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Biomedical subjects

Rudi G J Westendorp

Publications and source records attributed to Rudi G J Westendorp.

At least 19 recordsLinked to original sources
PubMed2006

Mental performance in old age dependent on cortisol and genetic variance in the mineralocorticoid and glucocorticoid receptors.

Depression and cognitive decline have been associated with changes in circulating cortisol concentrations. Cortisol exerts its functions through mineralocorticoid (MR) and glucocorticoid (GR) receptors. However, data on the influence of variations in the MR and GR genes on depressive symptoms and cognitive functioning in older adults are scarce. Therefore, we explored the impact of MR-215G/C, MR-I180V, GR-ER22/23EK, GR-N363S, and GR-BclI polymorphisms on these end points in the population-based Leiden 85-plus Study. This prospective study includes 563 participants aged 85 years and older, with a mean follow-up of 4.2 years. In this study, high morning cortisol levels (per 1 SD cortisol) associated with impairments in global cognitive functioning (p=0.002) at baseline (age 85). These impairments were mainly attributable to lower attention (p=0.057) and slower processing speed (p=0.014). Similar effects were also observed during follow-up (age 85-90), where participants with higher cortisol levels (per 1 SD cortisol) had impaired global cognitive functioning (p=0.003), as well as impairments in attention (p=0.034) and processing speed (p=0.013). Changes in depressive symptoms were observed for the MR-I180V single-nucleotide polymorphism (SNP), where during follow-up the prevalence of depressive symptoms was higher in the 180V-allele carriers (p=0.049) compared to noncarriers. Dependent on these polymorphisms, no differences in overall and in specific domains of cognitive functioning were observed. In conclusion, the MR-I180V SNP has a specific effect on depressive symptoms, independent from cognitive functioning, and other polymorphisms in the MR and GR genes. In contrast, these genetic variants in the MR and GR genes do not influence cognitive functioning in old age.

Aged, 80 and over↗
PubMed2006

Use of calcium antagonists and cognitive decline in old age. The Leiden 85-plus study.

The systolic hypertension in Europe (Syst-Eur) trial has been the only trial that has suggested a protective effect of antihypertensive treatment on incidence of dementia. It is unclear whether this protective effect has been caused by the blood pressure lowering effect of the calcium antagonist nitrendipine or by the calcium channel inhibition. From the Leiden 85-plus study, a population-based cohort study of 599 subjects aged 85 years, we selected 204 subjects who used at least one antihypertensive at baseline. Associations between use of antihypertensives at baseline and change in cognitive functioning over time were assessed with linear mixed models. After adjusting for gender, education, and use of other antihypertensives, only use of calcium antagonists was associated with a significant decelerated annual cognitive decline during follow-up (0.40 MMSE-points per year, p=0.001). Use of other antihypertensives was not associated with a decelerated annual cognitive decline (all p values >0.3). Our data support the interpretation that the reported prevention of dementia by calcium antagonists is exerted through its calcium channel inhibition rather than its blood pressure lowering properties.

Aged, 80 and over↗
PubMed2006

Prospective study of the effect of blood pressure on renal function in old age: the Leiden 85-Plus Study.

High BP is associated with decline of renal function. Whether this is true for very old people largely is unknown. Therefore, this study assessed the effect of BP on creatinine clearance over time in very old participants. A total of 550 inhabitants (34% men) of Leiden, The Netherlands, were enrolled in a population-based study at their 85th birthday and followed until death or age 90. BP was measured twice at baseline and at age 90 yr. Creatinine clearance was estimated annually (Cockcroft-Gault formula). The mean creatinine clearance at baseline was 45.4 ml/min (SD 11.5). Systolic BP was not associated with changes in creatinine clearance during follow-up. Those with diastolic BP (DBP) <70 mmHg had an accelerated decline of creatinine clearance (1.63 ml/min per yr) compared with those with DBP between 70 and 79 mmHg (1.21 ml/min per yr; P = 0.01), 80 to 89 mmHg (1.26 ml/min per yr; P = 0.03), and >89 mmHg (1.38 ml/min per yr; P = 0.32). Participants with a decline in systolic BP during follow-up had an accelerated decline of creatinine clearance compared with those with stable BP (1.54 [SE 0.09] versus 0.98 ml/min per yr [SE 0.09]; P < 0.001). Similar results were found for a decline in DBP (1.54 [SE 0.10] versus 1.06 ml/min per yr [SE 0.08]; P < 0.001). In the oldest individual, high BP is not associated with renal function. In contrast, low DBP is associated with an accelerated decline of renal function. The clinical implications of these findings have to be studied.

Aged, 80 and over↗
PubMed2006

Trade-off mediated effects on the genetics of human survival caused by increasingly benign living conditions.

It is sometimes suggested that modern life, with its planned fertility and medically assisted compensation for genetic disadvantage, has greatly reduced the power of natural selection to produce significant further human evolution. However, this overlooks the very recent and dramatic changes that have occurred in the patterns of human mortality, driven by the development of increasingly benign living conditions. Where the genetics of survival are significantly influenced by life history trade-offs, as is now thought to be the case for ageing and longevity, a change in the environment can shift the optimal balance that was established through natural selection under previous conditions. We examine this possibility in the context of the dramatic recent change in the mortality pressure exerted by infectious disease using a model of a hypothetical immunogenetic trade-off that weighs survival against fecundity. Our results predict that such a change might have a significant effect on population genetics over relatively short-timescales, and they may also resolve the paradox of genes that impair fertility in present-day populations by showing how such genes might be a legacy from a powerful trade-off that has acted until very recently.

Biological Evolution↗
PubMed2006

ApoE plasma levels and risk of cardiovascular mortality in old age.

BACKGROUND: The epsilon2, epsilon3, and epsilon4 alleles of the apolipoprotein E gene (APOE) encode three isoforms, apoE2, E3, and E4, respectively. The apoE isoforms circulate in different plasma concentrations, but plasma concentrations of the same isoform also differ between individuals. Whereas the isoforms have been associated with cardiovascular disease, the relation between plasma apoE levels and cardiovascular disease is unknown. METHODS AND FINDINGS: We assessed APOE genotypes, plasma levels of apoE, cardiovascular risk factors, and mortality in a population-based sample of 546 individuals aged 85 y who participated in the Leiden 85-plus Study and were prospectively followed for specific causes of death for 5 y. Participants in the highest tertile of apoE levels suffered a twofold-increased risk of cardiovascular mortality (hazard ratio compared to lowest tertile, 2.08; 95% confidence interval [CI], 1.30 to 3.33). Among the 324 participants with the epsilon3epsilon3 genotype, the hazard from cardiovascular disease was threefold increased (highest versus lowest tertile 3.01; 95% CI 1.60 to 5.66), with similar estimates for men and women. Other causes of death were not increased significantly. Plasma levels of apoE in epsilon3epsilon3 participants were positively correlated with total cholesterol (p < 0.001), low-density lipoprotein cholesterol (p < 0.001) and triglycerides (p < 0.001) and negatively with high-density lipoprotein cholesterol levels (p = 0.010). Adjustment for plasma lipids did not change the hazard ratios, whereas interaction was absent. The risk associated with high levels of apoE, however, was strongest in participants from the lowest tertile of C-reactive protein (CRP) levels and absent in those from the highest tertile (p(interaction) < 0.001). Among participants from the lowest tertile of CRP levels, those with a high apoE levels had a significantly steeper increase in CRP than those with low apoE levels (p = 0.020). Similar cardiovascular mortality risks as in epsilon3epsilon3 participants were found in epsilon2 and epsilon4 carriers. CONCLUSIONS: In old age, high plasma apoE levels precede an increase of circulating CRP and strongly associates with cardiovascular mortality, independent of APOE genotype and plasma lipids.

Age Factors↗
PubMed2006

Genetic variants in the glucocorticoid receptor gene (NR3C1) and cardiovascular disease risk. The Leiden 85-plus Study.

Recently, the ER22/23EK, N363S and BclI polymorphisms in the glucocorticoid receptor (GR) gene have been linked to altered cortisol sensitivity and to cortisol-associated disorders. The aim of this study was to investigate the effect of these genetic variants in the GR gene on cardiovascular disease and mortality in elderly persons aged 85 years and over. In the population-based Leiden 85-plus Study, 552 participants were genotyped for the ER22/23EK, N363S and BclI polymorphisms, and the effects of the polymorphisms on metabolic profile, body composition, and on the prevalence of cardiovascular pathologies at baseline, were assessed. Allcause and cardiovascular disease mortality risks dependent on the SNPs were calculated after a 4.2-year follow-up. The analyses of metabolic profile revealed that carriers of the ER22/23EK polymorphism have higher HbA1C levels (P<0.001) and carriers of the N363S SNP have higher LDL cholesterol (P<0.001) and triglyceride concentrations (P=0.03), compared to the non-carriers. The only significant association between genotype and body composition analyses was for height and the ER22/23EK polymorphism. Men carrying the ER22/23EK polymorphism were taller (P=0.02) compared to non-carriers. No associations with cardiovascular pathologies, allcause and cardiovascular mortality were observed for any of the polymorphisms. We conclude that, in spite the effect of the ER22/23EK and N363S SNPs on metabolism, these polymorphisms together with the BclI SNP, do not affect the risks of cardiovascular disease and survival at old age.

Age Distribution↗
PubMed2006

Randomised controlled trial of unsolicited occupational therapy in community-dwelling elderly people: the LOTIS trial.

OBJECTIVE: The objective of this trial, the Leiden 85-Plus Occupational Therapy Intervention Study (LOTIS), was to assess whether unsolicited occupational therapy, as compared to no therapy, can decelerate the increase in disability in high-risk elderly people. DESIGN: This was a randomised controlled trial with 2-y follow-up. SETTING: The study took place in the municipality of Leiden in the Netherlands. PARTICIPANTS: The participants were 402 community-dwelling 85-y-old people, with a Mini-Mental State Examination score of >18 points at baseline. INTERVENTIONS: Participants in the intervention group were visited by an occupational therapist who provided training and education about assistive devices that were already present and who gave recommendations and information about procedures, possibilities, and costs of assistive devices and community-based services. Control participants were not visited by an occupational therapist. OUTCOME MEASURES: The primary outcome measure was the score achieved on the Groningen Activity Restriction Scale. Secondary outcome measures included self-evaluations of well-being and feelings of loneliness. RESULTS: THE PARTICIPANTS WERE EVENLY DIVIDED BETWEEN THE TWO GROUPS: 202 participants were allocated to the intervention group and 200 participants to the control group. Of the 202 participants randomised to occupational therapy, 55 participants declined the proposed intervention. An occupational therapist indicated that of the remaining 147 participants, 66 (45%) needed an occupational therapy intervention. A total of 44 new assistive devices and five community-based services were implemented. During follow-up there was a progressive increase in disability in the intervention group (mean annual increase, 2.0 points; SE 0.2; p < 0.001) and control group (mean annual increase, 2.1 points; SE 0.2; p < 0.001). The increase in disability was not significantly different between study groups (0.08 points; 95% CI, -1.1-1.2; p = 0.75). There was also no difference between study groups for any of the secondary outcome measures. CONCLUSION: Unsolicited occupational therapy in high-risk elderly participants does not decelerate the increase in disability over time.

Journal Article↗
PubMed2006

Markers of autonomic tone on a standard ECG are predictive of mortality in old age.

BACKGROUND: To investigate markers of autonomic tone on a standard electrocardiogram in relation to mortality in old age. METHODS: A total of 599 inhabitants of Leiden, the Netherlands, were enrolled in a population-based follow-up study at their 85th birthday. Electrocardiograms (ECGs) were taken on entry and annually thereafter. ECGs were analysed automatically to determine four markers of autonomic tone, i.e. heart rate, the occurrence of ventricular extrasystoles and two time domain measures of heart rate variability. All participants were followed up for mortality. RESULTS: Participants with a heart rate in the highest quartile had a 1.8-fold increased total mortality risk (95% confidence interval (CI) 1.0-3.4), but not an increased cardiovascular mortality risk. The occurrence of at least one ventricular extrasystole was related with a 2.3-fold increased total mortality risk (95% CI 1.3-3.9) and a 3.6-fold increased cardiovascular mortality (95% CI 1.6-8.2). In stratified analyses, the prognostic effect was confined to males. Both measures of heart rate variability were not related to mortality. CONCLUSION: High heart rate and the occurrence of a ventricular extrasystole, both markers of sympathetic dominance, were predictive of mortality in old age. Two short-term measures of heart rate variability as measured on a standard 10-s ECG were not related to mortality, and hence may not reflect autonomic tone in old age.

Age Factors↗
PubMed2006

Impact of genetic variations in the WRN gene on age related pathologies and mortality.

Mutations in the WRN gene lead to the Werner syndrome (WS), which resembles premature aging. Here, we hypothesize that genetic variations in the WRN gene may also influence aging-trajectories in the population at large. To test this hypothesis, we assessed the impact of the i1-C/T, L1074F and C1367R polymorphisms in the WRN gene on the occurrence of cardiovascular pathologies, on cognitive performance and on the risks of all-cause, cardiovascular and cancer mortalities in the population-based Leiden 85-plus Study. This prospective follow-up study includes 1,245 participants aged 85 years and older, with a total follow-up of 5,164 person-years. At baseline the risks of myocardial infarction, myocardial ischemia, intermittent claudication, arterial surgery and stroke dependent on the i1-C/T, L1074F and C1367R polymorphisms, did not vary between the different genotypes. Also no differences in cognitive functioning were observed, except for attention, where carriers of the 1367R allele performed worse compared to the 1367C homozygotes (94.2 (4.35) versus 84.8 (1.84), p=0.04). Mortality risks, calculated separately for all SNPs, were similar between the different genotype carriers of the i1-C/T, L1074F and C1367R polymorphisms, showing no evidence of altered survival. In conclusion, the i1-C/T, L1074F and C1367R polymorphisms in the WRN gene do not influence the aging-trajectories and survival in the population at large.

Adult↗
PubMed2006

Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study.

We conducted a sib pair study in very old subjects for the purpose of mapping longevity loci. In the present analysis, we explore whether our recruitment strategy has resulted in a population enriched for a heritable component for exceptional longevity. Our study includes families with at least two long-living siblings (men aged 89 years or above; women aged 91 years or above). Data were collected on date of birth and, if applicable, date of death of parents, brothers and sisters, offspring, and spouses of the long-living participants. Standardised mortality ratios (SMRs) compared with the general Dutch population, were calculated. The SMR for all siblings of the long-living participants was 0.66 (95% CI 0.60-0.73). A similar survival benefit was also observed in the parents (SMR=0.76, 95% CI 0.66-0.87) and in the offspring of the long-living subjects (SMR=0.65, 95% CI 0.51-0.80). The SMR of the spouses of the long-living subjects was 0.95 (95% CI 0.82-1.12). The familial clustering of extended survival is unlikely to be caused by ascertainment bias, because in all analyses the long-living participants were excluded. Moreover, it is also unlikely to be caused by environmental factors, because the spouses of the long-living participants had a mortality risk comparable with the general Dutch population, whereas they share the same environment. We conclude that our sample is genetically enriched for extreme survival.

Aged, 80 and over↗
PubMed2006

What is healthy aging in the 21st century?

In the coming years, human aging will be one of the biggest challenges faced by industrialized countries. The average life expectancy is continuously increasing and we may be faced with spending more years in poor health. Because aging is a relatively modern phenomenon, we lack knowledge for a proper understanding of this process. Current biological thinking emphasizes that organisms are encoded for early survival and reproduction, humans not excluded. Aging is not programmed nor is it inevitable. Life span is the result of the interactions between genes and the environment in which we live. In the original habitat, genes encoding early survival and reproduction were optimized in an everlasting attempt to increase fitness and prevent the species from extinction. Aging is best explained as a cost of optimizing fitness because investments in body maintenance and repair cannot be maximized. The environment also determines how a gene influencing life span is expressed over a lifetime. When the conditions in which we live significantly improve, mortality decreases, evolutionary pressures for early survival and reproduction relax, and further resources can be invested in body maintenance and repair, which increases both average life expectancy and maximum life span. Increasing our understanding of the aging process and applying available interventions will help to protect and preserve healthy aging.

Aged↗
PubMed2006

Chromosome 4q25, microsomal transfer protein gene, and human longevity: novel data and a meta-analysis of association studies.

Recently, chromosome 4q25 was linked to exceptional human longevity, and a haplotype of the positional candidate microsomal transfer protein (MTP) gene was associated to the phenotype in U.S. Caucasians. We investigated whether linkage to 4q25 could be detected in 164 nonagenarian sibships of the Leiden Longevity Study. Additionally, we compared the MTP -493G/T and Q95H allele and haplotype frequencies in the Leiden Longevity Study (379 nonagenarians, 525 of their offspring, and 251 partners of their offspring) and in the Leiden 85-Plus Study (655 octogenarians and 244 young controls). The latter study population was followed for at least 7 years, providing the opportunity to perform also prospective analyses using the longitudinal data. We found neither evidence for linkage at 4q25 nor association of the MTP locus with longevity in nonagenarian individuals. Meta-analyses of all previous studies implied that the association in U.S. Caucasians may have its source in admixture of the U.S. control population rather than in the genetic effect of the locus on exceptional longevity.

Adult↗
PubMed2006

In a population-based prospective study, no association between high blood pressure and mortality after age 85 years.

OBJECTIVE: To study the impact of a history of hypertension and current blood pressure on mortality in the oldest old. DESIGN: An observational population-based cohort study. SETTING: Community city of Leiden, The Netherlands. PARTICIPANTS: Five hundred and ninety-nine inhabitants of the birth-cohort 1912-1914 were enrolled on their 85th birthday. There were no selection criteria related to health or demographic characteristics. INTERVENTIONS: The mean follow-up was 4.2 years. Medical histories were obtained from general practitioners. Medication histories were obtained from the participant's pharmacist. Blood pressure was measured twice at baseline. MAIN OUTCOME MEASURES: All cause and cardiovascular mortality. RESULTS: Five hundred and seventy-one participants were included, 39.2% had a history of hypertension. During follow-up 290 participants died, 119 due to cardiovascular causes. Compared to participants without a history of hypertension, those with a history of hypertension had increased mortality from cardiovascular causes [relative risk (RR) 1.60, confidence interval (CI) 1.06-2.40] but equal mortality from all causes (RR 1.19, CI 0.91-1.55). High blood pressure at baseline (age 85) was not a risk factor for mortality. Baseline blood pressure values below 140/70 mmHg (n = 48) were associated with excess mortality, predominantly in participants with a history of hypertension. CONCLUSION: In the oldest old, high blood pressure is not a risk factor for mortality, irrespective of a history of hypertension. Blood pressure values below 140/70 mmHg are associated with excess mortality.

Aged↗
PubMed2006

Natural history of depression in the oldest old: population-based prospective study.

BACKGROUND: Despite its negative consequences, little is known about the natural history of depression in the oldest old. AIMS: To study the incidence, course and predictors of depression in the general population of the oldest old. METHOD: The Leiden 85-plus Study is a prospective population-based study of 500 people from their 85th to their 89th birthdays. Depressive symptoms were annually assessed with the 15-item Geriatric Depression Scale, using a cut-off of 4 points. RESULTS: During a mean follow-up of 3.9 years, the annual risk for the emergence of depression was 6.8%. Poor daily functioning and institutionalisation predicted depression. Among the 77 participants with depression at baseline (prevalence 15%) the annual remission rate was ony 14%. In more than half of the participants with a remission of depression, we observed a relapse of depression during follow-up. No predictors of remission could be identified. CONCLUSIONS: Among the oldest old, depression is frequent and highly persistent. More active case-finding and treatment would be potentially rewarding.

Aged, 80 and over↗
PubMed2006

Lipoprotein particle profiles mark familial and sporadic human longevity.

BACKGROUND: Genetic and biochemical studies have indicated an important role for lipid metabolism in human longevity. Ashkenazi Jewish centenarians and their offspring have large low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles as compared with control individuals. This profile also coincided with a lower prevalence of disease. Here, we investigate whether this observation can be confirmed for familial longevity in an outbred European population and whether it can be extended to sporadic longevity in the general population. METHODS AND FINDINGS: NMR-measured lipoprotein profiles were analyzed in 165 families from the Leiden Longevity Study, consisting of 340 long-lived siblings (females >91 y, males >89 y), 511 of their offspring, and 243 partners of the offspring. Offspring had larger (21.3 versus 21.1 nm; p = 0.020) and fewer (1,470 versus 1,561 nmol/l; p = 0.011) LDL particles than their same-aged partners. This effect was even more prominent in the long-lived siblings (p < 10(-3)) and could be pinpointed to a reduction specifically in the concentration of small LDL particles. No differences were observed for HDL particle phenotypes. The mean LDL particle sizes in 259 90-y-old singletons from a population-based study were similar to those in the long-lived siblings and thus significantly larger than in partners of the offspring, suggesting that the relevance of this phenotype extends beyond familial longevity. A low concentration of small LDL particles was associated with better overall health among both long-lived siblings (p = 0.003) and 90-y-old singletons (p = 0.007). CONCLUSIONS: Our study indicates that LDL particle profiles mark both familial and sporadic human longevity already in middle age.

Aged↗