Virtual histology of multi-modal magnetic resonance imaging of cerebral cortex in young men

Neurobiology underlying inter-regional variations - across the human cerebral cortex - in measures derived with multi-modal magnetic resonance imaging (MRI) is poorly understood. Here, we characterize inter-regional variations in a large number of such measures, including T1 and T2 relaxation times, myelin water fraction (MWF), T1w/T2w ratio, mean diffusivity (MD), fractional anisotropy (FA), magnetization transfer ratio (MTR) and cortical thickness. We then employ a virtual-histology approach and relate these inter-regional profiles to those in cell-specific gene expression. Virtual histology revealed that most MRI-derived measures, including T1, T2 relaxation time, MWF, T1w/T2w ratio, MTR, FA and cortical thickness, are associated with expression profiles of genes specific to CA1 pyramidal cells; these genes are enriched in biological processes related to dendritic arborisation. In addition, T2 relaxation time, MWF and T1w/T2w ratio are associated with oligodendrocyte-specific gene-expression profiles, supporting their use as measures sensitive to intra-cortical myelin. MWF contributes more variance than T1w/T2w ratio to the mean oligodendrocyte expression profile, suggesting greater sensitivity to myelin. These cell-specific MRI associations may help provide a framework for determining which MRI sequences to acquire in studies with specific neurobiological hypotheses

Saguenay Youth Study : a multi-generational approach to studying virtual trajectories of the brain and cardio-metabolic health

This paper provides an overview of the Saguenay Youth Study (SYS) and its parental arm. The overarching goal of this effort is to develop trans-generational models of developmental cascades contributing to the emergence of common chronic disorders, such as depression, addictions, dementia and cardio-metabolic diseases. Over the past 10 years, we have acquired detailed brain and cardio-metabolic phenotypes, and genome-wide genotypes, in 1029 adolescents recruited in a population with a known genetic founder effect. At present, we are extending this dataset to acquire comparable phenotypes and genotypes in the biological parents of these individuals. After providing conceptual background for this work (transactions across time, systems and organs), we describe briefly the tools employed in the adolescent arm of this cohort and highlight some of the initial accomplishments. We then outline in detail the phenotyping protocol used to acquire comparable data in the parents

Income inequality, gene expression, and brain maturation during adolescence

Income inequality is associated with poor health and social outcomes. Negative social comparisons and competition may involve the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes in underlying some of these complex inter-relationships. Here we investigate brain maturation, indexed by age-related decreases in cortical thickness, in adolescents living in neighborhoods with differing levels of income inequality and household income. We examine whether inter-regional variations relate to those in glucocorticoid receptor (HPA) and androgen receptor (HPG) gene expression. For each sex, we used a median split of income inequality and household income (income-to-needs ratio) to create four subgroups. In female adolescents, the high-inequality low-income group displayed the greatest age-related decreases in cortical thickness. In this group, expression of glucocorticoid and androgen receptor genes explained the most variance in these age-related decreases in thickness across the cortex. We speculate that female adolescents living in high-inequality neighborhoods and low-income households may experience greater HPA and HPG activity, leading to steeper decreases in cortical thickness with age

Prenatal exposure to maternal cigarette smoking, amygdala volume, and fat intake in adolescence

Context : Prenatal exposure to maternal cigarette smoking is a well-established risk factor for obesity, but the underlying mechanisms are not known. Preference for fatty foods, regulated in part by the brain reward system, may contribute to the development of obesity. Objective : To examine whether prenatal exposure to maternal cigarette smoking is associated with enhanced fat intake and risk for obesity, and whether these associations may be related to subtle structural variations in brain regions involved in reward processing. Design : Cross-sectional study of a population-based cohort. Setting : The Saguenay Youth Study, Quebec, Canada. Participants : A total of 378 adolescents (aged 13 to 19 years; Tanner stage 4 and 5 of sexual maturation), half of whom were exposed prenatally to maternal cigarette smoking (mean [SD], 11.1 [6.8] cigarettes/d). Main Outcome Measures : Fat intake was assessed with a 24-hour food recall (percentage of energy intake consumed as fat). Body adiposity was measured with anthropometry and multifrequency bioimpedance. Volumes of key brain structures involved in reward processing, namely the amygdala, nucleus accumbens, and orbitofrontal cortex, were measured with magnetic resonance imaging. Results : Exposed vs nonexposed subjects exhibited a higher total body fat (by approximately 1.7 kg; P = .009) and fat intake (by 2.7%; P = .001). They also exhibited a lower volume of the amygdala (by 95 mm3; P < .001) but not of the other 2 brain structures. Consistent with its possible role in limiting fat intake, amygdala volume correlated inversely with fat intake (r = −0.15; P = .006). Conclusions : Prenatal exposure to maternal cigarette smoking may promote obesity by enhancing dietary preference for fat, and this effect may be mediated in part through subtle structural variations in the amygdala

Contribution of Autosomal Loci and the Y Chromosome to the Stress Response in Rats

Stress is a critical contributor to cardiovascular diseases through its impact on blood pressure variability and cardiac function. Familial clustering of reactivity to stress has been demonstrated in human subjects, and some rodent models of hypertension are hyperresponsive to stress. Therefore, the present study was designed to uncover the genetic determinants of the stress response. We performed a total genome linkage search to identify the loci of the body temperature response to immobilization stress in a set of recombinant inbred strains (RIS) originating from reciprocal crosses of spontaneously hypertensive rats (SHR) with a normotensive Brown Norway Lx strain. Two quantitative trait loci (QTLs) were revealed on chromosomes (Chrs) 10 and 12 (logarithm of odds scores, 2.2 and 1.3, respectively). The effects of these QTLs were enhanced by a high sodium diet (logarithm of odds scores, 4.0 and 3.3 for Chrs 10 and 12, respectively), which is suggestive of a salt-sensitive component for the phenotype, Congenics for Chr 10 confirmed both the QTL and the salt effect in RIS. Negatively associated loci were also identified on Chrs 8 and 11. Interaction between the loci of Chrs 10 and 12 was demonstrated, with the rat strains bearing SHR alleles at both loci having the highest thermal response to stress. Furthermore, the Y Chr of SHR origin enhanced the response to immobilization stress, as demonstrated in 2 independent models, RIS and Y Chr consomics. However, its full effect requires autosomes of the SHR strain. These findings provide the first evidence for the genetic determination of reactivity to stress with interactions between autosomal loci and between the Y and autosomal Chrs that contribute to the explanation of the 46% of variance in the stress response

Growth of white matter in the adolescent brain: role of testosterone and androgen receptor

The growth of white matter during human adolescence shows a striking sexual dimorphism; the volume of white matter increases with age slightly in girls and steeply in boys. Here, we provide evidence supporting the role of androgen receptor (AR) in mediating the effect of testosterone on white matter. In a large sample of typically developing adolescents (n = 408, 204 males), we used magnetic resonance imaging and acquired T1-weighted and magnetization transfer ratio (MTR) images. We also measured plasma levels of testosterone and genotyped a functional polymorphism in the AR gene, namely the number of CAG repeats in exon 1 believed to be inversely proportional to the AR transcriptional activity. We found that the testosterone-related increase of white-matter volume was stronger in male adolescents with the lower versus higher number of CAG repeats in the AR gene, with testosterone explaining, respectively, 26 and 8% of variance in the volume. The MTR results suggest that this growth is not related to myelination; the MTR decreased with age in male adolescents. We speculate that testosterone affects axonal caliber rather than the thickness of the myelin sheath

Orbitofrontal cortex and drug use during adolescence : role of prenatal exposure to maternal smoking and BDNF genotype

Context : Prenatal exposure to maternal cigarette smoking (PEMCS) may affect brain development and behavior in adolescent offspring. Objective : To evaluate the involvement of the orbitofrontal cortex (OFC) in mediating the relationship between PEMCS and substance use. Design : Cross-sectional analyses from the Saguenay Youth Study aimed at evaluating the effects of PEMCS on brain development and behavior among adolescents. Nonexposed adolescents were matched with adolescents exposed prenatally to cigarette smoking by maternal educational level. Participants and Setting : A French Canadian founder population of the Saguenay–Lac-Saint-Jean region of Quebec, Canada.The behavioral data set included 597 adolescents (275 sibships; 12-18 years of age), half of whom were exposed in utero to maternal cigarette smoking. Analysis of cortical thickness and genotyping were performed using available data from 314 adolescents. Main Outcome Measures : The likelihood of substance use was assessed with the Diagnostic Interview Schedule for Children Predictive Scales. The number of different drugs tried by each adolescent was assessed using another questionnaire. Thickness of the OFC was estimated from T1-weighted magnetic resonance images using FreeSurfer software. Results : Prenatal exposure to maternal cigarette smoking is associated with an increased likelihood of substance use. Among exposed adolescents, the likelihood of drug experimentation correlates with the degree of OFC thinning. In nonexposed adolescents, the thickness of the OFC increases as a function of the number of drugs tried. The latter effect is moderated by a brain-derived neurotrophic factor (BDNF) genotype (Val66Met). Conclusions : We speculate that PEMCS interferes with the development of the OFC and, in turn, increases the likelihood of drug use among adolescents. In contrast, we suggest that, among nonexposed adolescents, drug experimentation influences the OFC thickness via processes akin to experience-induced plasticity

Screening for Multiple Endocrine Neoplasia Type 2A with DNA-Polymorphism Analysis

Nine chromosome 10 DNA markers (FNRB, D10S34, D10Z1, MEN203, D10S94, RBP3, D10S15, MBP [48.11], D10S22) were typed in two large Canadian pedigrees with multiple endocrine neoplasia type 2A (MEN 2A). These markers and the gene for MEN 2A (MEN2A) are believed to be in one linkage group spanning approximately 15 cM (male). MEN203 and D10S94 were informative and tightly linked to MEN2A with no recombinants observed in 26 meiotic events. D10S15 (MCK2), widely used in DNA genotyping predictions, demonstrated two recombinants in these two families. The use of multiple flanking markers increases both the likelihood of informativeness and the accuracy of risk assessments for predictive testing. We were able to assign a risk estimate for all 10 at-risk individuals

Visceral adiposity is associated with metabolic profiles predictive of type 2 diabetes and myocardial infarction

Background: Visceral fat (VF) increases risk for cardiometabolic disease (CMD), the leading cause of morbidity and mortality. Variations in the circulating metabolome predict the risk for CMD but whether or not this is related to VF is unknown. Further, CMD is now also present in adolescents, and the relationships between VF, circulating metabolome, and CMD may vary between adolescents and adults. Methods: With an aim to add understanding to the metabolic variations in visceral obesity, we tested associations between VF, measured directly with magnetic resonance imaging, and 228 fasting serum metabolomic measures, quantified with nuclear magnetic resonance spectroscopy, in 507 adults (36-65 years) and 938 adolescents (12-18 years). We further utilized data from published studies to estimate similarities between VF and CMD-associated metabolic profiles. Results: Here we show that VF, independently of body mass index (BMI) or subcutaneous fat, is associated with triglyceride-rich lipoproteins, fatty acids, and inflammation in both adults and adolescents, whereas the associations with amino acids, glucose, and intermediary metabolites are significant in adults only. BMI-adjusted metabolomic profile of VF resembles those predicting type 2 diabetes in adults (R 2 = 0.88) and adolescents (R 2 = 0.70), and myocardial infarction in adults (R 2 = 0.59) and adolescents (R 2 = 0.40); this is not the case for ischemic stroke (adults: R 2 = 0.05, adolescents: R 2 = 0.08). Conclusions: Visceral adiposity is associated with metabolomic profiles predictive of type 2 diabetes and myocardial infarction even in normal-weight individuals and already in adolescence. Targeting factors contributing to the emergence and maintenance of these profiles might ameliorate their cumulative effects on cardiometabolic health