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1.
Artigo em Inglês | MEDLINE | ID: mdl-31575746

RESUMO

The gap between predicted brain age using magnetic resonance imaging (MRI) and chronological age may serve as a biomarker for early-stage neurodegeneration. However, owing to the lack of large longitudinal studies, it has been challenging to validate this link. We aimed to investigate the utility of such a gap as a risk biomarker for incident dementia using a deep learning approach for predicting brain age based on MRI-derived gray matter (GM). We built a convolutional neural network (CNN) model to predict brain age trained on 3,688 dementia-free participants of the Rotterdam Study (mean age 66 ± 11 y, 55% women). Logistic regressions and Cox proportional hazards were used to assess the association of the age gap with incident dementia, adjusted for age, sex, intracranial volume, GM volume, hippocampal volume, white matter hyperintensities, years of education, and APOE ε4 allele carriership. Additionally, we computed the attention maps, which shows which regions are important for age prediction. Logistic regression and Cox proportional hazard models showed that the age gap was significantly related to incident dementia (odds ratio [OR] = 1.11 and 95% confidence intervals [CI] = 1.05-1.16; hazard ratio [HR] = 1.11, and 95% CI = 1.06-1.15, respectively). Attention maps indicated that GM density around the amygdala and hippocampi primarily drove the age estimation. We showed that the gap between predicted and chronological brain age is a biomarker, complimentary to those that are known, associated with risk of dementia, and could possibly be used for early-stage dementia risk screening.

2.
JCI Insight ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31600170

RESUMO

BACKGROUND: The presence of an early repolarization pattern (ERP) on the surface electrocardiogram (ECG) is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait but molecular genetic determinants are unknown. METHODS: To identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry. RESULTS: We identified a genome-wide significant (p<5E-8) locus in the KCND3 (potassium voltage gated channel subfamily D member 3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, p=7.7E-12), but did not reveal additional loci. Co-localization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery. CONCLUSIONS: In this study we identified for the first time a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene not only provide insights into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies. FUNDING: For detailed information per study, see Acknowledgments.

3.
Alzheimers Dement ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31515066

RESUMO

INTRODUCTION: Poor gait has recently emerged as a potential prodromal feature of cognitive decline and dementia. We assessed to what extent various aspects of poor gait are independently associated with cognitive decline and incident dementia. METHODS: We leveraged detailed quantitative gait (GAITRite™) and cognitive assessments in 4258 dementia-free participants (median age 67 years, 55% women) of the population-based Rotterdam Study (baseline 2009-2013). We summarized 30 gait parameters into seven mutually independent gait domains and a Global Gait score. Participants underwent follow-up cognitive assessments between 2014 and 2016 and were followed up for incident dementia until 2016 (median 4 years). RESULTS: Three independent gait domains (Base of Support, Pace, and Rhythm) and Global Gait were associated with cognitive decline. Two independent gait domains (Pace and Variability) and Global Gait were associated with incident dementia. Associations of gait with cognitive decline and incident dementia were only present in individuals who had been cognitively unimpaired at baseline. DISCUSSION: Poor performance on several independent gait domains precedes cognitive decline and incident dementia.

4.
Neurobiol Aging ; 84: 9-16, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31491596

RESUMO

Brain imaging data are increasingly made publicly accessible, and volumetric imaging measures derived from population-based cohorts may serve as normative data for individual patient diagnostic assessment. Yet, these normative cohorts are usually not a perfect reflection of a patient's base population, nor are imaging parameters such as field strength or scanner type similar. In this proof of principle study, we assessed differences between reference curves of subcortical structure volumes of normal controls derived from two population-based studies and a case-control study. We assessed the impact of any differences on individual assessment of brain structure volumes. Percentile curves were fitted on the three healthy cohorts. Next, percentile values for these subcortical structures for individual patients from these three cohorts, 91 mild cognitive impairment and 95 Alzheimer's disease cases and patients from the Alzheimer Center, were calculated, based on the distributions of each of the three cohorts. Overall, we found that the subcortical volume normative data from these cohorts are highly interchangeable, suggesting more flexibility in clinical implementation.

5.
Eur J Epidemiol ; 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31494793

RESUMO

Inferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 ± 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUCcrossvalidation 0.925 ± 0.021, AUCexternalvalidation0.914), former (0.766 ± 0.023, 0.699) and never smoking (0.830 ± 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 ± 0.068, 0.796; 15 pack-years 0.767 ± 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 ± 0.024, 0.760; 10 years 0.766 ± 0.033, 0.764; 15 years 0.767 ± 0.020, 0.754). Model application to children revealed highly accurate inference of the true non-smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications.

6.
PLoS One ; 14(9): e0222809, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31536581

RESUMO

OBJECTIVES: Cardiovascular disease (CVD) is one of the major causes of death worldwide. For improved accuracy of CVD prediction, risk classification was performed using national time-series health examination data. The data offers an opportunity to access deep learning (RNN-LSTM), which is widely known as an outstanding algorithm for analyzing time-series datasets. The objective of this study was to show the improved accuracy of deep learning by comparing the performance of a Cox hazard regression and RNN-LSTM based on survival analysis. METHODS AND FINDINGS: We selected 361,239 subjects (age 40 to 79 years) with more than two health examination records from 2002-2006 using the National Health Insurance System-National Health Screening Cohort (NHIS-HEALS). The average number of health screenings (from 2002-2013) used in the analysis was 2.9 ± 1.0. Two CVD prediction models were developed from the NHIS-HEALS data: a Cox hazard regression model and a deep learning model. In an internal validation of the NHIS-HEALS dataset, the Cox regression model showed a highest time-dependent area under the curve (AUC) of 0.79 (95% CI 0.70 to 0.87) for in females and 0.75 (95% CI 0.70 to 0.80) in males at 2 years. The deep learning model showed a highest time-dependent AUC of 0.94 (95% CI 0.91 to 0.97) for in females and 0.96 (95% CI 0.95 to 0.97) in males at 2 years. Layer-wise Relevance Propagation (LRP) revealed that age was the variable that had the greatest effect on CVD, followed by systolic blood pressure (SBP) and diastolic blood pressure (DBP), in that order. CONCLUSION: The performance of the deep learning model for predicting CVD occurrences was better than that of the Cox regression model. In addition, it was confirmed that the known risk factors shown to be important by previous clinical studies were extracted from the study results using LRP.

7.
J Natl Cancer Inst ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31498410

RESUMO

BACKGROUND: An emerging body of research suggests that non-central nervous system (CNS) cancer may negatively impact the brain apart from effects of cancer treatment. However, studies assessing cognitive function in newly diagnosed cancer patients cannot exclude selection bias and psychological effects of cancer diagnosis. To overcome these limitations, we investigated trajectories of cognitive function of patients before cancer diagnosis. METHODS: Between 1989 and 2013, 2059 participants from the population-based Rotterdam Study were diagnosed with non-CNS cancer. Cognitive assessments were performed every three-five years using a neuropsychological battery. The general cognitive factor was composed of individual cognitive tests to assess global cognition. Using linear mixed models we compared change in cognitive function of cancer cases before diagnosis with cognitive change of age-matched cancer-free controls (1:2). In addition we performed sensitivity analyses by discarding assessments of controls five years before the end of follow-up to exclude effects from potential undiagnosed cancer. All statistical tests were two-sided. RESULTS: The Word Learning Test immediate recall declined faster among cases than among controls (-0.05 [95%CI=-0.09;-0.01] versus 0.01 [95%CI=-0.01;0.03], P for difference=.003). However, this difference was not statistically significant in sensitivity analyses. Furthermore, no statistically significant differences were observed in change of other individual cognitive tests and of the general cognitive factor. CONCLUSION: In this study we evaluated cognitive function in a large group of cancer patients prior to diagnosis, thereby excluding the psychological impact of cancer diagnosis and biased patient selection. In contrast to previous studies shortly after cancer diagnosis, we found no difference in change of cognitive function between cancer patients and controls.

9.
Headache ; 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31559635

RESUMO

OBJECTIVE: To investigate the association of migraine genetic variants with cerebral blood flow (CBF). BACKGROUND: Migraine is a common disorder with many genetic and non-genetic factors affecting its occurrence. The exact pathophysiological mechanisms underlying the disease remain unclear, but are known to involve hemodynamic and vascular disruptions. Recent genome-wide association studies have identified 44 genetic variants in 38 genetic loci that affect the risk of migraine, which provide the opportunity to further disentangle these mechanisms. METHODS: We included 4665 participants of the population-based Rotterdam Study (mean age 65.0 ± 10.9 years, 55.6% women). Cross-sectional area (mm2 ), flow velocity (mm/s), and blood flow (mL/min) were measured in both carotids and the basilar artery using 2-dimensional phase-contrast magnetic resonance imaging. We analyzed 43 previously identified migraine variants separately and calculated a genetic risk score (GRS). To assess the association with CBF, we used linear regression models adjusted for age, sex, and total brain volume. Hierarchical clustering was performed based on the associations with CBF measures and tissue enrichment. RESULTS: The rs67338227 risk allele was associated with higher flow velocity and smaller cross-sectional area in the carotids (Pminimum  = 3.7 × 10-8 ). Other variants were related to CBF with opposite directions of effect, but not significantly after multiple testing adjustments (P < 1.4 × 10-4 ). The migraine GRS was not associated with CBF after multiple testing corrections. Migraine risk variants were found to be enriched for flow in the basilar artery (λ = 2.39). CONCLUSIONS: These findings show that genetic migraine risk is complexly associated with alterations in cerebral hemodynamics.

10.
Neurology ; 93(9): e917-e926, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31366722

RESUMO

OBJECTIVE: To determine the long-term association of hemoglobin levels and anemia with risk of dementia, and explore underlying substrates on brain MRI in the general population. METHODS: Serum hemoglobin was measured in 12,305 participants without dementia of the population-based Rotterdam Study (mean age 64.6 years, 57.7% women). We determined risk of dementia and Alzheimer disease (AD) (until 2016) in relation to hemoglobin and anemia. Among 5,267 participants without dementia with brain MRI, we assessed hemoglobin in relation to vascular brain disease, structural connectivity, and global cerebral perfusion. RESULTS: During a mean follow-up of 12.1 years, 1,520 individuals developed dementia, 1,194 of whom had AD. We observed a U-shaped association between hemoglobin levels and dementia (p = 0.005), such that both low and high hemoglobin levels were associated with increased dementia risk (hazard ratio [95% confidence interval (CI)], lowest vs middle quintile 1.29 [1.09-1.52]; highest vs middle quintile 1.20 [1.00-1.44]). Overall prevalence of anemia was 6.1%, and anemia was associated with a 34% increased risk of dementia (95% CI 11%-62%) and 41% (15%-74%) for AD. Among individuals without dementia with brain MRI, similar U-shaped associations were seen of hemoglobin with white matter hyperintensity volume (p = 0.03), and structural connectivity (for mean diffusivity, p < 0.0001), but not with presence of cortical and lacunar infarcts. Cerebral microbleeds were more common with anemia. Hemoglobin levels inversely correlated to cerebral perfusion (p < 0.0001). CONCLUSION: Low and high levels of hemoglobin are associated with an increased risk of dementia, including AD, which may relate to differences in white matter integrity and cerebral perfusion.

11.
Stroke ; 50(9): 2293-2298, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31390971

RESUMO

Background and Purpose- Recent findings suggest that vitamin D, a neuroprotective prohormone, is involved in the pathogenesis of cardiovascular disease. However, previous studies investigating the association between vitamin D and stroke have shown inconsistent findings. In view of these discrepancies, we determined the association of vitamin D status with stroke using data from a population-based study. Methods- Within the RS (Rotterdam Study), an ongoing prospective population-based study, we measured serum 25-hydroxyvitamin D concentrations between 1997 and 2008 in 9680 participants (56.8% women) aged ≥45 years. We assessed a history of stroke at baseline and subsequently followed for incident stroke until January 1, 2016. Regression models were used to investigate the association of serum 25-hydroxyvitamin D with prevalent and incident stroke separately, adjusted for age, sex, study cohort, season of blood sampling, and other cardiovascular risk factors. Results- Of 9680 participants, 339 had a history of stroke at baseline. Serum 25-hydroxyvitamin D concentration was associated with prevalent stroke, adjusted odds ratio per SD decrease, 1.31; 95% CI, 1.14-1.51. After excluding participants with prevalent stroke, we followed 9338 participants for a total of 98 529 person-years. During follow-up, 735 participants developed a stroke. Lower serum 25-hydroxyvitamin D concentration was not associated with a higher stroke risk, adjusted hazard ratio per SD decrease, 1.06; 95% CI, 0.97-1.16. However, severe vitamin D deficiency did show a significant association: hazard ratio, 1.25; 95% CI, 1.05-1.50. Conclusions- In this population-based cohort, we found an association between vitamin D and prevalent stroke. Only severe vitamin D deficiency was associated with incident stroke. This suggests that lower vitamin D levels do not lead to a higher stroke risk but are instead a consequence of stroke.

12.
Nat Commun ; 10(1): 3346, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431621

RESUMO

Predicting longer-term mortality risk requires collection of clinical data, which is often cumbersome. Therefore, we use a well-standardized metabolomics platform to identify metabolic predictors of long-term mortality in the circulation of 44,168 individuals (age at baseline 18-109), of whom 5512 died during follow-up. We apply a stepwise (forward-backward) procedure based on meta-analysis results and identify 14 circulating biomarkers independently associating with all-cause mortality. Overall, these associations are similar in men and women and across different age strata. We subsequently show that the prediction accuracy of 5- and 10-year mortality based on a model containing the identified biomarkers and sex (C-statistic = 0.837 and 0.830, respectively) is better than that of a model containing conventional risk factors for mortality (C-statistic = 0.772 and 0.790, respectively). The use of the identified metabolic profile as a predictor of mortality or surrogate endpoint in clinical studies needs further investigation.

13.
Korean Circ J ; 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31456363

RESUMO

BACKGROUND AND OBJECTIVES: We aim to explore the additional discriminative accuracy of a deep learning (DL) algorithm using repeated-measures data for identifying people at high risk for cardiovascular disease (CVD), compared to Cox hazard regression. METHODS: Two CVD prediction models were developed from National Health Insurance Service-Health Screening Cohort (NHIS-HEALS): a Cox regression model and a DL model. Performance of each model was assessed in the internal and 2 external validation cohorts in Koreans (National Health Insurance Service-National Sample Cohort; NHIS-NSC) and in Europeans (Rotterdam Study). A total of 412,030 adults in the NHIS-HEALS; 178,875 adults in the NHIS-NSC; and the 4,296 adults in Rotterdam Study were included. RESULTS: Mean ages was 52 years (46% women) and there were 25,777 events (6.3%) in NHIS-HEALS during the follow-up. In internal validation, the DL approach demonstrated a C-statistic of 0.896 (95% confidence interval, 0.886-0.907) in men and 0.921 (0.908-0.934) in women and improved reclassification compared with Cox regression (net reclassification index [NRI], 24.8% in men, 29.0% in women). In external validation with NHIS-NSC, DL demonstrated a C-statistic of 0.868 (0.860-0.876) in men and 0.889 (0.876-0.898) in women, and improved reclassification compared with Cox regression (NRI, 24.9% in men, 26.2% in women). In external validation applied to the Rotterdam Study, DL demonstrated a C-statistic of 0.860 (0.824-0.897) in men and 0.867 (0.830-0.903) in women, and improved reclassification compared with Cox regression (NRI, 36.9% in men, 31.8% in women). CONCLUSIONS: A DL algorithm exhibited greater discriminative accuracy than Cox model approaches. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02931500.

14.
Neurology ; 93(11): e1058-e1067, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31391244

RESUMO

OBJECTIVE: To examine the association of diffusion-weighted image (DWI) lesions with markers of cerebrovascular disease, neurodegeneration, and cognitive functioning and to further explore the evolution of these DWI lesions and their link to risk of dementia, stroke, or TIA in the Rotterdam Study. METHODS: Two thousand one hundred seventy-six participants with baseline MRI scans (assessed between January 2009 and December 2013) and data on incident clinical outcomes (until January 2016) were included. DWIs were inspected for presence of acute or subacute lesions. Markers of cerebrovascular disease, brain tissue segmentation, and microstructural integrity were collected. Cognition was assessed with a detailed neuropsychological test. Evolution of DWI lesions was evaluated on follow-up scans. RESULTS: Thirty-three individuals (1.5%) had ≥1 DWI lesions. Persons with lacunes, white matter hyperintensities (WMHs), and reduced white matter microstructural integrity were more likely to have DWI lesions. Persons with DWI lesions performed worse on Stroop test 1. For 17 of 33 persons, follow-up scans were available to determine lesion evolution. During a mean follow-up of 4.7 years, 58.8% of DWI lesions appeared as WMHs, 17.6% developed cavitation, 5.9% changed into cortical cerebral microinfarcts, and 17.6% disappeared. People with DWI lesions at baseline were at increased risk of strokes (hazard ratio 3.72, 95% confidence interval 1.35-10.27). CONCLUSION: Asymptomatic DWI lesions in community-dwelling persons are associated with markers of cerebral small vessel disease, reduced microstructural integrity, and worse cognition. Presence of DWI lesions increases the risk of further strokes. Future investigations will have to show whether screening and treating persons with DWI lesions can effectively reduce the burden of stroke.

15.
J Am Med Dir Assoc ; 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31399361

RESUMO

OBJECTIVES: Cardiovascular disease may be linked to hearing loss through narrowing of the nutrient arteries of the cochlea, but large-scale population-based evidence for this association remains scarce. We investigated the association of carotid atherosclerosis as a marker of generalized cardiovascular disease with hearing loss in a population-based cohort. DESIGN: Cross-sectional. SETTING: A population-based cohort study. PARTICIPANTS: 3724 participants [mean age: 65.5 years, standard deviation (SD): 7.5, 55.4% female]. METHODS: Ultrasound and pure-tone audiograms to assess carotid atherosclerosis and hearing loss. RESULTS: We investigated associations of carotid plaque burden and carotid intima-media thickness (IMT) (overall and side-specific carotid atherosclerosis) with hearing loss (in the best hearing ear and side-specific hearing loss) using multivariable linear and ordinal regression models. We found that higher maximum IMT was related to poorer hearing in the best hearing ear [difference in decibel hearing level per 1-mm increase in IMT: 2.09 dB, 95% confidence interval (CI): 0.08, 4.10]. Additionally, third and fourth quartile plaque burden as compared to first quartile was related to poorer hearing in the best hearing ear (difference: 1.06 dB, 95% CI: 0.04, 2.08; and difference: 1.55 dB, 95% CI: 0.49, 2.60, respectively). Larger IMT (difference: 2.97 dB, 95% CI: 0.79, 5.14), third quartile plaque burden compared to first quartile (difference: 1.24 dB, 95% CI: 0.14, 2.35), and fourth plaque quartile compared to first quartile (difference: 2.12 dB, 95% CI: 0.98, 3.26) in the right carotid were associated with poorer hearing in the right ear. CONCLUSIONS AND IMPLICATIONS: Carotid atherosclerosis is associated with poorer hearing in older adults, almost exclusively with poorer hearing in the right ear. Based on our results, it seems that current therapies for the prevention of cardiovascular disease may also prove beneficial for hearing loss in older adults by promoting and maintaining inner ear health.

16.
Eur J Epidemiol ; 34(9): 853-861, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31399939

RESUMO

Intake of individual antioxidants has been related to a lower risk of type 2 diabetes. However, the overall diet may contain many antioxidants with additive or synergistic effects. Therefore, we aimed to determine associations between total dietary antioxidant capacity and risk of type 2 diabetes, prediabetes and insulin resistance. We estimated the dietary antioxidant capacity for 5796 participants of the Rotterdam Study using a ferric reducing ability of plasma (FRAP) score. Of these participants, 4957 had normoglycaemia and 839 had prediabetes at baseline. We used covariate-adjusted proportional hazards models to estimate associations between FRAP and risk of type 2 diabetes, risk of type 2 diabetes among participants with prediabetes, and risk of prediabetes. We used linear regression models to determine the association between FRAP score and insulin resistance (HOMA-IR). We observed 532 cases of incident type 2 diabetes, of which 259 among participants with prediabetes, and 794 cases of incident prediabetes during up to 15 years of follow-up. A higher FRAP score was associated with a lower risk of type 2 diabetes among the total population (HR per SD FRAP 0.84, 95% CI 0.75; 0.95) and among participants with prediabetes (HR 0.85, 95% CI 0.73; 0.99), but was not associated with risk of prediabetes. Dietary FRAP was also inversely associated with HOMA-IR (ß - 0.04, 95% CI - 0.06; - 0.03). Effect estimates were generally similar between sexes. The findings of this population-based study emphasize the putative beneficial effects of a diet rich in antioxidants on insulin resistance and risk of type 2 diabetes.


Assuntos
Antioxidantes/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta , Resistência à Insulina , Avaliação Nutricional , Estado Pré-Diabético/metabolismo , Adulto , Idoso , Antioxidantes/administração & dosagem , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Frutas , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/fisiologia , Estado Pré-Diabético/sangue , Estado Pré-Diabético/epidemiologia , Fatores de Risco
17.
Nat Med ; 25(9): 1364-1369, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31451782

RESUMO

The exact etiology of dementia is still unclear, but both genetic and lifestyle factors are thought to be key drivers of this complex disease. The recognition of familial patterns of dementia has led to the discovery of genetic factors that have a role in the pathogenesis of dementia, including the apolipoprotein E (APOE) genotype and a large and still-growing number of genetic variants1,2. Beyond genetic architecture, several modifiable risk factors have been implicated in the development of dementia3. Prevention trials of measures to halt or delay cognitive decline are increasingly recruiting older individuals who are genetically predisposed to dementia. However, it remains unclear whether targeted health and lifestyle interventions can attenuate or even offset increased genetic risk. Here, we leverage long-term data on both genetic and modifiable risk factors from 6,352 individuals aged 55 years and older in the population-based Rotterdam Study. In this study, we demonstrate that, in individuals at low and intermediate genetic risk, favorable modifiable-risk profiles are related to a lower risk of dementia compared to unfavorable profiles. In contrast, these protective associations were not found in those at high genetic risk.

18.
Arterioscler Thromb Vasc Biol ; 39(8): 1542-1549, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31294622

RESUMO

The notion of what qualifies as vascular dementia has varied greatly since the first mention of dementia after apoplexy in ancient literature. Current insight points towards a multifactorial cause of cognitive decline at old age, in which vascular components like atherosclerosis, arterio(lo)sclerosis, (micro)infarcts, and amyloid angiopathy play an important role alongside other markers of neurodegeneration. Cerebrovascular disease will be present in most individuals with dementia, but-just like other causes-rarely a cause on its own. The consequent limitations of nosology may be alleviated by addition of a vascular component to the recently introduced amyloid/tau/neurodegeneration etiological classification system for dementia. Meanwhile, risk of dementia is increased about 2-fold after stroke, and the prevention of (recurrent) stroke remains a cornerstone in the prevention of vascular dementia. Similarly, control of cardiovascular risk factors from middle age onwards is likely to have contributed to the reported decline in the age-specific incidence of dementia over the past decades. In conjunction with experimental studies, large-scale observational evidence from imaging, genomics, metabolomics, and alike will continue to improve our understanding of the underlying pathophysiological processes. To prevent ecological fallacies, such etiological studies in patients with dementia are best served by inclusion of subjects regardless of the presumed (single) cause of their disease.

19.
Hum Mutat ; 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31322790

RESUMO

Noncoding RNAs have been widely recognized as essential mediators of gene regulation. However, in contrast to protein-coding genes, much less is known about the influence of noncoding RNAs on human diseases. Here we examined the association of genetic variants located in primary microRNA sequences and long noncoding RNAs (lncRNAs) with Alzheimer disease (AD) by leveraging data from the largest genome-wide association meta-analysis of late-onset AD. Variants annotated to 5 miRNAs and 10 lncRNAs (in seven distinct loci) exceeded the Bonferroni-corrected significance threshold (p < 1.02 × 10-6 ). Among these, a leading variant (rs2526377:A>G) at the 17q22 locus annotated to two noncoding RNAs (MIR142 and BZRAP1-AS) was significantly associated with a reduced risk of AD and fulfilled predefined criteria for being a functional variant. Our functional genomic analyses revealed that rs2526377 affects the promoter activity and decreases the expression of miR-142. Moreover, differential expression analysis by RNA-Seq in human iPSC-derived neural progenitor cells and the hippocampus of miR-142 knockout mice demonstrated multiple target genes of miR-142 in the brain that are likely to be involved in the inflammatory and neurodegenerative manifestations of AD. These include TGFBR1 and PICALM, of which their derepression in the brain due to reduced expression levels of miR-142-3p may reduce the risk of AD.

20.
PLoS One ; 14(7): e0219668, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31356640

RESUMO

BACKGROUND: Apolipoprotein E is a glycoprotein best known as a mediator and regulator of lipid transport and uptake. The APOE-ε4 allele has long been associated with increased risks of Alzheimer's disease and mortality, but the effect of the less prevalent APOE-ε2 allele on diseases in the elderly and survival remains elusive. METHODS: We aggregated data of 38,537 individuals of European ancestry (mean age 65.5 years; 55.6% women) from six population-based cohort studies (Rotterdam Study, AGES-Reykjavik Study, Cardiovascular Health Study, Health-ABC Study, and the family-based Framingham Heart Study and Long Life Family Study) to determine the association of APOE, and in particular APOE-ε2, with survival in the population. RESULTS: During a mean follow-up of 11.7 years, 17,021 individuals died. Compared with homozygous APOE-ε3 carriers, APOE-ε2 carriers were at lower risk of death (hazard ratio,95% confidence interval: 0.94,0.90-0.99; P = 1.1*10-2), whereas APOE-ε4 carriers were at increased risk of death (HR 1.17,1.12-1.21; P = 2.8*10-16). APOE was associated with mortality risk in a dose-dependent manner, with risk estimates lowest for homozygous APOE-ε2 (HR 0.89,0.74-1.08), and highest for homozygous APOE-ε4 (HR 1.52,1.37-1.70). After censoring for dementia, effect estimates remained similar for APOE-ε2 (HR 0.95,0.90-1.01), but attenuated for APOE-ε4 (HR 1.07,1.01-1.12). Results were broadly similar across cohorts, and did not differ by age or sex. APOE genotype was associated with baseline lipid fractions (e.g. mean difference(95%CI) in LDL(mg/dL) for ε2 versus ε33: -17.1(-18.1-16.0), and ε4 versus ε33: +5.7(4.8;6.5)), but the association between APOE and mortality was unaltered after adjustment for baseline LDL or cardiovascular disease. Given the European ancestry of the study population, results may not apply to other ethnicities. CONCLUSION: Compared with APOE-ε3, APOE-ε2 is associated with prolonged survival, whereas mortality risk is increased for APOE-ε4 carriers. Further collaborative efforts are needed to unravel the role of APOE and in particular APOE-ε2 in health and disease.

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