Benzodiazepine use in relation to long-term dementia risk and imaging markers of neurodegeneration: a population-based study.

BACKGROUND: Benzodiazepine use is common, particularly in older adults. Benzodiazepines have well-established acute adverse effects on cognition, but long-term effects on neurodegeneration and dementia risk remain uncertain. METHODS: We included 5443 cognitively healthy (MMSE ≥ 26) participants from the population-based Rotterdam Study (57.4% women, mean age 70.6 years). Benzodiazepine use from 1991 until baseline (2005-2008) was derived from pharmacy dispensing records, from which we determined drug type and cumulative dose. Benzodiazepine use was defined as prescription of anxiolytics (ATC-code: N05BA) or sedative-hypnotics (ATC-code: N05CD) between inception of pharmacy records and study baseline. Cumulative dose was calculated as the sum of the defined daily doses for all prescriptions. We determined the association with dementia risk until 2020 using Cox regression. Among 4836 participants with repeated brain MRI, we further determined the association of benzodiazepine use with changes in neuroimaging markers using linear mixed models. RESULTS: Of all 5443 participants, 2697 (49.5%) had used benzodiazepines at any time in the 15 years preceding baseline, of whom 1263 (46.8%) used anxiolytics, 530 (19.7%) sedative-hypnotics, and 904 (33.5%) used both; 345 (12.8%) participants were still using at baseline assessment. During a mean follow-up of 11.2 years, 726 participants (13.3%) developed dementia. Overall, use of benzodiazepines was not associated with dementia risk compared to never use (HR [95% CI]: 1.06 [0.90-1.25]), irrespective of cumulative dose. Risk estimates were somewhat higher for any use of anxiolytics than for sedative-hypnotics (HR 1.17 [0.96-1.41] vs 0.92 [0.70-1.21]), with strongest associations for high cumulative dose of anxiolytics (HR [95% CI] 1.33 [1.04-1.71]). In imaging analyses, current use of benzodiazepine was associated cross-sectionally with lower brain volumes of the hippocampus, amygdala, and thalamus and longitudinally with accelerated volume loss of the hippocampus and to a lesser extent amygdala. However, imaging findings did not differ by type of benzodiazepines or cumulative dose. CONCLUSIONS: In this population-based sample of cognitively healthy adults, overall use of benzodiazepines was not associated with increased dementia risk, but potential class-dependent adverse effects and associations with subclinical markers of neurodegeneration may warrant further investigation.

Sex-Specific Association of Cardiovascular Risk Factors With Migraine: The Population-Based Rotterdam Study.

BACKGROUND AND OBJECTIVES: Although several lines of evidence suggest a link between migraine and cardiovascular events, less is known about the association between cardiovascular risk factors (CVRFs) and migraine. This knowledge is clinically important to provide directions on mitigating the cardiovascular risk in patients with migraine. We hypothesized that CVRFs are associated with a higher migraine prevalence. Therefore, our primary objective was to investigate sex-specific associations between CVRFs and lifetime prevalence of migraine. METHODS: We performed cross-sectional analyses within an ongoing population-based cohort study (Rotterdam Study), including middle-aged and elderly individuals. By means of (structured) interviews, physical examinations, and blood sampling, we obtained information on the lifetime prevalence of migraine and the following traditional CVRFs: current smoking, obesity, hypercholesterolemia, hypertension, and diabetes mellitus. Similarly, we obtained information on quantitative component data on these CVRFs, including pack-years of smoking, lipid levels, systolic and diastolic blood pressure (BP), body mass index, and fasting glucose levels. Patients with migraine were age-matched to individuals without migraine, and we performed conditional logistic regression analyses to investigate the sex-stratified association of CVRFs with migraine. RESULTS: In total, 7,266 community-dwelling middle-aged and elderly persons were included (median age 66.6 [IQR 56.4-74.8] years, 57.5% females). The lifetime prevalence of migraine was 14.9%. In females, current smoking (odds ratio (OR) 0.72, 95% CI 0.58-0.90), more pack-years (OR per SD increase 0.91, 95% CI 0.84-1.00), diabetes mellitus (OR 0.74, 95% CI 0.56-0.98), and higher fasting glucose levels (OR per SD increase in glucose 0.90, 95% CI 0.82 - 0.98) were all related to a lower migraine prevalence while a higher diastolic BP related to a higher migraine prevalence (OR per SD increase 1.16, 95% CI 1.04-1.29). In males, no significant associations between CVRFs and migraine were observed. DISCUSSION: Traditional CVRFs were either unrelated or inversely related to migraine in middle-aged and elderly individuals, but only in females. In males, we did not find any association between CVRFs and migraine. Because only an increased diastolic BP was related to a higher migraine prevalence in females, our study contributes to the hypothesis that migraine is not directly associated with traditional CVRFs. Future studies are warranted to extrapolate these findings to younger populations.

Trends in population attributable fraction of modifiable risk factors for cardiovascular diseases across three decades.

AIM: To evaluate temporal trends, across three decades, in the population attributable fractions (PAFs) of modifiable risk factors for 5-year risk of cardiovascular diseases (CVDs). METHODS: Within population-based Rotterdam Study, we defined three time-groups of individuals without established CVD at 'baseline' with a mean age of 70 years, and followed for five years: Epoch 1990s (1989-1993, N=6195), Epoch 2000s (1997-2001, N=5572) and Epoch 2010s (2009-2014, N=5135). The prevalence of risk factors and related relative risks were combined to quantify PAFs. RESULTS: The PAF of the six risk factors combined for global CVD was 0.57 (95% confidence interval [CI] 0.47 to 0.65), 0.52 (0.39 to 0.62) and 0.39 (0.18 to 0.54) in three respective epochs. Hypertension contributed the highest PAF to global CVD in Epoch 1990s (0.37, 95% CI: 0.28 to 0.44) and 2000s (0.34, 95% CI: 0.22 to 0.43), while smoking was the largest contributor in Epoch 2010s (0.20, 95% CI: 0.06 to 0.32). Dyslipidemia changed population-level coronary heart disease risk over time. For stroke, hypertension became a less significant contributor over time, but smoking became a larger contributor. For heart failure, all risk factors showed non-significant PAFs in Epoch 2010s. PAFs related to individual risk factor varied among women and men. CONCLUSION: Six modifiable risk factors to population-level global CVD risk decreased over time, but still explained 39% of total CVD in the latest decade. PAFs changed considerably for hypertension, dyslipidemia, and smoking. Risk factors had different PAFs for different CVDs with pronounced sex differences.

The contribution of the individual cardiovascular risk factors to population CVD risk considerably changed over the past 3 decades, especially for hypertension, dyslipidemia, and smoking. Traditional modifiable risk factors exerted declining contributions to population burden of total CVD over the past three decades, suggesting good progress in CVD prevention. Nonetheless, in the latest decade, unfavorable risk factors accounted for 39% of total CVD burden. Sex differences in the contributions of abdominal obesity, diabetes and smoking to cardiovascular outcomes were observed.

Healthcare avoidance during the early stages of the COVID-19 pandemic and all-cause mortality: a longitudinal community-based study.

Background During the COVID-19 pandemic, global trends of reduced healthcare-seeking behaviour were observed. This raises concerns about the consequences of healthcare avoidance for population health. Aim To determine the association between healthcare avoidance during the early stages of the COVID-19 pandemic and all-cause mortality. Design and setting 32-month follow-up within the population-based Rotterdam Study, after sending a COVID-19 questionnaire at the onset of the pandemic in April 2020 to all non-institutionalised participants (response rate 73%). Method Cox proportional hazards models assessed the risk of all-cause mortality among respondents who avoided healthcare because of the COVID-19 pandemic. Mortality status was collected through municipality registries and medical records. Results Of 5656 respondents, one-fifth avoided healthcare due to the COVID-19 pandemic (N=1143). Compared to non-avoiders, those who avoided healthcare more often reported symptoms of depression (31.2% versus 12.3%) and anxiety (29.7% versus 12.2%), and more often valued their health as poor to fair (29.4% versus 10.1%). Healthcare avoiders had an increased adjusted risk of all-cause mortality (HR: 1.30; 95%CI 1.01-1.67), which remained nearly identical after adjustment for history of any non-communicable disease (1.20;0.93-1.54). However, this association attenuated after additional adjustment for mental and self-appreciated health factors (0.96;0.74-1.24). Conclusion We found an increased risk of all-cause mortality among individuals who avoided healthcare during COVID-19. These individuals were characterised by poor mental and physical self-appreciated health. Therefore, interventions should be targeted to these vulnerable individuals to safeguard their access to primary and specialist care in order to limit health disparities, inside and beyond healthcare crises.

Antidepressant use in relation to dementia risk, cognitive decline, and brain atrophy.

INTRODUCTION: We aimed to assess the effect of antidepressant use on dementia risk, cognitive decline, and brain atrophy. METHODS: In this prospective cohort study, we included 5511 dementia-free participants (Mini-Mental State Examination [MMSE] > 25) of the Rotterdam study (57.5% women, mean age 70.6 years). Antidepressant use was extracted from pharmacy records from 1991 until baseline (2002-2008). Incident dementia was monitored from baseline until 2018, with repeated cognitive assessment and magnetic resonance imaging (MRI) every 4 years. RESULTS: Compared to never use, any antidepressant use was not associated with dementia risk (hazard ratio [HR] 1.14, 95% confidence interval [CI] 0.92-1.41), or with accelerated cognitive decline or atrophy of white and gray matter. Compared to never use, dementia risk was somewhat higher with tricyclic antidepressants (HR 1.36, 95% CI 1.01-1.83) than with selective serotonin reuptake inhibitors (HR 1.12, 95% CI 0.81-1.54), but without dose-response relationships, accelerated cognitive decline, or atrophy in either group. DISCUSSION: Antidepressant medication in adults without indication of cognitive impairment was not consistently associated with long-term adverse cognitive effects. HIGHLIGHTS: Antidepressant medications are frequently prescribed, especially among older adults. In this study, antidepressant use was not associated with long-term dementia risk. Antidepressant use was not associated with cognitive decline or brain atrophy. Our results support safe prescription in an older, cognitively healthy population.

Lifetime prevalence and associated factors of itch with skin conditions: atopic dermatitis, psoriasis and dry skin in individuals aged > 50†years.

BACKGROUND: Itch, common in dermatological conditions, is often accompanied by psychological distress and reduced quality of life. However, research on the prevalence and associated factors of itch with skin conditions in general populations is limited. OBJECTIVES: This cross-sectional study aimed to determine the lifetime prevalence of itch with skin conditions and to identify its associated factors in individuals aged > 50 years. METHODS: Participants from the Rotterdam Study, a population-based cohort, were interviewed to assess whether they had ever had an itchy skin condition, defining lifetime itch with skin conditions. Over 20 demographic, lifestyle, dermatological and nondermatological factors were recorded. Multivariable logistic regression analysis explored associations between these factors and itch with skin conditions, reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: In total, 5246 eligible participants were included (age range 51-100 years, median age 67; 56.0% women). The results revealed a -lifetime prevalence of 33.7% for itch with skin conditions. Factors significantly associated with itch were female sex (OR 1.26, 95% CI 1.11-1.43), body mass index (1.02, 1.01-1.03), self-reported atopic dermatitis (4.29, 3.74-4.92), presence of atopic dermatitis (1.97, 1.60-2.43), self--reported psoriasis (2.31, 1.77-3.01), presence of psoriasis (2.11, 1.55-2.87), self-reported dry skin (1.95, 1.73-2.20), self-reported asthma (1.40, 1.08-1.83), renal impairment (1.45, 1.17-1.79), and clinically relevant depressive (1.85, 1.52-2.25) and anxiety symptoms (1.36, 1.11-1.66). CONCLUSIONS: This study reveals a substantial one-third lifetime prevalence of itch with skin conditions in individuals aged > 50 years. Significant associations with diverse lifestyle, demographic, dermatological and, intriguingly, nondermatological factors, including renal impairment, imply additional contributors to induction or persistence of itch in individuals with skin conditions.

Burden of intracranial artery calcification in white patients with ischemic stroke.

INTRODUCTION: The diagnostic workup of stroke doesn't identify an underlying cause in two-fifths of ischemic strokes. Intracranial arteriosclerosis is acknowledged as a cause of stroke in Asian and Black populations, but is underappreciated as such in whites. We explored the burden of Intracranial Artery Calcification (IAC), a marker of intracranial arteriosclerosis, as a potential cause of stroke among white patients with recent ischemic stroke or TIA. PATIENTS AND METHODS: Between December 2005 and October 2010, 943 patients (mean age 63.8 (SD ± 14.0) years, 47.9% female) were recruited, of whom 561 had ischemic stroke and 382 a TIA. CT-angiography was conducted according to stroke analysis protocols. The burden of IAC was quantified on these images, whereafter we assessed the presence of IAC per TOAST etiology underlying the stroke and assessed associations between IAC burden, symptom severity, and short-term functional outcome. RESULTS: IAC was present in 62.4% of patients. Furthermore, IAC was seen in 84.8% of atherosclerotic strokes, and also in the majority of strokes with an undetermined etiology (58.5%). Additionally, patients with larger IAC burden presented with heavier symptoms (adjusted OR 1.56 (95% CI [1.06-2.29]), but there was no difference in short-term functional outcome (1.14 [0.80-1.61]). CONCLUSION: IAC is seen in the majority of white ischemic stroke patients, aligning with findings from patient studies in other ethnicities. Furthermore, over half of patients with a stroke of undetermined etiology presented with IAC. Assessing IAC burden may help identify the cause in ischemic stroke of undetermined etiology, and could offer important prognostic information.

The Rotterdam Study. Design update and major findings between 2020 and 2024.

The Rotterdam Study is a population-based cohort study, started in 1990 in the district of Ommoord in the city of Rotterdam, the Netherlands, with the aim to describe the prevalence and incidence, unravel the etiology, and identify targets for prediction, prevention or intervention of multifactorial diseases in mid-life and elderly. The study currently includes 17,931 participants (overall response rate 65%), aged 40 years and over, who are examined in-person every 3 to 5 years in a dedicated research facility, and who are followed-up continuously through automated linkage with health care providers, both regionally and nationally. Research within the Rotterdam Study is carried out along two axes. First, research lines are oriented around diseases and clinical conditions, which are reflective of medical specializations. Second, cross-cutting research lines transverse these clinical demarcations allowing for inter- and multidisciplinary research. These research lines generally reflect subdomains within epidemiology. This paper describes recent methodological updates and main findings from each of these research lines. Also, future perspective for coming years highlighted.

Brain artery diameters and risk of dementia and stroke.

INTRODUCTION: We tested the association of brain artery diameters with dementia and stroke risk in three distinct population-based studies using conventional T2-weighted brain magnetic resonance imaging (MRI) images. METHODS: We included 8420 adults > 40 years old from three longitudinal population-based studies with brain MRI scans. We estimated and meta-analyzed the hazard ratios (HRs) of the brain and carotids and basilar diameters associated with dementia and stroke. RESULT: Overall and carotid artery diameters > 95th percentile increased the risk for dementia by 1.74 (95% confidence interval [CI], 1.13-2.68) and 1.48 (95% CI, 1.12-1.96) fold, respectively. For stroke, meta-analyses yielded HRs of 1.59 (95% CI, 1.04-2.42) for overall arteries and 2.11 (95% CI, 1.45-3.08) for basilar artery diameters > 95th percentile. DISCUSSION: Individuals with dilated brain arteries are at higher risk for dementia and stroke, across distinct populations. Our findings underline the potential value of T2-weighted brain MRI-based brain diameter assessment in estimating the risk of dementia and stroke.

Burden of cardiometabolic disorders and lifetime risk of new-onset atrial fibrillation among men and women: the Rotterdam Study.

AIMS: To examine the association between the burden of cardiometabolic disorders with new-onset atrial fibrillation (AF) and lifetime risk of AF incidence among men and women. METHODS AND RESULTS: Four thousand one hundred and one men and 5421 women free of AF at baseline (1996-2008) from the population-based Rotterdam Study were included. Sex-specific Cox proportional-hazards regression models were used to assess the association between the burden of cardiometabolic disorders and risk of new-onset AF. The remaining lifetime risk for AF was estimated at index ages of 55, 65, and 75 years up to age 108. Mean age at baseline was 65.5 ± 9.4 years. Median follow-up time was 12.8 years. In the fully adjusted model, a stronger association was found between a larger burden of cardiometabolic disorders and incident AF among women [hazard ratio (HR): 1.33% and 95% conference interval (CI): 1.22-1.46], compared to men [1.18 (1.08-1.29)] (P for sex-interaction <0.05). The lifetime risk for AF significantly increased with the number of cardiometabolic disorders among both sexes. At an index age of 55 years, the lifetime risks (95% CIs) for AF were 27.1% (20.8-33.4), 26.5% (22.8-30.5), 29.9% (26.7-33.2), 30.8% (25.7-35.8), and 33.3% (23.1-43.6) among men, for 0, 1, 2, 3, and ≥4 comorbid cardiometabolic disorders. Corresponding risks were 15.8% (10.5-21.2), 23.0% (19.8-26.2), 29.7% (26.8-32.6), 26.2% (20.8-31.6), and 34.2% (17.3-51.1) among women. CONCLUSION: We observed a significant combined impact of cardiometabolic disorders on AF risk, in particular among women. Participants with cardiometabolic multimorbidity had a significantly higher lifetime risk of AF, especially at a young index age.

The present study examined the association between the burden of cardiometabolic disorders with new-onset atrial fibrillation (AF) and lifetime risk of AF incidence among 4101 men and 5421 women from the Rotterdam Study cohort. We observed a significant combined impact of cardiometabolic disorders on AF risk, in particular among women. Participants with cardiometabolic multimorbidity had a significantly higher lifetime risk of AF, especially at a young index age.A stronger association was found between a larger burden of cardiometabolic disorders and incident AF among women [hazard ratio: 1.33% and 95% conference interval: 1.22­1.46], compared to men [1.18 (1.08­1.29)] (P for sex-interaction <0.05).Among participants aged 55 years or older, the lifetime risk of AF was 25.2% among healthy men and 16.3% among healthy women. Individuals with cardiometabolic multimorbidity exhibited a markedly escalated lifetime risk of AF, particularly evident at a younger age.

Skin autofluorescence, reflecting accumulation of advanced glycation end products, and the risk of dementia in a population-based cohort.

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.

Sleep and 24-H Activity Rhythms and the Risk of Stroke: A Prospective Cohort Study.

INTRODUCTION: Short and long self-reported sleep durations are associated with a higher risk of stroke, but the association between objective estimates of sleep and 24-h activity rhythms is less clear. We studied the association of actigraphy-estimated sleep and 24-h activity rhythms with the risk of stroke in a population-based cohort of middle-aged and elderly. METHODS: We included 1,718 stroke-free participants (mean age 62.2 ± 9.3 years, 55.1% women) from the prospective, population-based Rotterdam Study. Actigraphy-estimated sleep (total sleep time, sleep efficiency, sleep onset latency, and wake after sleep onset) and 24-h activity rhythms (interdaily stability, intradaily variability, and onset of the least active 5 h) were measured during a median of 7 days (Q1-Q3: 6-7 days). The association of sleep and 24-h activity rhythms with risk of stroke was analyzed using Cox proportional hazards models. RESULTS: During a mean follow-up of 12.2 years (SD: 3.2), 105 participants developed a stroke, of whom 81 had an ischemic event. Although there was no clear association between actigraphy-estimated sleep and the risk of stroke, a more fragmented 24-h activity rhythm was associated with a higher risk of stroke (hazard ratio [HR] per SD increase 1.28, 95% confidence interval [CI] 1.07-1.53). A less stable (HR per SD increase in stability 0.78, 95% CI: 0.63-0.97) and more fragmented (HR 1.28, 95% CI: 1.04-1.58) 24-h activity rhythm was also associated with a higher risk of ischemic stroke. CONCLUSIONS: Disturbed 24-h activity rhythms, but not sleep, are associated with a higher risk of stroke in middle-aged and elderly persons. This suggests that unstable and fragmented activity rhythms may play a more prominent role in the risk of stroke than sleep per se.

No association between blood-based markers of immune system and migraine status: a population-based cohort study.

BACKGROUND: Although some evidence implicates the immune system in migraine attacks, its role during attack-free periods remains largely unexplored. Therefore, we assessed the association between the immune system and migraine status. METHODS: From the population-based Rotterdam Study, we included 6593 participants who underwent blood sampling and migraine assessments. In the blood samples, we measured white blood-cell-based immune markers. As a marker for the innate immune system, granulocyte and platelet counts were determined, whereas lymphocyte counts were used as a marker for the adaptive immune system. Migraine was assessed using a validated questionnaire based on ICHD-2 criteria. We investigated associations between blood-cell counts and migraine using logistic regression models adjusting for age, sex and other variables. RESULTS: Mean age of participants was 65.6 ± 11.2 years and 56.7% were female. The lifetime prevalence of migraine was 15.1% (995/6593). We found no statistically significant associations between granulocyte (odds ratio [OR] per standard deviation increase 1.01 95% Confidence Interval [CI]: 0.93-1.09), platelet (OR 1.01 CI: 0.94-1.09) or lymphocyte counts (OR 1.01 CI: 0.93-1.08) and migraine status. CONCLUSIONS: Our results do not support an association between white blood-cell-based immunity markers and migraine status.

Plant-based dietary patterns and the risk of dementia: a population-based study.

BACKGROUND: Plant-based dietary patterns are increasingly popular in western countries and are supported by many governments and health organisations for their potential beneficial role in the prevention of chronic diseases. Yet, the potential role of plant-based dietary patterns in the development of dementia remains unclear. OBJECTIVE: To evaluate the association between plant-based dietary patterns and the risk of dementia. METHODS: Dietary intake was measured at baseline in 9,543 dementia-free participants (mean age 64 years, birth years 1897-1960, 58% women) of the prospective population-based Rotterdam Study, using food frequency questionnaires. Based on these questionnaires, we calculated an overall plant-based dietary index (PDI), healthy PDI (hPDI) and unhealthy PDI (uPDI), with higher scores reflecting higher consumption of (any, healthy and unhealthy, respectively) plant-based foods and lower consumption of animal-based foods. We analysed the association of the PDIs with incident dementia using Cox proportional hazard models. RESULTS: During a mean follow-up of 14.5 years, 1,472 participants developed dementia. Overall, the PDIs were not associated with the risk of dementia (hazard ratio [95% confidence interval] per 10-point increase: 0.99 [0.91-1.08] for PDI, 0.93 [0.86-1.01] for hPDI, 1.02 [0.94-1.10] for uPDI). However, among men and APOE ε4 carriers, a higher hPDI was linearly associated with a lower risk of dementia (0.86 [0.75-0.99] and 0.83 [0.73-0.95], respectively), while this association was U-shaped among APOE ε4 non-carriers (P value for non-linearity = 0.01). CONCLUSIONS: We found no strong evidence for an overall association between plant-based eating and the risk of dementia. Our findings in stratified analyses warranted further investigation.

The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis.

BACKGROUND: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT4 based on the risk of cardiovascular disease and mortality. METHODS: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT4, and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT4, thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. FINDINGS: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality. INTERPRETATION: There was a J-shaped association of FT4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes. FUNDING: None.

Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality.

BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.).

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

BACKGROUND: Nitric 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. OBJECTIVES: This 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. METHODS: Between 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). RESULTS: Participants 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. CONCLUSIONS: A 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.

Patient perspectives on telemedicine during the COVID-19 pandemic: a mixed-methods community-based study.

BACKGROUND: Detailed community-based perspectives on patient experiences with telemedicine are currently lacking, yet essential to assess clinical applicability of telemedicine during and beyond pandemics, alike COVID-19. The aim of this study was to expose patient perspectives on virtual compared to in-person consultations, including determinants of these preferences. METHODS: We invited 5864 participants of the population-based Rotterdam Study to fill in a validated questionnaire using both close-ended and free-text questions. The questionnaire was sent on 30 July 2020, following a period of lockdowns and closures of non-essential workplaces. It assessed preferences for physician contact, healthcare utilisation, socioeconomic factors, and overall health. Those who experienced at least one virtual consultation (telephone or video call) between March 2020 and the beginning of July 2020 were asked whether those consultations were more, equally or less pleasant than in-person consultations, and to detail their experiences through free-text comments. These narrative data were examined using thematic analysis. RESULTS: 4514 participants completed the questionnaire (response rate 77.0%, 58.7% women, mean age 70.8 ± 10.5 years). 1103 participants (24.4%) reported having had experience with virtual consultations. Half of these participants considered virtual consultations less pleasant than in-person consultations (N = 556; 50.4%), while 11.5% found it more pleasant. In total, we coded free-text comments of 752 participants. Prominent themes behind patient preferences for virtual or in-person consultations were lack of nonverbal communication, lack of physical examination, consultation scheduling, personal circumstances, and the presence of somatic and/or language barriers. CONCLUSIONS: Based on the experiences of a large elderly patient population, we showed that preference for virtual or in-person consultations is dependent on personal and situational variety, and their interplay. Healthcare providers should consider patients' complex care needs and evaluate the potential added value of nonverbal communication and physical examination before scheduling a virtual consultation.

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.