mini-Mental State Examination (MMSE). RESULTS: Participants in the highest gender-specific tertile of hs-cTnT had a 2.0-point lower baseline MMSE score than participants in the lowest tertile (95% confidence interval (CI) (95% CI 0.73-3.3), and had a 0.58-point steeper annual decline in MMSE during follow-up (95% CI 0.06-1.1). The associations remained after adjusting for sociodemographic and cardiovascular risk factors excluding those without a history of overt cardiac disease. CONCLUSION: In a population-based sample of the oldest old, higher levels of hs-cTnT were associated with worse cognitive function and faster cognitive decline, independently from cardiovascular risk factors and a history of overt cardiac disease.

Left Ventricular Hypertrophy and Cognitive Decline in Old Age.

BACKGROUND: Patients with advanced heart failure run a greater risk of dementia. Whether early cardiac structural changes also associate with cognitive decline is yet to be determined. OBJECTIVE: We tested whether left ventricular hypertrophy (LVH) derived from electrocardiogram associates with cognitive decline in older subjects at risk of cardiovascular disease. METHODS: We included 4,233 participants (mean age 75.2 years, 47.8% male) from PROSPER (PROspective Study of Pravastatin in the Elderly at Risk). LVH was assessed from baseline electrocardiograms by measuring the Sokolow-Lyon index. Higher levels of Sokolow-Lyon index indicate higher degrees of LVH. Cognitive domains involving selective attention, processing speed, and immediate and delayed memory were measured at baseline and repeated during a mean follow-up of 3.2 years. RESULTS: At baseline, LVH was not associated with worse cognitive function. During follow-up, participants with higher levels of LVH had a steeper decline in cognitive function including in selective attention (p = 0.009), processing speed (p = 0.010), immediate memory (p < 0.001), and delayed memory (p = 0.002). These associations were independent of cardiovascular risk factors, co-morbidities, and medications. CONCLUSION: LVH assessed by electrocardiogram associates with steeper decline in cognitive function of older subjects independent of cardiovascular risk factors and co-morbidities. This study provides further evidence on the link between subclinical cardiac structural changes and cognitive decline in older subjects.

Diabetes incidence and glucose intolerance prevalence increase with higher outdoor temperature.

OBJECTIVE: Rising global temperatures might contribute to the current worldwide diabetes epidemic, as higher ambient temperature can negatively impact glucose metabolism via a reduction in brown adipose tissue activity. Therefore, we examined the association between outdoor temperature and diabetes incidence in the USA as well as the prevalence of glucose intolerance worldwide. RESEARCH DESIGN AND METHODS: Using meta-regression, we determined the association between mean annual temperature and diabetes incidence during 1996-2009 for each US state separately. Subsequently, results were pooled in a meta-analysis. On a global scale, we performed a meta-regression analysis to assess the association between mean annual temperature and the prevalence of glucose intolerance. RESULTS: We demonstrated that, on average, per 1°C increase in temperature, age-adjusted diabetes incidence increased with 0.314 (95% CI 0.194 to 0.434) per 1000. Similarly, the worldwide prevalence of glucose intolerance increased by 0.170% (95% CI 0.107% to 0.234%) per 1°C rise in temperature. These associations persisted after adjustment for obesity. CONCLUSIONS: Our findings indicate that the diabetes incidence rate in the USA and prevalence of glucose intolerance worldwide increase with higher outdoor temperature.

Examining the construct and known-group validity of a composite endpoint for The Older Persons and Informal Caregivers Survey Minimum Data Set (TOPICS-MDS); A large-scale data sharing initiative.

BACKGROUND: Preference-weighted multi-faceted endpoints have the potential to facilitate comparative effectiveness research that incorporates patient preferences. The Older Persons and Informal Caregivers Survey-Composite endpoint (TOPICS-CEP) is potentially a valuable outcome measure for evaluating interventions in geriatric care as it combines multiple outcomes relevant to older persons in a single metric. The objective of this study was to validate TOPICS-CEP across different study settings (general population, primary care and hospital). METHODS: Data were extracted from TOPICS Minimum Dataset (MDS), a pooled public-access national database with information on older persons throughout the Netherlands. Data of 17,603 older persons were used. Meta-correlations were performed between TOPICS-CEP indexed scores, EuroQol5-D utility scores and Cantril's ladder life satisfaction scores. Mixed linear regression analyses were performed to compare TOPICS-CEP indexed scores between known groups, e.g. persons with versus without depression. RESULTS: In the complete sample and when stratified by study setting TOPICS-CEP and Cantril's ladder were moderately correlated, whereas TOPICS-CEP and EQ-5D were highly correlated. Higher mean TOPICS-CEP scores were found in persons who were: married, lived independently and had an education at university level. Moreover, higher mean TOPICS-CEP scores were found in persons without dementia, depression, and dizziness with falls, respectively. Similar results were found when stratified by subgroup. CONCLUSION: This study supports that TOPICS-CEP is a robust measure which can potentially be used in broad settings to identify the effect of intervention or of prevention in elderly care.

Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study.

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

Thyroid Status and Mortality Risk in Older Adults With Normal Thyrotropin: Sex Differences in the Milan Geriatrics 75+ Cohort Study.

BACKGROUND: Thresholds of optimal thyroid status in old age are controversial. We investigated the longitudinal association between thyroid parameters and 10-year all-cause mortality risk in older outpatients with normal thyrotropin (TSH) and modification by sex and age. METHODS: Baseline TSH, free thyroxine (fT4), and free triiodothyronine (fT3) were assessed in the Milan Geriatrics 75+ Cohort Study. 324 men and 609 women older than 75 years had normal TSH. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for the associations between thyroid parameters and mortality risk using Cox regression. Sex-stratified analyses were adjusted for sociodemographic factors and comorbidities. RESULTS: 233 men and 367 women died during follow-up. After adjustment, each 1-mU/L higher TSH was associated with decreased mortality risk in men (HR 0.83, 95% CI 0.69-0.98), but not in women (HR 1.09, 95% CI 0.95-1.24) (p for sex interaction = .006). Each 1-ng/L higher fT4 was associated with increased mortality risk in men (HR 1.11, 95% CI 1.02-1.22), but not in women (HR 0.98, 95% CI 0.93-1.04) (p for sex interaction = .013). Each 1-pg/mL higher fT3 was associated with decreased mortality risk in women (HR 0.77, 95% CI 0.60-0.98), but not in men (HR 0.80, 95% CI 0.57-1.13). The inverse association between TSH and mortality was most pronounced in men older than 85 years. CONCLUSIONS: Among older outpatients with normal TSH, higher TSH and lower fT4 were associated with decreased mortality risk in men but not in women. When assessing thyroid status, sex and age should be taken into account.

How is Change in Physical Health Status Reflected by Reports of Nurses and Older People Themselves?

BACKGROUND: Self-rated health is assumed to closely reflect actual health status, but older people's shifting norms and values may influence this association. We investigated how older people's change in self-ratings, in comparison to their retrospective appreciation and change in nurse ratings, reflect functional decline and mortality risk. METHODS: A representative sample of 85-year olds from a middle-sized city in the Netherlands, excluding those with severe cognitive dysfunction, was followed for 6 years. Participants and a research nurse annually provided ratings of health, and participants retrospectively appreciated their annual change in health. Functional status was assessed with the Groningen Activity Rating Scale and all were followed for vital status. RESULTS: Functional decline was reflected by all reports of change in health (all p < .001). When incongruent, change in nurse-ratings reflected functional decline better than change in self-ratings but retrospective appreciation reflected functional decline best (p < .001 vs change in self-ratings and p < .05 vs change in nurse-ratings). Mortality risk was only reflected by retrospective appreciation (p < .01). CONCLUSIONS: Retrospective appreciation of health by older people is superior to change in self-ratings and nurse-ratings in reflecting change in physical health, possibly because similar norms and values are applied in the assessment. The nurse's norms, like the norms of older people, may shift with the ageing of the researched cohort. Asking people to retrospectively appreciate their change in health is a valuable addition to usual enquiries in practice and research.

Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10-7, range P = 9.2 × 10-8 to 6.0 × 10-46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10-6, range P = 5.5 × 10-6 to 6.1 × 10-35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.

Personalized absolute benefit of statin treatment for primary or secondary prevention of vascular disease in individual elderly patients.

OBJECTIVE: To estimate the absolute treatment effect of statin therapy on major adverse cardiovascular events (MACE; myocardial infarction, stroke and vascular death) for the individual patient aged ≥70 years. METHODS: Prediction models for MACE were derived in patients aged ≥70 years with (n = 2550) and without (n = 3253) vascular disease from the "PROspective Study of Pravastatin in Elderly at Risk" (PROSPER) trial and validated in the "Secondary Manifestations of ARTerial disease" (SMART) cohort study (n = 1442) and the "Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm" (ASCOT-LLA) trial (n = 1893), respectively, using competing risk analysis. Prespecified predictors were various clinical characteristics including statin treatment. Individual absolute risk reductions (ARRs) for MACE in 5 and 10 years were estimated by subtracting on-treatment from off-treatment risk. RESULTS: Individual ARRs were higher in elderly patients with vascular disease [5-year ARRs: median 5.1 %, interquartile range (IQR) 4.0-6.2 %, 10-year ARRs: median 7.8 %, IQR 6.8-8.6 %] than in patients without vascular disease (5-year ARRs: median 1.7 %, IQR 1.3-2.1 %, 10-year ARRs: 2.9 %, IQR 2.3-3.6 %). Ninety-eight percent of patients with vascular disease had a 5-year ARR ≥2.0 %, compared to 31 % of patients without vascular disease. CONCLUSIONS: With a multivariable prediction model the absolute treatment effect of a statin on MACE for individual elderly patients with and without vascular disease can be quantified. Because of high ARRs, treating all patients is more beneficial than prediction-based treatment for secondary prevention of MACE. For primary prevention of MACE, the prediction model can be used to identify those patients who benefit meaningfully from statin therapy.

Validity of the three apathy items of the Geriatric Depression Scale (GDS-3A) in measuring apathy in older persons.

OBJECTIVE: The Geriatric Depression Scale (GDS)-3A, a three-item subset of the GDS-15, is increasingly used as a measure for apathy in research settings to assess factors associating with this neuropsychiatric syndrome. We aimed to assess how accurately the GDS-3A discriminates between presence and absence of apathy in two populations of community-dwelling older persons, using the Apathy Scale as reference standard. METHODS: Baseline data were used from 427 participants of the Discontinuation of Antihypertensive Treatment in Elderly people (DANTE) Study Leiden and 1118 participants of the PROactive Management Of Depression in the Elderly (PROMODE) Study, all ≥75 years and with available GDS-3A and Apathy Scale measurements. A cut-off score of ≥14 was used for presence of apathy according to the Apathy Scale. Areas under the receiver operating characteristic curve (AUC) were calculated. Based on the likelihood ratios for GDS-3A scores, a cut-off of ≥2 was used for presence of apathy according to the GDS-3A to calculate test characteristics. RESULTS: The AUC was 0.68 (95% confidence interval 0.62-0.73) in the DANTE Study and 0.72 (0.67-0.77) in the PROMODE Study. In the DANTE Study sensitivity was 29.3% (21.4-38.1) and specificity was 88.5% (84.4-91.8), whereas in the PROMODE Study sensitivity was 32.8% (24.5-41.1) and specificity 92.6% (90.9-94.2). Stratification on population characteristics did not yield more favourable test characteristics. CONCLUSION: The GDS-3A has low sensitivity and high specificity as a measure of apathy in two populations of older persons. Using the GDS-3A in research might yield estimates biassed towards the null in case of non-differential misclassification. Copyright © 2016 John Wiley & Sons, Ltd.

Predicting Risk of Cognitive Decline in Very Old Adults Using Three Models: The Framingham Stroke Risk Profile; the Cardiovascular Risk Factors, Aging, and Dementia Model; and Oxi-Inflammatory Biomarkers.

OBJECTIVES: To examine the Framingham Stroke Risk Profile (FSRP); the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) risk score, and oxi-inflammatory load (cumulative risk score of three blood biomarkers-homocysteine, interleukin-6, C-reactive protein) for associations with cognitive decline using three cohort studies of very old adults and to examine whether incorporating these biomarkers with the risk scores can affect the association with cognitive decline. DESIGN: Three longitudinal, population-based cohort studies. SETTING: Newcastle-upon-Tyne, United Kingdom; Leiden, the Netherlands; and Lakes and Bay of Plenty District Health Board areas, New Zealand. PARTICIPANTS: Newcastle 85+ Study participants (n = 616), Leiden 85-plus Study participants (n = 444), and Life and Living in Advanced Age, a Cohort Study in New Zealand (LiLACS NZ Study) participants (n = 396). MEASUREMENTS: FSRP, CAIDE risk score, oxi-inflammatory load, FSRP incorporating oxi-inflammatory load, and CAIDE risk score incorporating oxi-inflammatory load. Oxi-inflammatory load could be calculated only in the Newcastle 85+ and the Leiden 85-plus studies. Measures of global cognitive function were available for all three data sets. Domain-specific measures were available for the Newcastle 85+ and the Leiden 85-plus studies. RESULTS: Meta-analysis of pooled results showed greater risk of incident global cognitive impairment with higher FSRP (hazard ratio (HR) = 1.46, 95% confidence interval (CI) = 1.08-1.98), CAIDE (HR = 1.53, 95% CI = 1.09-2.14), and oxi-inflammatory load (HR = 1.73, 95% CI = 1.04-2.88) scores. Adding oxi-inflammatory load to the risk scores increased the risk of cognitive impairment for the FSRP (HR = 1.65, 95% CI = 1.17-2.33) and the CAIDE model (HR = 1.93, 95% CI = 1.39-2.67). CONCLUSION: Adding oxi-inflammatory load to cardiovascular risk scores may be useful for determining risk of cognitive impairment in very old adults.

Temporal Relationship Between Cognitive and Physical Performance in Middle-Aged to Oldest Old People.

BACKGROUND: Cognitive and physical impairment frequently co-occur in older people. The aim of this study was to assess the temporal order of these age-related changes in cognitive and physical performance and to assess whether a relationship was different across specific cognitive and physical domains and age groups. METHODS: Cognitive domains included global, executive, and memory function; physical domains included gait speed and handgrip strength. These domains were assessed in two population-based longitudinal cohorts covering the age ranges of 55-64, 65-74, 75-85, and 85-90 years with a follow-up of 5-12 years. Cross-lagged panel models were applied to assess the temporal relationships between the different cognitive and physical domains adjusting for age, sex, education, comorbidity, depressive symptoms, and physical activity. RESULTS: Over all age groups, poorer executive function was associated with a steeper decline in gait speed (p < .05). From the age of 85 years, this relationship was found across all cognitive and physical domains (p < .02). From the age of 65 years, slower gait speed and/or weaker handgrip strength were associated with steeper declines in global cognitive function (p < .02), with statistically significant results across all cognitive domains in the age group of 75-85 years (p < .04). CONCLUSIONS: The temporal relationship between cognitive and physical performance differs across domains and age, suggesting a specific rather than a general relationship. This emphasizes the importance of repeated measurements on different domains and encourages future research to the development of domain- and age-specific interventions.