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Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes.

ABSTRACT: The neuroinflammatory hypothesis of major depressive disorder is supported by several main findings. First, in humans and animals, activation of the immune system causes sickness behaviors that present during a major depressive episode (MDE), such as low mood, anhedonia, anorexia, and weight loss. Second, peripheral markers of inflammation are frequently reported in major depressive disorder. Third, neuroinflammatory illnesses are associated with high rates of MDEs. However, a fundamental limitation of the neuroinflammatory hypothesis is a paucity of evidence of brain inflammation during MDE. Translocator protein density measured by distribution volume (TSPO VT) is increased in activated microglia, an important aspect of neuroinflammation.To determine whether TSPO VT is elevated in the prefrontal cortex, anterior cingulate cortex (ACC), and insula in patients with MDE secondary to major depressive disorder.Case-control study in a tertiary care psychiatric hospital from May 1, 2010, through February 1, 2014. Twenty patients with MDE secondary to major depressive disorder and 20 healthy control participants underwent positron emission tomography with fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA). Patients with MDE were medication free for at least 6 weeks. All participants were otherwise healthy and nonsmokers.Values of TSPO VT in the prefrontal cortex, ACC, and insula.In MDE, TSPO VT was significantly elevated in all brain regions examined (multivariate analysis of variance, F15,23?=?4.5 [P?=?.001]). The magnitude of TSPO VT elevation was 26% in the prefrontal cortex (mean [SD] TSPO VT, 12.5 [3.6] in patients with MDE and 10.0 [2.4] in controls), 32% in the ACC (mean [SD] TSPO VT, 12.3 [3.5] in patients with MDE and 9.3 [2.2] in controls), and 33% in the insula (mean [SD] TSPO VT, 12.9 [3.7] in patients with MDE and 9.7 [2.3] in controls). In MDE, greater TSPO VT in the ACC correlated with greater depression severity (r?=?0.63 [P?=?.005]).This finding provides the most compelling evidence to date of brain inflammation, and more specifically microglial activation, in MDE. This finding is important for improving treatment because it implies that therapeutics that reduce microglial activation should be promising for MDE. The correlation between higher ACC TSPO VT and the severity of MDE is consistent with the concept that neuroinflammation in specific regions may contribute to sickness behaviors that overlap with the symptoms of MDE.

SUBMITTER: Setiawan E

PROVIDER: S-EPMC4836849 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes.

Setiawan Elaine E Wilson Alan A AA Mizrahi Romina R Rusjan Pablo M PM Miler Laura L Rajkowska Grazyna G Suridjan Ivonne I Kennedy James L JL Rekkas P Vivien PV Houle Sylvain S Meyer Jeffrey H JH

JAMA psychiatry 20150301 3

<h4>Importance</h4>The neuroinflammatory hypothesis of major depressive disorder is supported by several main findings. First, in humans and animals, activation of the immune system causes sickness behaviors that present during a major depressive episode (MDE), such as low mood, anhedonia, anorexia, and weight loss. Second, peripheral markers of inflammation are frequently reported in major depressive disorder. Third, neuroinflammatory illnesses are associated with high rates of MDEs. However, a ...[more]

PMID: 25629589

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Project description:Background: Major depressive disorder (MDD) is a serious public health problem with high lifetime prevalence (4.4-20%) in the general population. The monoamine hypothesis is the most widespread etiological theory of MDD. Also, recent scientific data has emphasized the importance of immuno-inflammatory pathways in the pathophysiology of MDD. The lack of data on the magnitude of brain neuroinflammation in MDD is the main limitation of this inflammatory hypothesis. Our team has previously demonstrated the relevance of [18F] DPA-714 as a neuroinflammation biomarker in humans. We formulated the following hypotheses for the current study: (i) Neuroinflammation in MDD can be measured by [18F] DPA-714; (ii) its levels are associated with clinical severity; (iii) it is accompanied by anatomical and functional alterations within the frontal-subcortical circuits; (iv) it is a marker of treatment resistance. Methods: Depressed patients will be recruited throughout 4 centers (Bordeaux, Montpellier, Tours, and Toulouse) of the French network from 13 expert centers for resistant depression. The patient population will be divided into 3 groups: (i) experimental group-patients with current MDD (n = 20), (ii) remitted depressed group-patients in remission but still being treated (n = 20); and, (iii) control group without any history of MDD (n = 20). The primary objective will be to compare PET data (i.e., distribution pattern of neuroinflammation) between the currently depressed group and the control group. Secondary objectives will be to: (i) compare neuroinflammation across groups (currently depressed group vs. remitted depressed group vs. control group); (ii) correlate neuroinflammation with clinical severity across groups; (iii) correlate neuroinflammation with MRI parameters for structural and functional integrity across groups; (iv) correlate neuroinflammation and peripheral markers of inflammation across groups. Discussion: This study will assess the effects of antidepressants on neuroinflammation as well as its role in the treatment response. It will contribute to clarify the putative relationships between neuroinflammation quantified by brain neuroimaging techniques and peripheral markers of inflammation. Lastly, it is expected to open innovative and promising therapeutic perspectives based on anti-inflammatory strategies for the management of treatment-resistant forms of MDD commonly seen in clinical practice. Clinical trial registration (reference: NCT03314155): https://www.clinicaltrials.gov/ct2/show/NCT03314155?term=neuroinflammation&cond=depression&cntry=FR&rank=1.

Project description:Micro-RNAs (miRNAs) are small, non-coding RNAs that regulate gene networks, helping to control cell function and phenotype. MiRNAs in the central nervous system (CNS) are considered to be involved in development, function, and homeostasis. Past genomic studies focused on messenger-RNA (mRNA) expression using large-scale hybridization-based arrays for elucidating gene expression in the brain during HIV-infection. Because miRNAs affect the downstream functions of mRNAs, it is desirable to understand both mRNA and miRNA perturbations, together in the same clinical specimens. HIV infection affects the CNS through inflammation and glial cell activation leading to long-term changes in cellular function of neurons and glia. One mechanism by which this may occur is through changes in the miRNA repertoire. The goals of this study were to: 1. Identify changes in miRNA expression that occurred in HIV; 2. Determine whether detectable miRNA expression of the frontal cortex (FC) could differentiate HIV from HIV/Major Depressive Disorder (MDD, neurobehavioral diagnostic category); 3. Adapt a method to meaningfully integrate gene expression data and miRNA expression data in clinical samples. The present study was performed by pooling RNA isolated from the FC of 3 patients from each of three groups: Control, HIV+, and HIV/MDD, and assessing miRNA expression profile using Applied Biosystems Taqman MicroRNA Array v2.0. A larger sample size of 4 HIV+ patients and 4 HIV/MDD patients were used and non-pooled for gene expression analysis on Affymetrix U133 Plus 2.0 array. We present a method for integrating the two datasets in a Target Bias Analysis. Micro-RNAs were clustered into three types: A) Those with many dysregulated mRNA targets of less stringent significance; B) Fewer dysregulated target-genes of highly stringent significance; C) Spectrum from non-bias to combinations of A and B. In HIV/MDD, more miRNAs were down-regulated than in HIV alone. The dysregulated miRNAs clustered on Chromosomes 14, 17, 19, and X. A small subset of dysregulated genes had many 3’UTR target-sites for dysregulated miRNAs. Specific miRNA families at targeted chromosomal loci are dysregulated. Certain miRNAs serve as key circuits in gene regulatory networks in the adult human brain, and this is affected by HIV, and may be implicated in neurobehavioral disorder. Some genes may serve as hubs of miRNA activity.

Project description:Objective: Clinically, it is very difficult to distinguish between major depressive disorder (MDD) and bipolar disorder (BD) in the period of depression. Increasing evidence shows that the insula plays an important role in depression. We aimed to compare the resting-state functional connectivity (rsFC) of insular subregions in patients with MDD and BD in depressive episodes (BDD), who had never experienced manic or hypomanic episodes when they were scanned to identify biomarkers for the identification of two diseases. Methods: We recruited 21 BDD patients, 40 MDD patients and 70 healthy controls (HC). Resting-state functional magnetic resonance imaging (rs-fMRI) was performed. BDD patients had never had manic or hypomanic episodes when they were scanned, and the diagnoses were determined by follow-up. We divided the insula into three parts including the ventral anterior insular cortex (v-AIN), dorsal anterior insular cortex (d-AIN), and posterior insula (PI). The insular-based rsFC was compared among the three groups, and an analysis of the correlation between the rsFC value and Hamilton depression and anxiety scales was carried out. Results: BDD and MDD patients demonstrated decreased rsFC from the v-AIN to the left superior/middle frontal gyrus compared with the HC group. Versus MDD and HC groups, BDD patients exhibited decreased rsFC from the v-AIN to the area in the left orbital frontal gyrus and left superior temporal gyrus (included temporal pole), from the PI to the right lateral postcentral gyrus and from all three insular subregions to the somatosensory and motor cortex. Meanwhile, a correlation between the rsFC value of the PI-right lateral postcentral gyrus and anxiety score was observed in patients. Conclusion: Our findings show BDD and MDD patients have similar decreases in insular connectivity in the dorsal lateral frontal regions, and BDD patients have specific decreased insular connectivity, especially in the somatosensory and motor cortex, which may be used as imaging evidence for clinical identification.

Project description:ObjectivesComposite diagnostic criteria alone are likely to create and introduce biases into diagnoses that subsequently have poor relationships with input symptoms. This study aims to understand the relationships between the diagnoses and the input symptoms, as well as the magnitudes of biases created by diagnostic criteria and introduced into the diagnoses of mental illnesses with large disease burdens (major depressive episodes, dysthymic disorder, and manic episodes).SettingsGeneral psychiatric care.ParticipantsWithout real-world data available to the public, 100 000 subjects were simulated and the input symptoms were assigned based on the assumed prevalence rates (0.05, 0.1, 0.3, 0.5 and 0.7) and correlations between symptoms (0, 0.1, 0.4, 0.7 and 0.9). The input symptoms were extracted from the diagnostic criteria. The diagnostic criteria were transformed into mathematical equations to demonstrate the sources of biases and convert the input symptoms into diagnoses.Primary and secondary outcomesThe relationships between the input symptoms and diagnoses were interpreted using forward stepwise linear regressions. Biases due to data censoring or categorisation introduced into the intermediate variables, and the three diagnoses were measured.ResultsThe prevalence rates of the diagnoses were lower than those of the input symptoms and proportional to the assumed prevalence rates and the correlations between the input symptoms. Certain input or bias variables consistently explained the diagnoses better than the others. Except for 0 correlations and 0.7 prevalence rates of the input symptoms for the diagnosis of dysthymic disorder, the input symptoms could not fully explain the diagnoses.ConclusionsThere are biases created due to composite diagnostic criteria and introduced into the diagnoses. The design of the diagnostic criteria determines the prevalence of the diagnoses and the relationships between the input symptoms, the diagnoses, and the biases. The importance of the input symptoms has been distorted largely by the diagnostic criteria.

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Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes.

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Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes.

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