Netherlands Consortium for Healthy Ageing

Leiden, Netherlands

Netherlands Consortium for Healthy Ageing

Leiden, Netherlands
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Jukema J.W.,Leiden University | Jukema J.W.,Durrer Center for Cardiogenetic Research | Jukema J.W.,Interuniversity Cardiology | Cannon C.P.,Brigham and Women's Hospital | And 7 more authors.
Journal of the American College of Cardiology | Year: 2012

The debate whether statins, 3-hydroxymethyl-3-methylglutaryl coenzyme A reductase inhibitors, are safe to use has been raging since their introduction in 1987. Statins are generally well tolerated and are believed to have minimal adverse effects. However, individual, specific rare adverse events have been reported, such as elevations of liver enzymes, muscle aches, and very rarely, rhabdomyolysis. Discontinuation and/or reduction in the dose of the statin usually leads to resolution of these side effects. Recently, however, debate has focused on the possible negative long-term effects of statin treatment on cognitive decline, the incidence of cancer, and the development of diabetes mellitus. Recently, the U.S. Food and Drug Administration has expanded the warning for statins with a statement that statin use may lead to cognitive impairment. In this review, we discuss all levels of evidence, from case reports to large randomized controlled clinical trials, for the possible adverse effects of statins on cognitive decline, cancer, and diabetes. After careful consideration of all discussed scientific evidence, we conclude that there is no increased risk of cognitive decline or cancer with statin use. However, statin use is related to a small increased risk of type 2 diabetes mellitus. In view of the overwhelming benefit of statins in the reduction of cardiovascular events, we believe the small absolute risk for development of diabetes is outweighed by the cardiovascular benefits in patients for whom statin therapy is recommended. We, therefore, suggest that clinical practice for statin therapy should not be changed on the basis of the most recent Food and Drug Administration informational warnings. © 2012 American College of Cardiology Foundation.


Meulenbelt I.,LUMC | Meulenbelt I.,Netherlands Consortium for Healthy Ageing | Kraus V.B.,Duke University | Sandell L.J.,Washington University in St. Louis | Loughlin J.,Newcastle University
Osteoarthritis and Cartilage | Year: 2011

On November fourth and fifth 2010 a group of more than 100 international investigators gathered in Atlanta for the second Osteoarthritis (OA) Biomarkers Global Initiative workshop titled "Genetics and Genomics: New Targets in OA" The first workshop took place in April 2009 and focused on in vitro (soluble) biomarkers whilst the third and final workshop will take place in 2012 and will focus on imaging biomarkers. The OA Research Society International (OARSI) has organized the workshops. In addition to OARSI, the National Institute of Arthritis, Musculoskeletal and Skin Diseases, the Arthritis Foundation, Amgen, Genzyme, the American Orthopaedic Society for Sports Medicine and Pfizer sponsored the second meeting. It was clear from this meeting that experiments in the genetics, epigenetics and genomics of OA, are yielding valuable insights into the etiology of this heterogeneous disease but that much still needs to be learnt. Combining genetic insights with conventional biomarkers and imaging modalities may provide scientists with the enhanced tools to understand this complex disease. With those tools in hand, clinicians and industry can develop protocols to ultimately improve patient care. © 2011 Osteoarthritis Research Society International.


Zhang Y.,Leiden University | Lameijer E.,Leiden University | t hoen P.A.C.,Leiden University | Ning Z.,Wellcome Trust Genome Campus | And 3 more authors.
Bioinformatics | Year: 2012

Motivation: RNA-seq is a powerful technology for the study of transcriptome profiles that uses deep-sequencing technologies. Moreover, it may be used for cellular phenotyping and help establishing the etiology of diseases characterized by abnormal splicing patterns. In RNA-Seq, the exact nature of splicing events is buried in the reads that span exon-exon boundaries. The accurate and efficient mapping of these reads to the reference genome is a major challenge. Results: We developed PASSion, a pattern growth algorithm-based pipeline for splice site detection in paired-end RNA-Seq reads. Comparing the performance of PASSion to three existing RNA-Seq analysis pipelines, TopHat, MapSplice and HMMSplicer, revealed that PASSion is competitive with these packages. Moreover, the performance of PASSion is not affected by read length and coverage. It performs better than the other three approaches when detecting junctions in highly abundant transcripts. PASSion has the ability to detect junctions that do not have known splicing motifs, which cannot be found by the other tools. Of the two public RNA-Seq datasets, PASSion predicted ∼ 137 000 and 173 000 splicing events, of which on average 82 are known junctions annotated in the Ensembl transcript database and 18% are novel. In addition, our package can discover differential and shared splicing patterns among multiple samples. © The Author(s) 2012. Published by Oxford University Press.


Talens R.P.,Leiden University | Christensen K.,University of Southern Denmark | Putter H.,Leiden University | Willemsen G.,VU University Amsterdam | And 8 more authors.
Aging Cell | Year: 2012

The accumulation of epigenetic changes was proposed to contribute to the age-related increase in the risk of most common diseases. In this study on 230 monozygotic twin pairs (MZ pairs), aged 18-89years, we investigated the occurrence of epigenetic changes over the adult lifespan. Using mass spectrometry, we investigated variation in global (LINE1) DNA methylation and in DNA methylation at INS, KCNQ1OT1, IGF2, GNASAS, ABCA1, LEP, and CRH, candidate loci for common diseases. Except for KCNQ1OT1, interindividual variation in locus-specific DNA methylation was larger in old individuals than in young individuals, ranging from 1.2-fold larger at ABCA1 (P=0.010) to 1.6-fold larger at INS (P=3.7×10 -07). Similarly, there was more within-MZ-pair discordance in old as compared with young MZ pairs, except for GNASAS, ranging from an 8% increase in discordance each decade at CRH (P=8.9×10 -06) to a 16% increase each decade at LEP (P=2.0×10 -08). Still, old MZ pairs with strikingly similar DNA methylation were also observed at these loci. After 10-year follow-up in elderly twins, the variation in DNA methylation showed a similar pattern of change as observed cross-sectionally. The age-related increase in methylation variation was generally attributable to unique environmental factors, except for CRH, for which familial factors may play a more important role. In conclusion, sustained epigenetic differences arise from early adulthood to old age and contribute to an increasing discordance of MZ twins during aging. © 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.


Rostamian S.,Leiden University | Mahinrad S.,Leiden University | Stijnen T.,Leiden University | Sabayan B.,Leiden University | And 2 more authors.
Stroke | Year: 2014

BACKGROUND AND PURPOSE-: Cognitive impairment is linked to vascular risk factors and brain vascular pathologies. Several studies have tested whether subjects with cognitive impairment have higher risk for stroke. The aim of this study was to systematically review available evidence on the association between cognitive impairment and risk of stroke to obtain precise effect estimates of the association and to identify which cognitive domains associate most with incident stroke. METHODS-: PubMed, EMBASE, and Web of Science were searched from January 1, 1980, to October 1, 2013, without language restriction. Only prospective cohort studies were included. From each study, data on the association between cognitive impairment and stroke estimated with hazard ratios or relative risks with 95% confidence interval (CI) were extracted. For each study, risk of stroke per SD lower performance in various cognitive tests was calculated. RESULTS-: Twelve studies were included, comprising 82 899 participants of whom 3043 had an incident stroke. The pooled relative risk per SD lower global cognitive performance was 1.19 (95% CI, 1.12-1.27). Each SD lower score in executive function or attention was associated with 1.14-fold (95% CI, 1.06-1.24) higher risk of stroke. Lower scores in memory were associated with 1.07-fold (95% CI, 1.02-1.12) higher risk of stroke, and lower scores in language were associated with 1.08-fold (95% CI, 1.02-1.16) higher risk of stroke. CONCLUSIONS-: Cognitive impairment is associated with higher risk of stroke. The associations were not significantly different for executive function, memory, and language. © 2014 American Heart Association, Inc.


Sabayan B.,Leiden University | Gussekloo J.,Leiden University | De Ruijter W.,Leiden University | Westendorp R.G.J.,Leiden University | And 3 more authors.
Stroke | Year: 2013

BACKGROUND AND PURPOSE - : Predictive value of the conventional risk factors for stroke attenuates with age. Cognitive impairment has been implicated as a potential predictor for stroke in older subjects. Our aim was to compare the Framingham stroke risk score with cognitive functioning for predicting first-time stroke in a cohort of the oldest old individuals. METHODS - : We included 480 subjects, aged 85 years, from the Leiden 85-plus Study. At baseline, data on the Framingham stroke risk score and the Mini-Mental State Examination (MMSE) score were obtained. Risk of first-time stroke was estimated in tertiles of Framingham and MMSE scores. Receiver operating characteristic curves with corresponding areas under the curves (AUCs) and 95% confidence intervals (CIs) were constructed for both Framingham and MMSE scores. RESULTS - : Subjects with high Framingham risk score compared with those with low Framingham risk score did not have a higher risk of stroke (hazard ratio, 0.77; 95% CI, 0.39-1.54). Conversely, subjects with high levels of cognitive impairment compared with those with low levels of cognitive impairment had a higher risk of stroke (hazard ratio, 2.85; 95% CI, 1.48-5.51). In contrast to the Framingham risk score (AUCs, 0.48; 95% CI, 0.40-0.56), MMSE score had discriminative power to predict stroke (AUCs, 0.65; 95% CI, 0.57-0.72). There was a significant difference between AUCs for Framingham risk score and MMSE score (P=0.006). CONCLUSIONS - : In the oldest old, the Framingham stroke risk score is not predictive for first-time stroke. In contrast, cognitive impairment, as assessed by MMSE score, identifies subjects at higher risk for stroke. © 2013 American Heart Association, Inc.


Sabayan B.,Leiden University | Van Vliet P.,Leiden University | De Ruijter W.,Leiden University | Gussekloo J.,Leiden University | And 4 more authors.
Stroke | Year: 2013

Background and Purpose-: Epidemiological studies have shown mixed findings on the association between hypertension and stroke in the oldest old. Heterogeneity of the populations under study may underlie variation in outcomes. We examined whether the level of physical and cognitive function moderates the association between blood pressure and stroke. Methods-: We included 513 subjects aged 85 years old from the population-based Leiden 85-plus Study. Systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure were measured at baseline. Activities of daily living and Mini-Mental State Examination were assessed to estimate level of physical and cognitive function, respectively. Five-year risk of stroke was estimated with Cox regression analysis. Results-: In the entire cohort, there were no associations between various measures of blood pressure and risk of stroke except for the inverse relation between pulse pressure and stroke risk (hazard ratio [HR], 0.80 [95% confidence interval [CI], 0.66-0.98]). Among subjects with impaired physical functioning, higher systolic blood pressure (HR, 0.74 [95% CI, 0.59-0.92]), mean arterial pressure (HR: 0.68 [95% CI, 0.47-0.97]), and pulse pressure (HR, 0.71 [95% CI, 0.55-0.93]) were associated with reduced risk of stroke. Likewise, among subjects with impaired cognitive functioning, higher systolic blood pressure was associated with reduced risk of stroke (HR, 0.80 [95% CI, 0.65-0.98]). In subjects with unimpaired cognitive functioning, higher diastolic blood pressure (HR: 1.98 [95% CI, 1.21-3.22]) and mean arterial pressure (HR, 1.70 [95% CI, 1.08-2.68]) were associated with higher risk of stroke. Conclusions-: Our findings suggest that impaired physical and cognitive function moderates the association between blood pressure and stroke. © 2012 American Heart Association, Inc.


Talens R.P.,Leiden University | Boomsma D.I.,VU University Amsterdam | Tobi E.W.,Leiden University | Kremer D.,Leiden University | And 7 more authors.
FASEB Journal | Year: 2010

The prospect of finding epigenetic risk factors for complex diseases would be greatly enhanced if DNA from existing biobanks, which is generally extracted from whole blood, could be used to perform epigenetic association studies. We characterized features of DNA methylation at 16 candidate loci, 8 of which were imprinted, in DNA samples from the Netherlands Twin Register biobank. Except for unmethylated or fully methylated sites, CpG methylation varied considerably in a sample of 30 unrelated individuals. This variation remained after accounting for the cellular heterogeneity of blood. Methylation of CpG sites was correlated within loci and, for 4 imprinted loci, across chromosomes. In 34 additional individuals, we investigated the DNA methylation of 8 representative loci in 2 longitudinal blood and 2 longitudinal buccal cell samples (follow-up 11-20 and 2-8 yr, respectively). Five of 8 loci were stable over time (ρ>0.75) in both tissues, indicating that prospective epigenetic studies may be possible. For 4 loci, the DNA methylation in blood (mesoderm) correlated with that in the buccal cells (ectoderm) (ρ>0.75). Our data suggest that epigenetic studies on complex diseases may be feasible for a proportion of genomic loci provided that they are carefully designed. © FASEB.


Verhoeven V.J.M.,Erasmus Medical Center | Wong K.T.,Erasmus Medical Center | Buitendijk G.H.S.,Erasmus Medical Center | Hofman A.,Erasmus Medical Center | And 3 more authors.
Ophthalmology | Year: 2015

Objective: To study the frequency and causes of visual impairment in relation to refractive error. Design: Population-based cohort study. Participants: A total of 6597 participants from Rotterdam Study I (baseline and 4 follow-up examinations) and 2579 participants from Rotterdam Study II (baseline and 2 follow-up examinations), all 55 years or older, were included. Methods: Participants underwent an extensive ophthalmic examination, including best-corrected visual acuity and objective refraction, fundus photography, visual field perimetry, and optical coherence tomography imaging of macula and optic disc. We calculated cumulative risks and odds ratios of visual impairment for various refractive error categories and determined causes by using all screening information as well as medical records. Main Outcome Measures: Unilateral and bilateral low vision (World Health Organization [WHO] criteria, VA <0.3 and VA ≥0.05; United States (US) criteria, VA <0.5 and VA ≥0.1) and blindness (WHO criteria, VA <0.05; US criteria, VA<0.1). Results: Cumulative risks of visual impairment ranged from virtually 0 in all refractive error categories at 55 years of age to 9.5% (standard error, 0.01) for emmetropia and 15.3% (standard error, 0.06) for high hyperopia to 33.7% (standard error, 0.08) for high myopia at 85 years of age. The major causes of visual impairment in highly hyperopic persons were age-related macular degeneration (AMD), cataract, and combined causes (each 25%); in highly myopic persons, the major cause was myopic macular degeneration (38.9%). The major causes of visual impairment for the other refractive error categories were AMD and cataract. Compared with those with emmetropia, those with high myopia had a significantly increased lifetime risk of visual impairment; those with -6 diopters (D) or less and -10 D or more had an odds ratio (OR) risk of 3.4 (95% confidence interval [CI], 1.4-8.2) of visual impairment; those with less than -10 D had an OR of 22.0 (95% CI, 9.2-52.6). Conclusions: Of all refractive errors, highmyopia has themost severe visual consequences. Irreversible macular pathologic features are the most common cause of visual impairment in this group. © 2015 by the American Academy of Ophthalmology.


Portegies M.L.P.,Erasmus Medical Center | De Bruijn R.F.A.G.,Erasmus Medical Center | De Bruijn R.F.A.G.,Netherlands Consortium for Healthy Ageing | Hofman A.,Erasmus Medical Center | And 3 more authors.
Stroke | Year: 2014

Background and Purpose-Accumulating vascular pathology in cerebral arteries leads to impaired cerebral vasomotor reactivity. In turn, impaired cerebral vasomotor reactivity is a risk factor for stroke in clinical populations. It remains unclear whether impaired cerebral vasomotor reactivity also reflects more systemic vascular damage. We investigated whether cerebral vasomotor reactivity is associated with the risk of mortality, focusing particularly on cardiovascular mortality independent from stroke. Methods-Between 1997 and 1999, 1695 participants from the Rotterdam Study underwent cerebral vasomotor reactivity measurements using transcranial Doppler. Follow-up was complete until January 1, 2011. We assessed the associations between cerebral vasomotor reactivity and mortality using Cox proportional hazards models, adjusting for age, sex, and blood pressure changes and subsequently for cardiovascular risk factors. We additionally censored for incident stroke. Results-During 17 004 person-years, 557 participants died, of whom 181 due to a cardiovascular cause. In the fully adjusted model, the hazard ratio per SD decrease in vasomotor reactivity was 1.10 (95% confidence interval [CI], 1.01-1.19) for all-cause mortality, 1.09 (95% CI, 0.94-1.26) for cardiovascular mortality, and 1.10 (95% CI, 0.99-1.21) for noncardiovascular mortality. These associations remained unchanged after censoring for incident stroke. Conclusions-We found that lower cerebral vasomotor reactivity is associated with an increased risk of death. Incident stroke does not affect this association, suggesting that a lower cerebral vasomotor reactivity reflects a generally impaired vascular system. © 2013 American Heart Association, Inc.

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