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1.
Nat Commun ; 11(1): 4796, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963231

RESUMO

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


Assuntos
Envelhecimento/genética , Encéfalo , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Doenças Neurodegenerativas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estruturas Cromossômicas , Cognição , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
2.
Nat Commun ; 11(1): 4799, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968074

RESUMO

Genetic association studies have identified 44 common genome-wide significant risk loci for late-onset Alzheimer's disease (LOAD). However, LOAD genetic architecture and prediction are unclear. Here we estimate the optimal P-threshold (Poptimal) of a genetic risk score (GRS) for prediction of LOAD in three independent datasets comprising 676 cases and 35,675 family history proxy cases. We show that the discriminative ability of GRS in LOAD prediction is maximised when selecting a small number of SNPs. Both simulation results and direct estimation indicate that the number of causal common SNPs for LOAD may be less than 100, suggesting LOAD is more oligogenic than polygenic. The best GRS explains approximately 75% of SNP-heritability, and individuals in the top decile of GRS have ten-fold increased odds when compared to those in the bottom decile. In addition, 14 variants are identified that contribute to both LOAD risk and age at onset of LOAD.


Assuntos
Doença de Alzheimer/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Adulto , Idade de Início , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
3.
Elife ; 92020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32697195

RESUMO

The critical role of blood lipids in a broad range of health and disease states is well recognised but less explored is the interplay of genetics and environment within the broader blood lipidome. We examined heritability of the plasma lipidome among healthy older-aged twins (75 monozygotic/55 dizygotic pairs) enrolled in the Older Australian Twins Study (OATS) and explored corresponding gene expression and DNA methylation associations. 27/209 lipids (13.3%) detected by liquid chromatography-coupled mass spectrometry (LC-MS) were significantly heritable under the classical ACE twin model (h2 = 0.28-0.59), which included ceramides (Cer) and triglycerides (TG). Relative to non-significantly heritable TGs, heritable TGs had a greater number of associations with gene transcripts, not directly associated with lipid metabolism, but with immune function, signalling and transcriptional regulation. Genome-wide average DNA methylation (GWAM) levels accounted for variability in some non-heritable lipids. We reveal a complex interplay of genetic and environmental influences on the ageing plasma lipidome.

4.
Alzheimers Res Ther ; 12(1): 59, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32414413

RESUMO

BACKGROUND: Peripheral blood microRNAs (miRNA) have been identified as potential biomarkers for Alzheimer's disease (AD). Study results have generally been inconsistent and limited by sample heterogeneity. The aim of this study is to establish candidate blood miRNA biomarkers for AD by comparing differences in miRNA expression between participants with brain amyloid imaging-defined AD and normal cognition. METHODS: Blood RNA was extracted from a subset of participants from the Australian Imaging Biomarkers Lifestyle Study of Ageing cohort (AIBL) with brain amyloid imaging results. MiRNA profiling was performed using small RNA sequencing on 71 participants, comprising 40 AD with high brain amyloid burden on imaging (amyloid positive) and 31 cognitively normal controls with low brain amyloid burden (amyloid negative). Cross-sectional comparisons were made between groups to examine differential miRNA expression levels using Fisher's exact tests. Replication of results was undertaken using a publicly available dataset of blood miRNA data of AD and controls. In silico analysis of downstream messenger RNA targets of candidate miRNAs was performed to elucidate potential biological function. RESULTS: After quality control, 816 miRNAs were available for analysis. There were 71 significantly differentially expressed miRNAs between the AD and control groups (p < 0.05). Two of these miRNAs, miR-146b-5p and miR-15b-5p, were also significant in the replication cohort. Pathways analysis showed these miRNAs to be involved in innate immune system and regulation of the cell cycle, respectively, both of which have relevance to AD pathogenesis. CONCLUSION: Blood miR-146b-5p and miR15b-5p showed consistent differential expression in AD compared to controls. Further replication and translational studies in strictly phenotyped cohorts are needed to establish their role as biomarkers for AD to have clinical utility.

5.
Mol Psychiatry ; 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32467648

RESUMO

Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = -0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

7.
Cereb Cortex ; 30(7): 4121-4139, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32198502

RESUMO

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one's occupation.

8.
Neurosci Biobehav Rev ; 113: 98-110, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32169413

RESUMO

This systematic review examines the genetic and epigenetic factors associated with resting-state functional connectivity (RSFC) in healthy human adult brains across the lifespan, with a focus on genes associated with Alzheimer's disease (AD). There were 58 studies included. The key findings are: (i) genetic factors have a low to moderate contribution; (ii) the apolipoprotein E ε2/3/4 polymorphism was the most studied genetic variant, with the APOE-ε4 allele most consistently associated with deficits of the default mode network, but there were insufficient studies to determine the relationships with other AD candidate risk genes; (iii) a single genome-wide association study identified several variants related to RSFC; (iv) two epigenetic independent studies showed a positive relationship between blood DNA methylation of the SLC6A4 promoter and RSFC measures. Thus, there is emerging evidence that genetic and epigenetic variation influence the brain's functional organisation and connectivity over the adult lifespan. However, more studies are required to elucidate the roles genetic and epigenetic factors play in RSFC measures across the adult lifespan.

9.
J Affect Disord ; 267: 42-48, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32063571

RESUMO

BACKGROUND: At present, no predictive markers for Major Depressive Disorder (MDD) exist. The search for such markers has been challenging due to clinical and molecular heterogeneity of MDD, the lack of statistical power in studies and suboptimal statistical tools applied to multidimensional data. Machine learning is a powerful approach to mitigate some of these limitations. METHODS: We aimed to identify the predictive markers of recurrent MDD in the elderly using peripheral whole blood from the Sydney Memory and Aging Study (SMAS) (N = 521, aged over 65) and adopting machine learning methodology on transcriptome data. Fuzzy Forests is a Random Forests-based classification algorithm that takes advantage of the co-expression network structure between genes; it allows to alleviate the problem of p >> n via reducing the dimensionality of transcriptomic feature space. RESULTS: By adopting Fuzzy Forests on transcriptome data, we found that the downregulated TFRC (transferrin receptor) can predict recurrent MDD with an accuracy of 63%. LIMITATIONS: Although we corrected our data for several important confounders, we were not able to account for the comorbidities and medication taken, which may be numerous in the elderly and might have affected the levels of gene transcription. CONCLUSIONS: We found that downregulated TFRC is predictive of recurrent MDD, which is consistent with the previous literature, indicating the role of the innate immune system in depression. This study is the first to successfully apply Fuzzy Forests methodology on psychiatric condition, opening, therefore, a methodological avenue that can lead to clinically useful predictive markers of complex traits.

10.
Transl Psychiatry ; 9(1): 285, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712550

RESUMO

Machine learning methods show promise to translate univariate biomarker findings into clinically useful multivariate decision support systems. At current, works in major depressive disorder have predominantly focused on neuroimaging and clinical predictor modalities, with genetic, blood-biomarker, and cardiovascular modalities lacking. In addition, the prediction of rehospitalization after an initial inpatient major depressive episode is yet to be explored, despite its clinical importance. To address this gap in the literature, we have used baseline clinical, structural imaging, blood-biomarker, genetic (polygenic risk scores), bioelectrical impedance and electrocardiography predictors to predict rehospitalization within 2 years of an initial inpatient episode of major depression. Three hundred and eighty patients from the ongoing 12-year Bidirect study were included in the analysis (rehospitalized: yes = 102, no = 278). Inclusion criteria was age ≥35 and <66 years, a current or recent hospitalisation for a major depressive episode and complete structural imaging and genetic data. Optimal performance was achieved with a multimodal panel containing structural imaging, blood-biomarker, clinical, medication type, and sleep quality predictors, attaining a test AUC of 67.74 (p = 9.99-05). This multimodal solution outperformed models based on clinical variables alone, combined biomarkers, and individual data modality prognostication for rehospitalization prediction. This finding points to the potential of predictive models that combine multimodal clinical and biomarker data in the development of clinical decision support systems.

11.
Front Aging Neurosci ; 11: 169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31333444

RESUMO

Adequate cerebral blood flow (CBF) is necessary to maintain brain metabolism and function. Arterial spin labeling (ASL) is an emerging MRI technique offering a non-invasive and reliable quantification of CBF. The genetic basis of CBF has not been well documented, and one approach to investigate this is to examine its heritability. The current study aimed to examine the heritability of CBF using ASL data from a cohort of community-dwelling older twins (41 monozygotic (MZ) and 25 dizygotic (DZ) twin pairs; age range, 65-93 years; 56.4% female). The results showed that the cortex had higher CBF than subcortical gray matter (GM) regions, and CBF in the GM regions of the anterior cerebral artery (ACA) territory was lower than that of the middle (MCA) and posterior (PCA) cerebral arteries. After accounting for the effects of age, sex and scanner, moderate heritability was identified for global CBF (h 2 = 0.611; 95% CI = 0.380-0.761), as well as for cortical and subcortical GM and the GM in the major arterial territories (h 2 = 0.500-0.612). Strong genetic correlations (GCs) were found between CBF in subcortical and cortical GM regions, as well as among the three arterial territories (ACA, MCA, PCA), suggesting a largely convergent genetic control for the CBF in brain GM. The moderate heritability of CBF warrants future investigations to uncover the genetic variants and genes that regulate CBF.

12.
PLoS Med ; 16(7): e1002853, 2019 07.
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.


Assuntos
Cognição , Disfunção Cognitiva/etnologia , Grupos Étnicos/psicologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Comorbidade , Diabetes Mellitus/etnologia , Exercício Físico , Feminino , Educação em Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Fumar/efeitos adversos , Fumar/etnologia , Acidente Vascular Cerebral/etnologia
13.
Front Neurol ; 10: 552, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191441

RESUMO

Theoretical background: The Apolipoprotein E (APOE) ε4 genotype is known to be one of the strongest single-gene predictors for Alzheimer disease, which is characterized by widespread brain structural degeneration progressing along with cognitive impairment. The ε4 allele status has been associated with brain structural alterations and lower cognitive ability in non-demented subjects. However, it remains unclear to what extent the visuospatial cognitive domain is affected, from what age onward changes are detectable and if alterations may interact with cognitive deficits in major depressive disorder (MDD). The current work investigated the effect of APOE ε4 homozygosity on visuospatial working memory (vWM) capacity, and on hippocampal morphometry. Furthermore, potential moderating roles of age and MDD were assessed. Methods: A sample of n = 31 homozygous ε4 carriers was contrasted with n = 31 non-ε4 carriers in a cross-sectional design. The sample consisted of non-demented, young to mid-age participants (mean age = 34.47; SD = 13.48; 51.6% female). Among them were n = 12 homozygous ε4 carriers and n = 12 non-ε4 carriers suffering from MDD (39%). VWM was assessed using the Corsi block-tapping task. Region of interest analyses of hippocampal gray matter density and volume were conducted using voxel-based morphometry (CAT12), and Freesurfer, respectively. Results: Homozygous ε4 carriers showed significantly lower Corsi span capacity than non-ε4 carriers did, and Corsi span capacity was associated with higher gray matter density of the hippocampus. APOE group differences in hippocampal volume could be detected but were no longer present when controlling for total intracranial volume. Hippocampal gray matter density did not differ between APOE groups. We did not find any interaction effects of age and MDD diagnosis on hippocampal morphometry. Conclusion: Our results point toward a negative association of homozygous ε4 allele status with vWM capacity already during mid-adulthood, which emerges independently of MDD diagnosis and age. APOE genotype seems to be associated with global brain structural rather than hippocampus specific alterations in young- to mid-age participants.

15.
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.


Assuntos
Doenças Cardiovasculares/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Longevidade , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/sangue , HDL-Colesterol/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Medição de Risco , Triglicerídeos/sangue
16.
Curr Opin Psychiatry ; 32(2): 130-137, 2019 03.
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.


Assuntos
Envelhecimento , Biomarcadores , Qualidade de Vida , Envelhecimento/fisiologia , Envelhecimento/psicologia , Nível de Saúde , Envelhecimento Saudável , Humanos
17.
Psychoneuroendocrinology ; 100: 18-26, 2019 02.
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.


Assuntos
Sobreviventes Adultos de Maus-Tratos Infantis/psicologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Transtorno Depressivo Maior , Carga Genética , Obesidade/genética , Recompensa , Adulto , Antidepressivos/uso terapêutico , Índice de Massa Corporal , Encéfalo/diagnóstico por imagem , Criança , Maus-Tratos Infantis/psicologia , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/patologia , Transtorno Depressivo Maior/fisiopatologia , Feminino , Predisposição Genética para Doença , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/psicologia , Estudos Retrospectivos , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
18.
Brain Imaging Behav ; 13(3): 750-761, 2019 Jun.
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.


Assuntos
Hemorragia Cerebral/fisiopatologia , Cognição/fisiologia , Demência/etiologia , Idoso , Idoso de 80 Anos ou mais , Encéfalo/fisiologia , Hemorragia Cerebral/complicações , Transtornos Cognitivos/etiologia , Disfunção Cognitiva/complicações , Estudos Transversais , Demência/fisiopatologia , Progressão da Doença , Função Executiva/fisiologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Fatores de Risco
19.
J Psychiatr Res ; 107: 19-27, 2018 12.
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.


Assuntos
Imunidade Adaptativa/imunologia , Transtorno Depressivo Maior , Retículo Endoplasmático/metabolismo , Perfilação da Expressão Gênica , Expressão Gênica , Redes Reguladoras de Genes , Imunidade Inata/imunologia , Idoso , Idoso de 80 Anos ou mais , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/imunologia , Transtorno Depressivo Maior/metabolismo , Regulação para Baixo , Retículo Endoplasmático/genética , Feminino , Humanos , Masculino , Recidiva
20.
J Fluency Disord ; 58: 11-21, 2018 12.
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.


Assuntos
Gagueira/epidemiologia , Gagueira/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Índia , Masculino
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