Anxiety Associated Increased CpG Methylation in the Promoter of Asb1: A Translational Approach Evidenced by Epidemiological and Clinical Studies and a Murine Model

Epigenetic regulation in anxiety is suggested, but evidence from large studies is needed. We conducted an epigenome-wide association study (EWAS) on anxiety in a population-based cohort and validated our finding in a clinical cohort as well as a murine model. In the KORA cohort, participants (n= 1522, age 32–72 years) were administered the Generalized Anxiety Disorder (GAD-7) instrument, whole blood DNA methylation was measured (Illumina 450K BeadChip), and circulating levels of hs-CRP and IL-18 were assessed in the association between anxiety and methylation. DNA methylation was measured using the same instrument in a study of patients with anxiety disorders recruited at the Max Planck Institute of Psychiatry (MPIP, 131 non-medicated cases and 169 controls). To expand our mechanistic understanding, these findings were reverse translated in a mouse model of acute social defeat stress. In the KORA study, participants were classified according to mild, moderate, or severe levels of anxiety (29.4%/6.0%/1.5%, respectively). Severe anxiety was associated with 48.5% increased methylation at a single CpG site (cg12701571) located in the promoter of the gene encoding Asb1 (β-coefficient = 0.56 standard error (SE) =0.10, p (Bonferroni) = 0.005), a protein hypothetically involved in regulation of cytokine signaling. An interaction between IL-18 and severe anxiety with methylation of this CpG cite showed a tendency towards significance in the total population (p =0.083) and a significant interaction among women (p =0.014). Methylation of the same CpG was positively associated with Panic and Agoraphobia scale (PAS) scores (β= 0.005, SE= 0.002, p=0.021, n= 131) among cases in the MPIP study. In a murine model of acute social defeat stress, Asb1 gene expression was significantly upregulated in a tissue-specific manner (p= 0.006), which correlated with upregulation of the neuroimmunomodulating cytokine interleukin 1 beta. Our findings suggest epigenetic regulation of the stress-responsive Asb1 gene in anxiety-related phenotypes. Further studies are necessary to elucidate the causal direction of this association and the potential role of Asb1-mediated immune dysregulation in anxiety disorders

Prenatal adverse environment is associated with epigenetic age deceleration at birth and hypomethylation at the hypoxia-responsive EP300 gene

Abstract Background: Obstetric complications have long been retrospectively associated with a wide range of short- and long-term health consequences, including neurodevelopmental alterations such as those observed in schizophrenia and other psychiatric disorders. However, prospective studies assessing fetal well-being during pregnancy tend to focus on perinatal complications as the final outcome of interest, while there is a scarcity of postnatal follow-up studies. In this study, the cerebroplacental ratio (CPR), a hemodynamic parameter reflecting fetal adaptation to hypoxic conditions, was analyzed in a sample of monozygotic monochorionic twins (60 subjects), part of them with prenatal complications, with regard to (i) epigenetic age acceleration, and (ii) DNA methylation at genes included in the polygenic risk score (PRS) for schizophrenia, and highly expressed in placental tissue. Results: Decreased CPR measured during the third trimester was associated with epigenetic age deceleration (β = 0.21, t = 3.362, p = 0.002). Exploration of DNA methylation at placentally expressed genes of the PRS for schizophrenia revealed methylation at cg06793497 (EP300 gene) to be associated with CPR (β = 0.021, t = 4.385; p = 0.00008, FDR-adjusted p = 0.11). This association was reinforced by means of an intrapair analysis in monozygotic twins discordant for prenatal suffering (β = 0.027, t = 3.924, p = 0.001). Conclusions: Prenatal adverse environment during the third trimester of pregnancy is associated with both (i) developmental immaturity in terms of epigenetic age, and (ii) decreased CpG-specific methylation in a gene involved in hypoxia response and schizophrenia genetic liability. Keywords: DNA methylation, Obstetric complications, Prenatal stress, Hypoxia, EP300 gene, Epigenetic clock, Monozygotic twins, Schizophreni

Designing UHF RFID tag antennas with Barcode shape for dual-technology identification

In this paper, a novel methodology to design Ultra High Frequency Radio-Frequency IDentification (UHF RFID) tag antennas with Barcode layout is proposed with the challenging goal of "fusing" both technologies in a single device. Specifically, after a brief recall of the well-known barcode standard, a procedure to design meandered barcode-shaped UHF RFID tags is introduced and discussed leveraging on electromagnetic evidence. The main steps of the proposed method are described by highlighting the constraints inherited by both the adopted technologies, as well as the useful opportunities to automatise the entire antenna design process after a preliminary simulation campaign through a full-wave simulator. Different RFID-Barcode tag antennas are designed, manufactured, and characterised in terms of maximum reading range and tag sensitivity. Obtained results demonstrate the validity of the proposed approach

Amygdalar MicroRNA-15a Is Essential for Coping with Chronic Stress.

MicroRNAs are important regulators of gene expression and associated with stress-related psychiatric disorders. Here, we report that exposing mice tochronic stress led to a specific increase in microRNA-15a levels in the amygdala-Ago2 complex and a concomitant reduction in the levels of its predicted target, FKBP51, which is implicated in stress-related psychiatric disorders. Reciprocally, mice expressing reduced levels of amygdalar microRNA-15a following exposure to chronic stress exhibited increased anxiety-like behaviors. In humans, pharmacological activation of the glucocorticoid receptor, as well as exposure to childhood trauma, was associated with increased microRNA-15a levels in peripheral blood. Taken together, our results support an important role for microRNA-15ain stress adaptation and the pathogenesis of stress-related psychopathologies

Utility of Amyloid and FDG-PET in Clinical Practice: Differences Between Secondary and Tertiary Care Memory Units

The clinical utility of amyloid positron emission tomography (PET) has not been fully established. Our aim was to evaluate the effect of amyloid imaging on clinical decision making in a secondary care unit and compare our results with a previous study in a tertiary center following the same methods. We reviewed retrospectively 151 cognitively impaired patients who underwent amyloid (Pittsburgh compound B [PiB]) PET and were evaluated clinically before and after the scan in a secondary care unit. One hundred and fifty concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed changes between the pre- and post-PET clinical diagnosis and Alzheimer's disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using ?2 and multivariate logistic regression. Concordance between classification based on scan readings and baseline diagnosis was 66% for PiB and 47% for FDG. The primary diagnosis changed after PET in 17.2% of cases. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (p = 0.0002). Changes in treatment were associated with concordant PiB (p = 0.009) while FDG had no effect on treatment decisions. Based on our regression model, patients with diagnostic dilemmas, a suspected non-amyloid syndrome, and Clinical Dementia Rating <1 were more likely to benefit from amyloid PET due to a higher likelihood of diagnostic change. We found that changes in diagnosis after PET in our secondary center almost doubled those of our previous analysis of a tertiary unit (9% versus 17.2%). Our results offer some clues about the rational use of amyloid PET in a secondary care memory unit stressing its utility in mild cognitive impairment patients

Heritability and reliability of automatically segmented human hippocampal formation subregions

The human hippocampal formation can be divided into a set of cytoarchitecturally and functionally distinct subregions, involved in different aspects of memory formation. Neuroanatomical disruptions within these subregions are associated with several debilitating brain disorders including Alzheimer's disease, major depression, schizophrenia, and bipolar disorder. Multi-center brain imaging consortia, such as the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium, are interested in studying disease effects on these subregions, and in the genetic factors that affect them. For large-scale studies, automated extraction and subsequent genomic association studies of these hippocampal subregion measures may provide additional insight. Here, we evaluated the test-retest reliability and transplatform reliability (1.5 T versus 3 T) of the subregion segmentation module in the FreeSurfer software package using three independent cohorts of healthy adults, one young (Queensland Twins Imaging Study, N=39), another elderly (Alzheimer's Disease Neuroimaging Initiative, ADNI-2, N=163) and another mixed cohort of healthy and depressed participants (Max Planck Institute, MPIP, N=598). We also investigated agreement between the most recent version of this algorithm (v6.0) and an older version (v5.3), again using the ADNI-2 and MPIP cohorts in addition to a sample from the Netherlands Study for Depression and Anxiety (NESDA) (N=221). Finally, we estimated the heritability (h(2)) of the segmented subregion volumes using the full sample of young, healthy QTIM twins (N=728). Test-retest reliability was high for all twelve subregions in the 3 T ADNI-2 sample (intraclass correlation coefficient (ICC)=0.70-0.97) and moderate-to-high in the 4 TQTIM sample (ICC=0.5-0.89). Transplatform reliability was strong for eleven of the twelve subregions (ICC=0.66-0.96); however, the hippocampal fissure was not consistently reconstructed across 1.5 T and 3 T field strengths (ICC=0.47-0.57). Between-version agreement was moderate for the hippocampal tail, subiculum and presubiculum (ICC=0.78-0.84; Dice Similarity Coefficient (DSC)=0.55-0.70), and poor for all other subregions (ICC=0.34-0.81; DSC=0.28-0.51). All hippocampal subregion volumes were highly heritable (h(2)=0.67-0.91). Our findings indicate that eleven of the twelve human hippocampal subregions segmented using FreeSurfer version 6.0 may serve as reliable and informative quantitative phenotypes for future multi-site imaging genetics initiatives such as those of the ENIGMA consortium. (C) 2016 The Authors. Published by Elsevier Inc

Dietary intervention modifies DNA methylation age assessed by the epigenetic clock

Scope: Alterations in DNA methylation patterns are correlated with aging, environmental exposures and disease pathophysiology; the possibility of reverting or preventing these processes through dietary intervention is gaining momentum. In particular, methyl donors that provide S-adenosyl-methionine for one-carbon metabolism and polyphenols such as flavanols that inhibit the activity of DNA methyltransferases (DNMTs) could be key modifiers of epigenetic patterns. Methods and results: We assessed DNA methylation patterns in publicly available Illumina Infinium 450K methylation datasets from intervention studies with either folic acid + vitamin B12 (GSE74548) or monomeric and oligomeric flavanols (MOF) (GSE54690) in 44 and 13 participants, respectively. Global DNA methylation levels increased in unmethylated regions such as CpG islands and shores following folic acid + vitamin B12 supplementation and decreased in highly methylated regions, including shelves and open-seas following intervention with MOF. After supplementation with folic acid + vitamin B12, epigenetic age, estimated by the Horvath ‘epigenetic clock’ model, was reduced in women with the MTHFR 677CC genotype. Conclusions: The effects of supplementation with folic acid + vitamin B12 and MOF on DNA methylation age are dependent upon gender and MTHFR genotype. Additionally, our findings demonstrate the potential for these dietary factors to modulate global DNA methylation profiles