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1.
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.

2.
Brain ; 142(4): 1009-1023, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30859180

RESUMO

We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.

3.
JAMA Neurol ; 76(4): 480-491, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30726504

RESUMO

Importance: Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. Objective: To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) ε4 alleles, the most potent genetic risk factor for ICH. Design, Setting, and Participants: This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. Main Outcomes and Measures: Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. Results: In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE ε2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE ε4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE ε4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE ε2 and ε4 did not show an association with nonlobar ICH risk in any race/ethnicity. Conclusions and Relevance: APOE ε4 and ε2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.

4.
Neurology ; 2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651383

RESUMO

OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. CONCLUSION: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

5.
Muscle Nerve ; 59(4): 484-486, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30536747

RESUMO

INTRODUCTION: Mutations in the BICD2 gene are causative for an autosomal dominant form of spinal muscular atrophy (SMALED2). Further, BICD2 mutations have been implicated in hereditary spastic paraplegia (HSP), but only very few such patients have been described. In this report we aimed to investigate the frequency of BICD2 mutations in patients with HSP and hereditary motor and sensory neuropathy (HMSN) who were negative for the most common known genetic causes. METHODS: The cohorts comprised 171 HSP and 189 HMSN patients. Mutational analysis was performed with high-resolution melting analysis followed by Sanger sequencing. RESULTS: In both cohorts, we found no known or likely pathogenic mutations in the BICD2 gene. DISCUSSION: BICD2 mutations appear rather unlikely to cause a phenotype of HMSN and are a very rare cause of the HSP phenotype. Muscle Nerve 59:484-486, 2019.


Assuntos
Análise Mutacional de DNA , Neuropatia Hereditária Motora e Sensorial/genética , Proteínas Associadas aos Microtúbulos/genética , Paraplegia Espástica Hereditária/genética , Adulto , Estudos de Coortes , Feminino , Ligação Genética , Humanos , Masculino , Mutação de Sentido Incorreto/genética
6.
J Sci Food Agric ; 99(7): 3307-3317, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30569496

RESUMO

BACKGROUND: The consumption of native tropical fruits represents an important source of bioactive food and vitamins for consumers. The aim of this study was to determine the composition of vitamins, bioactive compounds and the antioxidant activity of seven native fruits of the Myrtaceae family from south Brazil. RESULTS: Sample 1 of Eugenia pyriformis presented the highest value of ß-carotene (0.1021 g kg-1 ), lutein (0.0511 g kg-1 ), zeaxanthin (0.0370 g kg-1 ), and α-carotene (0.0112 g kg-1 ), of all analyzed samples. The three samples of Eugenia uniflora L presented the highest lycopene (0.1876, 0.1240 and 0.1615 g kg-1 ) and vitamin A content (0.106, 0.035 and 0.178 g kg-1 RAE) of all seven species analyzed. The cyanidin 3-glucoside was the most common anthocyanin found in fruits in the present study. Two samples of Plinia peruviana presented higher antioxidant capacity by the ABTS radical method (0.80 and 0.67 mol TEs kg-1 ) among the fruits analyzed. The samples of Campomanesia xanthocarpa analyzed stood out owing to the high content of vitamin C present (23.89, 36.83 and 35.05 g kg-1 ). The values of pantothenic acid in Plinia peruviana account for 20% of daily requirements. CONCLUSION: In conclusion, the native fruits studied can provide an appreciable amount of vitamins and bioactive compounds. © 2018 Society of Chemical Industry.


Assuntos
Frutas/química , Myrtaceae/química , Extratos Vegetais/análise , Antocianinas/análise , Brasil , Carotenoides/análise , Frutas/classificação , Luteína/análise , Myrtaceae/classificação , Vitaminas/análise , beta Caroteno/análise
7.
Sci Rep ; 7(1): 13230, 2017 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-29038561

RESUMO

The causal nature of the association between hypovitaminosis D and poor cognitive function in mid- to later-life is uncertain. Using a Mendelian randomisation(MR) approach, we examined the causal relationship between 25(OH)D and cognitive function. Data came from 172,349 participants from 17 cohorts. DHCR7(rs12785878), CYP2R1 rs12794714) and their combined synthesis score were chosen to proxy 25(OH)D. Cognitive tests were standardised into global and memory scores. Analyses were stratified by 25(OH)D tertiles, sex and age. Random effects meta-analyses assessed associations between 25(OH)D and cognitive function. Associations of serum 25(OH)D with global and memory-related cognitive function were non-linear (lower cognitive scores for both low and high 25(OH)D, p curvature ≤ 0.006), with much of the curvature attributed to a single study. DHCR7, CYP2R1, and the synthesis score were associated with small reductions in 25(OH)D per vitamin D-decreasing allele. However, coefficients for associations with global or memory-related cognitive function were non-significant and in opposing directions for DHCR7 and CYP2R1, with no overall association observed for the synthesis score. Coefficients for the synthesis score and global and memory cognition were similar when stratified by 25(OH)D tertiles, sex and age. We found no evidence for serum 25(OH)D concentration as a causal factor for cognitive performance in mid- to later life.

8.
BMC Med ; 15(1): 48, 2017 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-28260527

RESUMO

BACKGROUND: Vascular dementia is a common disorder resulting in considerable morbidity and mortality. Determining the extent to which genes play a role in disease susceptibility and their pathophysiological mechanisms could improve our understanding of vascular dementia, leading to a potential translation of this knowledge to clinical practice. DISCUSSION: In this review, we discuss what is currently known about the genetics of vascular dementia. The identification of causal genes remains limited to monogenic forms of the disease, with findings for sporadic vascular dementia being less robust. However, progress in genetic research on associated phenotypes, such as cerebral small vessel disease, Alzheimer's disease, and stroke, have the potential to inform on the genetics of vascular dementia. We conclude by providing an overview of future developments in the field and how such work could impact patients and clinicians. CONCLUSION: The genetic background of vascular dementia is well established for monogenic disorders, but remains relatively obscure for the sporadic form. More work is needed for providing robust findings that might eventually lead to clinical translation.


Assuntos
Demência Vascular/diagnóstico por imagem , Demência Vascular/genética , Apolipoproteínas E/genética , Arildialquilfosfatase/genética , Demência/etiologia , Progressão da Doença , Humanos , Imagem por Ressonância Magnética , Polimorfismo Genético
9.
Hum Brain Mapp ; 38(5): 2408-2423, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28145022

RESUMO

BACKGROUND: The combination of genetics and imaging has improved their understanding of the brain through studies of aggregate measures obtained from high-resolution structural imaging. Voxel-wise analyses have the potential to provide more detailed information of genetic influences on the brain. Here they report a large-scale study of the heritability of gray matter at voxel resolution (1 × 1 × 1 mm). METHODS: Validated voxel-based morphometry (VBM) protocols were applied to process magnetic resonance imaging data of 3,239 unrelated subjects from a population-based study and 491 subjects from two family-based studies. Genome-wide genetic data was used to estimate voxel-wise gray matter heritability of the unrelated subjects and pedigree-structure was used to estimate heritability in families. They subsequently associated two genetic variants, known to be linked with subcortical brain volume, with most heritable voxels to determine if this would enhance their association signals. RESULTS: Voxels significantly heritable in both estimates mapped to subcortical structures, but also voxels in the language areas of the left hemisphere were found significantly heritable. When comparing regional patterns of heritability, family-based estimates were higher than population-based estimates. However, regional consistency of the heritability measures across study designs was high (Pearson's correlation coefficient = 0.73, P = 2.6 × 10-13 ). They further show enhancement of the association signal of two previously discovered genetic loci with subcortical volume by using only the most heritable voxels. CONCLUSION: Gray matter voxel-wise heritability can be reliably estimated with different methods. Combining heritability estimates from multiple studies is feasible to construct reliable heritability maps of gray matter voxels. Hum Brain Mapp 38:2408-2423, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Saúde da Família , Ligação Genética , Substância Cinzenta/diagnóstico por imagem , Imagem por Ressonância Magnética , Idoso , Idoso de 80 Anos ou mais , Áustria , Mapeamento Encefálico , Estudos de Coortes , Planejamento em Saúde Comunitária , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Países Baixos
10.
Am J Hum Genet ; 100(1): 51-63, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28017375

RESUMO

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.


Assuntos
Grupos de Populações Continentais/genética , Eritrócitos/metabolismo , Eritropoese/genética , Proteínas de Ligação a RNA/genética , África/etnologia , Alelos , Animais , Teorema de Bayes , Grupos Étnicos/genética , Europa (Continente)/etnologia , Extremo Oriente/etnologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Peixe-Zebra/genética
11.
Ann Neurol ; 80(5): 730-740, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27717122

RESUMO

OBJECTIVE: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. METHODS: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk. RESULTS: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10-4 ) with no heterogeneity across studies (I2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10-6 ). INTERPRETATION: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.


Assuntos
Hemorragia Cerebral/genética , Proteínas de Transferência de Ésteres de Colesterol/genética , Predisposição Genética para Doença/genética , Adulto , Idoso , HDL-Colesterol/sangue , HDL-Colesterol/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
12.
Twin Res Hum Genet ; 19(5): 407-17, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27546527

RESUMO

Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes <0.05%) were observed between the extraversion polygenic score and wellbeing measures, and a negative association was observed between the polygenic neuroticism score and life satisfaction. Furthermore, using GWA data, genetic correlations of -0.49 and -0.55 were estimated between neuroticism with life satisfaction and positive affect, respectively. The moderate genetic correlation between neuroticism and wellbeing is in line with twin research showing that genetic influences on wellbeing are also shared with other independent personality domains.


Assuntos
Afeto , Herança Multifatorial , Satisfação Pessoal , Desenvolvimento da Personalidade , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Metanálise como Assunto , Reino Unido
13.
Neurology ; 86(5): 418-24, 2016 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-26740674

RESUMO

OBJECTIVE: To investigate whether greater cardiorespiratory fitness is associated with better global and domain-specific cognitive function. METHODS: We investigated 877 participants (aged 65 ± 7 years, 55% women) of the Austrian Stroke Prevention Study. For cardiorespiratory fitness, the maximum oxygen consumption (V̇o2max) was calculated based on weight and maximum and resting heart rate on a treadmill test (mL·kg(-1)·min(-1)). A test battery assessing memory (Bäumler's Lern-und Gedächtnistest), executive function (Wisconsin Card Sorting Test, Trail Making Test-Part B, Digit Span Backward, Alters Konzentrationstest, a computerized complex reaction time task) and motor skills (Purdue Pegboard Test) was administered. Summary measures for cognitive domains and for global cognition were calculated. White matter lesions, lacunes, and brain atrophy were assessed using MRI. RESULTS: Higher V̇o2max was associated with better global (B = 0.024; p = 0.000) and domain-specific cognitive function (memory B = 0.026, p = 0.000; executive function B = 0.009, p = 0.003; motor skills B = 0.012, p = 0.018) after adjustment for age, sex, education years, and Ca(2+) channel antagonists or ß-blockers. White matter lesions, lacunes, or brain atrophy did not mediate the effect (p > 0.05 for all mediators). The interactions of V̇o2max with age, overweight, and APOE ε4 on cognition were not statistically significant (p > 0.05 for all interaction terms) with the exception of a modulating effect of body mass index on V̇o2max in the memory domain. CONCLUSIONS: Higher V̇o2max is associated with better global cognitive function and with better performance in the cognitive domains of memory, executive function, and motor skills in the middle-aged and elderly. The association is not mediated by the presence of white matter lesions, lacunes, and brain atrophy.


Assuntos
Cognição/fisiologia , Teste de Esforço/métodos , Consumo de Oxigênio/fisiologia , Aptidão Física/fisiologia , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Idoso , Áustria/epidemiologia , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/diagnóstico
14.
J Neural Transm (Vienna) ; 123(3): 297-316, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26411482

RESUMO

We analyzed the relation of several synchrony markers in the electroencephalogram (EEG) and Alzheimer's disease (AD) severity as measured by Mini-Mental State Examination (MMSE) scores. The study sample consisted of 79 subjects diagnosed with probable AD. All subjects were participants in the PRODEM-Austria study. Following a homogeneous protocol, the EEG was recorded both in resting state and during a cognitive task. We employed quadratic least squares regression to describe the relation between MMSE and the EEG markers. Factor analysis was used for estimating a potentially lower number of unobserved synchrony factors. These common factors were then related to MMSE scores as well. Most markers displayed an initial increase of EEG synchrony with MMSE scores from 26 to 21 or 20, and a decrease below. This effect was most prominent during the cognitive task and may be owed to cerebral compensatory mechanisms. Factor analysis provided interesting insights in the synchrony structures and the first common factors were related to MMSE scores with coefficients of determination up to 0.433. We conclude that several of the proposed EEG markers are related to AD severity for the overall sample with a wide dispersion for individual subjects. Part of these fluctuations may be owed to fluctuations and day-to-day variability associated with MMSE measurements. Our study provides a systematic analysis of EEG synchrony based on a large and homogeneous sample. The results indicate that the individual markers capture different aspects of EEG synchrony and may reflect cerebral compensatory mechanisms in the early stages of AD.


Assuntos
Doença de Alzheimer/fisiopatologia , Encéfalo/fisiopatologia , Sincronização Cortical/fisiologia , Idoso , Idoso de 80 Anos ou mais , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Processamento de Sinais Assistido por Computador
15.
Neurobiol Aging ; 36(4): 1765.e7-1765.e16, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25670335

RESUMO

Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta ± SE = -0.047 ± 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.


Assuntos
Envelhecimento/genética , Envelhecimento/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/patologia , Estudo de Associação Genômica Ampla , Imagem por Ressonância Magnética , Alelos , Apolipoproteínas E/genética , Feminino , Hipocampo/patologia , Humanos , Masculino , Tamanho do Órgão/genética , Polimorfismo de Nucleotídeo Único , Risco , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética
16.
Kidney Int ; 87(5): 1017-29, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25493955

RESUMO

Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m(2) or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.


Assuntos
Caderinas/genética , N-Acetilgalactosaminiltransferases/genética , Insuficiência Renal/genética , Uromodulina/genética , Animais , Grupo com Ancestrais do Continente Europeu/genética , Genoma Humano , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular/genética , Humanos
17.
Neurobiol Aging ; 36(2): 925-32, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25443291

RESUMO

Brain iron accumulates during aging and has been associated with neurodegenerative disorders including Alzheimer's disease. Magnetic resonance (MR)-based R2* mapping enables the in vivo detection of iron content in brain tissue. We investigated if during normal brain aging iron load relates to cognitive impairment in region-specific patterns in a community-dwelling cohort of 336 healthy, middle aged, and older adults from the Austrian Stroke Prevention Family Study. MR imaging and R2* mapping in the basal ganglia and neocortex were done at 3T. Comprehensive neuropsychological testing assessed memory, executive function, and psychomotor speed. We found the highest iron concentration in the globus pallidus, and pallidal and putaminal iron was significantly and inversely associated with cognitive performance in all cognitive domains, except memory. These associations were iron load dependent. Vascular brain lesions and brain volume did not mediate the relationship between iron and cognitive performance. We conclude that higher R2*-determined iron in the basal ganglia correlates with cognitive impairment during brain aging independent of concomitant brain abnormalities. The prognostic significance of this finding needs to be determined.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/psicologia , Mapeamento Encefálico/métodos , Encéfalo/metabolismo , Cognição , Ferro/metabolismo , Imagem por Ressonância Magnética , Idoso , Gânglios da Base/metabolismo , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/psicologia
18.
Clin Neurophysiol ; 126(3): 505-13, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25091343

RESUMO

OBJECTIVE: To investigate which single quantitative electro-encephalographic (QEEG) marker or which combination of markers correlates best with Alzheimer's disease (AD) severity as measured by the Mini-Mental State Examination (MMSE). METHODS: We compared quantitative EEG markers for slowing (relative band powers), synchrony (coherence, canonical correlation, Granger causality) and complexity (auto-mutual information, Shannon/Tsallis entropy) in 118 AD patients from the multi-centric study PRODEM Austria. Signal spectra were determined using an indirect spectral estimator. Analyses were adjusted for age, sex, duration of dementia, and level of education. RESULTS: For the whole group (39 possible, 79 probable AD cases) MMSE scores explained 33% of the variations in relative theta power during face encoding, and 31% of auto-mutual information in resting state with eyes closed. MMSE scores explained also 25% of the overall QEEG factor. This factor was thus subordinate to individual markers. In probable AD, QEEG coefficients of determination were always higher than in the whole group, where MMSE scores explained 51% of the variations in relative theta power. CONCLUSIONS: Selected QEEG markers show strong associations with AD severity. Both cognitive and resting state should be used for QEEG assessments. SIGNIFICANCE: Our data indicate theta power measured during face-name encoding to be most closely related to AD severity.


Assuntos
Doença de Alzheimer/diagnóstico , Encéfalo/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Áustria , Biomarcadores , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Prospectivos , Sistema de Registros , Índice de Gravidade de Doença
19.
PLoS One ; 9(6): e94661, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24922517

RESUMO

BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.


Assuntos
Doença de Alzheimer/genética , Proteínas de Transporte/genética , Proteínas de Choque Térmico/genética , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Receptores de Antígenos de Linfócitos B/genética
20.
Int J Psychophysiol ; 93(3): 390-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24933410

RESUMO

BACKGROUND: Quantitative electroencephalogram (qEEG) recorded during cognitive tasks has been shown to differentiate between patients with Alzheimer's disease (AD) and healthy individuals. However, the association between various qEEG markers recorded during mnestic paradigms and clinical measures of AD has not been studied in detail. OBJECTIVE: To evaluate if 'cognitive' qEEG is a useful diagnostic option, particularly if memory paradigms are used as cognitive stimulators. METHODS: This study is part of the Prospective Registry on Dementia in Austria (PRODEM), a multicenter dementia research project. A cohort of 79 probable AD patients was included in a cross-sectional analysis. qEEG recordings performed in resting states were compared with recordings during cognitively active states. Cognition was evoked with a face-name paradigm and a paired-associate word list task, respectively. Relative band powers, coherence and auto-mutual information were computed as functions of MMSE scores for the memory paradigms and during rest. Analyses were adjusted for the co-variables age, sex, duration of dementia and educational level. RESULTS: MMSE scores explained 36-51% of the variances of qEEG-markers. Face-name encoding with eyes open was superior to resting state with eyes closed in relative theta and beta1 power as well as coherence, whereas relative alpha power and auto-mutual information yielded more significant results during resting state with eyes closed. The face-name task yielded stronger correlations with MMSE scores than the verbal memory task. CONCLUSION: qEEG alterations recorded during mnestic activity, particularly face-name encoding showed the highest association with the MMSE and may serve as a clinically valuable marker for disease severity.


Assuntos
Doença de Alzheimer/complicações , Transtornos Cognitivos/etiologia , Eletroencefalografia , Potenciais Evocados Visuais/fisiologia , Descanso/fisiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Aprendizagem por Associação/fisiologia , Ondas Encefálicas/fisiologia , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estimulação Luminosa
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