FTO variation and early frontostriatal brain development in children.

OBJECTIVE: Common obesity-associated genetic variants at the fat mass and obesity-associated (FTO) locus have been associated with appetitive behaviors and altered structure and function of frontostriatal brain regions. The authors aimed to investigate the influence of FTO variation on frontostriatal appetite circuits in early life. METHODS: Data were drawn from RESONANCE, a longitudinal study of early brain development. Growth trajectories of nucleus accumbens and frontal lobe volumes, as well as total gray matter and white matter volume, by risk allele (AA) carrier status on FTO single-nucleotide polymorphism rs9939609 were examined in 228 children (102 female, 126 male) using magnetic resonance imaging assessments obtained from infancy through middle childhood. The authors fit functional concurrent regression models with brain volume outcomes over age as functional responses, and FTO genotype, sex, BMI z score, and maternal education were included as predictors. RESULTS: Bootstrap pointwise 95% CI for regression coefficient functions in the functional concurrent regression models showed that the AA group versus the group with no risk allele (TT) had greater nucleus accumbens volume (adjusted for total brain volume) in the interval of 750 to 2250 days (2-6 years). CONCLUSIONS: These findings suggest that common genetic risk for obesity is associated with differences in early development of brain reward circuitry and argue for investigating dynamic relationships among genotype, brain, behavior, and weight throughout development.

Transcriptional profiling of multiple system atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease.

Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n = 66) and healthy controls (HC; n = 66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type.We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for ß-amyloid related functional classes, including the known Alzheimer's disease (AD) genes, APP and PSEN1.This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and AD-related genes despite the clinical and neuropathological distinctions between the two diseases.

Family history of Alzheimer's disease alters cognition and is modified by medical and genetic factors.

In humans, a first-degree family history of dementia (FH) is a well-documented risk factor for Alzheimer's disease (AD); however, the influence of FH on cognition across the lifespan is poorly understood. To address this issue, we developed an internet-based paired-associates learning (PAL) task and tested 59,571 participants between the ages of 18-85. FH was associated with lower PAL performance in both sexes under 65 years old. Modifiers of this effect of FH on PAL performance included age, sex, education, and diabetes. The Apolipoprotein E ε4 allele was also associated with lower PAL scores in FH positive individuals. Here we show, FH is associated with reduced PAL performance four decades before the typical onset of AD; additionally, several heritable and non-heritable modifiers of this effect were identified.

Transcriptome response of human skeletal muscle to divergent exercise stimuli.

Aerobic (AE) and resistance exercise (RE) elicit unique adaptations in skeletal muscle that have distinct implications for health and performance. The purpose of this study was to identify the unique transcriptome response of skeletal muscle to acute AE and RE. In a counterbalanced, crossover design, six healthy, recreationally active young men (27 ± 3 yr) completed acute AE (40 min of cycling, ∼70% maximal HR) and RE [8 sets, 10 reps, ∼65% 1-repetition maximum (1RM)], separated by ∼1 wk. Muscle biopsies (vastus lateralis) were obtained before and at 1 and 4 h postexercise. Whole transcriptome RNA sequencing (HiSeq2500; Illumina) was performed on cDNA synthesized from skeletal muscle RNA. Sequencing data were analyzed using HTSeq, and differential gene expression was identified using DESeq2 [adjusted P value (FDR) <0.05, >1.5-fold change from preexercise]. RE resulted in a greater number of differentially expressed genes at 1 (67 vs. 48) and 4 h (523 vs. 221) compared with AE. We identified 348 genes that were differentially expressed only following RE, whereas 48 genes were differentially expressed only following AE. Gene clustering indicated that AE targeted functions related to zinc interaction, angiogenesis, and ubiquitination, whereas RE targeted functions related to transcription regulation, cytokine activity, cell adhesion, kinase activity, and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. ESRRG and TNFSRF12A were identified as potential targets related to the specific response of skeletal muscle to AE and RE, respectively. These data describe the early postexercise transcriptome response of skeletal muscle to acute AE and RE and further highlight that different forms of exercise stimulate unique molecular activity in skeletal muscle. NEW & NOTEWORTHY Whole transcriptome RNA sequencing was used to determine the early postexercise transcriptome response of skeletal muscle to acute aerobic (AE) and resistance exercise (RE) in untrained individuals. Although a number of shared genes were stimulated following both AE and RE, several genes were uniquely responsive to each exercise mode. These findings support the need for future research focused to better identify the role of exercise mode as it relates to targeting specific cellular skeletal muscle abnormalities.