Apart from blood pressure level itself, variation in blood pressure has been implicated in the development of stroke in subgroups at high cardiovascular risk. We determined the association between ...visit-to-visit blood pressure variability and stroke risk in the general population, taking into account the size and direction of variation and several time intervals prior to stroke diagnosis.
From 1990 to 2016, we included 9,958 stroke-free participants of the population-based Rotterdam Study in the Netherlands. This is a prospective cohort study including participants aged 45 years and older. Systolic blood pressure (SBP) variability was calculated as absolute SBP difference divided by mean SBP over 2 sequential visits (median 4.6 years apart). Directional SBP variability was defined as SBP difference over 2 visits divided by mean SBP. Using time-varying Cox proportional hazards models adjusted for age, sex, mean SBP, and cardiovascular risk factors, hazard ratios (HRs) for stroke up to January 2016 were estimated per SD increase and in tertiles of variability. We also conducted analyses with 3-, 6-, and 9-year intervals between variability measurement and stroke assessment. These analyses were repeated for diastolic blood pressure (DBP). The mean age of the study population was 67.4 ± 8.2 years and 5,776 (58.0%) were women. During a median follow-up of 10.1 years, 971 (9.8%) participants had a stroke, including 641 ischemic, 89 hemorrhagic, and 241 unspecified strokes. SBP variability was associated with an increased risk of hemorrhagic stroke (HR per SD 1.27, 95% CI 1.05-1.54, p = 0.02) and unspecified stroke (HR per SD 1.21, 95% CI 1.09-1.34, p < 0.001). The associations were stronger for all stroke subtypes with longer time intervals; the HR for any stroke was 1.29 (95% CI 1.21-1.36, p < 0.001) at 3 years, 1.47 (95% CI 1.35-1.59, p < 0.001) at 6 years, and 1.38 (95%CI 1.24-1.51, p < 0.001) at 9 years. For DBP variability, we found an association with unspecified stroke risk. Both the rise and fall of SBP and the fall of DBP were associated with an increased risk for unspecified stroke. Limitations of the study include that, due to an average interval of 4 years between visits, our findings may not be generalizable to blood pressure variability over shorter periods.
In this population-based study, we found that visit-to-visit blood pressure variation was associated with an increased risk of unspecified and hemorrhagic stroke, independent of direction of variation or mean blood pressure.
Sleep disturbances may signal presence of prodromal parkinsonism, including Parkinson's disease. Whether general sleep quality or duration in otherwise healthy subjects is related to the risk of ...parkinsonism remains unclear. We hypothesized that both worse self-reported sleep quality and duration, as well as a longitudinal deterioration in these measures, are associated with the risk of parkinsonism, including Parkinson's disease. In the prospective population-based Rotterdam Study, we assessed sleep quality and duration with the Pittsburgh Sleep Quality Index in 7726 subjects (mean age 65 years, 57% female) between 2002 and 2008, and again in 5450 subjects between 2009 and 2014. Participants were followed until 2015 for a diagnosis of parkinsonism and Parkinson's disease. Outcomes were assessed using multiple modalities: interviews, physical examination, and continuous monitoring of pharmacy records and medical records of general practitioners. We used Cox regression to associate sleep, and changes in sleep over time, with incident parkinsonism and Parkinson's disease, adjusting for age, sex, education and smoking status. Over 64 855 person-years in 13 years of follow-up (mean: 8.4 years), 75 participants developed parkinsonism, of whom 47 developed Parkinson's disease. We showed that within the first 2 years of follow-up, worse sleep quality {hazard ratio (HR) 2.38 per standard deviation increase 95% confidence interval (CI 0.91-6.23)} and shorter sleep duration HR 0.61 per standard deviation increase (95% CI 0.31-1.21) related to a higher risk of parkinsonism. Associations of worse sleep quality HR 3.86 (95% CI 1.19-12.47) and shorter sleep duration HR 0.48 (95% CI 0.23-0.99) with Parkinson's disease were more pronounced, and statistically significant, compared to parkinsonism. This increased risk disappeared with longer follow-up duration. Worsening of sleep quality HR 1.76 per standard deviation increase (95% CI 1.12-2.78), as well as shortening of sleep duration HR 1.72 per standard deviation decrease (95% CI 1.08-2.72), were related to Parkinson's disease risk in the subsequent 6 years. Therefore, we argue that in the general population, deterioration of sleep quality and duration are markers of the prodromal phase of parkinsonism, including Parkinson's disease.
The exact etiology of dementia is still unclear, but both genetic and lifestyle factors are thought to be key drivers of this complex disease. The recognition of familial patterns of dementia has led ...to the discovery of genetic factors that have a role in the pathogenesis of dementia, including the apolipoprotein E (APOE) genotype and a large and still-growing number of genetic variants
. Beyond genetic architecture, several modifiable risk factors have been implicated in the development of dementia
. Prevention trials of measures to halt or delay cognitive decline are increasingly recruiting older individuals who are genetically predisposed to dementia. However, it remains unclear whether targeted health and lifestyle interventions can attenuate or even offset increased genetic risk. Here, we leverage long-term data on both genetic and modifiable risk factors from 6,352 individuals aged 55 years and older in the population-based Rotterdam Study. In this study, we demonstrate that, in individuals at low and intermediate genetic risk, favorable modifiable-risk profiles are related to a lower risk of dementia compared to unfavorable profiles. In contrast, these protective associations were not found in those at high genetic risk.
Alzheimer's disease is one of the most heritable diseases in elderly people and the most common type of dementia. In addition to the major genetic determinant of Alzheimer's disease, the APOE gene, ...23 genetic variants have been associated with the disease. We assessed the effects of these variants and APOE on cumulative risk and age at onset of Alzheimer's disease and all-cause dementia.
We studied incident dementia in cognitively healthy participants (aged >45 years) from the community-based Rotterdam Study, an ongoing prospective cohort study based in Rotterdam, the Netherlands, focusing on neurological, cardiovascular, endocrine, and ophthalmological disorders, and other diseases in elderly people. The Rotterdam Study comprises participants in three baseline cohorts (initiated in 1990, 2000, and 2006), who are re-invited to the research centre every 3–4 years, and continuously monitored by records from general practitioners and medical specialists. Cumulative incidence curves up to age 100 years were calculated for Alzheimer's disease and dementia, taking into account mortality as a competing event. These risk curves were stratified by APOE genotypes, tertiles of a weighted genetic risk score (GRS) of 23 Alzheimer's disease-associated genetic variants, and parental history of dementia.
12 255 of 14 926 participants (58·5% women) from the Rotterdam Study were included in this study. During a median follow-up of 11·0 years (IQR 4·9–15·9; 133 123 person years), 1609 participants developed dementia, of whom 1262 (78%) were classified as having Alzheimer's disease; 3310 people died of causes other than dementia. Both APOE and the GRS significantly modified the risks of Alzheimer's disease and dementia. There was evidence for a significant interaction between APOE genotypes and the GRS for the association with Alzheimer's disease (p=0·03) and dementia (p=0·04); the risk for carriers homozygous for APOE ε4 was modified most by the GRS. In carriers homozygous for APOE ε4, the difference between the high-risk tertile and the low-risk tertile by age 85 years was 27·0% for Alzheimer's disease (p=8·5 × 10−3) and 37·2% for dementia (p=2·2 × 10−4), which translates to a 7–10 year difference in age at onset. Comparing the risk extremes, which were carriers homozygous for APOE ε2 or heterozygous with one copy each of the ε2 and ε3 alleles in the low-risk tertile of the GRS versus carriers homozygous for APOE ε4 in the high-risk tertile of the GRS, the difference in risk by age 85 years was 58·6% (4·1% vs 62·7%; p=6·2 × 10−13) for Alzheimer's disease, and 70·3% (7·2% vs 77·5%; p=3·0 × 10−23) for dementia. These risk differences translate into an 18–29 years difference in age at onset for Alzheimer's disease and an 18–23 year difference in age at onset dementia. This difference becomes more pronounced when parental history of dementia is considered (difference in risk 83·8%; p=1·1 × 10−20).
Common variants with small individual effects jointly modify the risk and age at onset of Alzheimer's disease and dementia, particularly in APOE ε4 carriers. These findings highlight the potential of common variants in determining Alzheimer's disease risk.
None.
The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines introduced a prediction model and lowered the threshold for treatment with statins to a 7.5% 10-year hard ...atherosclerotic cardiovascular disease (ASCVD) risk. Implications of the new guideline's threshold and model have not been addressed in non-US populations or compared with previous guidelines.
To determine population-wide implications of the ACC/AHA, the Adult Treatment Panel III (ATP-III), and the European Society of Cardiology (ESC) guidelines using a cohort of Dutch individuals aged 55 years or older.
We included 4854 Rotterdam Study participants recruited in 1997-2001. We calculated 10-year risks for "hard" ASCVD events (including fatal and nonfatal coronary heart disease CHD and stroke) (ACC/AHA), hard CHD events (fatal and nonfatal myocardial infarction, CHD mortality) (ATP-III), and atherosclerotic CVD mortality (ESC).
Events were assessed until January 1, 2012. Per guideline, we calculated proportions of individuals for whom statins would be recommended and determined calibration and discrimination of risk models.
The mean age was 65.5 (SD, 5.2) years. Statins would be recommended for 96.4% (95% CI, 95.4%-97.1%; n = 1825) of men and 65.8% (95% CI, 63.8%-67.7%; n = 1523) of women by the ACC/AHA, 52.0% (95% CI, 49.8%-54.3%; n = 985) of men and 35.5% (95% CI, 33.5%-37.5%; n = 821) of women by the ATP-III, and 66.1% (95% CI, 64.0%-68.3%; n = 1253) of men and 39.1% (95% CI, 37.1%-41.2%; n = 906) of women by ESC guidelines. With the ACC/AHA model, average predicted risk vs observed cumulative incidence of hard ASCVD events was 21.5% (95% CI, 20.9%-22.1%) vs 12.7% (95% CI, 11.1%-14.5%) for men (192 events) and 11.6% (95% CI, 11.2%-12.0%) vs 7.9% (95% CI, 6.7%-9.2%) for women (151 events). Similar overestimation occurred with the ATP-III model (98 events in men and 62 events in women) and ESC model (50 events in men and 37 events in women). The C statistic was 0.67 (95% CI, 0.63-0.71) in men and 0.68 (95% CI, 0.64-0.73) in women for hard ASCVD (ACC/AHA), 0.67 (95% CI, 0.62-0.72) in men and 0.69 (95% CI, 0.63-0.75) in women for hard CHD (ATP-III), and 0.76 (95% CI, 0.70-0.82) in men and 0.77 (95% CI, 0.71-0.83) in women for CVD mortality (ESC).
In this European population aged 55 years or older, proportions of individuals eligible for statins differed substantially among the guidelines. The ACC/AHA guideline would recommend statins for nearly all men and two-thirds of women, proportions exceeding those with the ATP-III or ESC guidelines. All 3 risk models provided poor calibration and moderate to good discrimination. Improving risk predictions and setting appropriate population-wide thresholds are necessary to facilitate better clinical decision making.
Exercise may be a promising target for depression interventions. However, evidence for a beneficial effect of exercise interventions on the prevention of depression differs substantially across ...different studies.
A systematic search was performed up to July 2018 using PubMed, Embase, PsycINFO, and Cochrane. Articles were included if a meta-analysis of randomized controlled trials was performed that examined the effect of exercise interventions on the onset of depression or depressive symptoms in the general population. Meta-analyses focusing on treatment of diagnosed depression were excluded. Two authors independently screened the articles and graded the quality of included meta-analyses using AMSTAR 2.
Eight meta-analyses were included that showed little overlap in 134 included studies. All meta-analyses reported on depressive symptoms rather than onset of depression. Five of these were rated as moderate quality and three of low quality. Six meta-analyses found significant effects, and two found non-significant effects of exercise interventions in reducing depressive symptoms in children, adolescents, adults and the elderly (effect sizes ranging from - 0.10 to - 0.81). Scarce evidence did not allow to draw conclusions about the role of sex and characteristics of exercise on depression. However, some findings suggest that low intensity exercise was as effective as high intensity exercise. Heterogeneity among primary studies was high, likely caused by differences in study quality and exercise characteristics.
The evidence from this study suggests that exercise interventions have a beneficial effect on depressive symptoms in the general population across a wide age-range.
Non-communicable diseases (NCDs) are leading causes of premature disability and death worldwide. However, the lifetime risk of developing any NCD is unknown, as are the effects of shared common risk ...factors on this risk.
Between July 6, 1989, and January 1, 2012, we followed participants from the prospective Rotterdam Study aged 45 years and older who were free from NCDs at baseline for incident stroke, heart disease, diabetes, chronic respiratory disease, cancer, and neurodegenerative disease. We quantified occurrence/co-occurrence and remaining lifetime risk of any NCD in a competing risk framework. We additionally studied the lifetime risk of any NCD, age at onset, and overall life expectancy for strata of 3 shared risk factors at baseline: smoking, hypertension, and overweight. During 75,354 person-years of follow-up from a total of 9,061 participants (mean age 63.9 years, 60.1% women), 814 participants were diagnosed with stroke, 1,571 with heart disease, 625 with diabetes, 1,004 with chronic respiratory disease, 1,538 with cancer, and 1,065 with neurodegenerative disease. NCDs tended to co-occur substantially, with 1,563 participants (33.7% of those who developed any NCD) diagnosed with multiple diseases during follow-up. The lifetime risk of any NCD from the age of 45 years onwards was 94.0% (95% CI 92.9%-95.1%) for men and 92.8% (95% CI 91.8%-93.8%) for women. These risks remained high (>90.0%) even for those without the 3 risk factors of smoking, hypertension, and overweight. Absence of smoking, hypertension, and overweight was associated with a 9.0-year delay (95% CI 6.3-11.6) in the age at onset of any NCD. Furthermore, the overall life expectancy for participants without these risk factors was 6.0 years (95% CI 5.2-6.8) longer than for those with all 3 risk factors. Participants aged 45 years and older without the 3 risk factors of smoking, hypertension, and overweight at baseline spent 21.6% of their remaining lifetime with 1 or more NCDs, compared to 31.8% of their remaining life for participants with all of these risk factors at baseline. This difference corresponds to a 2-year compression of morbidity of NCDs. Limitations of this study include potential residual confounding, unmeasured changes in risk factor profiles during follow-up, and potentially limited generalisability to different healthcare settings and populations not of European descent.
Our study suggests that in this western European community, 9 out of 10 individuals aged 45 years and older develop an NCD during their remaining lifetime. Among those individuals who develop an NCD, at least a third are subsequently diagnosed with multiple NCDs. Absence of 3 common shared risk factors is associated with compression of morbidity of NCDs. These findings underscore the importance of avoidance of these common shared risk factors to reduce the premature morbidity and mortality attributable to NCDs.
Gut microbiota has been implicated in major diseases affecting the human population and has also been linked to triglycerides and high-density lipoprotein levels in the circulation. Recent ...development in metabolomics allows classifying the lipoprotein particles into more details. Here, we examine the impact of gut microbiota on circulating metabolites measured by Nuclear Magnetic Resonance technology in 2309 individuals from the Rotterdam Study and the LifeLines-DEEP cohort. We assess the relationship between gut microbiota and metabolites by linear regression analysis while adjusting for age, sex, body-mass index, technical covariates, medication use, and multiple testing. We report an association of 32 microbial families and genera with very-low-density and high-density subfractions, serum lipid measures, glycolysis-related metabolites, ketone bodies, amino acids, and acute-phase reaction markers. These observations provide insights into the role of microbiota in host metabolism and support the potential of gut microbiota as a target for therapeutic and preventive interventions.
Herpes simplex virus 1 (HSV1) is a neuroinvasive virus capable of entering the brain which makes it a candidate pathogen for increasing risk of dementia. Previous studies are inconsistent in their ...findings regarding the link between HSV1 and dementia, therefore, we investigated how HSV1 relates to cognitive decline and dementia risk using data from a population-based study. We measured HSV1 immunoglobulin (IgG) antibodies in serum collected between 2002 and 2005 from participants of the Rotterdam Study. We used linear regression to determine HSV1 in relation to change in cognitive performance during 2 consecutive examination rounds on average 6.5 years apart. Next, we determined the association of HSV1 with risk of dementia (until 2016) using a Cox regression model. We repeated analyses for Alzheimer's disease. All models were adjusted for age, sex, cardiovascular risk factors, and apolipoprotein E genotype. Of 1915 non-demented participants (mean age 71.3 years, 56.7% women), with an average follow-up time of 9.1 years, 244 participants developed dementia (of whom 203 Alzheimer's disease). HSV1 seropositivity was associated with decline in global cognition (mean difference of HSV1 seropositive vs seronegative per standard deviation decrease in global cognition - 0.16; 95% confidence interval (95%CI), - 0.26; - 0.07), as well as separate cognitive domains, namely memory, information processing, and executive function, but not motor function. Finally, HSV1 seropositivity was not associated with risk of dementia (adjusted hazard ratio 1.18, 95% CI 0.83; 1.68), similar for Alzheimer's disease. HSV1 is associated with cognitive decline but not with incident dementia in the general population. These data suggest HSV1 to be associated only with subtle cognitive disturbances but not with greater cognitive disorders that result in dementia.
The Rotterdam Study is an ongoing prospective cohort study that started in 1990 in the city of Rotterdam, The Netherlands. The study aims to unravel etiology, preclinical course, natural history and ...potential targets for intervention for chronic diseases in mid-life and late-life. The study focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1700 research articles and reports. This article provides an update on the rationale and design of the study. It also presents a summary of the major findings from the preceding 3 years and outlines developments for the coming period.
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