Atrial fibrillation (AF) has been suggested as a risk factor for dementia since it may lead to chronic cerebral hypoperfusion and stroke. However, longitudinal studies assessing the association ...between AF and dementia have shown inconsistent results.
To determine the effect of AF on the risk of developing dementia during 20 years of follow-up.
The association of prevalent and incident AF with incident dementia was assessed from July 6, 1989, to February 4, 2010, in 6514 dementia-free participants in the prospective population-based Rotterdam Study. Data analysis was conducted from September 18, 2014, to April 17, 2015. Cox proportional hazards regression models adjusting for age, sex, and cardiovascular risk factors; censored for stroke; and stratified by median age were used. In addition, we investigated whether the association between incident AF and dementia varied according to the duration of exposure, categorized in 6-year time bands.
Prevalent and incident AF.
Incident dementia, determined according to the Diagnostic and Statistical Manual of Mental Disorders (Third Edition Revised) and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria.
At baseline, 318 of 6514 participants (4.9%) had prevalent AF, and during 81 483 person-years of follow-up, 994 participants (15.3%) developed incident dementia. With findings presented as adjusted hazard ratio (95% CI), prevalent AF was related to an increased risk of dementia (1.33; 1.02-1.73). Among 6196 participants without prevalent AF during 79 003 person-years of follow-up, 723 participants (11.7%) developed incident AF and 932 individuals (15.0%) developed incident dementia. Incident AF was associated with an increased risk of dementia in younger participants (<67 years: 1.81; 1.11-2.94 vs ≥67 years: 1.12; 0.85-1.46; P = .02 for interaction). The risk of dementia was strongly associated with duration of exposure to AF in the younger participants (in the highest stratum: 3.30; 1.16-9.38; P = .003 for trend) but not in the elder participants (0.25; 0.04-1.86; P = .94 for trend).
Atrial fibrillation is associated with an increased risk of dementia, independent of clinical stroke. This association was strongest for younger participants with the longest duration of AF. Future studies should investigate whether optimal treatment of AF can prevent or postpone dementia.
Abstract
Case-control studies are an important part of the epidemiologic literature, yet confusion remains about how to interpret estimates from different case-control study designs. We demonstrate ...that not all case-control study designs estimate odds ratios. On the contrary, case-control studies in the literature often report odds ratios as their main parameter even when using designs that do not estimate odds ratios. Only studies using specific case-control designs should report odds ratios, whereas the case-cohort and incidence-density sampled case-control studies must report risk ratio and incidence rate ratios, respectively. This also applies to case-control studies conducted in open cohorts, which often estimate incidence rate ratios. We also demonstrate the misinterpretation of case-control study estimates in a small sample of highly cited case-control studies in general epidemiologic and medical journals. We therefore suggest that greater care be taken when considering which parameter is to be reported from a case-control study.
Cerebral microbleeds are frequently seen in the general elderly population, but it is unknown at what rate they occur with aging and whether once present can disappear over time.
As part of the ...Rotterdam Scan Study, 831 persons (mean age, 68.5 years) underwent repeated brain MRI with a mean interval of 3.4 years. We assessed determinants of incident microbleeds in relation to their location with multiple logistic regressions.
Overall prevalence of microbleeds increased from 24.4% at baseline to 28.0% at follow-up. Eighty-five persons (10.2%) developed new microbleeds. Microbleeds at baseline predicted development of new microbleeds (OR, 5.38; 95% CI, 3.34 to 8.67). In only 6 persons with microbleeds at baseline, fewer microbleeds were present at the follow-up examination. Cardiovascular risk factors, presence of lacunar infarcts, and larger white matter lesion volume at baseline were all associated with incident deep or infratentorial microbleeds, whereas people with the apolipoprotein E ε4/ε4 genotype or larger white matter lesion volume had a higher risk of incident strictly lobar microbleeds.
Incidence of microbleeds in the general population over a 3-year interval was substantial and microbleeds rarely disappeared. Risk factors for incident microbleeds were similar to those for prevalent microbleeds and differed according to microbleed location. These results support the assessment of microbleeds on T2-weighted MRI as a possible marker of both cerebral amyloid angiopathy and hypertensive vasculopathy progression.
We aimed to assess whether individuals with type 2 diabetes (T2D) have increased risk of vertebral fractures (VFs) and to estimate nonvertebral fracture and mortality risk among individuals with both ...prevalent T2D and VFs.
A systematic PubMed search was performed to identify studies that investigated the relationship between T2D and VFs. Cohorts providing individual participant data (IPD) were also included. Estimates from published summary data and IPD cohorts were pooled in a random-effects meta-analysis. Multivariate Cox regression models were used to estimate nonvertebral fracture and mortality risk among individuals with T2D and VFs.
Across 15 studies comprising 852,705 men and women, individuals with T2D had lower risk of prevalent (odds ratio OR 0.84 95% CI 0.74-0.95;
= 0.0%;
= 0.54) but increased risk of incident VFs (OR 1.35 95% CI 1.27-1.44;
= 0.6%;
= 0.43). In the IPD cohorts (
= 19,820), risk of nonvertebral fractures was higher in those with both T2D and VFs compared with those without T2D or VFs (hazard ratio HR 2.42 95% CI 1.86-3.15) or with VFs (HR 1.73 95% CI 1.32-2.27) or T2D (HR 1.94 95% CI 1.46-2.59) alone. Individuals with both T2D and VFs had increased mortality compared with individuals without T2D and VFs (HR 2.11 95% CI 1.72-2.59) or with VFs alone (HR 1.84 95% CI 1.49-2.28) and borderline increased compared with individuals with T2D alone (HR 1.23 95% CI 0.99-1.52).
Based on our findings, individuals with T2D should be systematically assessed for presence of VFs, and, as in individuals without T2D, their presence constitutes an indication to start osteoporosis treatment for the prevention of future fractures.
Arteriosclerosis in the vertebrobasilar arteries may play an important role in the etiology of posterior circulation strokes, but little is known on its prevalence, its correlation with ...arteriosclerosis in other major arteries, and its risk factors. Hence, we investigated these aspects of vertebrobasilar artery calcification (VBAC) as marker of vertebrobasilar arteriosclerosis.
To quantify VBAC, 2483 participants (mean age: 69.2 years, 52% female) from the Rotterdam Study underwent non-enhanced computed tomography. We determined the presence and volume of VBAC. Next, using Spearman's rank correlation, we examined the correlation between the volume of VBAC and the volume of coronary artery calcification (CAC), aortic arch calcification (AAC), and both extracranial- (ECAC), and intracranial carotid artery calcification (ICAC). Finally, we investigated associations of cardiovascular risk factors with the presence and volume of VBAC using logistic and linear regression models.
The overall prevalence of VBAC was 21.0% (median volume: 7.3 mm3 IQR: 2.0–25.6). Correlations between VBAC and CAC, AAC, ECAC, and ICAC were weak to moderate (men: 0.33, 0.28, 0.30, 0.36; women: 0.26, 0.24, 0.24, 0.35, respectively). Hypertension, diabetes, and current smoking were associated with the presence of VBAC in both sexes (men: OR 1.67 95%-CI, 1.14–2.46, 1.60 95%-CI, 1.10–2.34, 1.48 95%-CI, 1.02–2.14; women: OR 1.51 95%-CI, 1.01–2.26, 1.56 95%-CI, 1.02–2.39, 1.53 95%CI, 1.00–2.33, respectively). In men, obesity was also associated with VBAC (1.42 95%-CI, 1.00–2.02).
VBAC occurs in over 20% of elderly community dwelling persons. Cardiovascular risk factors are associated with VBAC with similar patterns for men and women.
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•In this large population-based study, calcification in the vertebrobasilar arteries was prevalent in 21% of the elderly.•Calcification in the vertebrobasilar arteries was weak to moderately correlated with calcification in other arteries.•Traditional cardiovascular risk factors were associated with vertebrobasilar artery calcification.•Our findings suggest a different pathophysiology of arteriosclerosis in the posterior- compared to anterior circulation.
Fracture incidence needs to be evaluated over time to assess the impact of the enlarging population burden of fractures (due to increase in lifespan) and the efficacy of fracture prevention ...strategies. Therefore, we aimed to evaluate the association of femoral neck bone mineral density (FN-BMD) measured using dual-energy X-ray absorptiometry (DXA) at baseline with fracture risk over a long follow-up time period. Incident non-vertebral fractures were assessed in 14,613 individuals participating in the Rotterdam Study with up to 20 years of follow-up. During a mean follow-up of 10.7 ± 6.2 years, 2971 (20.3%) participants had at least one incident non-vertebral fracture. The risk for any non-vertebral fracture was 1.37 (95% Confidence Interval (CI): 1.25–1.49) and 1.42 (95%CI: 1.35–1.50) for men and women, respectively. The majority (79% in men and 75% in women) of all fractures occurred among participants a normal or osteopenic T-score. The incidence rates per 1000 person-years for the most common fractures were 5.3 95%CI: 5.0–5.7 for hip, 4.9 95%CI: 4.6–5.3 for wrist and 2.3 95%CI: 2.0–2.5 for humerus. To examine the predictive ability of BMD through follow-up time we determined fracture hazard ratios (HR) per standard deviation decrease in femoral neck BMD across five year bins. No differences were observed, with a HR of 2.5 (95%CI: 2.0–3.1) after the first 5 years, and of 1.9 (95%CI: 1.1–3.3) after 20 years. To assess secular trends in fracture incidence at all skeletal sites we compared participants at an age of 70–80 years across two time periods: 1989–2001 (n = 2481, 60% women) and 2001–2013 (n = 2936, 58% women) and found no statistically significant difference (p < 0.05) between fracture incidence rates (i.e., incidence of non-vertebral fractures of 26.4 per 1000 PY 95%CI: 24.4–28.5) between 1989 and 2001, and of 25.4 per 1000 PY 95%CI: 23.0–28.0 between 2001 and 2013. In conclusion, BMD is still predictive of future fracture over a long period of time. While no secular changes in fractures rates seem to be observed after a decade, the majority of fractures still occur above the osteoporosis threshold, emphasizing the need to improve the screening of osteopenic patients.
•Age is the most important determinant of fracture with those of the hip, wrist and proximal humerus having the highest rates•Bone mineral density is still predictive of fractures for up to 20 years•No secular trend differences in fracture incidence rates were observed between the 1989-2001 and 2001-2013 periods
Conditions such as hyperglycemia and oxidative stress lead to the formation of advanced glycation end products (AGEs), which are harmful compounds that have been implicated in dementia. Within the ...Rotterdam Study, we measured skin AGEs as skin autofluorescence, reflecting long-term accumulation of AGEs, and determined their association with the risk of dementia and with brain magnetic resonance imaging (MRI) measures. Skin autofluorescence was measured between 2013 and 2016 in 2922 participants without dementia. Of these, 1504 also underwent brain MRI, on which measures of brain atrophy and cerebral small vessel disease were assessed. All participants were followed for the incidence of dementia until 2020. Of 2922 participants (mean age 72.6 years, 57% women), 123 developed dementia. Higher skin autofluorescence (per standard deviation) was associated with an increased risk of dementia (hazard ratio 1.21 95% confidence interval 1.01-1.46) and Alzheimer's disease (1.19 0.97-1.47), independently of age and other studied potential confounders. Stronger effects were seen in apolipoprotein E (APOE) ε4 carriers (1.34 0.98-1.82) and in participants with diabetes (1.35 0.94-1.94). Participants with higher skin autofluorescence levels also had smaller total brain volumes and smaller hippocampus volumes on MRI, and they had more often lacunes. These results suggest that AGEs may be involved in dementia pathophysiology.
Orthostatic hypotension (OH) is a common cause of transient cerebral hypoperfusion in the population. Cerebral hypoperfusion is widely implicated in cognitive impairment, but whether OH contributes ...to cognitive decline and dementia is uncertain. We aimed to determine the association between OH and the risk of developing dementia in the general population.
Between 4 October 1989 and 17 June 1993, we assessed OH in non-demented, stroke-free participants of the population-based Rotterdam Study. OH was defined as a ≥20 mm Hg drop in systolic blood pressure (SBP) or ≥10 mm Hg drop in diastolic blood pressure (DBP) within 3 min from postural change. We furthermore calculated within participant variability in SBP related to postural change, expressed as coefficient of variation. Follow-up for dementia was conducted until 1 January 2014. We determined the risk of dementia in relation to OH and SBP variability, using a Cox regression model, adjusted for age; sex; smoking status; alcohol intake; SBP; DBP; cholesterol:high-density lipoprotein ratio; diabetes; body mass index; use of antihypertensive, lipid-lowering, or anticholinergic medication; and apolipoprotein E genotype. Finally, we explored whether associations varied according to compensatory increase in heart rate. Among 6,204 participants (mean ± standard deviation SD age 68.5 ± 8.6 y, 59.7% female) with a median follow-up of 15.3 y, 1,176 developed dementia, of whom 935 (79.5%) had Alzheimer disease and 95 (8.1%) had vascular dementia. OH was associated with an increased risk of dementia (adjusted hazard ratio aHR 1.15, 95% CI 1.00-1.34, p = 0.05), which was similar for Alzheimer disease and vascular dementia. Similarly, greater SBP variability with postural change was associated with an increased risk of dementia (aHR per SD increase 1.08, 95% CI 1.01-1.16, p = 0.02), which was similar when excluding those who fulfilled the formal criteria for OH (aHR 1.08, 95% CI 1.00-1.17, p = 0.06). The risk of dementia was particularly increased in those with OH who lacked a compensatory increase in heart rate (within lowest quartile of heart rate response: aHR 1.39, 95% CI 1.04-1.85, p-interaction = 0.05). Limitations of this study include potential residual confounding despite rigorous adjustments, and potentially limited generalisability to populations not of European descent.
In this population predominantly of European descent, OH was associated with an increase in long-term risk of dementia.
Stroke incidence rates have decreased in developed countries over the past 40 years, but trends vary across populations. We investigated whether age-and-sexspecific stroke incidence rates and ...associated risk factors as well as preventive medication use have changed in Rotterdam in the Netherlands during the last two decades. The study was part of the Rotterdam Study, a large populationbased cohort study among elderly people. Participants were 10,994 men and women aged 55-94 years who were stroke-free at baseline. Trends were calculated by comparing the 1990 subcohort (n = 7516; baseline 1990-1993) with the 2000 subcohort (n = 2883; baseline 2000-2001). Poisson regression was used to calculate incidence rates and incidence rate ratios in age-and-sex-specific strata. We further compared the prevalence of stroke risk factors and preventive medication use in the two subcohorts. In the 1990 subcohort 467 strokes occurred during 45,428 person years; in the 2000 subcohort 115 strokes occurred in 18,356 person years. Comparing the subcohorts, incidence rates decreased by 34% in men, but remained unchanged in women. Blood pressure levels increased between 1990 and 2000, whereas the proportion of current cigarette smokers decreased in men, but not in women. There was a strong increase in medication use for treatment of stroke risk factors across all age categories in both sexes. Our findings suggest that in Rotterdam between 1990 and 2008 stroke incidence rates have decreased in men but not in women.
Enlarged perivascular spaces (PVS) are structural brain changes visible in MRI, are common in aging, and are considered a reflection of cerebral small vessel disease. As such, assessing the burden of ...PVS has promise as a brain imaging marker. Visual and manual scoring of PVS is a tedious and observer-dependent task. Automated methods would advance research into the etiology of PVS, could aid to assess what a “normal” burden is in aging, and could evaluate the potential of PVS as a biomarker of cerebral small vessel disease. In this work, we propose and evaluate an automated method to quantify PVS in the midbrain, hippocampi, basal ganglia and centrum semiovale. We also compare associations between (earlier established) determinants of PVS and visual PVS scores versus the automated PVS scores, to verify whether automated PVS scores could replace visual scoring of PVS in epidemiological and clinical studies. Our approach is a deep learning algorithm based on convolutional neural network regression, and is contingent on successful brain structure segmentation. In our work we used FreeSurfer segmentations. We trained and validated our method on T2-contrast MR images acquired from 2115 subjects participating in a population-based study. These scans were visually scored by an expert rater, who counted the number of PVS in each brain region. Agreement between visual and automated scores was found to be excellent for all four regions, with intraclass correlation coefficients (ICCs) between 0.75 and 0.88. These values were higher than the inter-observer agreement of visual scoring (ICCs between 0.62 and 0.80). Scan-rescan reproducibility was high (ICCs between 0.82 and 0.93). The association between 20 determinants of PVS, including aging, and the automated scores were similar to those between the same 20 determinants of PVS and visual scores. We conclude that this method may replace visual scoring and facilitate large epidemiological and clinical studies of PVS.
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