Publications by authors named "Albert Hofman"

1,755 Publications

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Immune age and biological age as determinants of vaccine responsiveness among elderly populations: the Human Immunomics Initiative research program.

Eur J Epidemiol 2021 Jun 12. Epub 2021 Jun 12.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

The Human Immunomics Initiative (HII), a joint project between the Harvard T.H. Chan School of Public Health and the Human Vaccines Project (HVP), focuses on studying immunity and the predictability of immuneresponsiveness to vaccines in aging populations. This paper describes the hypotheses and methodological approaches of this new collaborative initiative. Central to our thinking is the idea that predictors of age-related non-communicable diseases are the same as predictors for infectious diseases like COVID-19 and influenza. Fundamental to our approach is to differentiate between chronological, biological and immune age, and to use existing large-scale population cohorts. The latter provide well-typed phenotypic data on individuals' health status over time, readouts of routine clinical biochemical biomarkers to determine biological age, and bio-banked plasma samples to deep phenotype humoral immune responses as biomarkers of immune age. The first phase of the program involves 1. the exploration of biological age, humoral biomarkers of immune age, and genetics in a large multigenerational cohort, and 2. the subsequent development of models of immunity in relation to health status in a second, prospective cohort of an aging population. In the second phase, vaccine responses and efficacy of licensed COVID-19 vaccines in the presence and absence of influenza-, pneumococcal- and pertussis vaccines routinely offered to elderly, will be studied in older aged participants of prospective population-based cohorts in different geographical locations who will be selected for representing distinct biological and immune ages. The HII research program is aimed at relating vaccine responsiveness to biological and immune age, and identifying aging-related pathways crucial to enhance vaccine effectiveness in aging populations.
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http://dx.doi.org/10.1007/s10654-021-00767-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196271PMC
June 2021

Strengthening Health Services Research Using Target Trial Emulation: An Application to Volume-Outcomes Studies.

Am J Epidemiol 2021 Jun 4. Epub 2021 Jun 4.

Harvard T.H. Chan School of Public Health, Department of Epidemiology, Boston, Massachusetts, United States.

The number of operations that surgeons have previously performed is associated with their patients' outcomes. However, this association may not be causal because previous studies have often been cross-sectional and their analyses have not considered time-varying confounding or positivity violations. Using the example of surgeons who perform coronary artery bypass grafting, we first describe (hypothetical) target trials to estimate the causal effect of the surgeons' operative volumes on patient mortality. We then demonstrate how to emulate these target trials using data from United States Medicare claims and provide effect estimates. Our target trial emulations suggest that interventions on physicians' volume of coronary artery bypass grafting operations have little effect on patient mortality. The target trial framework highlights key assumptions and draws attention to areas of bias in previous observational analyses that deviated from their implicit target trial. The principles of the presented methodology may be adapted to other scenarios of substantive interest in health services research.
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http://dx.doi.org/10.1093/aje/kwab170DOI Listing
June 2021

Visit-to-Visit Blood Pressure Variability, Neuropathology, and Cognitive Decline.

Neurology 2021 06 26;96(23):e2812-e2823. Epub 2021 Apr 26.

From the Department of Epidemiology (Y.M., D. Blacker, A.H.), Harvard T.H. Chan School of Public Health; Departments of Neurology (Y.M., A.V., S.J.v.V., B.T.H., S.D.) and Psychiatry (D. Blacker), Massachusetts General Hospital, Harvard Medical School, Boston; Departments of Epidemiology (D. Bos, M.W.V., A.H.) and Radiology and Nuclear Medicine (D. Bos, M.W.V.), Erasmus MC University Medical Center, Rotterdam, the Netherlands; and University of Bordeaux (C.T.), Inserm, Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux, France.

Objective: Large systolic blood pressure (SBP) variability has been proposed as a novel risk factor for dementia above and beyond SBP levels, but the underlying neuropathology is largely unknown. We investigated the relationship among visit-to-visit SBP variability, cognitive deterioration, and underlying neuropathologic changes.

Methods: We used longitudinal data (between 2005 and 2019) from the National Alzheimer's Coordinating Center. A total of 13,284 dementia-free participants ≥50 years of age were followed up over a median of 5.0 (interquartile range 3.1-7.6) years. Neuropathology data were available in 1,400 autopsied participants. Visit-to-visit SBP variability was quantified from repeated annual SBP measurements. Cognitive deterioration was defined as conversion from normal cognition to mild cognitive impairment (MCI) or dementia or from MCI to dementia.

Results: Larger visit-to-visit SBP variability was associated with cognitive deterioration (adjusted odds ratio comparing extreme quintiles 2.64, 95% confidence interval 2.29-3.04, < 0.001). It was also associated with a higher burden of vascular pathology (including microinfarcts, white matter lesions, atherosclerosis of the circle of Willis, and arteriolosclerosis) and with neurofibrillary tangle pathology assessed by Braak staging (all < 0.05). The association with cognitive deterioration and vascular pathology appeared stronger among those with normal cognition vs those with MCI at baseline. These findings were observed after adjustment for age, sex, mean SBP, and other confounding variables. Similar results were observed for diastolic blood pressure variability.

Conclusion: Larger visit-to-visit SBP variability was associated with cognitive deterioration. It was also associated with cerebrovascular pathology and neurofibrillary tangles. These results suggest the intertwined role of vascular and Alzheimer disease pathology in the etiology of dementia.
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http://dx.doi.org/10.1212/WNL.0000000000012065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205457PMC
June 2021

Lower complexity and higher variability in beat-to-beat systolic blood pressure are associated with elevated long-term risk of dementia: The Rotterdam Study.

Alzheimers Dement 2021 Jul 15;17(7):1134-1144. Epub 2021 Apr 15.

Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Introduction: We hypothesized that subclinical disruption in blood pressure (BP) dynamics, captured by lower complexity and higher variability, may contribute to dementia risk, above and beyond BP levels.

Methods: This prospective cohort study followed 1835 older adults from 1997 to 2016, with BP complexity quantified by sample entropy and BP variability quantified by coefficient of variation using beat-to-beat BP measured at baseline.

Results: Three hundred thirty-four participants developed dementia over 20 years. Reduced systolic BP (SBP) complexity was associated with a higher risk of dementia (hazard ratio [HR] comparing extreme quintiles: 1.55; 95% confidence interval [CI]: 1.09-2.20). Higher SBP variability was also associated with a higher risk of dementia (HR comparing extreme quintiles: 1.57; 95% CI: 1.11-2.22. These findings were observed after adjusting for age, sex, apolipoprotein E (APOE) genotype, mean SBP, and other confounding factors.

Discussions: Our findings suggest that lower complexity and higher variability of beat-to-beat SBP are potential novel risk factors or biomarkers for dementia.
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http://dx.doi.org/10.1002/alz.12288DOI Listing
July 2021

External validity of phase III trials on vaccines against SARS-CoV-2 to a middle-aged and elderly Western European population.

Eur J Epidemiol 2021 Mar 26;36(3):319-324. Epub 2021 Feb 26.

Department of Epidemiology, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, the Netherlands.

Initial results from various phase-III trials on vaccines against SARS-CoV-2 are promising. For proper translation of these results to clinical guidelines, it is essential to determine how well the general population is reflected in the study populations of these trials. This study was conducted among 7162 participants (age-range: 51-106 years; 58% women) from the Rotterdam Study. We quantified the proportion of participants that would be eligible for the nine ongoing phase-III trials. We further quantified the eligibility among participants at high risk to develop severe COVID-19. Since many trials were not explicit in their exclusion criterion with respect to 'acute' or 'unstable preexisting' diseases, we performed two analyses. First, we included all participants irrespective of this criterion. Second, we excluded persons with acute or 'unstable preexisting' diseases. 97% of 7162 participants was eligible for any trial with eligibility for separate trials ranging between 11-97%. For high-risk individuals the corresponding numbers were 96% for any trial with separate trials ranging from 5-96%. Importantly, considering persons ineligible due to 'acute' or 'unstable pre-existing' disease drastically dropped the eligibilities for all trials below 43% for the total population and below 36% for high-risk individuals. The eligibility for ongoing vaccine trials against SARS-CoV-2 can reduce by half depending on interpretation and application of a single unspecified exclusion criterion. This exclusion criterion in our study would especially affect the elderly and those with pre-existing morbidities. These findings thus indicate the difficulty as well as importance of developing clinical recommendations for vaccination and applying these to the appropriate target populations. This becomes especially paramount considering the fact that many countries worldwide have initiated their vaccination programs by first targeting the elderly and most vulnerable persons.
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http://dx.doi.org/10.1007/s10654-021-00729-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906827PMC
March 2021

Cognitive and social activities and long-term dementia risk: the prospective UK Million Women Study.

Lancet Public Health 2021 02;6(2):e116-e123

Cancer Epidemiology Unit, University of Oxford, Oxford, UK.

Background: Although dementia is associated with non-participation in cognitive and social activities, this association might merely reflect the consequences of dementia, rather than any direct effect of non-participation on the subsequent incidence of dementia. Because of the slowness with which dementia can develop, unbiased assessment of any such direct effects must relate non-participation in such activities to dementia detection rates many years later. Prospective studies with long-term follow-up can help achieve this by analysing separately the first and second decade of follow-up. We report such analyses of a large, 20-year study.

Methods: The UK Million Women Study is a population-based prospective study of 1·3 million women invited for National Health Service (NHS) breast cancer screening in median year 1998 (IQR 1997-1999). In median year 2001 (IQR 2001-2003), women were asked about participation in adult education, groups for art, craft, or music, and voluntary work, and in median year 2006 (IQR 2006-2006), they were asked about reading. All participants were followed up through electronic linkage to NHS records of hospital admission with mention of dementia, the first mention of which was the main outcome. Comparing non-participation with participation in a particular activity, we used Cox regression to assess fully adjusted dementia risk ratios (RRs) during 0-4, 5-9, and 10 or more years, after information on that activity was obtained.

Findings: In 2001, 851 307 women with a mean age of 60 years (SD 5) provided information on participation in adult education, groups for art, craft, or music, and voluntary work. After 10 years, only 9591 (1%) had been lost to follow-up and 789 339 (93%) remained alive with no recorded dementia. Follow-up was for a mean of 16 years (SD 3), during which 31 187 (4%) had at least one hospital admission with mention of dementia, including 25 636 (3%) with a hospital admission with dementia mentioned for the first time 10 years or more after follow-up began. Non-participation in cognitive or social activities was associated with higher relative risks of dementia detection only during the first decade after participation was recorded. During the second decade, there was little association. This was true for non-participation in adult education (RR 1·04, 99% CI 0·98-1·09), in groups for art, craft, or music (RR 1·04, 0·99-1·09), in voluntary work (RR 0·96, 0·92-1·00), or in any of these three (RR 0·99, 0·95-1·03). In 2006, 655 118 women provided information on reading. For non-reading versus any reading, there were similar associations with dementia, again with strong attenuation over time since reading was recorded, but longer follow-up is needed to assess this reliably.

Interpretation: Life has to be lived forwards, but can be understood only backwards. Long before dementia is diagnosed, there is a progressive reduction in various mental and physical activities, but this is chiefly because its gradual onset causes inactivity and not because inactivity causes dementia.

Funding: UK Medical Research Council, Cancer Research UK.
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http://dx.doi.org/10.1016/S2468-2667(20)30284-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848753PMC
February 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

PLoS One 2020 13;15(11):e0230035. Epub 2020 Nov 13.

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, United States of America.

Background: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

Methods And Results: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.

Conclusion: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230035PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665790PMC
December 2020

Population-Based Prevalence of Gastrointestinal Abnormalities at Colon Capsule Endoscopy.

Clin Gastroenterol Hepatol 2020 Oct 31. Epub 2020 Oct 31.

Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address:

Background & Aims: The population prevalence of gastrointestinal (GI) disease is unclear and difficult to assess in an asymptomatic population. The aim of this study was to determine prevalence of GI lesions in a largely asymptomatic population undergoing colon capsule endoscopy (CCE).

Methods: Participants aged between 50-75years were retrieved from the Rotterdam Study, a longitudinal epidemiological study, between 2017-2019. Participants received CCE with bowel preparation. Abnormalities defined as clinically relevant were Barrett segment>3cm, severe ulceration, polyp>10 mm or ≥3 polyps in small bowel(SB) or colon, and cancer.

Results: Of 2800 invited subjects, 462 (16.5%) participants (mean age 66.8 years, female 53.5%) ingested the colon capsule. A total of 451 videos were analyzed, and in 94.7% the capsule reached the descending colon. At least 1 abnormal finding was seen in 448 (99.3%) participants. The prevalence of abnormalities per GI segment, and the most common type of abnormality, were as follows: Esophageal 14.8% (Barrett's esophagus <3 cm in 8.3%), gastric 27.9% (fundic gland polyps in 18.1%), SB abnormalities 33.9% (erosions in 23.8%), colon 93.3% (diverticula in 81.2%). A total of 54 participants (12%) had clinically relevant abnormalities, 3 (0.7%) in esophagus/stomach (reflux esophagitis grade D, Mallory Weiss lesion and severe gastritis), 5 (1.1%) in SB (polyps > 10 mm n = 4, severe ulcer n = 1,) and 46 (10.2%) in colon (polyp > 10 mm or ≥3 polyps n = 46, colorectal cancer n = 1).

Conclusions: GI lesions are very common in a mostly asymptomatic Western population, and clinically relevant lesions were found in 12% at CCE. These findings provide a frame of reference for the prevalence rates of GI lesions in the general population.
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http://dx.doi.org/10.1016/j.cgh.2020.10.048DOI Listing
October 2020

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Nat Commun 2020 09 22;11(1):4796. Epub 2020 Sep 22.

Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
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http://dx.doi.org/10.1038/s41467-020-18367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508833PMC
September 2020

Predicting Progression to Advanced Age-Related Macular Degeneration from Clinical, Genetic, and Lifestyle Factors Using Machine Learning.

Ophthalmology 2021 04 2;128(4):587-597. Epub 2020 Sep 2.

Bordeaux Population Health Research Center, Inserm, Université de Bordeaux, Bordeaux, France. Electronic address:

Purpose: Current prediction models for advanced age-related macular degeneration (AMD) are based on a restrictive set of risk factors. The objective of this study was to develop a comprehensive prediction model applying a machine learning algorithm allowing selection of the most predictive risk factors automatically.

Design: Two population-based cohort studies.

Participants: The Rotterdam Study I (RS-I; training set) included 3838 participants 55 years of age or older, with a median follow-up period of 10.8 years, and 108 incident cases of advanced AMD. The Antioxydants, Lipids Essentiels, Nutrition et Maladies Oculaires (ALIENOR) study (test set) included 362 participants 73 years of age or older, with a median follow-up period of 6.5 years, and 33 incident cases of advanced AMD.

Methods: The prediction model used the bootstrap least absolute shrinkage and selection operator (LASSO) method for survival analysis to select the best predictors of incident advanced AMD in the training set. Predictive performance of the model was assessed using the area under the receiver operating characteristic curve (AUC).

Main Outcome Measures: Incident advanced AMD (atrophic, neovascular, or both), based on standardized interpretation of retinal photographs.

Results: The prediction model retained (1) age, (2) a combination of phenotypic predictors (based on the presence of intermediate drusen, hyperpigmentation in one or both eyes, and Age-Related Eye Disease Study simplified score), (3) a summary genetic risk score based on 49 single nucleotide polymorphisms, (4) smoking, (5) diet quality, (6) education, and (7) pulse pressure. The cross-validated AUC estimation in RS-I was 0.92 (95% confidence interval [CI], 0.88-0.97) at 5 years, 0.92 (95% CI, 0.90-0.95) at 10 years, and 0.91 (95% CI, 0.88-0.94) at 15 years. In ALIENOR, the AUC reached 0.92 at 5 years (95% CI, 0.87-0.98). In terms of calibration, the model tended to underestimate the cumulative incidence of advanced AMD for the high-risk groups, especially in ALIENOR.

Conclusions: This prediction model reached high discrimination abilities, paving the way toward making precision medicine for AMD patients a reality in the near future.
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http://dx.doi.org/10.1016/j.ophtha.2020.08.031DOI Listing
April 2021

Blood Pressure Variability and Dementia: A State-of-the-Art Review.

Am J Hypertens 2020 12;33(12):1059-1066

Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux, Bordeaux, France.

Accumulating evidence demonstrates that blood pressure variability (BPV) may contribute to target organ damage, causing coronary heart disease, stroke, and renal disease independent of the level of blood pressure (BP). Several lines of evidence have also linked increased BPV to a higher risk of cognitive decline and incident dementia. The estimated number of dementia cases worldwide is nearly 50 million, and this number continues to grow with increasing life expectancy. Because there is no effective treatment to modify the course of dementia, targeting modifiable vascular factors continues as a top priority for dementia prevention. A clear understanding of the role of BPV in dementia may shed light on the etiology, early prevention, and novel therapeutic targets of dementia, and has therefore gained substantial attention from researchers and clinicians. This review summarizes state-of-art evidence on the relationship between BPV and dementia, with a specific focus on the epidemiological evidence, the underlying mechanisms, and potential intervention strategies. We also discuss challenges and opportunities for future research to facilitate optimal BP management and the clinical translation of BPV for the risk assessment and prevention of dementia.
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http://dx.doi.org/10.1093/ajh/hpaa119DOI Listing
December 2020

Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium.

Neurology 2020 08 1;95(5):e519-e531. Epub 2020 Jul 1.

From the Department of Epidemiology (F.J.W., L.B.C., R.W., D. Blacker, D. Bos, J.G., A.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Departments of Epidemiology (F.J.W., D. Bos, S.K.L.D., M.A.I., M.K.I., A.H.), Radiology and Nuclear Medicine (D. Bos), and Neurology (M.K.I.), Erasmus MC, Rotterdam, the Netherlands; Department of Neurology (L.B.C.), Massachusetts General Hospital, Boston; Department of Infectious Disease Epidemiology (R.A., F.d.W., C. Hadjichrysanthou, K.M.-M., M.M.W.), School of Public Health, Imperial College London, UK; Neuropsychiatry and Epidemiology and Clinical Research (C. Berr), INSERM, UMR 1061 Montpellier, Universite de Montpellier, France; Boston University School of Medicine (A.B., M.P.P., C.L.S., S.S.); Framingham Heart Study (A.B., M.P.P., C.L.S., S.S.), MA; Department of Biostatistics (A.B., K.L.D.-P.), Boston University School of Public Health, MA; Cardiovascular Health Research Unit, Departments of Medicine (J.C.B., B.M.P.) and Epidemiology and Health Services (B.M.P.), University of Washington, Seattle; Department of Psychiatry (D. Blacker), Massachusetts General Hospital, Charlestown; University of Cambridge (C. Brayne), UK; Bordeaux Population Health Research Center (J.-F.D., S.D., C.D., L.G., C. Helmer), INSERM, UMR 1219, University of Bordeaux; Department of Neurology (S.D.), Memory Clinic, Bordeaux University Hospital, France; McGovern Medical School (M.F.), University of Texas Health Science Center at Houston; Icelandic Heart Association (V.G.), Kopavogur; Faculty of Medicine (V.G.), University of Iceland, Reykjavik; Institute of Neuroscience and Physiology (E.J., S.K., I.S., H.W., A.Z.), Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Epidemiology, Graduate School of Public Health (L.H.K.), and Departments of Neurology and Psychiatry (O.L.L.), University of Pittsburgh, PA; Laboratory of Epidemiology and Population Sciences (L.L., O.M.), National Institute on Aging, Bethesda, MD; Institute of Health and Society (F.E.M., B.C.M.S.), Newcastle University, Newcastle upon Tyne, UK; MIND Center (T.H.M.), University of Mississippi Medical Center, Jackson; Melbourne Dementia Research Centre (M.P.P.), The Florey Institute for Neuroscience and Mental Health, Melbourne, Australia; Kaiser Permanente Washington Health Research Institute (B.M.P.), Seattle; and The Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., S.S.), UT Health San Antonio, TX.

Objective: To determine changes in the incidence of dementia between 1988 and 2015.

Methods: This analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex.

Results: Of 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person-years in individuals aged 65-69 years to 65 per 1,000 person-years for those aged 85-89 years. The incidence rate of dementia declined by 13% per calendar decade (95% confidence interval [CI], 7%-19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%-32%] vs 8% [0%-15%]).

Conclusion: The incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations.
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http://dx.doi.org/10.1212/WNL.0000000000010022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455342PMC
August 2020

Long-term prognosis after kidney donation: a propensity score matched comparison of living donors and non-donors from two population cohorts.

Eur J Epidemiol 2020 Jul 21;35(7):699-707. Epub 2020 May 21.

Department of Surgery, Division of HPB and Transplant Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.

Background: Live donor nephrectomy is a safe procedure. However, long-term donor prognosis is debated, necessitating high-quality studies.

Methods: A follow-up study of 761 living kidney donors was conducted, who visited the outpatient clinic and were propensity score matched and compared to 1522 non-donors from population-based cohort studies. Primary outcome was kidney function. Secondary outcomes were BMI (kg/m), incidences of hypertension, diabetes, cardiovascular events, cardiovascular and overall mortality, and quality of life.

Results: Median follow-up after donation was 8.0 years. Donors had an increase in serum creatinine of 26 μmol/l (95% CI 24-28), a decrease in eGFR of 27 ml/min/1.73 m (95% CI - 29 to - 26), and an eGFR decline of 32% (95% CI 30-33) as compared to non-donors. There was no difference in outcomes between the groups for ESRD, microalbuminuria, BMI, incidence of diabetes or cardiovascular events, and mortality. A lower risk of new-onset hypertension (OR 0.45, 95% CI 0.33-0.62) was found among donors. The EQ-5D health-related scores were higher among donors, whereas the SF-12 physical and mental component scores were lower.

Conclusion: Loss of kidney mass after live donation does not translate into negative long-term outcomes in terms of morbidity and mortality compared to non-donors.

Trial Registration: Dutch Trial Register NTR3795.
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http://dx.doi.org/10.1007/s10654-020-00647-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387377PMC
July 2020

Blood Pressure Variation and Subclinical Brain Disease.

J Am Coll Cardiol 2020 05;75(19):2387-2399

Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Background: Large blood pressure (BP) variability may contribute to stroke and dementia, but the mechanisms are largely unknown.

Objectives: This study investigated the association of BP variation, considering its magnitude and direction, with the presence and progression of subclinical brain disease in the general population.

Methods: This study included 2,348 participants age ≥55 years from a prospective cohort study. BP was measured at each visit every 3 to 4 years from 1990 onward. Brain magnetic resonance imaging (MRI) was performed at all visits from 2005 onward. The authors primarily assessed variation as the absolute difference in BP divided by the mean over 2 sequential visits for both systolic BP (SBP) and diastolic BP (DBP), and further assessed the direction of the variation. The authors investigated the multivariate-adjusted associations of BP variation with subsequent measurements of MRI markers of cerebral small vessel disease, brain tissue volumes, and white matter microstructural integrity. Longitudinal changes in these markers also were assessed.

Results: A large SBP variation (top vs. bottom tertiles), measured on average 7 years preceding brain MRI, was associated with higher odds of having severe white matter hyperintensities (WMH) (odds ratio [OR]: 1.32; 95% confidence interval [CI]: 1.21 to 1.43), lacunes (OR: 1.25; 95% CI: 1.04 to 1.48), and microbleeds (OR: 1.16; 95% CI: 1.03 to 1.31). Similarly, this variation was associated with smaller total brain volume and worse white matter microstructural integrity (all p < 0.001). A large SBP variation was also associated with the progression of WMH (rate ratio [RR]: 1.14; 95% CI: 1.02 to 1.27). Higher burdens of these brain imaging markers were observed with both large rises and falls in SBP. Similar findings were observed for DBP variation.

Conclusions: Elevated BP variation was associated with a wide range of subclinical brain structural changes, including MRI markers of cerebral small vessel disease, smaller brain tissue volumes, and worse white matter microstructural integrity. These subclinical brain changes could be the underlying mechanisms linking BP variation to dementia and stroke.
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http://dx.doi.org/10.1016/j.jacc.2020.03.043DOI Listing
May 2020

Long-Term Intake of Dietary Carotenoids Is Positively Associated with Late-Life Subjective Cognitive Function in a Prospective Study in US Women.

J Nutr 2020 07;150(7):1871-1879

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: A protective association of dietary carotenoids with cognitive function has been suggested, but most studies have been relatively small with limited periods of follow-up.

Objectives: We examined prospectively long-term intakes of carotenoids in relation to subjective cognitive function (SCF), a self-reported, validated indicator of cognitive dysfunction.

Methods: Among 49,493 female registered nurses with a mean age of 48 y in 1984, we used multinomial logistic regression to estimate the ORs and 95% CIs relating intakes of carotenoids to self-reported SCF in 2012 and 2014. Mean intakes of carotenoids were calculated from 7 repeated FFQs collected in 1984, 1986, and every 4 y afterwards until 2006. Self-reported SCF was assessed by a 7-item questionnaire on changes in memory and cognition; validity was supported by strong associations with Apolipoprotein E (APOE) ε4 genotype and concurrent cognitive function and cognitive decline measured by telephone-based neuropsychological tests. The mean values of scores assessed in 2012 and 2014 were categorized as "good" (0 points, 40.8%), "moderate" (0.5-2.5 points, 46.9%), and "poor" (3-7 points, 12.3%).

Results: Higher intake of total carotenoids was associated with substantially lower odds of moderate or poor cognitive function after controlling for other dietary and nondietary risk factors and total energy intake. Comparing the top with the bottom quintile of total carotenoids, the multivariable ORs were 0.86 (95% CI: 0.80, 0.93; P-trend < 0.001) for moderate SCF and 0.67 (95% CI: 0.60, 0.75; P-trend < 0.001) for poor SCF. This lower OR was also seen for carotenoids consumed 28 y before SCF assessment. Similar associations were found for total β-carotene, dietary β-carotene, α-carotene, lycopene, lutein + zeaxanthin, and β-cryptoxanthin. The significant associations for β-cryptoxanthin, lycopene, and lutein + zeaxanthin persisted after mutual adjustment for each other.

Conclusions: Our findings support a long-term beneficial role of carotenoid consumption on cognitive function in women.
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http://dx.doi.org/10.1093/jn/nxaa087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330480PMC
July 2020

Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood.

Eur J Epidemiol 2020 Jul 7;35(7):685-697. Epub 2020 May 7.

Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Lund University, 21741, Malmö, Sweden.

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (β = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.
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http://dx.doi.org/10.1007/s10654-020-00638-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867117PMC
July 2020

Plasma tau, neurofilament light chain and amyloid-β levels and risk of dementia; a population-based cohort study.

Brain 2020 04;143(4):1220-1232

Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.

CSF biomarkers, including total-tau, neurofilament light chain (NfL) and amyloid-β, are increasingly being used to define and stage Alzheimer's disease. These biomarkers can be measured more quickly and less invasively in plasma and may provide important information for early diagnosis of Alzheimer's disease. We used stored plasma samples and clinical data obtained from 4444 non-demented participants in the Rotterdam study at baseline (between 2002 and 2005) and during follow-up until January 2016. Plasma concentrations of total-tau, NfL, amyloid-β40 and amyloid-β42 were measured using the Simoa NF-light® and N3PA assays. Associations between biomarker plasma levels and incident all-cause and Alzheimer's disease dementia during follow-up were assessed using Cox proportional-hazard regression models adjusted for age, sex, education, cardiovascular risk factors and APOE ε4 status. Moreover, biomarker plasma levels and rates of change over time of participants who developed Alzheimer's disease dementia during follow-up were compared with age and sex-matched dementia-free control subjects. During up to 14 years follow-up, 549 participants developed dementia, including 374 cases with Alzheimer's disease dementia. A log2 higher baseline amyloid-β42 plasma level was associated with a lower risk of developing all-cause or Alzheimer's disease dementia, adjusted hazard ratio (HR) 0.61 [95% confidence interval (CI), 0.47-0.78; P < 0.0001] and 0.59 (95% CI, 0.43-0.79; P = 0.0006), respectively. Conversely, a log2 higher baseline plasma NfL level was associated with a higher risk of all-cause dementia [adjusted HR 1.59 (95% CI, 1.38-1.83); P < 0.0001] or Alzheimer's disease [adjusted HR 1.50 (95% CI, 1.26-1.78); P < 0.0001]. Combining the lowest quartile group of amyloid-β42 with the highest of NfL resulted in a stronger association with all-cause dementia [adjusted HR 9.5 (95% CI, 2.3-40.4); P < 0.002] and with Alzheimer's disease [adjusted HR 15.7 (95% CI, 2.1-117.4); P < 0.0001], compared to the highest quartile group of amyloid-β42 and lowest of NfL. Total-tau and amyloid-β40 levels were not associated with all-cause or Alzheimer's disease dementia risk. Trajectory analyses of biomarkers revealed that mean NfL plasma levels increased 3.4 times faster in participants who developed Alzheimer's disease compared to those who remained dementia-free (P < 0.0001), plasma values for cases diverged from controls 9.6 years before Alzheimer's disease diagnosis. Amyloid-β42 levels began to decrease in Alzheimer's disease cases a few years before diagnosis, although the decline did not reach significance compared to dementia-free participants. In conclusion, our study shows that low amyloid-β42 and high NfL plasma levels are each independently and in combination strongly associated with risk of all-cause and Alzheimer's disease dementia. These data indicate that plasma NfL and amyloid-β42 levels can be used to assess the risk of developing dementia in a non-demented population. Plasma NfL levels, although not specific, may also be useful in monitoring progression of Alzheimer's disease dementia.
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http://dx.doi.org/10.1093/brain/awaa054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174054PMC
April 2020

Time Trends in Survival Following First Hemorrhagic or Ischemic Stroke Between 1991 and 2015 in the Rotterdam Study.

Stroke 2020 03 20;51(3):STROKEAHA119027198. Epub 2020 Feb 20.

Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands. (R.W., D.B., A. Heshmatollah, M.A.I., A. Hofman, M.K.I.).

Background and Purpose- The introduction of stroke units and the implementation of evidence-based interventions have been a breakthrough in the management of patients with stroke over the past decade. Survival following stroke is an important indicator in monitoring stroke burden. Recent data on survival by stroke subtype in the general population is scarce. We assessed (1) recent temporal time trends in survival; (2) age-standardized death rates; (3) survival probabilities at 6 months, 1, 2, and 3 years following first hemorrhagic or ischemic stroke. Methods- Within the population-based Rotterdam Study between 1991 and 2015, we assessed time trends in survival among 162 with first-ever hemorrhagic and 988 patients with first-ever ischemic stroke across 3 time periods (1991-1998; 1999-2007; 2008-2015) using time-varying Cox regression model and calculated age-standardized death rates according to the European 2010 census population. Results- In the hemorrhagic stroke group, a total of 144 deaths occurred during 386 person-years. Following a hemorrhagic stroke, we observed similar mortality rates over the years with 30 per 100 person-years in 2015 compared with 25/100 person-years in 1991. Similarly, compared with the earliest study period (1991-1998), mortality rates remained unchanged in the latest study period (2008-2015; hazard ratio, 0.97 [95% CI, 0.61-1.57]; =0.93). In the ischemic stroke group, a total of 711 deaths occurred during 4897 person-years. We observed a decline in mortality rates in 2015 (11 per 100 person-years) compared with 1991 (29/100 person-years). This translated to favorable trends in the latest study period 2008 to 2015 (hazard ratio, 0.71 [95% CI, 0.56-0.90]; <0.01). Conclusions- Survival following ischemic stroke has improved over the past decade, while no change was observed in survival following hemorrhagic stroke.
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http://dx.doi.org/10.1161/STROKEAHA.119.027198DOI Listing
March 2020

Perspectives on the Future of Epidemiology: A Framework for Training.

Am J Epidemiol 2020 07;189(7):634-639

Over the past century, the field of epidemiology has evolved and adapted to changing public health needs. Challenges include newly emerging public health concerns across broad and diverse content areas, new methods, and vast data sources. We recognize the need to engage and educate the next generation of epidemiologists and prepare them to tackle these issues of the 21st century. In this commentary, we suggest a skeleton framework upon which departments of epidemiology should build their curriculum. We propose domains that include applied epidemiology, biological and social determinants of health, communication, creativity and ability to collaborate and lead, statistical methods, and study design. We believe all students should gain skills across these domains to tackle the challenges posed to us. The aim is to train smart thinkers, not technicians, to embrace challenges and move the expanding field of epidemiology forward.
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http://dx.doi.org/10.1093/aje/kwaa013DOI Listing
July 2020

Risk of hemorrhagic and ischemic stroke in patients with Alzheimer disease: A synthesis of the literature.

Neurology 2020 02 16;94(6):265-272. Epub 2020 Jan 16.

From the Department of Epidemiology (R.W., L.B.C., D.B., A.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Epidemiology (R.W., D.B., M.K.I., A.H.), Department of Radiology and Nuclear Medicine (D.B.), and Department of Neurology (M.K.I.), Erasmus Medical Center, Rotterdam, The Netherlands.

Objective: To assess the risk of hemorrhagic and ischemic stroke in patients with Alzheimer disease (AD) compared with non-AD controls with similar risk profiles.

Methods: A search was conducted on EMBASE and MEDLINE for reports published up to September 26, 2018. Studies were included if they (1) assessed the incidence of stroke in patients diagnosed with AD; (2) included patients with no history of stroke; and (3) reported outcomes by stroke subtype. The main outcome was relative risk of ischemic or hemorrhagic stroke. Furthermore, the rate of stroke occurrence per 1,000 person-years was assessed. A random-effects meta-analysis was undertaken. The risk of bias in included studies was assessed in terms of selection, comparability, and outcome.

Results: A total of 3,605 studies were screened in the title and abstract phase after removing duplicates, and 88 eligible studies were screened for full text. Eight studies met the inclusion criteria representing 121,719 individuals (AD = 73,044; non-AD = 48,675). Five studies were included in the relative risk analysis, among which 4 studies applied formal matching criteria of 44,544 AD and 44,660 non-AD controls. The included studies were based on nationwide registries from Finland, Sweden, Taiwan (2), United Kingdom (2), 1 clinic-based study from the Netherlands, and 1 US population-based cohort. Among patients with AD, the incidence rate of hemorrhagic stroke was 3.41/1000 person-years (95% CI 2.70-4.32) and 2.23 (95% CI 1.72-2.88) among AD cases and non-AD controls, respectively. This is in contrast to 13.98 (95% CI 9.86-19.81) and 12.12 (95% CI 7.55-19.46) for ischemic stroke among AD cases and non-AD controls, respectively. Compared with non-AD controls with similar risk profiles, patients with AD had a relative risk of 1.42 (95% CI 1.23-1.64) for hemorrhagic stroke and 1.15 (95% CI 0.89-1.48) for ischemic stroke.

Conclusion: Compared with non-AD controls with similar risk profiles, patients with AD are likely at a higher risk of hemorrhagic but not ischemic stroke.
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http://dx.doi.org/10.1212/WNL.0000000000008924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136067PMC
February 2020

Body mass index, diet, physical inactivity, and the incidence of dementia in 1 million UK women.

Neurology 2020 01 18;94(2):e123-e132. Epub 2019 Dec 18.

From the Cancer Epidemiology Unit (S.F., R.F.S., A.B., A.B., A.G., G.K.R., J.G., V.B.) and MRC Population Health Research Unit (S.P.), Nuffield Department of Population Health (R.P.), and Department of Psychiatry (J.G.), University of Oxford; Centre for Medical Informatics (C.S.), Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, UK; Royal Prince Alfred Hospital (P.H.), Sydney, Australia; and Department of Epidemiology (A.H.), Harvard T.H. Chan School of Public Health, Boston, MA.

Objective: To help determine whether midlife obesity is a cause of dementia and whether low body mass index (BMI), low caloric intake, and physical inactivity are causes or merely consequences of the gradual onset of dementia by recording these factors early in a large 20-year prospective study and relating them to dementia detection rates separately during follow-up periods of <5, 5 to 9, 10 to 14, and 15+ years.

Methods: A total of 1,136,846 UK women, mean age 56 (SD 5) years, were recruited in 1996 to 2001 and asked about height, weight, caloric intake, and inactivity. They were followed up until 2017 by electronic linkage to National Health Service records, detecting hospital admissions with mention of dementia. Cox regression yielded adjusted rate ratios (RRs) for first dementia detection during particular follow-up periods.

Results: Fifteen years after the baseline survey, only 1% were lost to follow-up, and 89% remained alive with no detected dementia, of whom 18,695 had dementia detected later, at a mean age of 77 (SD 4) years. Dementia detection during years 15+ was associated with baseline obesity (BMI 30+ vs 20-24 kg/m: RR 1.21, 95% confidence interval 1.16-1.26, < 0.0001) but not clearly with low BMI, low caloric intake, or inactivity at baseline. The latter 3 factors were associated with increased dementia rates during the first decade, but these associations weakened substantially over time, approaching null after 15 years.

Conclusions: Midlife obesity may well be a cause of dementia. In contrast, behavioral changes due to preclinical disease could largely or wholly account for associations of low BMI, low caloric intake, and inactivity with dementia detection during the first decade of follow-up.
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http://dx.doi.org/10.1212/WNL.0000000000008779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988985PMC
January 2020

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Sci Adv 2019 09 4;5(9):eaaw3095. Epub 2019 Sep 4.

Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
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http://dx.doi.org/10.1126/sciadv.aaw3095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904961PMC
September 2019

Blood Pressure Variability and Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis of Population-Based Cohorts.

Stroke 2020 01 27;51(1):82-89. Epub 2019 Nov 27.

From the Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA (Y.M., D.B., A.H., S.P.).

Background and Purpose- Blood pressure (BP) variability may increase the risk of stroke and dementia. It remains inconclusive whether BP variability is associated with cerebral small vessel disease, a common and potentially devastating subclinical disease that contributes significantly to both stroke and dementia. Methods- A systematic review and meta-analysis of prospective cohort studies that examined the association between BP variability and the presence or progression of established markers of cerebral small vessel disease, including white matter hyperintensities, lacunes, and microbleeds on magnetic resonance imaging. We searched MEDLINE, EMBASE, and Web of Science. Ten studies met the criteria for qualitative synthesis and 7 could be included in the meta-analysis. Data were synthetized using random-effect models. Results- These studies included a total of 2796 individuals aged 74 (mean) ±4 (SD) years, with a median follow-up of 4.0 years. A one SD increase in systolic BP variability was associated with increased odds of the presence or progression of white matter hyperintensities (odds ratio, 1.26 [95% CI, 1.06-1.50]). The association of systolic BP variability with the presence of lacunes (odds ratio, 0.93 [95% CI, 0.74-1.16]) and the presence of microbleeds (odds ratio, 1.13 [95% CI, 0.89-1.44]) were not statistically significant. Conclusions- A larger BP variability may be associated with a higher risk of having a higher burden of white matter hyperintensities. Targeting large BP variability has the potential to prevent cerebral small vessel disease and thereby reducing the risk of stroke and dementia. The potential issue of reverse causation and the heterogeneity in the assessment of cerebral small vessel disease markers should be better addressed in future studies.
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http://dx.doi.org/10.1161/STROKEAHA.119.026739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050788PMC
January 2020

Corrigendum: Normal Values of Corrected Heart-Rate Variability in 10-Second Electrocardiograms for All Ages.

Front Physiol 2019;10:1373. Epub 2019 Nov 1.

Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, Netherlands.

[This corrects the article DOI: 10.3389/fphys.2018.00424.].
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http://dx.doi.org/10.3389/fphys.2019.01373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839701PMC
November 2019

Variation in blood pressure and long-term risk of dementia: A population-based cohort study.

PLoS Med 2019 11 12;16(11):e1002933. Epub 2019 Nov 12.

Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Background: Variation in blood pressure may relate to dementia risk via autonomic disturbance or hemodynamic mechanisms, but the long-term associations are unclear. We aimed to determine whether blood pressure variation over a period of years, considering both magnitude and direction, is associated with the risk of dementia.

Methods And Findings: In a prospective cohort study ongoing since 1989 in the Netherlands, 5,273 dementia-free participants (58.1% women; mean [SD] age, 67.6 [8.0] years) were included. As of 2016, 1,059 dementia cases occurred during a median follow-up of 14.6 years. Absolute variation in systolic blood pressure (SBP) was assessed as the absolute difference in SBP divided by the mean over two sequential visits every 4.2 (median) years, with the first quantile set as the reference level. The direction was the rise or fall in SBP, with the third quantile set as the reference level. We estimated the risk of dementia in relation to SBP variation measured at different time windows (i.e., at least 0, 5, 10, and 15 years) prior to dementia diagnosis, with adjustments for age, sex, education, apolipoprotein E (APOE) genotype, vascular risk factors, and history of cardiovascular disease. We repeated the above analysis for variation in diastolic blood pressure (DBP). A large SBP variation was associated with an increased dementia risk, which became more pronounced with longer intervals between the assessment of SBP variation and the diagnosis of dementia. The hazard ratio (HR) associated with large variation (the highest quintile) increased from 1.08 (95% confidence interval [CI] 0.88-1.34, P = 0.337) for risk within 5 years of SBP variation measurement to 3.13 (95% CI 2.05-4.77; P < 0.001) for risk after at least 15 years since the measurement of SBP variation. The increased long-term risk was associated with both large rises (HR for the highest quintile, 3.31 [95% CI 2.11-5.18], P < 0.001) and large falls in SBP (HR for the lowest quintile, 2.20 [95% CI 1.33-3.63], P = 0.002), whereas the higher short-term risk was only associated with large falls in SBP (HR, 1.21 [95% CI 1.00-1.48], P = 0.017). Similar findings were observed for variation in DBP. Despite our assessment of major confounders, potential residual confounding is possible, and the findings on blood pressure variability over periods of years may not be generalizable to variability over periods of days and other shorter periods.

Conclusions: Results of this study showed that a large blood pressure variation over a period of years was associated with an increased long-term risk of dementia. The association between blood pressure variation and dementia appears most pronounced when this variation occurred long before the diagnosis. An elevated long-term risk of dementia was observed with both a large rise and fall in blood pressure.
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http://dx.doi.org/10.1371/journal.pmed.1002933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850672PMC
November 2019

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

BMC Cardiovasc Disord 2019 10 29;19(1):240. Epub 2019 Oct 29.

Department Primary Care & Population Health, University College London, London, UK.

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.

Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration.

Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable.

Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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http://dx.doi.org/10.1186/s12872-019-1187-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820948PMC
October 2019

Prenatal folate, homocysteine and vitamin B levels and child brain volumes, cognitive development and psychological functioning: the Generation R Study.

Br J Nutr 2019 09 22;122(s1):S1-S9. Epub 2016 Jan 22.

Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Rotterdam 3000 CB, The Netherlands.

Previous studies have suggested that prenatal maternal folate deficiency is associated with reduced prenatal brain growth and psychological problems in offspring. However, little is known about the longer-term impact. The aims of this study were to investigate whether prenatal maternal folate insufficiency, high total homocysteine levels and low vitamin B12 levels are associated with altered brain morphology, cognitive and/or psychological problems in school-aged children. This study was embedded in Generation R, a prospective population-based cohort study. The study sample consisted of 256 Dutch children aged between 6 and 8 years from whom structural brain scans were collected using MRI. The mothers of sixty-two children had insufficient (<8 nmol/l) plasma folate concentrations in early pregnancy. Cognitive development was assessed by the Snijders-Oomen Niet-verbale intelligentietest - Revisie and the NEPSY-II-NL. Psychological problems were assessed at age 6 years using the parent report of the Child Behavior Checklist. Low prenatal folate levels were associated with a smaller total brain volume (B -33·34; 95 % CI -66·7, 0·02; P=050) and predicted poorer performance on the language (B -0·28; 95 % CI -0·52, -0·04; P=0·020) and visuo-spatial domains (B -0·27; 95 % CI -0·50, -0·04; P=0·021). High homocysteine levels (>9·1 µmol/l) predicted poorer performance on the language (B -0·31; 95 % CI -0·56, -0·06; P=0·014) and visuo-spatial domains (B -0·36; 95 % CI -0·60, -0·11; P=0·004). No associations with psychological problems were found. Our findings suggest that folate insufficiency in early pregnancy has a long-lasting, global effect on brain development and is, together with homocysteine levels, associated with poorer cognitive performance.
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http://dx.doi.org/10.1017/S0007114515002081DOI Listing
September 2019

Genetic architecture of subcortical brain structures in 38,851 individuals.

Nat Genet 2019 11 21;51(11):1624-1636. Epub 2019 Oct 21.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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http://dx.doi.org/10.1038/s41588-019-0511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055269PMC
November 2019
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