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In animal models, single-gene mutations in genes involved in insulin/IGF and target of rapamycin signalling pathways extend lifespan to a considerable extent. The genetic, genomic and epigenetic influences on human longevity are expected to be much more complex. Strikingly however, beneficial metabolic and cellular features of long-lived families resemble those in animals for whom the lifespan is extended by applying genetic manipulation and, especially, dietary restriction. Candidate gene studies in humans support the notion that human orthologues from longevity genes identified in lower species do contribute to longevity but that the influence of the genetic variants involved is small. Here we discuss how an integration of novel study designs, labour-intensive biobanking, deep phenotyping and genomic research may provide insights into the mechanisms that drive human longevity and healthy ageing, beyond the associations usually provided by molecular and genetic epidemiology. Although prospective studies of humans from the cradle to the grave have never been performed, it is feasible to extract life histories from different cohorts jointly covering the molecular changes that occur with age from early development all the way up to the age at death. By the integration of research in different study cohorts, and with research in animal models, biological research into human longevity is thus making considerable progress.

In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7years the number of families with all participating siblings aged 95years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity. In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7years the number of families with all participating siblings aged 95years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity.

Context: A relation between low thyroid activity and prolonged life span in humans has been observed. Several studies have demonstrated hereditary and genetic influences on thyroid function. Objective: The objective of the study was to test whether low thyroid activity associated with extreme longevity constitutes a heritable phenotype, which could contribute to the familial longevity observed in the Leiden Longevity Study. Design: This was a cross-sectional study. Setting: The study was conducted at a university hospital in the city of Leiden, The Netherlands. Participants: Eight hundred fifty-nine nonagenarian siblings (median age 92.9 yr) from 421 long-lived families participated in the study. Families were recruited from the entire Dutch population if at least two long-lived siblings were alive and fulfilled the age criterion of age of 89 yr or older for males and 91 yr or older for females. There were no selection criteria on health or demographic characteristics. Intervention: Blood samples were taken for determination of serum parameters of thyroid function. Main Outcome Measure: We calculated the family mortality history score of the parents of the nonagenarian siblings and related this to thyroid function parameters in the nonagenarian siblings. Results: We found that a lower family mortality history score (less mortality) of the parents of nonagenarian siblings was associated with higher serum TSH levels (P = 0.005) and lower free T-4 levels (P = 0.002) as well as lower free T-3 levels (P = 0.034) in the nonagenarian siblings. Conclusions: Our findings support the previous observation that low thyroid activity in humans constitutes a heritable phenotype that contributes to exceptional familial longevity observed in the Leiden Longevity Study. (J Clin Endocrinol Metab 95: 4979-4984, 2010)

There seem to be socioeconomically differences in survival for females with breast cancer, usually associated with a higher stage of disease. However, differences within tumor size have not been studied. Aim of this study is to assess differences in survival according to socioeconomic status (SES), stratified for tumor size and stage at diagnosis, for females with breast cancer in the Netherlands. All females diagnosed with breast cancer (1995-2005) were selected from the Netherlands Cancer Registry. Patients were linked to a SES database according to postal code. A multivariable logistic regression was used to assess factors associated with SES. Overall survival (OS) and relative survival (RS) were calculated. Overall, 127,599 patients were included. Higher SES was associated with lower T-stage (P < 0.0001). A decreased survival (OS and RS) was found for patients with a lower SES. Also within different size groups, RS was different. Overall, 10-year OS for the high SES group was 65 and 58% for the low SES group (hazard ratio 1.1, P < 0.001) and RS was 79 versus 74% (relative excess risk, RER 1.2; P < 0.001). The socioeconomic differences remained statistically significant (P < 0.001) after adjustment for age, year of diagnosis, grade, TNM stage, and treatment. For the lowest SES group 777 deaths could be avoided. Socioeconomic differences in survival of breast cancer patients were observed in the Netherlands. Higher stage at diagnosis of patients with a lower SES only partly explains the decreased survival. Policies aimed at the reduction of socioeconomic health inequalities might be important to improve survival of breast cancer.

OBJECTIVE To investigate progression of MRI-assessed manifestations of cerebral degeneration related to cognitive changes in a population of elderly patients with diabetes mellitus (DM) compared to age-matched control subjects. METHODS From a randomized controlled trial (PROSPER study), a study sample of 89 patients with DM and 438 control subjects without DM aged 70-82 years were included for brain MRI scanning and cognitive function testing at baseline and reexamination after 3 years. Changes in brain atrophy, white matter hyperintensities (WMHs), number of infarctions, and cognitive function test results were determined in patients with DM and subjects without DM. Linear regression analysis was performed with correction for age, gender, hypertension, pravastatin treatment, educational level, and baseline test results. In patients with DM, baseline MRI parameters were correlated with change in cognitive function test result using linear regression analysis with covariates age and gender. RESULTS Patients with DM showed increased progression of brain atrophy (p < 0.01) after follow-up compared to control subjects. No difference in progression of WMH volume or infarctions was found. Patients with DM showed increased decline in cognitive performance on Stroop Test (p = 0.04) and Picture Learning Test (p = 0.03). Furthermore, in patients with DM, change in Picture Learning Test was associated with baseline brain atrophy (p < 0.02). CONCLUSION Our data show that elderly patients with DM without dementia have accelerated progression of brain atrophy with significant consequences in cognition compared to subjects without DM. Our findings add further evidence to the hypothesis that diabetes exerts deleterious effects on neuronal integrity.

Background Apathy has recently been recognized as a distinct clinical syndrome although it is difficult to differentiate from late life depression. In old age, apathy as a syndrome in itself and depression may have different etiologies. Inflammatory markers have been associated with depression in the elderly, but the relation with apathy is unknown. Objective To assess the relation between C-reactive protein (CRP) and apathy as a syndrome in itself, apart from depression, in subjects aged 85 and older. Methods All data come from the Leiden 85-Plus Study, a prospective, population-based study of 599 elderly subjects. CRP was measured at baseline. In all subjects with a Mini Mental State Examination (MMSE) ≥19 points (n = 500), apathy and depression were assessed annually from age 85 to 90 using the three apathy and twelve depression questions of the 15-item Geriatric Depression Scale (GDS-15). The association between CRP and apathy or depressive symptoms was assessed both at baseline and longitudinally. Results At baseline, no association was found between CRP-concentration and apathy or depression. In subjects free of apathy and depression at baseline, subjects in the highest CRP-tertile at baseline had significantly more increase in depressive symptoms but not in apathy symptoms during follow-up. Conclusion Higher CRP concentrations increased the risk of depression but not apathy in a community-based cohort of 85 years old subjects. This suggests that apathy and depression in old age have different etiologies. Copyright © 2009 John Wiley & Sons, Ltd.

The APOE genotype and serum calcium levels have both been associated with cognitive impairment. Animal studies have shown variation in apoE isoforms to play a critical role in intraneuronal calcium homeostasis, but the contribution of this interaction to cognitive function in man is unknown. Here, we studied whether the APOE genotype modulates the association between serum calcium levels and cognition.Within the Leiden 85-plus Study, a prospective population-based study of 599 subjects aged 85 years, we measured serum calcium levels and APOE genotype at baseline. During a 5-year follow-up period, cognitive function was annually assessed using the Mini-Mental State Examination (MMSE) and a standardized neuropsychological test battery.Both at baseline and during follow-up, high serum calcium levels were associated with worse cognitive function in epsilon3epsilon4 carriers and to a lesser extent in epsilon3epsilon3 carriers, but not in epsilon2epsilon3 carriers. The MMSE score during the entire follow-up period differed between those with high and low serum calcium levels, with 5.5 points in epsilon3epsilon4 carriers (p0.001), 1.6 points in epsilon3epsilon3 carriers (p = 0.010), and 0.1 point in epsilon2epsilon3 carriers (p = 0.935). Formal testing showed an interaction between APOE genotype and serum calcium levels in relation to global cognitive function (p = 0.003).In old age, APOE genotype modulates the association between serum calcium levels and cognitive function. High serum calcium levels associate with worse cognitive function, especially in APOE epsilon4 allele carriers, but not in carriers of the epsilon2 allele.

Objectives To investigate whether statins reduce all cause mortality and major coronary and cerebrovascular events in people without established cardiovascular disease but with cardiovascular risk factors, and whether these effects are similar in men and women, in young and older (>65 years) people, and in people with diabetes mellitus. Design Meta-analysis of randomised trials. Data sources Cochrane controlled trials register, Embase, and Medline. Data abstraction Two independent investigators identified studies on the clinical effects of statins compared with a placebo or control group and with follow-up of at least one year, at least 80% or more participants without established cardiovascular disease, and outcome data on mortality and major cardiovascular disease events. Heterogeneity was assessed using the Q and I 2 statistics. Publication bias was assessed by visual examination of funnel plots and the Egger regression test. Results 10 trials enrolled a total of 70 388 people, of whom 23 681 (34%) were women and 16 078 (23%) had diabetes mellitus. Mean follow-up was 4.1 years. Treatment with statins significantly reduced the risk of all cause mortality (odds ratio 0.88, 95% confidence interval 0.81 to 0.96), major coronary events (0.70, 0.61 to0.81), and major cerebrovascular events (0.81, 0.71 to 0.93). No evidence of an increased risk of cancer was observed. There was no significant heterogeneity of the treatment effect in clinical subgroups. Conclusion In patients without established cardiovascular disease but with cardiovascular risk factors, statin use was associated with significantly improved survival and large reductions in the risk of major cardiovascular events.

The aim of this prospective study was to determine whether circulating intercellular adhesion molecule (ICAM) 1, as a potential surrogate of 'endothelial activation', is more strongly associated with risk of vascular events than with incident diabetes.We related baseline ICAM-1 levels to vascular events (866 CHD and stroke events in 5,685 participants) and incident diabetes (292 in 4,945 without baseline diabetes) in the elderly over 3.2 years of follow-up.ICAM-1 levels correlated positively with triacylglycerol but negatively with LDL- and HDL-cholesterol. ICAM-1 levels were higher in those who developed diabetes (388.6 +/- 1.42 vs 369.4 +/- 1.39 ng/ml [mean+/-SD], p = 0.011) and remained independently associated with new-onset diabetes (HR 1.84, 95% CI 1.26-2.69, p = 0.0015 per unit increase in log[ICAM-1] after adjusting for classical risk factors and C-reactive protein). By contrast, ICAM-1 levels were not significantly (p = 0.40) elevated in those who had an incident vascular event compared with those who remained event-free, and corresponding adjusted risk associations were null (HR 0.98, 95% CI 0.80-1.22, p = 0.89) in analyses adjusted for other risk factors.We show that elevated ICAM-1 levels are associated with risk of incident diabetes in the elderly at risk, despite no association with incident cardiovascular disease risk. We suggest that perturbations in circulating ICAM-1 levels are aligned more towards diabetes risk.

Innate propensity of immune activation is reflected in production of pro- and anti-inflammatory cytokines upon stimulation of Toll-like receptors (TLR) in whole-blood stimulation assays. The validity of the whole-blood stimulation assay under field conditions has not been evaluated extensively. Here, we have determined correlation of individually repeated whole-blood stimulation assays in a field-study in Ghana and compared it with that of two Dutch populations performed under optimal conditions. We also examined cytokine production to various TLR-agonists in order to create an assay that would mimic general innate immune responses. Under field conditions repeated assessments of lipopolysaccharide-induced Tumor Necrosis Factor-alpha (TNFalpha) production were poorly correlated (r=0.15, p=0.087). Correlation was relatively high for production of Interleukin-10 (IL10) (r=0.48, p

Inflammation is thought to play an important role in the development of cognitive decline and dementia in old age. The interleukin-1 signalling pathway may play a prominent role in this process. The gene encoding for interleukin-1 beta-converting enzyme (ICE) is likely to influence IL-1 beta levels. Inhibition of ICE decreases the age-related increase in IL-1 beta levels and may therefore improve memory function. We assessed whether genetic variation in the ICE gene associates with cognitive function in an elderly population. All 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) were genotyped for the 10643GC, 9323GA, 8996AG and 5352GA polymorphisms in the ICE gene. Cross-sectional associations between the polymorphisms and cognitive function were assessed with linear regression. Longitudinal associations between polymorphisms, haplotypes and cognitive function were assessed with linear mixed models. All associations were adjusted for sex, age, education, country, treatment with pravastatin and version of test where appropriate. Subjects carrying the variants 10643C and 5352A allele had significantly lower IL-1 beta production levels (P < 0.01). Furthermore, we demonstrated that homozygous carriers of the 10643C and the 5352A allele performed better on all executive function tests at baseline and during follow-up compared to homozygous carriers of the wild-type allele (all P < 0.02). The haplotype with two variants present (10643C and 5352A) was associated with better executive function (all P < 0.02) compared to the reference haplotype without variants. For memory function the same trend was observed, although not significant. Genetic variation in the ICE gene is associated with better performance on cognitive function and lower IL-1 beta production levels. This suggests that low levels of IL-1 beta are protective for memory and learning deficits. Inhibition of ICE may therefore be an important therapeutic target for maintaining cognitive function in old age.

Background Apathy is defined as an important loss of motivation in all domains of daily functioning. Especially in old age, apathy might be a specific neuropsychiatric syndrome separate from depression. There are indications that apathy in elderly subjects is related to vascular disease. Objective To assess the relation between vascular disease and apathy in subjects aged 85 years and older. Methods The Leiden 85-plus Study is a prospective, population-based study of 500 elderly subjects. Vascular disease including myocardial infarction, angina pectoris or myocardial ischemia, claudicatio intermittens, and arterial surgery was determined at baseline. Symptoms of apathy were assessed annually from age 85 through 90 years using the apathy questions of the 15-item Geriatric Depression Rating Scale (GDS). Diagnostic accuracy of the apathy questions was validated using the Apathy Scale at age 90 years. The association between vascular disease and apathy was estimated both at baseline and longitudinally. Results The apathy items of the GDS showed a sensitivity of 69% and a specificity of 85%. At baseline, 69 subjects with apathy but free of depression had significantly more cardiovascular pathologies compared to 287 subjects without apathy. In the 287 subjects who were free of apathy and depression, increase of apathy but not depression during follow-up was significantly higher for each additional cardiovascular pathology at baseline. Conclusion In community dwelling elderly, those with vascular disease were at higher risk of developing apathy but not depression. This suggests that apathy and depression in old age have different etiologies. Copyright © 2007 John Wiley & Sons, Ltd.

Summary Before the 1950s effective medical interventions were not available and epidemiological transition in developing countries was mostly initiated by the introduction of mains water, sewage systems and personal hygiene. Nowadays, effective medical interventions such as vaccination programmes, medication and vitamin supplements might aid a swift transition. We recorded mortality among a research population of 18 850 in Garu-Tempane district of Ghana from 2002 to 2005. We calculated the expected mortality based on the population structure in 2002 and compared the life expectancy of the region with other countries depending on their gross domestic product (GDP). Mortality in the age group 0–9 years was 8.1 per 1000 person-years and in the age group 10–19 years it was 4.1 per 1000 person-years. Cumulative survival probability up to age 20 years amounted to 89% and was far higher than expected. Observed and expected mortality in old age were similar. The life expectancy at birth was 59 years and much higher than the region's per capita annual income of US$100 would predict. We conclude that the population is in epidemiological transition. It shows that an epidemiological transition can be accelerated with low-cost interventions.

Objective:To test the cross-sectional and longitudinal association of heart rate variability measured from 10-second electrocardiogram recordings with cognitive function in older subjects at high risk of cardiovascular disease.Design and method:We studied 3,583 men and women, mean age 75.0 years, wh

There are only few experimental studies that assess the hypothesis that placebo analgesia is mediated by endogenous opioids. One of these studies [Grevert P, Albert LH, Goldstein A: Partial antagonism

The authors examined the effect of pravastatin 40 mg daily on the progression of ischemic brain lesions using repeated brain MRI. After a mean treatment period of 33 months, there was an increase in total ischemic lesion load of 1.1 cm3 (p < 0.001) in the 270 placebo-treated subjects and 1.1 cm3 (p < 0.001) in the 265 pravastatin-treated subjects. There was no difference between the two treatment groups (p = 0.73).

Cytokines are key players in numerous inflammatory processes. Demonstration of a heritable component in the variation of cytokine production would indicate that simultaneous occurrence of conditions might be caused by a heritable inflammatory characteristic. We applied an extended twin study approach to assess heritability estimates of interleukin (IL)-1beta, IL-1ra, IL-10, IL-6, and TNF-alpha production capacity after ex vivo stimulation with lipopolysaccharide. Cytokine production capacity was assessed in 42 monozygotic pairs, 52 dizygotic pairs, one trizygotic triplet, 33 single twins, and 83 additional siblings. Heritability estimates were derived from variance decomposition models using maximum likelihood estimation. For all cytokines, over 50% of the variance was genetically determined. IL-1ra and TNF-alpha had the lowest heritability estimate of 53%. Estimates for IL-6 and IL-10 were 57 and 62%, respectively. IL-1beta had the highest estimate of 86%. We conclude that the production of cytokines is under tight genetic control.

The authors investigated the progression of white matter hyperintensities (WMHs) in a large population of elderly men and women. After 3 years of follow-up, women had accumulated approximately twice as much deep WMH (DWMH) as men. The progression of periventricular WMH was the same for men and women. Gender differences may affect the pathogenesis of DWMH, which in turn may result in different clinical consequences in women.

OBJECTIVE: To test the hypothesis that a pro-inflammatory response is associated with cognitive impairment among individuals with cardiovascular disease.METHOD: All 85-year-old inhabitants of Leiden (n = 599) were visited at their place of residence. A history of cardiovascular disease and an EKG were used as indicators of atherosclerosis. Production of the pro-inflammatory cytokine tumor necrosis factor-alpha and the anti-inflammatory cytokine interleukin-10 was assessed in a whole-blood assay using lipopolysaccharide as a stimulus. Global cognitive functioning was determined with the Mini-Mental State Examination (MMSE); attention, cognitive speed, and memory were determined with four neuropsychological tests; and a history of dementia was obtained.RESULTS: In subjects with cardiovascular disease, median MMSE scores were lower in those with a pro-inflammatory response when compared with those with an anti-inflammatory response (p = 0.02). Similar associations were found for the Stroop Test, measuring attention (p < 0.01), the Coding Test measuring cognitive speed (p = 0.02), the Word Learning Test measuring memory (p < 0.01), and the presence of dementia (p = 0.04). The associations remained unaltered after adjustments for possible confounders such as gender, level of education, use of nonsteroidal anti-inflammatory drugs, use of cardiovascular drugs, and cardiovascular risk factors. In contrast, outcomes of the cognitive tests and presence of dementia were not dependent on the inflammatory response when cardiovascular disease was absent.CONCLUSION: The combination of cardiovascular disease and a pro-inflammatory cytokine response may be associated with cognitive impairment and dementia.

To analyze the impact of seizures on everyday life and the long-term effects of epilepsy on health status and psychosocial outcomes.Follow-up study was conducted of a cohort of consecutive patients newly diagnosed with epilepsy between 1953 and 1967. In 1995 (mean follow-up 34 years), a random sample of 333 patients received a questionnaire asking clinical and demographic information and validated measures for psychosocial outcomes. Comparisons were made with the general Dutch population.The response rate was 73% (116 men and 127 women); mean age was 49.9 years (SD 11.2 years). Mean age at epilepsy onset was 15 years (SD 11 years); mean duration was 24.4 years (SD 13.1 years). In total, 134 (55%; 72 men and 62 women) patients were seizure-free for the previous 5 years, and 81 patients still had seizures in the last year. One hundred twenty-seven patients were taking antiepileptic drugs, of which 51 were on monotherapy. Epilepsy patients have a positive health evaluation, comparable with the general Dutch population. Fewer epilepsy patients married or had children than the general Dutch population; more patients live at home with their parents or in foster homes or institutions (p0.001). Having epilepsy at school age has a significant negative effect on learning achievement (p0.01). Employment status is affected less, though more epilepsy patients are unfit to work than individuals from the general population (p0.05).Epilepsy has a marked negative impact on education and achievement in later life. Despite worse psychosocial outcomes than the Dutch population, patients with epilepsy cope well with their epilepsy, regardless of their handicaps.

progression). At baseline all patients underwent a geriatric screening using G8 and the Flemish version of the Triage Risk Screening Tool (TRST) followed by a uniform Comprehensive Geriatric Assessment (CGA) including social data (marital status, living situation, educational level), Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), presence of falls, Mobility-Tiredness Test (MOB-T), Mini Mental State Examination (MMSE), Geriatric Depression Scale (GDS-15), Mini Nutritional Assessment (MNA), ECOGPerformance Status (ECOG-PS), Charlson Comorbidity Index (CCI) and polypharmacy assessment. Functionality of patients was followed 2 to 3 months after treatment decision by repeating ADL, IADL and presence of falls. Worsening of ADL and IADL was calculated on total scores. Worsening of ADL was defined as an increase of ≥2 points at follow-up compared to baseline score. Worsening of IADL was defined as a decrease of ≥1 points at follow-up compared to baseline score. In the group of patients receiving chemotherapy, treatment related toxicity grades III–IV were recorded using the NCI CTCAE, version 4.0 for adverse events. Univariate analysis was performed, followed by multivariate logistic regressions to identify predictive markers. Results: A total of 937 patientswere included from10/2009 till 07/2011 with a median age of 76 years and 63.5% women. Breast cancer was the most common malignancy (40.4%) followed by colorectal cancer (20.6%), hematological malignancies (15.9%), prostate cancer (9%), lung cancer (7.8%) and ovarian cancer (6.3%). Data from 811 patients were available at follow-up. Worsening of ADL and IADL was observed in 17.2% and 38.9% respectively. During follow-up, 17.5% of the patients had at least 1 fall. ADL worsening was predicted in multivariate model by baseline IADL, MNA and Flemish version of the TRST (all pb0.05). Worsening of IADL was predicted by baseline ECOG-PS, Flemish version of the TRST, GDS-15, and chemotherapy (all pb0.05). Presence of falls during follow-up could be predicted (pb0.05) by presence of falls during the year before inclusion, baseline ADL and G8, living situation and disease setting (new diagnosis or progression) at baseline. In the chemotherapy group (n=411), hematologic and nonhematologic grade III–IV toxicities developed both in 16% of the patients. Hematological disease (versus solid tumors) was the only baseline variable in univariate analysis predictive for severe hematological toxicity (pb0.05). G8 for hematologic toxicities, and MNA and IADL for non-hematologic toxicities were borderline associated (pb0.1). Conclusion: Parameters from CGA before treatment in older cancer patients can identify at-risk patients for decline in functionality and development of falls. Severe chemotherapy toxicity is not well predicted by baseline CGA parameters, but this effect might be obscured by the utilization of many different chemotherapy regimens with different toxicity profiles.

Background — Experimental evidence indicates that interleukin-10 (IL-10) deficiency is associated with the development of cardiovascular and cerebrovascular disease. We analyzed the relation between low IL-10 production levels, history of stroke, and incident fatal stroke. Summary of Report — All 85-year-old inhabitants of Leiden, Netherlands (n=599) were visited at their place of residence (response rate, 87%). Production levels of the anti-inflammatory cytokine IL-10 were assessed in a whole blood assay whereby lipopolysaccharide was used as a stimulus. Plasma concentrations of C-reactive protein (CRP) were also used as a marker of inflammation. A history of stroke was obtained at baseline (prevalence, 10%). The number of fatal strokes was prospectively obtained for a median follow-up of 2.6 years (incidence, 1.82 per 100 person-years at risk). Subjects with a history of stroke had significantly lower median IL-10 production levels at baseline than subjects without stroke (558 versus 764 pg/mL; P P Conclusions — Our data support the hypothesis that subjects with low IL-10 production levels have an increased risk of stroke.

by hematological malignancies (22.3%) and breast cancer (12.3%). Shortcomings in assessments were present in 35.5% by MNA, 30.2% by GFI, 12.9% by IQCODE and 11.0% by MMSE. In multivariable adjusted models, the MNA proved to be predictive for toxicity (n = 145; 29.4%), odds ratio (OR) 1.99 (95% confidence interval [CI]: 1.25-3.16; p = 0.004), while MNA and GFI were independently predictive for mortality with Hazard Ratio's (HR) of 1.63 (95% CI: 1.28-2.07; p b 0.001) and 1.51 (95% CI: 1.19-1.92; p = 0.001), respectively. Individual items of MNA and GFI ‘psychological distress and/or acute disease in the past 3 months’ and ‘using N3 prescription drugs’ were independently predictive for toxicity with OR of 2.40 (95% CI: 1.52-3.80; p b 0.001) and 1.88 (95% CI: 1.23-2.87; p = 0.004), respectively. The individual items ‘declining food intake in past 3 months’, ‘using N3 prescription drugs’, and ‘dependent shopping’ were independently predictive for mortality. In comparison with patients without any positive item, patients with one positive item showed a HR for mortality of 1.58 (95% CI: 1.24-2.02; p b 0.001), with two positive items 2.32 (95% CI: 1.76-3.06; p b 0.001) and with all three positive items 5.58 (95% CI: 3.48-8.61; p b 0.001). Based on these three items, a Geriatric Prognostic Index (GPI) was constructed, that was associated with significantly different median survival rates. Conclusion: Two items of the MNA were independently predictive for toxicity of chemotherapy. The three-item GPI scale (i.e., ‘declining food intake in past 3 months’, ‘using N3 prescription drugs’, and ‘dependent shopping’) strongly predicted for mortality. Hazard ratios increased linearly with sum scores increasing from 0 to 3 points. The GPI can help to identify the elderly patient with an elevated risk for mortality. Disclosure of Interest: None declared.

It is possible that gender differences in cognitive function in aged persons can be explained by limited formal education, which is more common in women than in men. This study measured cognitive speed and memory in 85-year-old men and women in Leiden, The Netherlands, to confirm whether sex influences cognition and whether differences in formal education are relevant. A total of 599 individuals, 87% of Leiden residents 85 years of age, were visited at their residences and completed the Mini-Mental State Examination (MMSE). Cognitive speed and memory were estimated by neuropsychological tests when the MMSE score exceeded 18 points. Cognitive speed was measured using the abbreviated 40-item Stroop test of attention and the letter-digit coding test of processing speed. Memory function was estimated with the 12-word learning test of immediate and delayed recall. Significantly more women than men had had no schooling or primary school education only (70 vs. 53%). Nevertheless, women had better scores for both cognitive speed and memory than did men. After adjusting for educational differences and depressive symptoms, the odds ratio for women having higher cognitive speed was 1.7, and for better memory, 1.8. Women recalled more words than men on the immediate word learning test but had similar test scores on the delayed word learning measure. Those with more education had significantly higher test scores for cognitive speed. Men and women lacking depressive symptoms scored significantly better on all tests. The effects of educational level and depression on cognitive function were similar in women and men. Despite a lower educational level, women aged 85 years in this study exhibited better overall cognitive function than did men of the same age. Rather than education being the controlling factor, better cognitive function in women is likelier to represent some biological factor, such as atherosclerotic disease.

OBJECTIVE: To investigate the discrepancies between outcomes for competence (can do) and actual performance (do do) in activities of daily living (ADLs).DESIGN: Baseline measurements of a population-based follow-up study.SETTING: Leiden 85-Plus Study, the Netherlands.PARTICIPANTS: Five hundred and ninety-nine persons, age 85. The response rate was 86%.MEASUREMENTS: Face-to-face interviews. Measurements of competence and actual performance were based on the Groningen Activity Restriction Scale. Help received was assessed for several domains. Prevalence rates for disability were assessed according to the concepts of both competence and actual performance. Analysis was performed separately for basic activities of daily living (BADLs) and instrumental activities of daily living (IADLs).RESULTS: Seventy-seven percent of the oldest old were competent to perform all the BADLs and performed them regularly. Fifteen percent were not competent to perform certain BADLs independently but performed them regularly with help from others. The prevalence of disability defined as inability in one or more BADLs was 22% for women and 10% for men. The prevalence of disability defined as inactivity in one or more BADLs was 16% for women and 17% for men. Only 5% of the oldest old were competent to perform all IADLs and performed them regularly. In spite of being competent, 70% did not perform certain IADLs regularly. The prevalence of disability defined as inability in one or more IADLs was 64% for women and 55% for men. The prevalence of disability defined as inactivity in one or more IADLs was 92% for women and 98% for men.CONCLUSION: The structural discrepancies between the outcomes of competence and actual performance have important consequences when estimating disability in old people. Promoting actual performance in IADLs may reduce disability.

cognition (using FACT scales); and provide DNA samples for APOE genotyping. Z-scores are calculated for each test using the control means and standard deviation as the reference standard. Domain Zscores are calculated as the average of tests in the domain and ageadjusted. Age-adjusted Z-scores are compared by case-control status and groups stratified by cognitive reserve (based on median WRAT scores) and APOE e4 allele carrier status. Relative cognitive deficits are defined as having any domain Z-score ≤ 2 SD or two or more domain Z-scores ≤ -1.5 SD. Results: To date, 162 cases and 160 controls have been recruited and successfully matched. Among the cases, 64.3% are AJCC stage 1, 31.6% stage 2, and 3.5% stage 3. Almost all are estrogen receptor positive (90%) and 14.2% are HER2 positive; 32% have planned chemotherapy, and the remainder will have hormonal or no adjuvant treatment. Cases have greater baseline depression (p = .02) and report lower physical and emotional function than controls (p b .0001). At baseline, 15% of cases and controls demonstrate relative cognitive deficits, with higher rates among those with lower vs. higher cognitive reserve (21.2% vs. 8.2%, p = .001). Cases and controls with less cognitive reserve also have lower mean baseline scores on virtually all cognitive tests and domains than those with higher reserve. However, there were no baseline differences between cases and controls in any domain or in self-reported cognition. Overall, 94% have provided biosamples: 20.6% have an APOE e4 allele (cases 17.4%, controls 25.3%, p = NS), but there are no differences in baseline cognitive domain scores or deficits by APOE status. Conclusion: The TLC study has successfully recruited a well-matched sample of older breast cancer patients and controls. Preliminary analyses do not demonstrate significant pre-treatment differences between cancer patients and controls. Since the groups are comparable at baseline, we are well positioned to assess longitudinal changes in cognition as a function of adjuvant therapy. Understandingwhich older breast cancer patients are vulnerable to cognitive deficits after cancer treatment should contribute to shared decision making about benefits and risks systemic therapy in the growing older cancer population.

Track 1 Solid Tumours in the Elderly Breast cancer in eldery patients O1 Omission of Surgical Treatment and Survival of Elderly Breast Cancer Patients N.A. De Glas, J. Jonker, E. Bastiaannet, A.J.M. de Craen, C.J.H. van de Velde, S. Siesling, G.-J. Liefers, J.E.A. Portielje, M.E. Hamaker. Surgery, Leiden University Medical Center, Leiden, Geriatrics, Rijnland Hospital, Leiderdorp, Gerontology & Geriatrics, Leiden University Medical Center, Leiden, Research, Comprehensive Cancer Centre, Utrecht, Medical Oncology, Haga Hospital, The Hague, Geriatrics, Diaconessenhuis, Utrecht, Netherlands

Purpose: Statin therapy is widely used in the prevention and treatment of cardiovascular events and is in general associated with significant risk reductions. However, there is considerable variation in response to statin therapy both in terms of LDL cholesterol reduction and clinical outcomes. It has been hypothesized that genetic variation contributes importantly to this variable drug response. Therefore we investigated the interaction between genetic variation and the effect of pravastatin therapy on the incidence of cardiovascular events. Methods: A genome-wide association study was performed in the participants of the PROSPER/PHASE study (n=5244). We used a logistic regression model with an interaction term between pravastatin treatment and genetic variation adjusted for sex and age, and country to correct for the within-study population structure. SNPs with p-values < 1x10-4 were replicated in two pravastatin trials, CARE (n=711) and WOSCOPS (n=522). Results: We did not find genome-wide significant (p

OBJECTIVE: To study the trend in hospital admission rates for heart failure in the Netherlands from 1980 to 1993. DESIGN: All hospital admissions in the Netherlands with a principal discharge diagnosis of heart failure were analysed. In addition, individual records of heart failure patients from a subset of 7 hospitals were analysed to estimate the frequency and timing of readmissions. RESULTS: The total number of discharges for men increased from 7377 in 1980 to 13 022 in 1993, and for women from 7064 to 12 944. From 1980 through 1993 age adjusted discharge rates rose 48% for men and 40% for women. Age adjusted in-hospital mortality for heart failure decreased from 19% in 1980 to 15% in 1993. For all age groups in-hospital mortality for men was higher than for women. The mean length of hospital admissions in 1993 was 14.0 days for men and 16.4 days for women. A review of individual patient records from a 6.3% sample of all hospital admissions in the Netherlands indicated that within a 2 year period 18% of the heart failure patients were admitted more than once and 5% more than twice. CONCLUSIONS: For both men and women a pronounced increase in age adjusted discharge rates for heart failure was observed in the Netherlands from 1980 to 1993. Readmissions were a prominent feature among heart failure patients. Higher survival rates after acute myocardial infarction and the longer survival of patients with heart disease, including heart failure may have contributed to the observed increase. The importance of advances in diagnostic tools and of possible changes in admission policy remain uncertain.

As the prevalence of disease rises with age, the number of people with unidentified abnormalities is also likely to increase. We assessed the number of previously known and newly identified patients with anaemia, diabetes mellitus, thyroid dysfunction, atrial fibrillation, and hypertension in a population based sample of 85 year old people.

Background The incidence of breast carcinoma in situ has increased at a fast rate. Most clinical series have focused on cancer recurrence, rather than risk of death per se. Aim of this study was to assess the incidence and treatment in the Netherlands and estimate the excess mortality risk of carcinoma in situ. Methods From the Netherlands Cancer Registry, adult females with carcinoma in situ were selected. Treatment was assessed according to age. Relative mortality at 10 years of follow-up was calculated by dividing observed mortality over expected mortality and stratified for age and treatment. Expected mortality was calculated using the Dutch general population matched by age and year. Results Overall, 8879 patients were included in this study. For patients aged 50–64 and 65–74 an increase in breast conserving surgery was observed over time (p Conclusion The present population-based study of almost 9000 patients showed no excess mortality in surgically treated women over 50 years with carcinoma in situ. The estimated risk of death from breast cancer within 10 years following diagnosis was low with every (surgical) treatment option.

Introduction In the Netherlands, breast cancer patients are treated according to national guidelines. Despite comprising a large proportion, elderly breast cancer patients are underrepresented in clinical trials. Therefore it is questionable whether guideline recommendations can be extrapolated from a young to a heterogeneous elderly population. Aim of this study was to assess age specific guideline adherence. Methods Data were extracted from the Dutch Cancer Registration. Overall, 83 982 patients without distant metastases, diagnosed between 2002 and 2008 were included. Adherence was assessed for breast surgery (BS), type of surgery (TS), axillary surgery (AS) and radiotherapy (RT). Analyses were stratified by age ( Results Adherence decreased with increasing age (BS Conclusion These results emphasise the different approach and treatment of elderly breast cancer patients. Further age specific studies in breast cancer patients are necessary to investigate whether adherence to current guidelines results in optimal outcomes for elderly patients.