Rotterdam Study Research Articles

Dietary nitrate intake in relation to the risk of dementia and imaging markers of vascular brain health: a population-based study

BackgroundNitric oxide is a free radical that can be produced from dietary nitrate and positively affects cardiovascular health. With cardiovascular health playing an important role in the etiology of dementia, we hypothesized a link between dietary nitrate intake and the risk of dementia. ObjectivesThis study aimed to find the association of total, vegetable, and nonvegetable dietary nitrate intake with the risk of dementia and imaging markers of vascular brain health, such as total brain volume, global cerebral perfusion, white matter hyperintensity volume, microbleeds, and lacunar infarcts. MethodsBetween 1990 and 2009, dietary intake was assessed using food-frequency questionnaires in 9543 dementia-free participants (mean age, 64 y; 58% female) from the prospective population-based Rotterdam Study. Participants were followed up for incidence dementia until January 2020. We used Cox models to determine the association between dietary nitrate intake and incident dementia. Using linear mixed models and logistic regression models, we assessed the association of dietary nitrate intake with changes in imaging markers across 3 consecutive examination rounds (mean interval between images 4.6 y). ResultsParticipants median dietary nitrate consumption was 85 mg/d (interquartile range, 55 mg/d), derived on average for 81% from vegetable sources. During a mean follow-up of 14.5 y, 1472 participants developed dementia. A higher intake of total and vegetable dietary nitrate was associated with a lower risk of dementia per 50-mg/d increase [hazard ratio (HR): 0.92; 95% confidence interval (CI): 0.87, 0.98; and HR: 0.92; 95% CI: 0.86, 0.97, respectively] but not with changes in neuroimaging markers. No association between nonvegetable dietary nitrate intake and the risk of dementia (HR: 1.15; 95% CI: 0.64, 2.07) or changes in neuroimaging markers were observed. ConclusionsA higher dietary nitrate intake from vegetable sources was associated with a lower risk of dementia. We found no evidence that this association was driven by vascular brain health.

P29-047-23 Healthy and Unhealthy Plant-Based Diets and the Risk of Cardiovascular Diseases: Results From the Rotterdam Study and an Updated Meta-Analysis

P29-047-23 Healthy and Unhealthy Plant-Based Diets and the Risk of Cardiovascular Diseases: Results From the Rotterdam Study and an Updated Meta-Analysis

Risk of recurrent stroke in Rotterdam between 1990 and 2020: a population-based cohort study.

After an initial stroke, current clinical practice is aimed at preventing recurrent stroke. Thus far, population-based estimates on the risk of recurrent stroke remain scarce. Here we describe the risk of recurrent stroke in a population-based cohort study. We included Rotterdam Study participants who developed a first-ever incident stroke during follow-up between 1990 until 2020. During further follow-up, these participants were monitored for the occurrence of a recurrent stroke. We determined stroke subtypes based on clinical and imaging information. We calculated ten-year overall and sex-specific cumulative incidences of first recurrent stroke. To reflect changing secondary preventive strategies employed in recent decades, we then calculated the risk of recurrent stroke within ten-year epochs based on first-ever stroke date (1990-2000, 2000-2010 and 2010-2020). In total, 1701 participants (mean age 80.3 years, 59.8% women) from 14,163 community-living individuals suffered a first stroke between 1990 and 2020. Of these strokes, 1111 (65.3%) were ischaemic, 141 (8.3%) haemorrhagic, and 449 (26.4%) unspecified. During 6585.3 person-years of follow-up, 331 (19.5%) suffered a recurrent stroke, of which 178 (53.8%) were ischaemic, 34 (10.3%) haemorrhagic and 119 (36.0%) unspecified. Median time between first and recurrent stroke was 1.8 (interquartile range 0.5-4.6) years. Overall ten-year recurrence risk following first-ever stroke was 18.0% (95% CI 16.2%-19.8%), 19.3% (16.3%-22.3%) in men and 17.1% (14.8%-19.4%) in women. Recurrent stroke risk declined over time, with a ten-year risk of 21.4% (17.9%-24.9%) between 1990 and 2000 and 11.0% (8.3%-13.8%) between 2010 and2020. In this population-based study, almost one in five people with first-ever stroke suffered a recurrence within ten years of the initial stroke. Furthermore, recurrence risk declined between 2010 and2020. Netherlands Organization for Health Research and Development, EU's Horizon 2020 research programme and the Erasmus Medical Centre MRACE grant.

Cross-Sectional Validation of a Novel Computed Tomography-Based Carotid Mean Calcium Density Measurement.

Background The purpose of this study was to validate a technique for measuring mean calcium density and to determine associations of cardiovascular risk factors with carotid calcium density. Methods and Results We performed a cross-sectional study in a random sample of 100 stroke-free participants from the population-based Rotterdam Study. The mean calcium density of the combined left and right carotid bifurcations was quantified with a threshold of 130 Hounsfield Units (HU) using a novel density technique. To validate the methodology, carotid calcium volumes acquired using the technique in the current study were compared with measurements computed using dedicated clinical software (semiautomatic technique based on a threshold of ≥130 HU). Next, we investigated the associations of participant demographics, total calcium volume, and known cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, obesity, and smoking status) with the newly derived mean carotid calcium density measurement using linear regression analyses. Calcium volumes obtained with the 2 methods showed a high agreement (intraclass correlation coefficient=0.99, P<0.001), underlining the validity of the density technique. The total calcium volume was statistically significantly associated with the mean calcium density (cardiovascular risk factors adjusted model (B: 0.48 [95% CI, 0.30-0.66], P<0.001). We also found an association between hypercholesterolemia and mean calcium density (0.46 [0.09-0.83], P=0.017). No other significant associations were found between participant demographics or cardiovascular risk factors and mean carotid calcium density. Conclusions We demonstrated the feasibility of a carotid calcium density measurement technique. The data warrant a subsequent longitudinal study to determine the association between carotid calcium density and the risk of cerebrovascular events.

Predicting amyloid-beta pathology in the general population.

Reliable models to predict amyloid beta (Aβ) positivity in the general aging population are lacking but could become cost-efficient tools to identify individuals at risk of developing Alzheimer's disease. We developed Aβ prediction models in the clinical Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study (n=4,119) including a broad range of easily ascertainable predictors (demographics, cognition and daily functioning, health and lifestyle factors). Importantly, we determined the generalizability of our models in the population-based Rotterdam Study (n=500). The best performing model in the A4 Study (area under the curve [AUC]=0.73 [0.69-0.76]), including age, apolipoprotein E (APOE) ε4 genotype, family history of dementia, and subjective and objective measures of cognition, walking duration and sleep behavior, was validated in the independent Rotterdam Study with higher accuracy (AUC=0.85 [0.81-0.89]). Yet, the improvement relative to a model including only age and APOE ε4 was marginal. Aβ prediction models including inexpensive and non-invasive measures were successfully applied to a general population-derived sample more representative of typical older non-demented adults.

Electrocardiographic parameters and the risk of new-onset atrial fibrillation in the general population: the Rotterdam Study.

We aimed to assess the (shape of the) association and sex differences in the link between electrocardiographic parameters and new-onset atrial fibrillation (AF). A total of 12 212 participants free of AF at baseline from the population-based Rotterdam Study were included. Up to five repeated measurements of electrocardiographic parameters including PR, QRS, QT, QT corrected for heart rate (QTc), JT, RR interval, and heart rate were assessed at baseline and follow-up examinations. Cox proportional hazards- and joint models, adjusted for cardiovascular risk factors, were used to determine the (shape of the) association between baseline and longitudinal electrocardiographic parameters with new-onset AF. Additionally, we evaluated potential sex differences. During a median follow-up of 9.3 years, 1282 incident AF cases occurred among 12 212 participants (mean age 64.9 years, 58.2% women). Penalized cubic splines revealed that associations between baseline electrocardiographic measures and risk of new-onset AF were generally U- and N-shaped. Sex differences in terms of the shape of the various associations were most apparent for baseline PR, QT, QTc, RR interval, and heart rate in relation to new-onset AF. Longitudinal measures of higher PR interval [fully adjusted hazard ratio (HR), 95% confidence interval (CI), 1.43, 1.02-2.04, P = 0.0393] and higher QTc interval (fully adjusted HR, 95% CI, 5.23, 2.18-12.45, P = 0.0002) were significantly associated with new-onset AF, in particular in men. Associations of baseline electrocardiographic measures and risk of new-onset AF were mostly U- and N-shaped. Longitudinal electrocardiographic measures of PR and QTc interval were significantly associated with new-onset AF, in particular among men.

Air pollution and the risk of dementia: The rotterdam study

AbstractBackgroundAir pollution has been suggested to increase the risk of dementia, by triggering neuro‐inflammation, oxidative stress, and cerebrovascular damage. However, studies on the association between exposure to air pollution and the risk of dementia yielded inconsistent results. We therefore determined exposure to air pollution in association with the risk of dementia and cognitive decline in the population‐based Rotterdam Study.MethodBetween 2009 and 2010, we determined air pollutant levels at participants residential addresses using land use regression models. Determined air pollutant levels included particulate matter with an aerodynamic diameter of less than 10 µm (PM10) and 2.5 µm (PM2.5), a proxy of elemental carbon (PM2.5 absorbance), nitrogen oxide (NOx), and nitrogen dioxide (NO2). As the individual air pollutant levels were highly correlated with each other (r = 0.71‐0.98), we obtained the first unrotated component of a principal component analyses (PCA) for all air pollutants. We followed participants up for dementia until 2018 and determined cognitive performance during two subsequent examination rounds. Using Cox proportional hazard models and linear mixed models, we determined the association of exposure to air pollution with the risk of dementia and cognitive decline.ResultOf the 7511 non‐demented participants at baseline (median age 68 years, 58.6% women), 545 developed dementia during a median follow‐up of 7 years. Mean ± standard deviation (SD) levels per µg/m3 were 26.1 ± 1.0 for PM10, 16.8 ± 0.4 for PM2.5, 1.5 ± 0.1 for PM2.5 absorbance, 46.1 ± 12.2 for NOx, and 32.6 ± 3.4 for NO2. The individual air pollutant levels were not significantly associated with the risk of dementia, neither was the first unrotated component of a PCA for all air pollutants (hazard ratio [95% confidence interval] per SD increase: 1.04 [0.95‐1.15], Figure 1). Air pollutant levels were also not associated with decline in cognitive function.ConclusionExposure to air pollution was not statistically significantly associated with the risk of dementia or cognitive decline. Yet, observed effect estimates were in the hypothesized direction and variability in pollutant levels may have been to limited to identify meaningful associations.

Adiposity and the risk of dementia: A population‐based study

AbstractBackgroundA higher body mass during mid‐life is a well‐established risk factor for dementia, while a higher body mass during late‐life has been linked to a decreased dementia risk. Yet, body mass may be an inaccurate measure of adiposity, especially in elderly. We therefore differentiated between body mass, fat mass, fat free mass, android fat mass and gynoid fat mass and examined the association between these measures and the risk of dementia. We also determined trajectories of body composition before the diagnosis of dementia.MethodIn the population‐based Rotterdam Study, body composition was measured using dual X‐ray absorptiometry every 4‐5 years between 2002‐2016. Incident dementia was recorded until 2020. We assessed the association between the first body composition measure and the risk of dementia using Cox models, adjusted for sex, age, height, education, smoking, alcohol intake, physical activity, depressive symptoms, and APOE ε4 status. Trajectories of body composition for patients before dementia diagnoses were constructed using linear mixed models and for dementia‐free participants, matched on birth year and sex. All analyses were done for men and women separately.ResultOf the 3,408 men (mean age 66.4 years) and 4,563 women (mean age 66.5 years) with at least one body composition measure available, 293 men and 526 women developed dementia during a mean follow‐up of 10.3 years. Higher body mass, fat mass, android fat mass and gynoid fat mass, but not fat free mass, tended to associate with a decreased risk of dementia in both men and women (Figure 1). After excluding the first five years of follow‐up only the association of gynoid fat mass in women remained statistically significant (hazard ratio [95% confidence interval]: 0.85 [0.75‐0.97]). No major differences in trajectories of body composition were observed, although a slight trend of a decrease in total, android and gynoid fat mass was observed in women up to 2 years before diagnosis.ConclusionA higher body mass, fat mass, android fat mass and gynoid fat mass were associated with a decreased risk of dementia. These results may be explained by reverse causality or competing risks, although a protective effect of adiposity cannot be excluded.

Levels of insulin pathway proteins in persons with concomitant Alzheimer’s disease dementia and type 2 diabetes mellitus

AbstractBackgroundAlzheimer’s disease (AD) is a gradual and progressive neurodegenerative disease characterized by predominant cortical atrophy in the medial temporal lobe. Since the results of the Rotterdam study in 1992, it has been known that type 2 diabetes mellitus (T2DM) increases the risk of dementia. Persons with T2DM have structural brain changes and cognitive impairment, with a high risk of developing AD. These data suggest that insulin may play a key role in brain activity and memory formation. The objective of this study was to verify if there are alterations in the levels of proteins of the insulin pathway in cognitively healthy individuals, with AD, with T2DM and with the concomitant presence of AD and T2DM.MethodThe study was approved by the UFSCar’s ethics committee (CAAE: 31634720.9.0000.5504) and recruited participants aged 60 years or older. The AD diagnosis was obtained using the criteria of the National Institute Aging Alzheimer’s Association (NIA/AA). T2DM was defined as self‐reported use of oral antidiabetic drugs. Specific inclusion and exclusion criteria and cognitive assessment of the MMSE and CDR were applied to all participants. Plasma was collected by venepuncture and protein levels of ISNR, IRS1, Akt1, PI3KCD, MAPK1, MAPK8, PTP1B and IDE (Life‐Span Biosciences) were analysed using ELISA (Enzyme Enzyme‐Linked Immunosorbent Assay).ResultSeveral proteins of the insulin pathway were found to be significantly different among patients with AD, T2DM and AD+T2DM, compared with healthy controls (figure 1), reinforcing the strong correlation between T2DM and AD. Main alterations were found for INSR, IRS1, Akt1, PIK3, MAPK, PTP1b and IDE among healthy participants and those with AD+T2DM.ConclusionThe peripheral alterations found in the levels of insulin pathway proteins confirm the possible relationship between T2DM and AD and reinforce the importance of the insulin signalling pathways, as they can play a fundamental role in AD. The clinical impact of this study is related to a new approach that could be used in the treatment of this type of dementia, also observing the metabolic and inflammatory states of the patients, in addition to contributing to a better understanding of the biology of the disease itself.

Advanced Glycation End Products (AGEs) in Diet and Skin in Relation to Stool Microbiota: The Rotterdam Study.

Advanced glycation end products (AGEs) are involved in age-related diseases, but the interaction of gut microbiota with dietary AGEs (dAGEs) and tissue AGEs in the population is unknown. Our objective was to investigate the association of dietary and tissue AGEs with gut microbiota in the population-based Rotterdam Study, using skin AGEs as a marker for tissue accumulation and stool microbiota as a surrogate for gut microbiota. Dietary intake of three AGEs (dAGEs), namely carboxymethyl-lysine (CML), N-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MGH1), and carboxyethyl-lysine (CEL), was quantified at baseline from food frequency questionnaires. Following up after a median of 5.7 years, skin AGEs were measured using skin autofluorescence (SAF), and stool microbiota samples were sequenced (16S rRNA) to measure microbial composition (including alpha-diversity, beta-dissimilarity, and taxonomic abundances) as well as predict microbial metabolic pathways. Associations of both dAGEs and SAF with microbial measures were investigated using multiple linear regression models in 1052 and 718 participants, respectively. dAGEs and SAF were not associated with either the alpha-diversity or beta-dissimilarity of the stool microbiota. After multiple-testing correction, dAGEs were not associated with any of the 188 genera tested, but were nominally inversely associated with the abundance of Barnesiella, Colidextribacter, Oscillospiraceae UCG-005, and Terrisporobacter, in addition to being positively associated with Coprococcus, Dorea, and Blautia. A higher abundance of Lactobacillus was associated with a higher SAF, along with several nominally significantly associated genera. dAGEs and SAF were nominally associated with several microbial pathways, but none were statistically significant after multiple-testing correction. Our findings did not solidify a link between habitual dAGEs, skin AGEs, and overall stool microbiota composition. Nominally significant associations with several genera and functional pathways suggested a potential interaction between gut microbiota and AGE metabolism, but validation is required. Future studies are warranted, to investigate whether gut microbiota modifies the potential impact of dAGEs on health.

Multi-task banded regression model: A novel individual survival analysis model for breast cancer

PurposeTo reveal the hazard probability of individual breast cancer patients, a multi-task banded regression model is proposed for individual survival analysis of breast cancer. MethodsA banded verification matrix is designed to construct the response transform function of the proposed multi-task banded regression model, which can solve the repeated switching of survival rate. A martingale process is introduced to construct different nonlinear regressions for different survival subintervals. The concordance index (C-index) is used to compare the proposed model with Cox proportional hazards (CoxPH) models and previous multi-task regression models. ResultsTwo commonly-used breast cancer datasets are employed to validate the proposed model. Specifically, the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) includes 1981 breast cancer patients, of which 57.7% died of breast cancer. The Rotterdam & German Breast Cancer Study Group (GBSG) includes 1546 patients with lymph node-positive breast cancer in a randomized clinical trial, of which 44.4% died. Experimental results indicate that the proposed model is superior to some existing models for overall and individual survival analysis of breast cancer, with the C-index of 0.6786 for the GBSG and 0.6701 for the METABRIC. ConclusionThe superiority of the proposed model can be contributed to three novel ideas. One is that a banded verification matrix can band the response of the survival process. Second, the martingale process can construct different nonlinear regressions for different survival subintervals. Third, the novel loss can adapt the model to making the multi-task regression similar to the real survival process.

NT-proBNP and changes in cognition and global brain structure: the Rotterdam Study.

To investigate the association between NT-proBNP and changes in cognition and global brain structure. In the Rotterdam Study, baseline NT-proBNP was assessed at baseline from 1997 to 2008. Between 1997-2016, participants without dementia or stroke at baseline (n= 9,566) had repeated cognitive tests (every 3-6 years) for global cognitive function, executive cognitive function, fine manual dexterity, and memory. Magnetic resonance imaging of the brain was performed repeatedly at re-examination visits between 2005 and 2015 for 2,607 participants to obtain brain volumes, focal brain lesions, and white matter microstructural integrity as measures of brain structure. Among 9,566 participants (mean age 65.1±9.8 years), 5,444 (56.9%) were women, and repeated measures of cognition were performed during a median follow-up time of 5.5 years (range = 1.1-17.9), of whom 2,607 participants completed at least one brain imaging scans. Higher levels of NT-proBNP were associated with a faster decline of scores in the global cognitive function (P value = 0.003), and the Word-Fluency test (P value = 0.003), but were not related to a steeper deterioration in brain volumes, global fractional anisotropy and mean diffusivity, as indicators of white matter microstructural integrity, or focal brain lesions. Higher baseline NT-proBNP levels were associated with a faster decline in cognition, however, no association with global brain structure was found.

Burden of cardiometabolic diseases and life expectancy with and without atrial fibrillation among men and women

Abstract Funding Acknowledgements Type of funding sources: None. Background Atrial fibrillation is the most common cardiac arrhythmia worldwide, with significant sex differences in its epidemiology. Cardiometabolic diseases commonly coexist with atrial fibrillation and associate with a larger mortality risk. However, how increasing burden of cardiometabolic diseases affect life expectancy lived with atrial fibrillation remains largely unknown. Purpose To determine the impact of burden of cardiometabolic diseases on life expectancy lived with and without atrial fibrillation. Methods From the population-based Rotterdam Study, 4045 men and 5526 women (mean age 62 years) were included. Participants with cardiometabolic diseases, including diabetes, coronary heart disease, stroke, and heart failure, were divided into three groups according to the number of prevalent disorders (0, 1, and ≥2). A multistate life table was developed to calculate the life expectancy lived with and without atrial fibrillation according to the burden of cardiometabolic disease. Results Men aged 55 with no cardiometabolic disease had a life expectancy of 22.0 years and lived 5.9 years longer than men aged 55 with ≥2 cardiometabolic diseases (life expectancy 16.1 years). Of the total life expectancy at age 55, men with no cardiometabolic disease spent 29.1% (6.4 years) of their remaining years with atrial fibrillation, whereas men with ≥2 cardiometabolic diseases spent 36.0% (5.8 years) of their remaining years with atrial fibrillation. Women aged 55 with no cardiometabolic disease had a total life expectancy of 25.2 years, which was 8.1 years longer than women aged 55 with ≥2 cardiometabolic diseases (life expectancy 17.1 years). Of the total life expectancy at age 55, women with no cardiometabolic disease spent 25.4% (6.4 years) of their remaining years with atrial fibrillation, and those with ≥2 cardiometabolic diseases spent 29.8% (5.1 years) of their remaining years with AF. Conclusions The larger burden of cardiometabolic diseases was associated with a lower life expectancy among men and women, and a larger proportion of remaining years spent in atrial fibrillation. Findings suggest that larger proportion of time spent in AF translates to a lower quality of life and larger health care costs at population level.

Left atrium volume is the predominant cardiac dimension related to new-onset atrial fibrillation in the general population

Abstract Funding Acknowledgements Type of funding sources: None. Background Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with significant sex differences in its epidemiology and etiology. Yet, sex-specific evidence comprehensively assessing the impact of cardiac volumes on AF development is sparse. Purpose To examine the association between cardiac volumes with new-onset AF among men and women. Methods From the population-based Rotterdam Study, 1021 men and 1179 women (mean age 69 years), free of AF, underwent non-contrast cardiac CT (2003 to 2006) to quantitatively assess cardiac structures in volumes (ml), except for aortic root diameter (expressed in mm). Sex-specific Cox proportional hazards regression models were used to assess the association between CT-assessed cardiac measures and risk of new-onset AF. Cardiac volumes were indexed to body surface area (BSA) and standardized to enable direct comparisons. Results After a median follow-up time of 9.1 years, 116 (11.0%) men and 81 (6.9%) women experienced new-onset AF. After adjustments for traditional cardiovascular risk factors, all assessed BSA-indexed cardiac volumes significantly associated with larger risk of AF among both men and women. Adjusted hazard ratios (HRs) per 1-standard deviation (SD) larger BSA-indexed volumes ranged from 1.20 [95% confidence interval (CI): 1.00-1.44] for right atrium to 1.66 (95% CI: 1.40-1.98) for left atrium in men; and ranged from 1.27 (95% CI: 1.01-1.61) for aortic root to 1.88 (95% CI: 1.56-2.27) for left atrium in women. A stronger association was found between right atrium and AF among women (HR; 95% CI: 1.59; 1.29-1.96), compared to men (p&amp;lt;0.01 for interaction). After further adjustment for left atrium, the association of all other cardiac volumes with AF, among both men and women, were no longer significant. Conclusions We observed significant associations between various cardiac volumes and increased AF risk, most evidently among women. Findings underscored the predominant role of left atrium size on AF development.

Coronary Artery Calcium Score and Polygenic Risk Score for the Prediction of Coronary Heart Disease Events

Coronary artery calcium score and polygenic risk score have each separately been proposed as novel markers to identify risk of coronary heart disease (CHD), but no prior studies have directly compared these markers in the same cohorts. To evaluate change in CHD risk prediction when a coronary artery calcium score, a polygenic risk score, or both are added to a traditional risk factor-based model. Two observational population-based studies involving individuals aged 45 years through 79 years of European ancestry and free of clinical CHD at baseline: the Multi-Ethnic Study of Atherosclerosis (MESA) study involved 1991 participants at 6 US centers and the Rotterdam Study (RS) involved 1217 in Rotterdam, the Netherlands. Traditional risk factors were used to calculate CHD risk (eg, pooled cohort equations [PCEs]), computed tomography for the coronary artery calcium score, and genotyped samples for a validated polygenic risk score. Model discrimination, calibration, and net reclassification improvement (at the recommended risk threshold of 7.5%) for prediction of incident CHD events were assessed. The median age was 61 years in MESA and 67 years in RS. Both log (coronary artery calcium+1) and polygenic risk score were significantly associated with 10-year risk of incident CHD (hazards ratio per SD, 2.60; 95% CI, 2.08-3.26 and 1.43; 95% CI, 1.20-1.71, respectively), in MESA. The C statistic for the coronary artery calcium score was 0.76 (95% CI, 0.71-0.79) and for the polygenic risk score, 0.69 (95% CI, 0.63-0.71). The change in the C statistic when each was added to the PCEs was 0.09 (95% CI, 0.06-0.13) for the coronary artery calcium score, 0.02 (95% CI, 0.00-0.04) for the polygenic risk score, and 0.10 (95% CI, 0.07-0.14) for both. Overall categorical net reclassification improvement was significant when the coronary artery calcium score (0.19; 95% CI, 0.06-0.28) but was not significant when the polygenic risk score (0.04; 95% CI, -0.05 to 0.10) was added to the PCEs. Calibration of the PCEs and models with coronary artery calcium and/or polygenic risk scores was adequate (all χ2<20). Subgroup analysis stratified by the median age demonstrated similar findings. Similar findings were observed for 10-year risk in RS and in longer-term follow-up in MESA (median, 16.0 years). In 2 cohorts of middle-aged to older adults from the US and the Netherlands, the coronary artery calcium score had better discrimination than the polygenic risk score for risk prediction of CHD. In addition, the coronary artery calcium score but not the polygenic risk score significantly improved risk discrimination and risk reclassification for CHD when added to traditional risk factors.

Sexual dimorphisms in serum calcium and phosphate concentrations in the Rotterdam Study

Sex differences in serum phosphate and calcium have been reported but the exact nature and underlying regulatory mechanisms remain unclear. We aimed to compare calcium and phosphate concentrations between sexes, and explore potential covariates to elucidate underlying mechanisms of sex differences in a prospective, population-based cohort study. Pooled data of subjects > 45 years from three independent cohorts of the Rotterdam Study (RS) were used: RS-I-3 (n = 3623), RS-II-1 (n = 2394), RS-III-1 (n = 3241), with separate analyses from an additional time point of the first cohort RS-I-1 (n = 2688). Compared to men, women had significantly higher total serum calcium and phosphate concentrations which was not explained by BMI, kidney function nor smoking. Adjustment for serum estradiol diminished sex differences in serum calcium while adjustment for serum testosterone diminished sex differences in serum phosphate. Adjustment for vitamin D and alkaline phosphatase did not change the association between sex and calcium or phosphate in RS-I-1. In the sex-combined group, both serum calcium and phosphate decreased with age with a significant interaction for sex differences for serum calcium but not phosphate. In sex-stratified analyses, serum estradiol but not testosterone was inversely associated with serum calcium in both sexes. Serum estradiol was inversely associated with serum phosphate in both sexes to a similar degree, while serum testosterone was inversely associated with serum phosphate in both sexes with an apparent stronger effect in men than in women. Premenopausal women had lower serum phosphate compared to postmenopausal women. Serum testosterone was inversely associated with serum phosphate in postmenopausal women only. In conclusion, women > 45 years have higher serum calcium and phosphate concentrations compared to men of similar age, not explained by vitamin D or alkaline phosphatase concentrations. Serum estradiol but not testosterone was inversely associated with serum calcium while serum testosterone was inversely associated with serum phosphate in both sexes. Serum testosterone may in part explain sex differences in serum phosphate while estradiol could partly explain sex differences in serum calcium.

Analysis of Rotterdam Study cohorts confirms a previously identified RIPOR2 in-frame deletion as a prevalent genetic factor in phenotypically variable adult-onset hearing loss (DFNA21) in the Netherlands

BackgroundA 12-nucleotide RIPOR2 in-frame deletion was recently identified as a relatively common and highly penetrant cause of autosomal dominant non-syndromic sensorineural hearing loss, type DFNA21, in the Netherlands. The associated...

Longitudinal Assessment of the Prevalence of Actinic Keratosis and Extensive Risk Factor Evaluation: An Update from the Rotterdam Study

Limited population-based studies are available to analyze the prevalence, risk factors, and longitudinal outlook of actinic keratoses (AK). These aforementioned features were assessed using Rotterdam Study participants aged 40 and older who underwent a full-body skin examination (FBSE) by a dermatology trained physician. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the associations between risk factors and the presence of AK. Among 8,239 eligible participants, the prevalence of one or more AKs was 21.1% (95% CI: 20.2-22.0) and was higher in men. Male sex, age, lighter hair and eye color, baldness, genetic risk score (GRS), and digital photoaging measures (digitally-assessed pigmented spots, telangiectasias and global facial wrinkling) had a positive association with AK. Cigarette smokers had reduced odds of having AK, with current smokers having the lowest risk. Among patients with two AK assessments, there was no difference in the presence of AK during follow-up between treated and untreated participants. In conclusion, GRS and digital photoaging measures showed associations with increased lesion count. At the individual level, patients were most likely to decrease in AK severity group (i.e. with less AKs) over time, possibly regardless of whether or not participants were treated.

Higher testosterone is associated with open-angle glaucoma in women: a genetic predisposition?

BackgroundTestosterone may be a possible modifiable risk factor for open-angle glaucoma (OAG) and intraocular pressure (IOP), but evidence has been scarce and conflicting. In this study we evaluated the association of testosterone and its genetic predisposition with incident (i) OAG, IOP, retinal nerve fiber layer (RNFL), and ganglion cell-inner plexiform layer (GCL +).MethodsParticipants aged 45–100 years were derived from the prospective, population-based Rotterdam Study. Ophthalmic examinations and serum testosterone measurements (including bioavailable and free testosterone) were performed from 1991 onwards. Follow-up took place every 4–5 years. A total of 187 out of 7898 participants were diagnosed with incident (i) OAG during follow-up. Genotyping was performed in 165 glaucoma cases and 6708 controls. We calculated sex-specific weighted genetic risk scores (GRS) for total and bioavailable testosterone. Associations with iOAG were analyzed using multivariable logistic regression. Associations with IOP, RNFL, and GCL + were analyzed with multivariable linear regression. Analyses were stratified on sex and adjusted for at least age, body mass index, and follow-up duration.ResultsIn men, testosterone was not associated with iOAG. However, the GRS for higher total testosterone was associated with an increased iOAG risk (odds ratio [OR] with 95% confidence interval [95% CI]: 2.48 [1.18; 5.22], per unit). In women, higher values of bioavailable testosterone (2.05 [1.00; 4.18] per nmol/L) and free testosterone (1.79 [1.00; 3.20] per ng/dL) were significantly associated with increased risk of iOAG. Moreover, the GRS for higher bioavailable testosterone was associated with an increased iOAG risk (2.48 [1.09; 5.65], per unit). Higher bioavailable and free testosterone were adversely associated with IOP (0.58 [0.05; 1.10] per nmol/L and 0.47 [0.04; 0.90] per ng/dL). Higher total testosterone was inversely associated with peripapillary RNFL and GCL + (Beta [95% CI]: − 3.54 [− 7.02; − 0.06] per nmol/L and − 2.18 [− 4.11; − 0.25] per nmol/L, respectively).ConclusionsIn women, higher testosterone levels increased the risk of iOAG. Both IOP-dependent and IOP-independent mechanisms may underlie this association. Managing testosterone levels may be particularly relevant for the prevention of neurodegeneration in the eye. Future research should confirm these findings.

Considering Questions Before Methods in Dementia Research With Competing Events and Causal Goals.

Studying causal exposure effects on dementia is challenging when death is a competing event. Researchers often interpret death as a potential source of bias, although bias cannot be defined or assessed if the causal question is not explicitly specified. Here we discuss 2 possible notions of a causal effect on dementia risk: the "controlled direct effect" and the "total effect." We provide definitions and discuss the "censoring" assumptions needed for identification in either case and their link to familiar statistical methods. We illustrate concepts in a hypothetical randomized trial on smoking cessation in late midlife, and emulate such a trial using observational data from the Rotterdam Study, the Netherlands, 1990-2015. We estimated a total effect of smoking cessation (compared with continued smoking) on 20-year dementia risk of 2.1 (95% confidence interval: -0.1, 4.2) percentage points and a controlled direct effect of smoking cessation on 20-year dementia risk had death been prevented of -2.7 (95% confidence interval: -6.1, 0.8) percentage points. Our study highlights how analyses corresponding to different causal questions can have different results, here with point estimates on opposite sides of the null. Having a clear causal question in view of the competing event and transparent and explicit assumptions are essential to interpreting results and potential bias.