Recurrent major depression and right hippocampal volume: A bivariate linkage and association study.
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ABSTRACT:
SUBMITTER: Mathias SR
PROVIDER: S-EPMC4981180 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundFor many patients with major depressive disorder (MDD) adequate treatment remains elusive. Neuroimaging techniques received attention for their potential use in guiding and predicting response, but were rarely investigated in real-world psychiatric settings.AimsTo identify structural and functional Magnetic Resonance Imaging (MRI) biomarkers associated with antidepressant response in a real-world clinical sample.MethodsWe studied 100 MDD inpatients admitted to our psychiatric ward, treated with various antidepressants upon clinical need. Hamilton Depression Rating Scale percentage decrease from admission to discharge was used as a measure of response. All patients underwent 3.0 T MRI scanning. Grey matter (GM) volumes were investigated both in a voxel-based morphometry (VBM), and in a regions of interest (ROI) analysis. In a subsample of patients, functional resting-state connectivity patterns were also explored.ResultsIn the VBM analysis, worse response was associated to lower GM volumes in two clusters, encompassing the left hippocampus and parahippocampal gyrus, and the right superior and middle temporal gyrus. Investigating ROIs, lower bilateral hippocampi and amygdalae volumes predicted worse treatment outcomes. Functional connectivity in the right temporal and parahippocampal gyrus was also associated to response.ConclusionOur results expand existing literature on the relationship between the structure and function of several brain regions and treatment response in MDD. While we are still far from routine use of MRI biomarkers in clinical practice, we confirm a possible role of these techniques in guiding treatment choices and predicting their efficacy.
| S-EPMC10647896 | biostudies-literature
Project description:ObjectiveGlycogen synthase kinase 3β (GSK3β) has been implicated in mood disorders. We previously reported associations between a GSK3β polymorphism and hippocampal volume in major depressive disorder (MDD). We then reported similar associations for a subset of GSK3β-regulated genes. We now investigate an algorithm-derived comprehensive list of genes encoding proteins that directly interact with GSK3β to identify a genotypic network influencing hippocampal volume in MDD.Participants and methodsWe used discovery (N=141) and replication (N=77) recurrent MDD samples. Our gene list was generated from the NetworKIN database. Hippocampal measures were derived using an optimized Freesurfer protocol. We identified interacting single nucleotide polymorphisms using the machine learning algorithm Random Forest and verified interactions using likelihood ratio tests between nested linear regression models.ResultsThe discovery sample showed multiple two-single nucleotide polymorphism interactions with hippocampal volume. The replication sample showed a replicable interaction (likelihood ratio test: P=0.0088, replication sample; P=0.017, discovery sample; Stouffer's combined P=0.0007) between genes associated previously with endoplasmic reticulum stress, calcium regulation and histone modifications.ConclusionOur results provide genetic evidence supporting associations between hippocampal volume and MDD, which may reflect underlying cellular stress responses. Our study provides evidence of biological mechanisms that should be further explored in the search for disease-modifying therapeutic targets for depression.
| S-EPMC6531290 | biostudies-literature
Project description:The role of the amygdala in emotion recognition is well established, and amygdala volume and emotion recognition performance have each been shown separately to be highly heritable traits, but the potential role of common genetic influences on both traits has not been explored. The authors investigated the pleiotropic influences of amygdala volume and emotion recognition performance.In a sample of randomly selected extended pedigrees (N=858), the authors used a combination of univariate and bivariate linkage to investigate pleiotropy between amygdala volume and emotion recognition performance and followed up with association analysis.The authors found a pleiotropic region for amygdala volume and emotion recognition performance on chromosome 4q26 (LOD score=4.40). Association analysis conducted in the region underlying the bivariate linkage peak revealed a variant meeting the corrected significance level (Bonferroni-corrected p=5.01×10(-5)) within an intron of PDE5A (rs2622497, p=4.4×10(-5)) as being jointly influential on both traits. PDE5A has been implicated previously in recognition-memory deficits and is expressed in subcortical structures that are thought to underlie memory ability, including the amygdala.This study extends our understanding of the shared etiology between the amygdala and emotion recognition by showing that the overlap between amygdala volume and emotion recognition performance is due at least in part to common genetic influences. Moreover, this study identifies a pleiotropic locus for the two traits and an associated variant, which localizes the genetic signal even more precisely. These results, when taken in the context of previous research, highlight the potential utility of PDE5 inhibitors for ameliorating emotion recognition deficits in individuals suffering from mental or neurodegenerative illness.
| S-EPMC4314438 | biostudies-literature
Project description:Background: Major Depressive Disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for MDD suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesized that regulatory genomic processes are involved in the pathology of both MDD and suicidality. Methods: Genome-wide patterns of DNA methylation were assessed in depressed MDD suicide completers (n=20) and compared to non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focussed on identifying differentially methylated regions (DMRs) associated with suicidal depression, and epigenetic variation was explored in the context of polygenic risk scores for major depression and MDD suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed MDD suicide completers and polygenic burden for MDD and MDD suicide attempt. Results: We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite-pyrosequencing and replicated in a second set of MDD suicide samples, which is characterized by significant hypomethylation in both cortical brain regions in MDD MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for MDD suicide attempt, but not major depression. MDD suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Conclusions: Our data suggest there are coordinated changes in DNA methylation associated with MDD suicide that may offer novel insights into the molecular pathology associated with depressed MDD suicide completers.
2016-11-01 | GSE88890 | GEO
Project description:Smaller hippocampal volume is reported in major depressive disorder (MDD). We hypothesize that it may be related to fewer granule neurons (GN) in the dentate gyrus (DG), a defect possibly reversible with antidepressants. We studied age-, sex-, and postmortem interval-matched groups: no major psychopathology (controls); unmedicated-MDD; and MDD treated with serotonin reuptake inhibitors (MDD*SSRI) or tricyclics (MDD*TCA). Frozen right hippocampi were fixed, sectioned (50 μm), immunostained with neuronal nuclear marker (NeuN), and counterstained with hematoxylin. GN and glial number, and DG and granule cell layer (GCL) volumes were stereologically estimated. Fewer GNs in the anterior DG were present in unmedicated-MDDs compared with controls (p=0.013). Younger age of MDD onset correlated with fewer GNs (p=0.021). Unmedicated-MDDs had fewer mid-DG GNs than MDD*SSRIs (p=0.028) and controls (p=0.032). Anterior GCL glial number did not differ between groups. Anterior/mid GCL volume was smaller in unmedicated-MDDs vs controls (p=0.008) and larger in MDD*SSRIs vs unmedicated-MDDs (p<0.001), MDD*TCAs (p<0.001), and controls (p<0.001). Anterior GCL volume and GN number (r=0.594, p=0.001), and mid DG volume and GN number (r=0.398, p=0.044) were correlated. Anterior DG capillary density correlated with GN number (p=0.027), and with GCL (p=0.024) and DG (r=0.400, p=0.047) volumes. Posterior DG volume and GN number did not differ between groups. Fewer GNs in unmedicated-MDD without fewer neuronal progenitor cells, as previously reported, suggests a cell maturation or survival defect, perhaps related to MDD duration. This may contribute to a smaller hippocampus and is potentially reversed by SSRIs. Postmortem studies are correlative and animal studies are needed to test implied causal relationships.
| S-EPMC3629406 | biostudies-other
Project description:Clinical depression can occur in young children as early as age three. This very early onset variant of depression shows the same clinical features with developmental adjustments as depression that onsets later in life. One robust neural feature of adult depression is reduced hippocampal volume. We measured hippocampal volume in a sample of 35 children aged 4-7 who were either in a clinical trial for preschool onset depression or were recruited from the community. We used T1 MPRAGE acquisitions on a Siemen's Scanner, with Freesurfer 5.3 used to segment the hippocampus. Depression was measured using the K-SADS early childhood (K-SADS-EC) to create a dimensional depression severity score and the Child Behavior Checklist (CBCL) Depression T-Score. Multilevel models indicated that greater depression severity as measured by either the CBCL Depression Score or the K-SADS-EC was associated with lower hippocampal volume, even controlling for total gray matter, maternal depression, income-to-needs ratio, and stressful life events. These data indicate evidence for reduced hippocampal volume among children with PO-MDD who were more severely depressed. Findings are consistent with the idea that hippocampal volume reductions are an early occurring associated neural marker of MDD, particularly for more severe depression.
| S-EPMC6550342 | biostudies-literature
Project description:At present, more than 100 disease mutations in mitochondrial DNA polymerase ? (POLG) have been indentified that are causally related to an array of neuropsychiatric diseases affecting multiple systems. Both autosomal recessive and autosomal dominant forms can be delineated, the latter being associated with Parkinsonism and depressive or psychotic syndromes. In this report, a middle-aged female patient with recurrent major depression with melancholic features, slowly progressive gait instability, and dilated cardiomyopathy is described. Detailed diagnostic evaluation was performed to elucidate the supposed relationship between ataxia, cardiomyopathy, and major depression with melancholia. After extensive genetic and metabolic investigation, a nucleotide substitution c.2207 A?G in the POLG gene resulting in amino acid change Asn 736Ser in exon 13 was demonstrated. This mutation was considered to be compatible with a mitochondrial disorder and implicated in the pathophysiology of the neuropsychiatric syndrome. It is concluded that this novel POLG mutation forms the most parsimonious etiological explanation for the here-described combination of ataxia, major depression, and cardiomyopathy. Therefore, in patients with a complex neuropsychiatric presentation, extensive diagnostic analysis is warranted, including the search for mitochondriopathies, in order to avoid unnecessary delay of adequate treatment.
| S-EPMC3101889 | biostudies-literature
Project description:Grip strength is an important biomarker reflecting muscle strength, and depression is a psychiatric disorder all over the world. Several studies found a significant inverse association between grip strength and depression, and there is also evidence for common physiological mechanisms between them. We used twin data from Qingdao, China to calculate genetic correlations, and we performed a bivariate GWAS to explore potential SNPs, genes, and pathways in common between grip strength and depression. 139 pairs of Dizygotic twins were used for bivariate GWAS. VEAGSE2 and PASCAL software were used for gene-based analysis and pathway enrichment analysis, respectively. And the resulting SNPs were subjected to eQTL analysis and pleiotropy analysis. The genetic correlation coefficient between grip strength and depression was -0.41 (-0.96, -0.15). In SNP-based analysis, 7 SNPs exceeded the genome-wide significance level (P<5×10-8) and a total of 336 SNPs reached the level of suggestive significance (P<1×10-5). Gene-based analysis and pathway-based analysis identified genes and pathways related to muscle strength and the nervous system. The results of eQTL analysis were mainly enriched in tissues such as the brain, thyroid, and skeletal muscle. Pleiotropy analysis shows that 9 of the 15 top SNPs were associated with both grip strength and depression. In conclusion, this bivariate GWAS identified potentially common pleiotropic SNPs, genes, and pathways in grip strength and depression.
| S-EPMC9754196 | biostudies-literature
Project description:Depression is a highly prevalent and recurrent neuropsychiatric disorder associated with alterations in emotional and cognitive domains. Neuroplastic phenomena are increasingly considered central to the etiopathogenesis of and recovery from depression. Nevertheless, a high number of remitted patients experience recurrent episodes of depression, remaining unclear how previous episodes impact on behavior and neuroplasticity and/or whether modulation of neuroplasticity is important to prevent recurrent depression. Through re-exposure to an unpredictable chronic mild stress protocol in rats, we observed the re-appearance of emotional and cognitive deficits. Furthermore, treatment with the antidepressants fluoxetine and imipramine was effective to promote sustained reversion of a depressive-like phenotype; however, their differential impact on adult hippocampal neuroplasticity triggered a distinct response to stress re-exposure: while imipramine re-established hippocampal neurogenesis and neuronal dendritic arborization contributing to resilience to recurrent depressive-like behavior, stress re-exposure in fluoxetine-treated animals resulted in an overproduction of adult-born neurons along with neuronal atrophy of granule neurons, accounting for an increased susceptibility to recurrent behavioral changes typical of depression. Strikingly, cell proliferation arrest compromised the behavior resilience induced by imipramine and buffered the susceptibility to recurrent behavioral changes promoted by fluoxetine. This study shows that previous exposure to a depressive-like episode impacts on the behavioral and neuroanatomical changes triggered by subsequent re-exposure to similar experimental conditions and reveals that the proper control of adult hippocampal neuroplasticity triggered by antidepressants is essential to counteract recurrent depressive-like episodes.
| S-EPMC5416672 | biostudies-literature
Project description:The pathophysiology of major depressive disorder (MDD) encompasses an array of changes at molecular and neurobiological levels. As chronic stress promotes neurotoxicity there are alterations in the expression of genes and gene-regulatory molecules. The hippocampus is particularly sensitive to the effects of stress and its posterior volumes can deliver clinically valuable information about the outcomes of antidepressant treatment. In the present work, we analyzed individuals with MDD (N = 201) and healthy controls (HC = 104), as part of the CAN-BIND-1 study. We used magnetic resonance imaging (MRI) to measure hippocampal volumes, evaluated gene expression with RNA sequencing, and assessed DNA methylation with the (Infinium MethylationEpic Beadchip), in order to investigate the association between hippocampal volume and both RNA expression and DNA methylation. We identified 60 RNAs which were differentially expressed between groups. Of these, 21 displayed differential methylation, and seven displayed a correlation between methylation and expression. We found a negative association between expression of Brain Abundant Membrane Attached Signal Protein 1 antisense 1 RNA (BASP1-AS1) and right hippocampal tail volume in the MDD group (β = -0.218, p = 0.021). There was a moderating effect of the duration of the current episode on the association between the expression of BASP1-AS1 and right hippocampal tail volume in the MDD group (β = -0.48, 95% C.I. [-0.80, -0.16]. t = -2.95 p = 0.004). In conclusion, we found that overexpression of BASP1-AS1 was correlated with DNA methylation, and was negatively associated with right tail hippocampal volume in MDD.
| S-EPMC8433329 | biostudies-literature