The dynamic role of genetics on cortical patterning during childhood and adolescence.
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ABSTRACT:
SUBMITTER: Schmitt JE
PROVIDER: S-EPMC4020057 | biostudies-other | 2014 May
REPOSITORIES: biostudies-other
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Project description:Neuroendocrine theories of brain development hold testosterone as the predominant factor mediating sex-specific cortical growth and the ensuing lateralization of hemispheric function. However, studies to date have focussed on prenatal testosterone rather than pubertal changes in testosterone. Yet, animal studies have shown a high density of androgen-sensitive receptors in multiple key cortical areas, and puberty is known to coincide with both a significant rise in testosterone and the emergence of behavioral sex differences, suggesting peripubertal influences of testosterone on brain development. Here, we used linear mixed models to examine sex-specific cortical maturation associated with changes in testosterone levels in a longitudinal sample of developmentally healthy children and adolescents. A significant "sex by age by testosterone" interaction on cortical thickness (CTh) involving widespread areas of the developing brain was found. Testosterone levels were associated with CTh changes in regions of the left hemisphere in males and of the right hemisphere in females. In both sexes, the relationship between testosterone and CTh varied across the age span. These findings show the association between testosterone and CTh to be complex, highly dynamic, and to vary, depending on sex and age; they also suggest sex-related hemispheric lateralization effects of testosterone in humans.
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Project description:ImportanceMany psychiatric disorders can be conceptualized as disorders of brain maturation during childhood and adolescence. Discovering the neurobiological underpinnings of brain maturation may elucidate molecular pathways of vulnerability and resilience to such disorders.ObjectiveTo investigate the underlying neurobiological mechanisms of age-associated cortical thinning during maturation and their implications for psychiatric disorders.Design, setting, and participantsThis multicohort analysis used data from 3 community-based studies. The Saguenay Youth Study provided data from 1024 adolescents who were recruited at a single site in Quebec, Canada. The IMAGEN cohort provided data from 1823 participants who were recruited in 8 European cities. The Brazil High Risk Cohort Study for the Development of Childhood Psychiatric Disorders provided data from 815 participants who were recruited in 2 Brazilian cities. Cortical thickness was estimated from the results of magnetic resonance imaging (MRI) scans, and age-associated cortical thinning was estimated in 34 cortical regions. Gene expression from the Allen Human Brain Atlas was aligned with the same regions. Similarities in the interregional profiles of gene expression and the profiles of age-associated cortical thinning were measured. The involvement of dendrites, dendritic spines, and myelin was tested using 3 gene panels. Enrichment for genes associated with psychiatric disorders was tested among the genes associated with thinning and their coexpression networks. Data analysis was conducted between March and October 2019.Main outcomes and measuresMRI-derived estimates of age-associated cortical thinning and gene expression in 34 cortical regions.ResultsA total of 3596 individuals aged 9 to 21 years were included in this study. Of those, 1803 participants (50.1%) were female, and the mean (SD) age was 15.2 (2.6) years. Interregional profiles of age-associated cortical thinning were associated with interregional gradients in the expression of genes associated with dendrites, dendritic spines, and myelin; the variance in thinning explained by the gene panels across different points ranged from 0.45% to 10.55% for the dendrite panel, 0.00% to 9.98% for the spine panel, and 0.19% to 26.39% for the myelin panel. These genes and their coexpression networks were enriched for genes associated with several psychiatric disorders.Conclusions and relevanceIn this study, genetic similarity between interregional variation in cortical thinning during maturation and multiple psychiatric disorders suggests overlapping molecular underpinnings. This finding adds to the understanding of the neurodevelopmental mechanisms of psychiatric disorders.
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Project description:Background and objectivesSurvival in pediatric kidney transplant recipients has improved over the past five decades, but changes in cause-specific mortality remain uncertain. The aim of this retrospective cohort study was to estimate the associations between transplant era and overall and cause-specific mortality for child and adolescent recipients of kidney transplants.Design, setting, participants, & measurementsData were obtained on all children and adolescents (aged <20 years) who received their first kidney transplant from 1970 to 2015 from the Australian and New Zealand Dialysis and Transplant Registry. Mortality rates were compared across eras using Cox regression, adjusted for confounders.ResultsA total of 1810 recipients (median age at transplantation 14 years, 58% male, 52% living donor) were followed for a median of 13.4 years. Of these, 431 (24%) died, 174 (40%) from cardiovascular causes, 74 (17%) from infection, 50 (12%) from cancer, and 133 (31%) from other causes. Survival rates improved over time, with 5-year survival rising from 85% for those first transplanted in 1970-1985 (95% confidence interval [95% CI], 81% to 88%) to 99% in 2005-2015 (95% CI, 98% to 100%). This was primarily because of reductions in deaths from cardiovascular causes (adjusted hazard ratio [aHR], 0.25; 95% CI, 0.08 to 0.68) and infections (aHR, 0.16; 95% CI, 0.04 to 0.70; both for 2005-2015 compared with 1970-1985). Compared with patients transplanted 1970-1985, mortality risk was 72% lower among those transplanted 2005-2015 (aHR, 0.28; 95% CI, 0.18 to 0.69), after adjusting for potential confounders.ConclusionsSurvival after pediatric kidney transplantation has improved considerably over the past four decades, predominantly because of marked reductions in cardiovascular- and infection-related deaths.
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The treating physicians initially check the existence of inclusion and exclusion criteria. Insofar as inclusion criteria are met but exclusion criteria are not present, there is detailed medical information and written information about the content, risks and benefits of the MET registry. If the patient and the legal guardian agree, the patient can be included in the MET registry. In some cases, pediatric oncology centers contact the MET Help Desk for clinical advice. Patient data in German-speaking countries is recorded via the GPOH platform MARVIN (XClinical) in so-called electronic Case Report Forms” (eCRFs).
The patient information and declarations of consent are then sent in this way.
Primary outcome(s): The primary objectives of the MET Registry include:
1. The prospective registration of all children and adolescents with an initial diagnosis of a malignant endocrine tumor between the ages of 0 and 18 years
2. The scientific evaluation with the aim of optimizing the therapy of affected patients
Study Design: Allocation: ; Masking: ; Control: ; Assignment: ; Study design purpose: Prognosis
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