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1.
PLoS Med ; 16(7): e1002853, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335910

RESUMO

BACKGROUND: With no effective treatments for cognitive decline or dementia, improving the evidence base for modifiable risk factors is a research priority. This study investigated associations between risk factors and late-life cognitive decline on a global scale, including comparisons between ethno-regional groups. METHODS AND FINDINGS: We harmonized longitudinal data from 20 population-based cohorts from 15 countries over 5 continents, including 48,522 individuals (58.4% women) aged 54-105 (mean = 72.7) years and without dementia at baseline. Studies had 2-15 years of follow-up. The risk factors investigated were age, sex, education, alcohol consumption, anxiety, apolipoprotein E ε4 allele (APOE*4) status, atrial fibrillation, blood pressure and pulse pressure, body mass index, cardiovascular disease, depression, diabetes, self-rated health, high cholesterol, hypertension, peripheral vascular disease, physical activity, smoking, and history of stroke. Associations with risk factors were determined for a global cognitive composite outcome (memory, language, processing speed, and executive functioning tests) and Mini-Mental State Examination score. Individual participant data meta-analyses of multivariable linear mixed model results pooled across cohorts revealed that for at least 1 cognitive outcome, age (B = -0.1, SE = 0.01), APOE*4 carriage (B = -0.31, SE = 0.11), depression (B = -0.11, SE = 0.06), diabetes (B = -0.23, SE = 0.10), current smoking (B = -0.20, SE = 0.08), and history of stroke (B = -0.22, SE = 0.09) were independently associated with poorer cognitive performance (p < 0.05 for all), and higher levels of education (B = 0.12, SE = 0.02) and vigorous physical activity (B = 0.17, SE = 0.06) were associated with better performance (p < 0.01 for both). Age (B = -0.07, SE = 0.01), APOE*4 carriage (B = -0.41, SE = 0.18), and diabetes (B = -0.18, SE = 0.10) were independently associated with faster cognitive decline (p < 0.05 for all). Different effects between Asian people and white people included stronger associations for Asian people between ever smoking and poorer cognition (group by risk factor interaction: B = -0.24, SE = 0.12), and between diabetes and cognitive decline (B = -0.66, SE = 0.27; p < 0.05 for both). Limitations of our study include a loss or distortion of risk factor data with harmonization, and not investigating factors at midlife. CONCLUSIONS: These results suggest that education, smoking, physical activity, diabetes, and stroke are all modifiable factors associated with cognitive decline. If these factors are determined to be causal, controlling them could minimize worldwide levels of cognitive decline. However, any global prevention strategy may need to consider ethno-regional differences.

3.
Genes (Basel) ; 10(3)2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30889929

RESUMO

Studies investigating exceptionally long-lived (ELL) individuals, including genetic studies, have linked cardiovascular-related pathways, particularly lipid and cholesterol homeostasis, with longevity. This study explored the genetic profiles of ELL individuals (cases: n = 294, 95⁻106 years; controls: n = 1105, 55⁻65 years) by assessing their polygenic risk scores (PRS) based on a genome wide association study (GWAS) threshold of p < 5 × 10-5. PRS were constructed using GWAS summary data from two exceptional longevity (EL) analyses and eight cardiovascular-related risk factors (lipids) and disease (myocardial infarction, coronary artery disease, stroke) analyses. A higher genetic risk for exceptional longevity (EL) was significantly associated with longevity in our sample (odds ratio (OR) = 1.19⁻1.20, p = 0.00804 and 0.00758, respectively). Two cardiovascular health PRS were nominally significant with longevity (HDL cholesterol, triglycerides), with higher PRS associated with EL, but these relationships did not survive correction for multiple testing. In conclusion, ELL individuals did not have significantly lower polygenic risk for the majority of the investigated cardiovascular health traits. Future work in larger cohorts is required to further explore the role of cardiovascular-related genetic variants in EL.

4.
Curr Opin Psychiatry ; 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30461440

RESUMO

PURPOSE OF REVIEW: Chronological age is a crude measure and may not be the best indicator of the ageing process. Establishing valid and reliable biomarkers to understand the true effect of ageing is of great interest. We provide an overview of biological and psychological characteristics that change with age and can potentially serve as markers of the ageing process, and discuss if an integration of these characteristics may more accurately measure the true age of a person. We also describe the clinicopathological continuum of these ageing-related changes. RECENT FINDINGS: Ageing-related changes in the biological and psychological systems of the body have been studied to varying degrees and with differing emphases. Despite the development of ageing indices, there is no single indicator that can holistically estimate the ageing process. Differential ageing of bodily systems remains poorly understood, and valid methods have not been developed for composite markers of biological and psychological processes. SUMMARY: The ageing process is complex and heterogeneous. Incorporating biological and psychological measures may improve accuracy in reflecting an individual's 'true age,' and elucidate why some people age successfully, whereas others show ageing-related decline and disease.

5.
J Fluency Disord ; 58: 11-21, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30343931

RESUMO

PURPOSE: Stuttering is a fluency disorder with a worldwide prevalence of 1%. Reports on the epidemiology of stuttering in India are limited. Our primary goal was to examine the prevalence of the disorder among school children. The study also aimed to examine risk factors associated with severity and the impact of parental consanguinity in stuttering. METHOD: Children from 97 schools in the State of Tamil Nadu, India were screened. Extensive speech characterization, epidemiological details and three-generational pedigrees were collected for 180 probands. The genetic basis of stuttering was examined using the analysis of genealogical index of families (GIF), kinship group and sibling recurrence risk (SRR) measures. Regression analysis and chi-square tests were performed to test the association of risk factors with severity of the disorder. RESULTS: Among the 74,544 school children screened, the prevalence of stuttering was found to be 0.46%. Pedigree analysis revealed a positive family history in 101 (56%) probands; overall familial incidence was 11%. We observed an overall male-favored sex ratio (4:1). Familial aggregation (GIF = 442.60, p-value <0.001) and sibling recurrence risk ratio (Ks = 0.197, SD = 0.041) was high among consanguineous families. Severity of stuttering was strongly associated with gender and moderately associated with age at onset. CONCLUSION: The prevalence of stuttering in Tamil Nadu is estimated for the first time in this study. High familial incidence, familial aggregation and sibling recurrence risk ratio point to the presence of a genetic basis. Familial aggregation was high among consanguineous families although consanguinity did not seem to play a role in severity.

6.
J Psychiatr Res ; 107: 19-27, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30312913

RESUMO

The molecular factors involved in the pathophysiology of major depressive disorder (MDD) remain poorly understood. One approach to examine the molecular basis of MDD is co-expression network analysis, which facilitates the examination of complex interactions between expression levels of individual genes and how they influence biological pathways affected in MDD. Here, we applied an unsupervised gene-network based approach to a prospective experimental design using microarray genome-wide gene expression from the peripheral whole blood of older adults. We utilised the Sydney Memory and Ageing Study (sMAS, N = 521) and the Older Australian Twins Study (OATS, N = 186) as discovery and replication cohorts, respectively. We constructed networks using Weighted Gene Co-expression Network Analysis (WGCNA), and correlated identified modules with four subtypes of depression: single episode, current, recurrent, and lifetime MDD. Four modules of highly co-expressed genes were associated with recurrent MDD (N = 27) in our discovery cohort (FDR<0.2), with no significant findings for a single episode, current or lifetime MDD. Functional characterisation of these modules revealed a complex interplay between dysregulated protein processing in the endoplasmic reticulum (ER), and innate and adaptive immune response signalling, with possible involvement of pathogen-related pathways. We were underpowered to replicate findings at the network level in an independent cohort (OATS), however; we found a significant overlap for 9 individual genes with similar co-expression and dysregulation patterns associated with recurrent MDD in both cohorts. Overall, our findings support other reports on dysregulated immune response and protein processing in the ER in MDD and provide novel insights into the pathophysiology of depression.

7.
Psychoneuroendocrinology ; 100: 18-26, 2018 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-30268003

RESUMO

Obesity is a clinically relevant and highly prevalent somatic comorbidity of major depression (MDD). Genetic predisposition and history of childhood trauma have both independently been demonstrated to act as risk factors for obesity and to be associated with alterations in reward related brain structure and function. We therefore aimed to investigate the influence of childhood maltreatment and genetic risk for obesity on structural and functional imaging correlates associated with reward processing in MDD. 161 MDD patients underwent structural and functional MRI during a frequently used card guessing paradigm. Main and interaction effects of a polygenic risk score for obesity (PRS) and childhood maltreatment experiences as assessed using the Childhood Trauma Questionnaire (CTQ) were investigated. We found that maltreatment experiences and polygenic risk for obesity significantly interacted on a) body mass index b) gray matter volume of the orbitofrontal cortex as well as on c) BOLD response in the right insula during reward processing. While polygenic risk for obesity was associated with elevated BMI as well as with decreased OFC gray matter and increased insular BOLD response in non-maltreated patients, these associations were absent in patients with a history of childhood trauma. No significant main effect of PRS or maltreatment on gray matter or BOLD response could be detected at the applied thresholds. The present study suggests that childhood maltreatment moderates the influence of genetic load for obesity on BMI as well as on altered brain structure and function in reward related brain circuits in MDD.

8.
Neurobiol Aging ; 70: 194-202, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30031232

RESUMO

Altered inhibition-excitation balance is implicated in brain aging. We hypothesized that expression of 14 genes encoding proteins localized to synapses or interneurons would show age-related changes relative to 1 another in postmortem tissue from the prefrontal cortex of 37 individuals (18-78 years) and that synaptic or interneuron markers would be differentially correlated with human brain volumes across aging. The majority of genes examined were differentially expressed with age, most being downregulated. Expression of 3 interneuron-related genes was significantly negatively associated with age (calbindin, somatostatin, cholecystokinin), whereas 3 synapse-related genes showed significant age-related expression change (PSD95, GAP43, VGLUT1). On covarying for 2 glial markers (GFAP, IBA1), all 3 interneuron genes and 1 synaptic gene (Growth-associated protein 43) remained significant. Two genes were significantly associated with total brain volume (calbindin, complexin 2) and a marker of synaptic density (synaptophysin) was significantly associated with cortical gray matter volume. Age-related change in expression of genes involved in maintenance of inhibition-excitation balance and regulation of prefrontocortical network dynamics suggests these pathways may contribute to brain aging.

9.
Mech Ageing Dev ; 175: 24-34, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29890178

RESUMO

BACKGROUND: Many factors contribute to exceptional longevity, with genetics playing a significant role. However, to date, genetic studies examining exceptional longevity have been inconclusive. This comprehensive review seeks to determine the genetic variants associated with exceptional longevity by undertaking meta-analyses. METHODS: Meta-analyses of genetic polymorphisms previously associated with exceptional longevity (85+) were undertaken. For each variant, meta-analyses were performed if there were data from at least three independent studies available, including two unpublished additional cohorts. RESULTS: Five polymorphisms, ACE rs4340, APOE ε2/3/4, FOXO3A rs2802292, KLOTHO KL-VS and IL6 rs1800795 were significantly associated with exceptional longevity, with the pooled effect sizes (odds ratios) ranging from 0.42 (APOE ε4) to 1.45 (FOXO3A males). CONCLUSION: In general, the observed modest effect sizes of the significant variants suggest many genes of small influence play a role in exceptional longevity, which is consistent with results for other polygenic traits. Our results also suggest that genes related to cardiovascular health may be implicated in exceptional longevity. Future studies should examine the roles of gender and ethnicity and carefully consider study design, including the selection of appropriate controls.

10.
Brain Imaging Behav ; 2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29802601

RESUMO

Cerebral microbleeds (CMB), suspected markers of hemorrhage-prone microangiopathy, are common in patients with cerebrovascular disease and in those with cognitive impairment. Their longitudinal relationship with cognitive decline and incident dementia in non-demented community-dwelling older individuals has been insufficiently examined. 302 adults aged 70-90 participating in the population-based Sydney Memory and Ageing Study underwent a susceptibility-weighted imaging (SWI) MRI sequence. The relationship of CMB with performance on neuropsychological tests was examined both cross-sectionally and longitudinally, over a mean of 4 years. The association with cases of incident dementia during this period was also examined. The prevalence of CMB was 20%. In cross-sectional analysis, after adjusting for demographics and vascular risk factors, there was a significant association between the presence of CMB and poorer executive function. CMB were not associated with global cognition or other cognitive domains. On longitudinal analysis, after adjusting for demographics and vascular risk factors, there was a greater decline in visuospatial ability in those with CMB compared to those without. The presence of CMB was not associated with increased progression to dementia. CMB are associated with impairments in specific cognitive domains: executive function and decline in visuospatial ability, independent of other markers of CVD including white matter hyperintensities. This suggests a direct contribution of CMB to cognitive impairment although no significant difference in incident dementia rates was observed.

11.
Nat Commun ; 9(1): 2098, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29844566

RESUMO

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

12.
Front Genet ; 9: 97, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29628937

RESUMO

Blood levels of growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), have been associated with various pathological processes and diseases, including cardiovascular disease and cancer. Prior studies suggest genetic factors play a role in regulating blood MIC-1/GDF-15 concentration. In the current study, we conducted the largest genome-wide association study (GWAS) to date using a sample of ∼5,400 community-based Caucasian participants, to determine the genetic variants associated with MIC-1/GDF-15 blood concentration. Conditional and joint (COJO), gene-based association, and gene-set enrichment analyses were also carried out to identify novel loci, genes, and pathways. Consistent with prior results, a locus on chromosome 19, which includes nine single nucleotide polymorphisms (SNPs) (top SNP, rs888663, p = 1.690 × 10-35), was significantly associated with blood MIC-1/GDF-15 concentration, and explained 21.47% of its variance. COJO analysis showed evidence for two independent signals within this locus. Gene-based analysis confirmed the chromosome 19 locus association and in addition, a putative locus on chromosome 1. Gene-set enrichment analyses showed that the"COPI-mediated anterograde transport" gene-set was associated with MIC-1/GDF15 blood concentration with marginal significance after FDR correction (p = 0.067). In conclusion, a locus on chromosome 19 was associated with MIC-1/GDF-15 blood concentration with genome-wide significance, with evidence for a new locus (chromosome 1). Future studies using independent cohorts are needed to confirm the observed associations especially for the chromosomes 1 locus, and to further investigate and identify the causal SNPs that contribute to MIC-1/GDF-15 levels.

13.
Int J Epidemiol ; 2018 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-29518222

RESUMO

Background: Investigating the genetic and environmental causes of variation in genome-wide average DNA methylation (GWAM), a global methylation measure from the HumanMethylation450 array, might give a better understanding of genetic and environmental influences on methylation. Methods: We measured GWAM for 2299 individuals aged 0 to 90 years from seven twin and/or family studies. We estimated familial correlations, modelled correlations with cohabitation history and fitted variance components models for GWAM. Results: The correlation in GWAM for twin pairs was ∼0.8 at birth, decreased with age during adolescence and was constant at ∼0.4 throughout adulthood, with no evidence that twin pair correlations differed by zygosity. Non-twin first-degree relatives were correlated, from 0.17 [95% confidence interval (CI): 0.05-0.30] to 0.28 (95% CI: 0.08-0.48), except for middle-aged siblings (0.01, 95% CI: -0.10-0.12), and the correlation increased with time living together and decreased with time living apart. Spouse pairs were correlated in all studies, from 0.23 (95% CI: 0.3-0.43) to 0.31 (95% CI: 0.05-0.52), and the correlation increased with time living together. The variance explained by environmental factors shared by twins alone was 90% (95% CI: 74-95%) at birth, decreased in early life and plateaued at 28% (95% CI: 17-39%) in middle age and beyond. There was a cohabitation-related environmental component of variance. Conclusions: GWAM is determined in utero by prenatal environmental factors, the effects of which persist throughout life. The variation of GWAM is also influenced by environmental factors shared by family members, as well as by individual-specific environmental factors.

14.
Schizophr Res ; 199: 189-194, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29599094

RESUMO

Schizophrenia is a complex psychiatric disorder involving multiple genes each contributing a small risk. Genome-wide association studies (GWASs) have identified hundreds of risk loci for schizophrenia including miR-137, a miRNA shown to be involved in neuronal development. Several genes regulated by miR-137 were also reported as top risk genes associated with schizophrenia and has been hypothesised that the dysregulation of miR-137 and its target could be involved in the aetiology of schizophrenia. Here, we replicated the four European GWAS hits, miR-137-rs1625579 and three of its validated target gene loci SNPs (ZNF804a-rs1344706, CACNA1C-rs4765905 and TCF4-rs9960767) by genotyping in 2074 samples (schizophrenia cases-1005; controls-1069) from South Indian Population. In this study, only the CACNA1C rs4765905 showed a significant association (OR=1.24, p=0.006). Three SNPs (rs1625579, rs1344706 and rs4765905) showed a consistent direction of effect with previous studies and the polygenic risk score constructed using the weighted sum of these three SNPs showed a significant association with Schizophrenia in this population (OR=3.78, p=0.005). Further, we carried out meta-analysis combining our results with the Psychiatric Genomics Consortium (PGC2) data and observed a considerable increase in GWAS significance.

15.
Brain Imaging Behav ; 2018 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-29464531

RESUMO

In previous studies, resting-state functional connectivity (FC) metrics of specific brain regions or networks based on prior hypotheses have been correlated with cognitive performance. Without constraining our analyses to specific regions or networks, we employed whole-brain voxel-based weighted degree (WD), a measure of local FC strength, to be correlated with three commonly used neuropsychological assessments of language, executive function and memory retrieval in both positive and negative directions in 67 cognitively healthy elderly adults. We also divided voxel-based WD into short-ranged and long-ranged WDs to evaluate the influence of FC distance on the WD-cognition relationship, and performed three validation tests. Our results showed that for language and executive function tests, positive WD correlates were located in the frontal and temporal cortices, and negative WD correlates in the precuneus and occipital cortices; for memory retrieval, positive WD correlates were located in the inferior temporal cortices, and negative WD correlates in the anterior cingulate cortices and supplementary motor areas. An FC-distance-dependent effect was also observed, with the short-ranged WD correlates of language and executive function tests located in the medial brain regions and the long-ranged WD correlates in the lateral regions. Our findings suggest that inter-individual differences in FC at rest are predictive of cognitive ability in the elderly adults. Moreover, the distinct patterns of positive and negative WD correlates of cognitive performance recapitulate the dichotomy between task-activated and task-deactivated neural systems, implying that a competition between distinct neural systems on functional network topology may have cognitive relevance.

16.
Brain Imaging Behav ; 12(3): 860-869, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28676986

RESUMO

Incidental findings on structural cerebral magnetic resonance imaging (MRI) are common in healthy subjects, and the prevalence increases with age. There is a paucity of data regarding incidental cerebral findings in twins. We examined brain MRI data acquired from community-dwelling older twins to determine the prevalence and concordance of incidental cerebral findings, as well as the associated clinical implications. Participants (n = 400) were drawn from the Older Australian Twins Study. T1-weighted and T2-weighted fluid-attenuated inversion recovery (FLAIR) cerebral MRI scans were systematically reviewed by a trained, blinded clinician. Incidental findings were recorded according to pre-determined categories, and the diagnosis confirmed by an experienced neuroradiologist. Periventricular and deep white matter hyperintensities (WMH) were scored visually. WMH heritability was calculated for those with the twin pair included in the study (n = 320 individuals; monozygotic (MZ) = 92 twin pairs, dizygotic (DZ) = 68 twin pairs). Excluding infarcts and WMH, a total of 47 (11.75%) incidental abnormalities were detected. The most common findings were hyperostosis frontalis interna (8 participants; 2%), meningiomas, (6 participants; 1.5%), and intracranial lipomas (5 participants; 1.25%). Only 3% of participants were referred for follow-up. Four twin pairs, all monozygotic, had lesions concordant with their twin. Periventricular WMH was moderately heritable (0.61, CI 0.43-0.75, p = 7.21E-08) and deep WMH highly heritable (0.80, CI 0.66-0.88, p = 1.76E-13). As in the general population, incidental findings on cerebral MRI in older twins are common, although concordance rates are low. Such findings can alter the clinical outcome of participants, and should be anticipated by researchers when designing trials involving cerebral imaging.

17.
Hum Brain Mapp ; 38(10): 5094-5114, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28685910

RESUMO

Healthy aging is accompanied by a constellation of changes in cognitive processes and alterations in functional brain networks. The relationships between brain networks and cognition during aging in later life are moderated by demographic and environmental factors, such as prior education, in a poorly understood manner. Using multivariate analyses, we identified three latent patterns (or modes) linking resting-state functional connectivity to demographic and cognitive measures in 101 cognitively normal elders. The first mode (P = 0.00043) captures an opposing association between age and core cognitive processes such as attention and processing speed on functional connectivity patterns. The functional subnetwork expressed by this mode links bilateral sensorimotor and visual regions through key areas such as the parietal operculum. A strong, independent association between years of education and functional connectivity loads onto a second mode (P = 0.012), characterized by the involvement of key hub regions. A third mode (P = 0.041) captures weak, residual brain-behavior relations. Our findings suggest that circuits supporting lower level cognitive processes are most sensitive to the influence of age in healthy older adults. Education, and to a lesser extent, executive functions, load independently onto functional networks-suggesting that the moderating effect of education acts upon networks distinct from those vulnerable with aging. This has important implications in understanding the contribution of education to cognitive reserve during healthy aging. Hum Brain Mapp 38:5094-5114, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Envelhecimento/fisiologia , Envelhecimento/psicologia , Encéfalo/fisiologia , Cognição , Escolaridade , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Cognição/fisiologia , Feminino , Humanos , Inteligência , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Análise Multivariada , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiologia , Testes Neuropsicológicos , Descanso , Caracteres Sexuais
18.
Hum Brain Mapp ; 38(9): 4444-4458, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28580697

RESUMO

Structural brain changes that occur during development and ageing are related to mental health and general cognitive functioning. Individuals differ in the extent to which their brain volumes change over time, but whether these differences can be attributed to differences in their genotypes has not been widely studied. Here we estimate heritability (h2 ) of changes in global and subcortical brain volumes in five longitudinal twin cohorts from across the world and in different stages of the lifespan (N = 861). Heritability estimates of brain changes were significant and ranged from 16% (caudate) to 42% (cerebellar gray matter) for all global and most subcortical volumes (with the exception of thalamus and pallidum). Heritability estimates of change rates were generally higher in adults than in children suggesting an increasing influence of genetic factors explaining individual differences in brain structural changes with age. In children, environmental influences in part explained individual differences in developmental changes in brain structure. Multivariate genetic modeling showed that genetic influences of change rates and baseline volume significantly overlapped for many structures. The genetic influences explaining individual differences in the change rate for cerebellum, cerebellar gray matter and lateral ventricles were independent of the genetic influences explaining differences in their baseline volumes. These results imply the existence of genetic variants that are specific for brain plasticity, rather than brain volume itself. Identifying these genes may increase our understanding of brain development and ageing and possibly have implications for diseases that are characterized by deviant developmental trajectories of brain structure. Hum Brain Mapp 38:4444-4458, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Variação Biológica Individual , Encéfalo/diagnóstico por imagem , Modelos Genéticos , Característica Quantitativa Herdável , Encéfalo/anatomia & histologia , Encéfalo/crescimento & desenvolvimento , Interação Gene-Ambiente , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Modelos Neurológicos , Tamanho do Órgão/genética , Estudos em Gêmeos como Assunto
19.
Epigenomics ; 9(5): 689-700, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28470125

RESUMO

AIM: To examine the relationships between two epigenetic clocks, aging and exceptional longevity. MATERIALS & METHODS: Participants were from three adult cohorts with blood DNA methylation data (Illumina 450 K, n = 275, 34-103 years). Epigenetic age (DNAmage) and age acceleration measures were calculated using the Hannum and Horvath epigenetic clocks. RESULTS: Across all cohorts, DNAmage was correlated with chronological age. In the long-lived cohort (Sydney Centenarian Study; 95+, n = 23), DNAmage was lower than chronological age for both clocks. Mean Sydney Centenarian Study Hannum age acceleration was negative, while the converse was observed for the Horvath model. CONCLUSION: Long-lived individuals have a young epigenetic age compared with their chronological age.


Assuntos
Metilação de DNA , Epigênese Genética , Longevidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ilhas de CpG , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
20.
PLoS Med ; 14(3): e1002261, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28323832

RESUMO

BACKGROUND: The prevalence of dementia varies around the world, potentially contributed to by international differences in rates of age-related cognitive decline. Our primary goal was to investigate how rates of age-related decline in cognitive test performance varied among international cohort studies of cognitive aging. We also determined the extent to which sex, educational attainment, and apolipoprotein E ε4 allele (APOE*4) carrier status were associated with decline. METHODS AND FINDINGS: We harmonized longitudinal data for 14 cohorts from 12 countries (Australia, Brazil, France, Greece, Hong Kong, Italy, Japan, Singapore, Spain, South Korea, United Kingdom, United States), for a total of 42,170 individuals aged 54-105 y (42% male), including 3.3% with dementia at baseline. The studies began between 1989 and 2011, with all but three ongoing, and each had 2-16 assessment waves (median = 3) and a follow-up duration of 2-15 y. We analyzed standardized Mini-Mental State Examination (MMSE) and memory, processing speed, language, and executive functioning test scores using linear mixed models, adjusted for sex and education, and meta-analytic techniques. Performance on all cognitive measures declined with age, with the most rapid rate of change pooled across cohorts a moderate -0.26 standard deviations per decade (SD/decade) (95% confidence interval [CI] [-0.35, -0.16], p < 0.001) for processing speed. Rates of decline accelerated slightly with age, with executive functioning showing the largest additional rate of decline with every further decade of age (-0.07 SD/decade, 95% CI [-0.10, -0.03], p = 0.002). There was a considerable degree of heterogeneity in the associations across cohorts, including a slightly faster decline (p = 0.021) on the MMSE for Asians (-0.20 SD/decade, 95% CI [-0.28, -0.12], p < 0.001) than for whites (-0.09 SD/decade, 95% CI [-0.16, -0.02], p = 0.009). Males declined on the MMSE at a slightly slower rate than females (difference = 0.023 SD/decade, 95% CI [0.011, 0.035], p < 0.001), and every additional year of education was associated with a rate of decline slightly slower for the MMSE (0.004 SD/decade less, 95% CI [0.002, 0.006], p = 0.001), but slightly faster for language (-0.007 SD/decade more, 95% CI [-0.011, -0.003], p = 0.001). APOE*4 carriers declined slightly more rapidly than non-carriers on most cognitive measures, with processing speed showing the greatest difference (-0.08 SD/decade, 95% CI [-0.15, -0.01], p = 0.019). The same overall pattern of results was found when analyses were repeated with baseline dementia cases excluded. We used only one test to represent cognitive domains, and though a prototypical one, we nevertheless urge caution in generalizing the results to domains rather than viewing them as test-specific associations. This study lacked cohorts from Africa, India, and mainland China. CONCLUSIONS: Cognitive performance declined with age, and more rapidly with increasing age, across samples from diverse ethnocultural groups and geographical regions. Associations varied across cohorts, suggesting that different rates of cognitive decline might contribute to the global variation in dementia prevalence. However, the many similarities and consistent associations with education and APOE genotype indicate a need to explore how international differences in associations with other risk factors such as genetics, cardiovascular health, and lifestyle are involved. Future studies should attempt to use multiple tests for each cognitive domain and feature populations from ethnocultural groups and geographical regions for which we lacked data.

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