[Show abstract][Hide abstract] ABSTRACT: Background
Cardiovascular factors and low education are important risk factors of dementia. We provide contemporary estimates of the proportion of dementia cases that could be prevented if modifiable risk factors were eliminated, i.e., population attributable risk (PAR). Furthermore, we studied whether the PAR has changed across the last two decades.
We included 7,003 participants of the original cohort (starting in 1990) and 2,953 participants of the extended cohort (starting in 2000) of the Rotterdam Study. Both cohorts were followed for dementia until ten years after baseline. We calculated the PAR of overweight, hypertension, diabetes mellitus, cholesterol, smoking, and education. Additionally, we assessed the PAR of stroke, coronary heart disease, heart failure, and atrial fibrillation. We calculated the PAR for each risk factor separately and the combined PAR taking into account the interaction of risk factors.
During 57,996 person-years, 624 participants of the original cohort developed dementia, and during 26,177 person-years, 145 participants of the extended cohort developed dementia. The combined PAR in the original cohort was 0.23 (95 % CI, 0.05–0.62). The PAR in the extended cohort was slightly higher at 0.30 (95 % CI, 0.06–0.76). The combined PAR including cardiovascular diseases was 0.25 (95 % CI, 0.07–0.62) in the original cohort and 0.33 (95 % CI, 0.07–0.77) in the extended cohort.
A substantial part of dementia cases could be prevented if modifiable risk factors would be eliminated. Although prevention and treatment options of cardiovascular risk factors and diseases have improved, the preventive potential for dementia has not declined over the last two decades.
BMC Medicine 12/2015; 13(1). DOI:10.1186/s12916-015-0377-5 · 7.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
Mortality after stroke remains high for years, mostly because of cardiovascular causes. Given that cardiovascular pathology plays an important role in causing the initial stroke, such prestroke pathology might also influence the prognosis after stroke. Within the population-based Rotterdam Study, we examined the proportion of deaths after stroke that are attributable to pre-existent cardiovascular risk factors before stroke (the population attributable risk).
We examined 1237 patients with first-ever stroke and 4928 stroke-free participants (between 1990 and 2012), matched on age, sex, examination round, and stroke date (index date). Cardiovascular risk factors measured on ≈4 years before index date were used as determinants. Participants were continuously followed up for mortality (≈6 years) after the index date. We calculated separate and combined population attributable risk of hypertension, total cholesterol, high-density lipoprotein-cholesterol, body mass index, diabetes mellitus, smoking, transient ischemic attack, and atrial fibrillation.
Nine hundred and nineteen patients with stroke and 2654 stroke-free participants died. The combined population attributable risk in patients with stroke was 27% (95% confidence interval, 14%-45%) and in stroke-free participants was 19% (95% confidence interval, 12%-29%). Population attributable risks of diabetes mellitus, smoking, and atrial fibrillation were higher in patients with stroke than in the reference group because of a higher prevalence of risk factors. In addition, people with atrial fibrillation and stroke had a higher hazard ratio for death than those with only atrial fibrillation.
One quarter of deaths after stroke could theoretically be prevented with rigorous cardiovascular prevention and treatment, but this should preferably start before stroke occurrence. In addition, research into factors explaining the remaining deaths needs to be encouraged.
[Show abstract][Hide abstract] ABSTRACT: Objective:
Cerebral vasoreactivity (CVR) is a key factor in maintenance of continuous cerebral perfusion and a marker of (micro)vascular damage. We aimed to determine the longitudinal relation between CVR and the risk of dementia in the general population.
Approach and results:
We determined CVR in nondemented participants who underwent transcranial Doppler with induced hypercapnia from 1997 to 1999, as part of the ongoing population-based Rotterdam Study. We used a Cox model to determine the risk of dementia in relation to CVR, adjusted for age, sex, cardiovascular risk factors, and carotid intima-media thickness. We furthermore determined decline on a cognitive test battery in relation to CVR, using linear mixed models. Among 1629 participants (mean±SD age 70.6±6.2 years, 46.2% female) with a mean follow-up of 11.5 years, 209 were diagnosed with dementia, of whom 171 had Alzheimer disease. Higher CVR at baseline was associated with lower risk of dementia (adjusted hazard ratio, 95% confidence interval, per SD increase: 0.87, 0.75-1.00) and Alzheimer disease (adjusted hazard ratio, 0.84; 0.71-0.99). This association was more profound in APOEε4 carriers than in noncarriers (adjusted hazard ratio for all dementia: 0.77, 0.60-0.98 versus 0.89, 0.73-1.07). Performance on cognitive tests at baseline was better with higher CVR (g-factor: P=0.02), but during 3 cognitive assessments during 11 years of follow-up, higher CVR at baseline was associated with less decline in test scores on the Stroop reading and interference tasks in APOEε4 carriers only (P=0.01 and 0.02, respectively).
Impaired CVR is associated with an increased risk of dementia in the general population.
[Show abstract][Hide abstract] ABSTRACT: Background:
-There is increasing evidence that retinal microvascular diameters are associated with cardio- and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size.
Methods and results:
-This study extends previous genome-wide association study results using 24,000+ multi-ethnic participants from 7 discovery and 5,000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single nucleotide polymorphisms (SNPs) and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent (CRVE) and the central retinal arteriole equivalent (CRAE). We report 4 new loci associated with CRVE, one of which is also associated with CRAE. The 4 SNPs are rs7926971 in TEAD1 (p=3.1×10(-11), minor allele frequency (MAF)=0.43), rs201259422 in TSPAN10 (p=4.4×10(-9), MAF=0.27), rs5442 in GNB3 (p=7.0×10(-10), MAF=0.05) and rs1800407 in OCA2 (p=3.4×10(-8), MAF=0.05). The latter SNP, rs1800407, was also associated with CRAE (p=6.5×10(-12)). Results from the gene-based burden tests were null. In phenotype look-ups, SNP rs201255422 was associated with both systolic (p=0.001) and diastolic blood pressure (p=8.3×10(-04)).
-Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.
[Show abstract][Hide abstract] ABSTRACT: Background and objectives:
The independent link between arterial stiffness and CKD remains unknown. We investigated the association of indicators of arterial stiffness with decline in kidney function.
Design, setting, participants, & measurements:
We studied 3666 participants (mean age =65 years old; 58% women) from the Rotterdam Study. Pulse pressure (PP), carotid stiffness, and pulse wave velocity (PWV) were measured. We created genetic risk scores for PP and PWV. Annual declines in kidney function and incident CKD were assessed using eGFR. To put our findings in context of the literature, we performed a meta-analysis of the available population-based studies.
After a median (interquartile range) follow-up time of 11 (10.7-11.3) years, 601 participants with incident CKD were recognized. In the model adjusted for age, sex, mean arterial pressure, heart rate, and baseline GFR, each SD higher PP was associated with 0.15-ml/min per 1.73 m(2) steeper annual eGFR decline (95% confidence interval [95% CI], 0.10 to 0.20) and 11% higher risk of incident CKD (95% CI, 1.05 to 1.18). Each SD greater carotid stiffness was associated with 0.08-ml/min per 1.73 m(2) steeper annual eGFR decline (95% CI, 0.04 to 0.13) and 13% higher risk of incident CKD (95% CI, 1.05 to 1.22). Each SD higher PWV was associated with 7% higher risk of incident CKD (95% CI, 1.00 to 1.14). Incorporating our findings in a meta-analysis, each SD higher PP and PWV were associated with 16% (95% CI, 1.12 to 1.21) and 8% (95% CI, 1.03 to 1.14) higher risks of incident CKD. Each SD higher PP genetic risk score was associated with 0.06-ml/min per 1.73 m(2) steeper annual eGFR decline (95% CI, 0.01 to 0.10) and 8% higher risk of incident CKD (95% CI, 1.03 to 1.14). There was no association between PWV genetic risk score and kidney function decline.
Higher indices of arterial stiffness are associated with steeper decline in kidney function. This suggests that vascular stiffness could be considered as a target for delaying decline in kidney function.
Clinical Journal of the American Society of Nephrology 11/2015; DOI:10.2215/CJN.03000315 · 4.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.
Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).
Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.
PLoS ONE 10/2015; 10(10):e0140496. DOI:10.1371/journal.pone.0140496 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ADAMTS13 (A Disintegrin and Metalloprotease with TromboSpondin motif repeats 13) has antithrombotic properties because it cleaves Von Willebrand factor (VWF) in smaller, less active multimers. The aim of our study was to investigate prospectively the association between ADAMTS13 activity and ischemic stroke. We included 5941 individuals ≥ 55 years without a history of stroke or Transient Ischemic Attack (TIA) of the Rotterdam Study, a population-based cohort study. ADAMTS13 activity was measured at inclusion with the FRETS-VWF73 assay and VWF antigen (VWF:Ag) levels by ELISA. We assessed the association between ADAMTS13 activity, VWF:Ag levels and ischemic stroke by Cox proportional hazard analysis. The added value of ADAMTS13 activity above the traditional risk factors for ischemic stroke risk prediction was examined by the c-statistic and the net reclassification improvement index (NRI). All individuals were followed for incident stroke or TIA. Over a median follow-up time of 10.7 years (56403 total person years), 461 participants experienced a stroke, 306 of which ischemic. After adjustment for cardiovascular risk factors, individuals with ADAMTS13 activity in the lowest quartile had a higher risk of ischemic stroke (absolute risk 7.3%) than those in the reference highest quartile (absolute risk 3.8%; HR 1.65, 95% CI 1.16-2.32). Adding ADAMTS13 to the model in prediction of ischemic stroke, increased the c-statistic by 0.013 (P=0.003) and provided 0.058 (95% CI -0.002-0.119) NRI. Low ADAMTS13 activity is associated with the risk of ischemic stroke and improves the accuracy of risk predictions for ischemic stroke beyond traditional risk factors.
[Show abstract][Hide abstract] ABSTRACT: Background:
Brazil has gone through fast demographic, epidemiologic and nutritional transitions and, despite recent improvements in wealth distribution, continues to present a high level of social and economic inequality. The ELSA-Brasil, a cohort study, aimed at investigating cardiovascular diseases and diabetes, offers a great opportunity to assess cognitive decline in this aging population through time-sequential analyses drawn from the same battery of tests over time. The purpose of this study is to analyze the influence of sex, age and education on cognitive tests performance of the participants at baseline.
Analyses pertain to 14,594 participants with aged 35 to 74 years, who were functionally independent and had no history of stroke or use of neuroleptics, anticonvulsants, cholinesterase inhibitors or antiparkinsonian agents. Mean age was 52.0 ± 9.0 years and 54.2 % of participants were women. Cognitive tests included the word memory tests (retention, recall and recognition), verbal fluency tests (VFT, animals and letter F) and Trail Making Test B. Multivariable linear regression analysis was used to determine the influence of sociodemographic characteristics on the distribution of the final score of each test.
Women had significant and slightly higher scores than men in all memory tests and VFT, but took more time to perform Trail B. Reduced performance in all tests was seen with an increase age and, more importantly, with decrease level of education. The word list and VFT scores decreased at about one word for every 10 years of age; whereas higher-educated participants scored four words more on the word list test, and six or seven more correct words on VFT, when compared to lower-educated participants. Additionally, the oldest and less educated participants showed significant lower response rates in all tests.
The higher influence of education than age in this Brazilian population reinforce the need for caution in analyzing and diagnosing cognitive impairments based on traditional cognitive tests and the importance of searching for education-free cognitive tests, especially in low and middle-income countries.
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.
A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.
Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.
[Show abstract][Hide abstract] ABSTRACT: Understanding of causal pathways in epidemiology involves the concepts of direct and indirect effects. Recently, causal mediation analysis has been formalized to quantify these direct and indirect effects in the presence of exposure-mediator interaction and even allows for four-way decomposition of the total effect: controlled direct effect, reference interaction, mediated interaction, pure indirect effect. Whereas the other three effects can be intuitively conceptualized, mediated interaction is often considered a nuisance in statistical analysis. In this paper, we focus on mediated interaction and contrast it against pure mediation. We also propose a clinical and biological interpretation of mediated interaction using three hypothetical examples. With these examples we aim to make researchers aware that mediated interaction can actually provide important clinical and biological information.
European Journal of Epidemiology 10/2015; DOI:10.1007/s10654-015-0087-5 · 5.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Structural brain magnetic resonance imaging (MRI) traits share part of their genetic variance with cognitive traits. Here, we use genetic association results from large meta-analytic studies of genome-wide association (GWA) for brain infarcts (BI), white matter hyperintensities, intracranial, hippocampal, and total brain volumes to estimate polygenic scores for these traits in three Scottish samples: Generation Scotland: Scottish Family Health Study (GS:SFHS), and the Lothian Birth Cohorts of 1936 (LBC1936) and 1921 (LBC1921). These five brain MRI trait polygenic scores were then used to: (1) predict corresponding MRI traits in the LBC1936 (numbers ranged 573 to 630 across traits), and (2) predict cognitive traits in all three cohorts (in 8,115–8,250 persons). In the LBC1936, all MRI phenotypic traits were correlated with at least one cognitive measure, and polygenic prediction of MRI traits was observed for intracranial volume. Meta-analysis of the correlations between MRI polygenic scores and cognitive traits revealed a significant negative correlation (maximal
= 0.08) between the HV polygenic score and measures of global cognitive ability collected in childhood and in old age in the Lothian Birth Cohorts. The lack of association to a related general cognitive measure when including the GS:SFHS points to either type 1 error or the importance of using prediction samples that closely match the demographics of the GWA samples from which prediction is based. Ideally, these analyses should be repeated in larger samples with data on both MRI and cognition, and using MRI GWA results from even larger meta-analysis studies.
Twin Research and Human Genetics 10/2015; DOI:10.1017/thg.2015.71 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Virchow-Robin spaces (VRS), or perivascular spaces, are compartments of interstitial fluid enclosing cerebral blood vessels and are potential imaging markers of various underlying brain pathologies. Despite a growing interest in the study of enlarged VRS, the heterogeneity in rating and quantification methods combined with small sample sizes have so far hampered advancement in the field.
[Show abstract][Hide abstract] ABSTRACT: Aims:
To investigate the association of diabetes mellitus and impaired fasting glucose with gait in the general middle-aged and elderly population.
We performed a cross-sectional study on 3019 participants from the population-based Rotterdam Study (aged >45years, 54% women). The presence of diabetes mellitus and impaired fasting glucose was evaluated by measuring serum glucose levels and by documenting anti-diabetic treatment. Participants underwent gait analysis using an electronic walkway. Thirty gait variables were summarized into five independent gait domains for normal walking (Rhythm, Variability, Phases, Pace and Base of Support), one for turning (Turning) and one for walking heel to toe (Tandem), which were averaged into Global Gait. Linear regression analyses were performed to determine the association of diabetes, impaired fasting glucose and continuous glucose levels within the normal range with gait.
Diabetes mellitus was associated with worse Global Gait (Z-score difference -0.19, 95% confidence interval (CI) -0.30; -0.07), worse Pace (-0.20, 95% CI -0.30; -0.10) and worse Tandem (-0.21, 95% CI -0.33; -0.09), after adjusting for age, sex, height and weight. The association with Tandem remained significant after additional adjustment for cardiovascular risk factors. Impaired fasting glucose and continuous glucose levels within the normal range were not associated with any of the gait domains.
In our population-based study diabetes mellitus was associated with worse Global Gait, which was mostly reflected in Pace and Tandem. These associations were partly driven by other cardiovascular risk factors, emphasizing the importance of optimal control of cardiovascular risk factor profiles in patients with diabetes.
Journal of diabetes and its complications 10/2015; DOI:10.1016/j.jdiacomp.2015.10.006 · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rationale:
Worldwide, chronic obstructive pulmonary disease (COPD) and stroke are leading causes of death. Increasing evidence suggests an association between both diseases, either caused by an increased atherosclerosis risk in patients with COPD, or as a consequence of shared risk factors between stroke and COPD.
To examine the associations between COPD and subtypes of stroke in the general population and to explore the role of cardiovascular risk factors and exacerbations on these associations.
Within the prospective population-based Rotterdam Study, we followed 13115 participants without history of stroke for occurrence of stroke. Follow-up started in 1990-2008 and ended in 2012. COPD was related to stroke using a time-dependent Cox proportional hazard model.
Measurements and main results:
COPD was diagnosed in 1566 participants. During 126347 person-years, 1250 participants suffered a stroke, of which 701 were ischemic and 107 hemorrhagic. Adjusted for age, age2, and sex, COPD was significantly associated with all stroke (HR 1.20; 95%CI 1.00-1.43), ischemic stroke (HR 1.27; 1.02-1.59), and hemorrhagic stroke (HR 1.70; 1.01-2.84). Adjusting for cardiovascular risk factors gave similar effect sizes. In contrast, additional adjusting for smoking attenuated the effect sizes: HR 1.09 (0.91-1.31) for all stroke, HR 1.13 (0.91-1.42) for ischemic stroke, and HR 1.53 (0.91-2.59) for hemorrhagic stroke. Following an acute severe exacerbation subjects with COPD had a 6.66-fold (2.42-18.20) increased risk of stroke.
Our cohort study demonstrated a higher risk of both ischemic and hemorrhagic stroke in subjects with COPD, and revealed the importance of smoking as a shared risk factor.
American Journal of Respiratory and Critical Care Medicine 09/2015; DOI:10.1164/rccm.201505-0962OC · 13.00 Impact Factor