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1.
Sci Rep ; 9(1): 15192, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645637

RESUMO

Previous research has shown that genes play a substantial role in determining a person's susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden.

3.
Cereb Cortex ; 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31240317

RESUMO

Exposures to life stressors accumulate across the lifespan, with possible impact on brain health. Little is known, however, about the mechanisms mediating age-related changes in brain structure. We use a lifespan sample of participants (n = 21 251; 4-97 years) to investigate the relationship between the thickness of cerebral cortex and the expression of the glucocorticoid- and the mineralocorticoid-receptor genes (NR3C1 and NR3C2, respectively), obtained from the Allen Human Brain Atlas. In all participants, cortical thickness correlated negatively with the expression of both NR3C1 and NR3C2 across 34 cortical regions. The magnitude of this correlation varied across the lifespan. From childhood through early adulthood, the profile similarity (between NR3C1/NR3C2 expression and thickness) increased with age. Conversely, both profile similarities decreased with age in late life. These variations do not reflect age-related changes in NR3C1 and NR3C2 expression, as observed in 5 databases of gene expression in the human cerebral cortex (502 donors). Based on the co-expression of NR3C1 (and NR3C2) with genes specific to neural cell types, we determine the potential involvement of microglia, astrocytes, and CA1 pyramidal cells in mediating the relationship between corticosteroid exposure and cortical thickness. Therefore, corticosteroids may influence brain structure to a variable degree throughout life.

4.
Cephalalgia ; 39(8): 1041-1048, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30961370

RESUMO

BACKGROUND: To explore the role of large-artery atherosclerosis in migraine, we investigated the association between migraine and arterial calcification in different intracranial and extracranial vessels. METHODS: 1856 participants were included, mean age (standard deviation) 67.4 (5.8) years, from the population-based Rotterdam Study cohort. Migraine was assessed by validated questionnaire and vascular calcification was assessed by computed tomography (expressed in Agatston score for the coronary arteries and volume in mm3 for the aortic arch, intracranial, and extracranial carotid arteries). Per vessel, the association of migraine with calcification was investigated by linear regression, adjusted for age, sex, cardiovascular risk factors, and calcification in other vessels. RESULTS: Of the participants, 279 (15%) were identified as persons with lifetime migraine. In multivariable adjusted models, migraine was associated with smaller intracranial carotid artery calcification volume (difference in log-transformed calcification volume in persons with migraine compared to persons without migraine: -0.19[-0.29, -0.08]). While subjects with migraine also showed a lower calcification burden in the remaining arterial beds, those associations did not reach statistical significance. CONCLUSIONS: Persons with migraine, compared to those without, had less arterial calcification in the intracranial carotid artery, but not in other arterial beds. Future studies are needed to confirm these findings.

6.
Neuroinformatics ; 17(4): 583-592, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30903541

RESUMO

Multivariate methods have the potential to better capture complex relationships that may exist between different biological levels. Multiple Factor Analysis (MFA) is one of the most popular methods to obtain factor scores and measures of discrepancy between data sets. However, singular value decomposition in MFA is based on PCA, which is adequate only if the data is normally distributed, linear or stationary. In addition, including strongly correlated variables can overemphasize the contribution of the estimated components. In this work, we introduced a novel method referred as Independent Multifactorial Analysis (ICA-MFA) to derive relevant features from multiscale data. This method is an extended implementation of MFA, where the component value decomposition is based on Independent Component Analysis. In addition, ICA-MFA incorporates a predictive step based on an Independent Component Regression. We evaluated and compared the performance of ICA-MFA with both, the MFA method and traditional univariate analyses, in a simulation study. We showed how ICA-MFA explained up to 10-fold more variance than MFA and univariate methods. We applied the proposed algorithm in a study of 4057 individuals belonging to the population-based Rotterdam Study with available genetic and neuroimaging data, as well as information about executive cognitive functioning. Specifically, we used ICA-MFA to detect relevant genetic features related to structural brain regions, which in turn were involved, in the mechanisms of executive cognitive function. The proposed strategy makes it possible to determine the degree to which the whole set of genetic and/or neuroimaging markers contribute to the variability of the symptomatology jointly, rather than individually. While univariate results and MFA combinations only explained a limited proportion of variance (less than 2%), our method increased the explained variance (10%) and allowed the identification of significant components that maximize the variance explained in the model. The potential application of the ICA-MFA algorithm constitutes an important aspect of integrating multivariate multiscale data, specifically in the field of Neurogenetics.

7.
Br J Nutr ; 122(5): 583-591, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30832747

RESUMO

The role of diet on breast cancer risk is not well elucidated but animal food sources may play a role through, for example, the pathway of the insulin-like growth factor 1 system or cholesterol metabolism. The aim of this study was to evaluate the association between animal foods and the risk of postmenopausal breast cancer. This study was embedded in the Rotterdam Study, a population-based prospective cohort study of subjects aged 55 years and over (61 % female). Dietary intake of different animal foods was assessed at baseline using a validated FFQ and adjusted for energy intake using the residual method. We performed Cox proportional hazards modelling to analyse the association between the intake of the different food sources and breast cancer risk after adjustment for socio-demographic, lifestyle and metabolic factors. During a median follow-up of 17 years, we identified 199 cases of breast cancer (6·2 %) among 3209 women. After adjustment for multiple confounders, no consistent association was found between the intake of red meat intake, poultry, fish or dairy products and breast cancer risk. However, we found that egg intake was significantly associated with a higher risk of breast cancer (hazard ratioQ4 v. Q1: 1·83; 95 % CI 1·20, 2·79; Ptrend=0·01). In conclusion, this study found that dietary egg intake but no other animal foods was associated with a higher risk of postmenopausal breast cancer. Further research on the potential mechanisms underlying this association is warranted.

8.
Int J Epidemiol ; 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30508110

RESUMO

Background: Recently, using a counterfactual framework, a causal mediation analysis has been formalized to decompose the total effect of a time-fixed exposure on an outcome into four components that can be loosely defined as being components due to mediation only, interaction only, mediated interaction and neither. The interpretation of the estimated effect sizes is challenging when these components of the total effect are of the opposite sign compared with each other. Particularly, a negative mediated interaction might be intuitively difficult to conceptualize and, so far, lacks an easy-to-understand biological or mechanical interpretation. Methods: In this paper, we focus on negative mediated interaction, and propose an interpretation using biological examples. For negative mediated interaction to be present, the effect of interaction on the outcome and the effect of the exposure on the mediator should be in opposite directions. Results: In this article, we give examples of biological and biochemical processes that may exhibit negative mediated interaction, such as drug treatment in clinical practice, allosteric effects of enzymes, different adaptations in the cardiovascular system and its effect on brain health, and antibiotic drug-drug interactions. Conclusions: We aim to make researchers realize that negative-effect estimates might reflect relevant biological processes in the mechanism under study.

9.
Menopause ; 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30300301

RESUMO

OBJECTIVE: Effective interventions of future health care require a better understanding of the health risks associated with early onset of menopause and diabetes, but the necessary data are scarce. Little quantitative information is available about the combined association of early menopause and diabetes on life expectancy and the number of years lived with and without diabetes. METHODS: We included 3,650 postmenopausal women aged 45+ years from the Rotterdam Study, a prospective population-based cohort study. Age at menopause categories were defined as follows: early (≤44 y old), normal (45-54 y old), and late (≥55 y old). For life table calculations, we used prevalence, incidence rates, and hazard ratios for three transitions (free of diabetes to diabetes, free of diabetes to death, and diabetes to death) stratifying by age at menopause categories and adjusting for confounders. RESULTS: Compared with late menopause, the difference in life expectancy for women who experienced early menopause was -3.5 (95% CI, -6.6 to -0.8) years overall and -4.6 (95% CI, -8.9 to -0.9) years without diabetes. Compared with age at normal menopause, the difference in life expectancy for women who experienced early menopause was -3.1 (95% CI, -5.1 to -1.1) years overall and -3.3 (95% CI, -6.0 to -0.6) years without diabetes. CONCLUSIONS: Women who experienced early menopause lived less long and spent fewer years without diabetes than women who experienced normal or late menopause.

10.
Eur J Epidemiol ; 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30255328

RESUMO

Advanced glycation end products (AGEs) accumulate in tissues with aging and may influence age-related diseases. They can be estimated non-invasively by skin autofluorescence (SAF) using the AGE Reader™. Serum 25-hydroxyvitamin D3 (25(OH)D3) may inhibit AGEs accumulation through anti-oxidative and anti-inflammatory properties but evidence in humans is scarce. The objective was to investigate the association between serum 25(OH)D3 and SAF in the population-based cohort study. Serum 25(OH)D3 and other covariates were measured at baseline. SAF was measured on average 11.5 years later. Known risk factors for AGE accumulation such as higher age, BMI, and coffee intake, male sex, smoking, diabetes, and decreased renal function were measured at baseline. Linear regression models were adopted to explore the association between 25(OH)D3 and SAF with adjustment for confounders. Interaction terms were tested to identify effect modification. The study was conducted in the general community. 2746 community-dwelling participants (age ≥ 45 years) from the Rotterdam Study were included. Serum 25(OH)D3 inversely associated with SAF and explained 1.5% of the variance (unstandardized B = - 0.002 (95% CI[- 0.003, - 0.002]), standardized ß = - 0.125), independently of known risk factors and medication intake. The association was present in both diabetics (B = - 0.004 (95% CI[- 0.008, - 0.001]), ß = - 0.192) and non-diabetics (B = - 0.002 (95% CI[- 0.003, - 0.002]), ß = - 0.122), both sexes, both smokers and non-smokers and in each RS subcohort. Serum 25(OH)D3 concentration was significantly and inversely associated with SAF measured prospectively, also after adjustment for known risk factors for high SAF and the number of medication used, but the causal chain is yet to be explored in future studies.Clinical Trial Registry (1) Netherlands National Trial Register: Trial ID: NTR6831 ( http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6831 ). (2) WHO International Clinical Trials Registry Platform: under shared catalogue number NTR6831 ( www.who.int/ictrp/network/primary/en/ ).

11.
Eur J Epidemiol ; 33(9): 883-893, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29948369

RESUMO

Vegan or vegetarian diets have been suggested to reduce type 2 diabetes (T2D) risk. However, not much is known on whether variation in the degree of having a plant-based versus animal-based diet may be beneficial for prevention of T2D. We aimed to investigate whether level of adherence to a diet high in plant-based foods and low in animal-based foods is associated with insulin resistance, prediabetes, and T2D. Our analysis included 6798 participants (62.7 ± 7.8 years) from the Rotterdam Study (RS), a prospective population-based cohort in the Netherlands. Dietary intake data were collected with food-frequency questionnaires at baseline of three sub-cohorts of RS (RS-I-1: 1989-1993, RS-II-1: 2000-2001, RS-III-1: 2006-2008). We constructed a continuous plant-based dietary index (range 0-92) assessing adherence to a plant-based versus animal-based diet. Insulin resistance at baseline and follow-up was assessed using homeostasis model assessment of insulin resistance (HOMA-IR). Prediabetes and T2D were collected from general practitioners' records, pharmacies' databases, and follow-up examinations in our research center until 2012. We used multivariable linear mixed models to examine association of the index with longitudinal HOMA-IR, and multivariable Cox proportional-hazards regression models to examine associations of the index with risk of prediabetes and T2D. During median 5.7, and 7.3 years of follow-up, we documented 928 prediabetes cases and 642 T2D cases. After adjusting for sociodemographic and lifestyle factors, a higher score on the plant-based dietary index was associated with lower insulin resistance (per 10 units higher score: ß = -0.09; 95% CI: - 0.10; - 0.08), lower prediabetes risk (HR = 0.89; 95% CI: 0.81; 0.98), and lower T2D risk [HR = 0.82 (0.73; 0.92)]. After additional adjustment for BMI, associations attenuated and remained statistically significant for longitudinal insulin resistance [ß = -0.05 (- 0.06; - 0.04)] and T2D risk [HR = 0.87 (0.79; 0.99)], but no longer for prediabetes risk [HR = 0.93 (0.85; 1.03)]. In conclusion, a more plant-based and less animal-based diet may lower risk of insulin resistance, prediabetes and T2D. These findings strengthen recent dietary recommendations to adopt a more plant-based diet.Clinical Trial Registry number and website NTR6831, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6831 .


Assuntos
Diabetes Mellitus Tipo 2/prevenção & controle , Dieta Vegetariana , Resistência à Insulina , Insulina/sangue , Carne , Estado Pré-Diabético/prevenção & controle , Idoso , Animais , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Dieta , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Estado Pré-Diabético/sangue , Estado Pré-Diabético/epidemiologia , Estudos Prospectivos
12.
Alzheimers Dement ; 14(11): 1493-1504, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29494808

RESUMO

INTRODUCTION: Cardiovascular risk factors are closely linked with dementia risk, but whether heart disease predisposes to dementia is uncertain. METHODS: We systematically reviewed the literature and meta-analyzed risk estimates from longitudinal studies reporting the association of coronary heart disease (CHD) or heart failure (HF) with risk of dementia. RESULTS: We identified 16 studies (1,309,483 individuals) regarding CHD, and seven studies (1,958,702 individuals) about HF. A history of CHD was associated with a 27% increased risk of dementia (pooled relative risk [RR] [95% confidence interval, CI]: 1.27 [1.07-1.50]), albeit with considerable heterogeneity across studies (I2 = 80%). HF was associated with 60% increased dementia risk (pooled RR 1.60 [1.19-2.13]) with moderate heterogeneity (I2 = 59%). Among prospective population-based cohorts, pooled estimates were similar (for CHD, RR 1.26 [1.06-1.49], nine studies; and HF, RR 1.80 [1.41-2.31], four studies) and highly consistent (I2 = 0%). CONCLUSION: CHD and HF are associated with an increased risk of dementia.

13.
Nephrol Dial Transplant ; 33(12): 2165-2172, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29566168

RESUMO

Background: Gait disturbance is proposed as a mechanism for higher risk of fall in kidney disease patients. We investigated the association of kidney function with gait pattern in the general population and tested whether the association between impaired kidney function and fall is more pronounced in subjects with lower gait function. Methods: We included 1430 participants (mean age: 60 years) from the Rotterdam Study. Kidney function was assessed using estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). We assessed global gait, gait velocity and seven independent gait domains: Rhythm, Phases, Variability, Pace, Tandem, Turning and Base of Support. Regression models adjusted for cardiometabolic and neurological factors were used. We evaluated whether participants with impaired kidney function and impaired gait fell more in the previous year. Results: The study population had a median (interquartile range) ACR of 3.6 (2.5-6.2) mg/g and mean ± SD eGFR of 87.6 ± 15 mL/min/1.73 m2. Higher ACR and lower eGFR were associated with lower global gait score [per doubling of ACR: -0.10, 95% confidence interval (CI): -0.14 to -0.06, and per SD eGFR:-0.09, 95% CI: -0.14 to -0.03] and slower gait speed (ACR: -1.44 cm/s, CI: -2.12 to -0.76; eGFR: -1.55 cm/s, CI: -2.43 to -0.67). Worse kidney function was associated with lower scores in Variability domain. The association between impaired kidney function and history of fall was present only in participants with lower gait scores [odds ratio (95% CI): ACR: 1.34 (1.09-1.65); eGFR: 1.58 (1.07-2.33)]. Conclusions: We observed a graded association between lower kidney function and impaired gait suggesting that individuals with decreased kidney function, even at an early stage, need to be evaluated for gait abnormalities and might benefit from fall prevention programmes.

14.
Menopause ; 25(4): 451-457, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29112599

RESUMO

OBJECTIVE: To better understand the relationship between cardiovascular disease risk and age-at-natural menopause using genetic data. METHODS: Early menopause is associated with cardiovascular disease risk. We constructed a genetic risk score comprising 56 age-at-natural menopause decreasing alleles in men and women from the Framingham Heart Study, the Atherosclerosis Risk in Communities Study, and the Rotterdam Study. If the genetic predisposition to earlier age-at-natural menopause is associated with increased cardiovascular disease risk, it is reasonable to ask whether the risk is shared by men carrying the alleles, despite not experiencing menopause. We estimated the hazard ratio for the score for time to first cardiovascular event. To investigate the possible genetic pleiotropy between age-at-natural menopause and cardiovascular disease, we performed cross-trait linkage disequilibrium score regressions between age-at-natural menopause and cardiovascular disease and risk factors using genome-wide association studies. RESULTS: Twenty-two thousand five hundred and sixty-eight cardiovascular disease-free participants at baseline were analyzed (9,808 men, 12,760 women). Each additional unit of the genetic propensity to earlier age-at-natural menopause increased the hazard of both cardiovascular disease and cardiac death in women (cardiovascular disease: hazard ratio 1.10 [1.04-1.16], P = 9.7 × 10; cardiac death: 1.12 [1.02-1.24], P = 0.03), whereas no effect was observed for either outcome in men (hazard ratio 0.99 [0.95-1.04], P = 0.71; 1.05 [0.94-1.16], P = 0.34). We found significant negative genetic correlations in women, but not men, between age-at-natural menopause and cardiovascular disease and risk factors. CONCLUSION: Genetic variants associated with earlier age-at-natural menopause are associated with increased cardiovascular disease risk in women, but not men, suggesting sex-specific genetic effects on cardiovascular disease risk.

15.
Metabolism ; 71: 171-181, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28521871

RESUMO

BACKGROUND: The role of dietary antioxidants and plasma oxidant-antioxidant status in low-grade chronic inflammation and adipocytokine levels is not established yet. OBJECTIVES: We aimed to evaluate whether total dietary antioxidant capacity (assessed by dietary ferric reducing antioxidant potential (FRAP)), serum uric acid (UA) and gamma glutamyltransferase (GGT) were associated with low-grade chronic inflammation and circulating adipocytokines. METHODS: Data of 4506 participants aged ≥55years from the Rotterdam Study were analyzed. Baseline (1990-1993) FRAP score was assessed by a food frequency questionnaire. Baseline UA and GGT levels were assessed in non-fasting serum samples. Serum high sensitivity C-reactive protein (hs-CRP) was measured at baseline and 10years later. Plasma leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1) and resistin levels were assessed 10years later. RESULTS: A high FRAP score was associated with lower levels of UA and GGT. Overall, no association was found between FRAP and hs-CRP levels. FRAP score was associated with lower levels of leptin and PAI-1, higher levels of adiponectin, and no difference in resistin levels. Increased levels of UA were associated with higher levels of hs-CRP, PAI-1 and leptin; lower levels of adiponectin and no difference in resistin levels. Similarly, GGT was associated with higher levels of hs-CRP whereas no association was observed between GGT and adipocytokines. CONCLUSION: These findings suggest that overall antioxidant capacity of diet and low levels of UA are associated with circulating adipocytokines whereas no consistent association was found with hs-CRP.


Assuntos
Adipocinas/análise , Antioxidantes/farmacologia , Proteína C-Reativa/análise , Dieta , Idoso , Inquéritos sobre Dietas , Feminino , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Países Baixos , Estudos Prospectivos , Caracteres Sexuais , Inquéritos e Questionários , Ácido Úrico/sangue , gama-Glutamiltransferase/sangue
16.
Eur J Epidemiol ; 32(3): 217-226, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28258520

RESUMO

The immune response involved in each phase of type 2 diabetes (T2D) development might be different. We aimed to identify novel inflammatory markers that predict progression from normoglycemia to pre-diabetes, incident T2D and insulin therapy. We used plasma levels of 26 inflammatory markers in 971 subjects from the Rotterdam Study. Among them 17 are novel and 9 previously studied. Cox regression models were built to perform survival analysis. MAIN OUTCOME MEASURES: During a follow-up of up to 14.7 years (between April 1, 1997, and Jan 1, 2012) 139 cases of pre-diabetes, 110 cases of T2D and 26 cases of insulin initiation were identified. In age and sex adjusted Cox models, IL13 (HR = 0.78), EN-RAGE (1.30), CFH (1.24), IL18 (1.22) and CRP (1.32) were associated with incident pre-diabetes. IL13 (0.62), IL17 (0.75), EN-RAGE (1.25), complement 3 (1.44), IL18 (1.35), TNFRII (1.27), IL1ra (1.24) and CRP (1.64) were associated with incident T2D. In multivariate models, IL13 (0.77), EN-RAGE (1.23) and CRP (1.26) remained associated with pre-diabetes. IL13 (0.67), IL17 (0.76) and CRP (1.32) remained associated with T2D. IL13 (0.55) was the only marker associated with initiation of insulin therapy in diabetics. Various inflammatory markers are associated with progression from normoglycemia to pre-diabetes (IL13, EN-RAGE, CRP), T2D (IL13, IL17, CRP) or insulin therapy start (IL13). Among them, EN-RAGE is a novel inflammatory marker for pre-diabetes, IL17 for incident T2D and IL13 for pre-diabetes, incident T2D and insulin therapy start.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Inflamação/sangue , Inflamação/epidemiologia , Estado Pré-Diabético/sangue , Estado Pré-Diabético/epidemiologia , Idoso , Biomarcadores/sangue , Estudos de Coortes , Comorbidade , Feminino , Humanos , Incidência , Masculino , Países Baixos/epidemiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco
17.
Mult Scler ; 23(13): 1697-1706, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28273768

RESUMO

BACKGROUND: Multiple sclerosis (MS) affects brain structure and cognitive function and has a heritable component. Over a 100 common genetic risk variants have been identified, but most carriers do not develop MS. For other neurodegenerative diseases, risk variants have effects outside patient populations, but this remains uninvestigated for MS. OBJECTIVES: To study the effect of MS-associated genetic variants on brain structure and cognitive function in the general population. METHODS: We studied middle-aged and elderly individuals (mean age = 65.7 years) from the population-based Rotterdam Study. We determined 107 MS variants and additionally created a risk score combining all variants. Magnetic resonance imaging ( N = 4710) was performed to obtain measures of brain macrostructure, white matter microstructure, and gray matter voxel-based morphometry. A cognitive test battery ( N = 7556) was used to test a variety of cognitive domains. RESULTS: The MS risk score was associated with smaller gray matter volume over the whole brain (ßstandardized = -0.016; p = 0.044), but region-specific analyses did not survive multiple testing correction. Similarly, no significant associations with brain structure were observed for individual variants. For cognition, rs2283792 was significantly associated with poorer memory (ß = -0.064; p = 3.4 × 10-5). CONCLUSION: Increased genetic susceptibility to MS may affect brain structure and cognition in persons without disease, pointing to a "hidden burden" of MS.


Assuntos
Disfunção Cognitiva/fisiopatologia , Predisposição Genética para Doença , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Idoso , Disfunção Cognitiva/etiologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Países Baixos
18.
Neurobiol Aging ; 51: 97-103, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28063366

RESUMO

White matter lesions play a role in cognitive decline and dementia. One presumed pathway is through disconnection of functional networks. Little is known about location-specific effects of lesions on functional connectivity. This study examined location-specific effects within anatomically-defined white matter tracts in 1584 participants of the Rotterdam Study, aged 50-95. Tracts were delineated from diffusion magnetic resonance images using probabilistic tractography. Lesions were segmented on fluid-attenuated inversion recovery images. Functional connectivity was defined across each tract on resting-state functional magnetic resonance images by using gray matter parcellations corresponding to the tract ends and calculating the correlation of the mean functional activity between the gray matter regions. A significant relationship between both local and brain-wide lesion load and tract-specific functional connectivity was found in several tracts using linear regressions, also after Bonferroni correction. Indirect connectivity analyses revealed that tract-specific functional connectivity is affected by lesions in several tracts simultaneously. These results suggest that local white matter lesions can decrease tract-specific functional connectivity, both in direct and indirect connections.


Assuntos
Transtornos Cognitivos/etiologia , Demência/etiologia , Substância Branca/diagnóstico por imagem , Substância Branca/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Imagem de Difusão por Ressonância Magnética , Feminino , Substância Cinzenta , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
19.
Nutrients ; 7(11): 9590-601, 2015 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-26610556

RESUMO

BACKGROUND: Coffee is one of the most consumed beverages worldwide and the effect on cognition appears to be task specific and vary by age. METHOD: In cohort of 14,563 public service workers (35-74 years old) we assessed coffee consumption habits and examined cognitive function using standardized neuropsychological test battery. By linear regression and generalize linear regression with logarithmic link and gamma distribution we investigated the relation of coffee consumption (never/almost never, ≤1 cup/day, 2-3 cups/day, ≥3 cups/day) in the last 12 months to performance on specific domains of cognition for adults and elderly separately. RESULTS: Among elderly, after adjustments, coffee consumption was associated only with an increase in the mean words remembered on learning, recall, and word recognition tests when comparing the 2-3 cups/day to never/almost never category (arithmetic mean ratio (AMR): 1.03; 95% Confidence Interval (CI): 1.00 to 1.07), and to an increase in the mean words pronounced in semantic verbal fluency test when comparing the ≥3 cups/day to never/almost never category (difference of the mean: 1.23; 95% CI: 0.16 to 2.29). However, coffee consumption was not associated with any cognitive function tests in adults and also was not associated with the phonemic verbal fluency test and trail-making test B in elderly. CONCLUSIONS: RESULTS suggest that coffee consumption might be slightly beneficial to memory in elderly but lacks a dose response relationship. Longitudinal analyses are needed to investigate possible, even if subtle, positive effects of coffee drinking on specific cognitive domains in elderly.


Assuntos
Café , Cognição , Adulto , Idoso , Brasil , Estudos Transversais , Feminino , Humanos , Modelos Lineares , Masculino , Rememoração Mental , Pessoa de Meia-Idade , Testes Neuropsicológicos , Reprodutibilidade dos Testes
20.
Mol Psychiatry ; 20(5): 647-656, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25288136

RESUMO

Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.


Assuntos
Coffea/metabolismo , Comportamento Alimentar , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Citocromo P-450 CYP1A2/genética , Humanos , Fenótipo
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