BDNF Val66Met polymorphism and peripheral protein levels in pediatric bipolar disorder and attention-deficit/hyperactivity disorder.

OBJECTIVE: Frontiers between pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD) are not well defined. Few studies have addressed potentially different neurobiological factors between the two disorders. Brain-derived neurotrophic factor (BDNF) has been increasingly recognized for its etiologic and prognostic role in adult bipolar disorder (BD) studies. This study aimed to examine the BDNF gene polymorphism and potential alterations in BDNF serum levels in the pediatric ADHD patients with or without comorbid BD illness. METHOD: We assessed the non-synonymous single-nucleotide polymorphism in the BDNF gene (rs6265/Val66Met) and its serum levels in children and adolescents with BD comorbid with ADHD (BD + ADHD) and ADHD alone. Children and adolescents were assessed for psychiatric diagnoses using the Kiddie-Sads-Present and Lifetime Version (K-SADS-PL). RESULTS: Using Analysis of covariance (ancova) we detected a significant group effect (patients with BD + ADHD had higher serum levels than those with ADHD - F80,3 = 8.73, P = 0.005). CONCLUSION: Although the Val66Met polymorphism at the BDNF gene does not seem to play a significant role in children and adolescents with BD or ADHD, BDNF serum levels deserve further attention in future research on neurobiological aspects of BD and ADHD.

Inflammation, neurotrophism and oxidative stress and childhood psychopathology in a large community sample.

OBJECTIVE: To investigate the association between peripheral biomarkers and child psychopathology in a large community sample. METHOD: A total of 625 aged 6- to 13-year old subjects were recruited from a community school-based study. Psychopathology was assessed using the Child Behaviour Checklist (CBCL). Psychiatric diagnosis was evaluated using the Development and Well-Being Assessment. The following biomarkers were examined in peripheral blood: brain-derived neurotrophic factor, cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, IFN-g, and TNF-α), chemokines (eotaxin/CCL11, IP-10, MCP-1), cytokine receptors (sTNFR1 and sTNFR2), and the oxidative stress marker TBARS. RESULTS: We found significant associations between sTNFR2, eotaxin/CCL11 and CBCL total score, as well as with specific dimensions of psychopathology. There were different patterns of association between these biomarkers and psychological and behavioural symptoms in children with and without a mental disorder. TBARS, IL-6 and MCP-1 were more specific to some clusters of symptoms in children with a psychiatric diagnosis. CONCLUSION: Our data support the potential use of biomarkers, especially those involved in immune-inflammatory pathways, in investigating neurodevelopmental psychopathology. Their association with different dimensions of symptoms might be of useful when analyzing illness severity and clusters of symptoms within specific disorders.

Damage-associated molecular patterns and immune activation in bipolar disorder.

OBJECTIVE: Immune activation in bipolar disorder (BD) has been frequently reported. Damage-associated molecular patterns (DAMPs) are key players in the immune activation reaction. The aim of this study was to assess DAMP levels in drug-free patients with BD during acute episodes. METHOD: Serum levels of a predetermined set of DAMPs were assessed in drug-free patients with BD (n = 20) during an acute mood episode. We also included two control groups: healthy subjects, used as a negative control (n = 20); and patients with sepsis, used as a positive control for severe immune activation (n = 20). RESULTS: Multivariate analysis using generalized linear mixed model indicated that all DAMPs differed as a function of group membership after controlling for age and addressing multiplicity (P < 0.0006 for all comparisons). Follow-up analyses showed higher levels in BD subjects of circulating cell-free (ccf) nuclear (n)DNA (P = 0.02), HSP70 (P = 0.03) and HSP90α (P = 0.02) as compared to healthy subjects. Also, patients with BD showed lower levels of ccf nDNA (P = 0.04), HSP60 (P = 0.03), HSP70 (P = 0.01), and HSP90α (P = 0.002) as compared to patients with sepsis and higher levels of ccf mitochondrial DNA (P < 0.0001). CONCLUSION: The present findings may be linked to the inflammatory activity previously described among patients with BD and may help in the development of more targeted and personalized treatments for patients under acute episodes of BD.

Staging bipolar disorder: clinical, biochemical, and functional correlates.

OBJECTIVE: There are several models of staging in bipolar disorder (BD), but none has been validated. The aims of this study were to empirically investigate clinical variables that may be useful to classify patients in clusters according to stage and study the association with biomarkers as biological validators. METHOD: This was a historical cohort study. Patients (n = 115) diagnosed with BD and not in an acute episode and first-degree relatives of patients diagnosed with BD (n = 25) were recruited. Sociodemographic, clinical, and functional data were collected. Serum cytokines, brain-derived neurotrophic factor, and biomarkers of lipid and protein oxidation were assessed. Cluster analysis was carried out to build a model of staging, and logistic regression was conducted to study associations between the model and biomarkers. RESULTS: Cluster analysis divided the sample into two equitable groups, denominated early and late stage, with empirical cutoffs for the Functioning Assessment Short Test score, number of episodes, age at onset of the disorder, and time elapsed since first episode. In the logistic regression, IL-6 was associated with late stage (P = 0.029). CONCLUSION: This study supports that clinical, functional, and biochemical variables may help to define a classification of staging in BD.

Val66Met polymorphism and serum brain-derived neurotrophic factor in bipolar disorder: an open-label trial.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is consistently associated with acute mood episodes in bipolar disorder, but there is a lack of longitudinal data to support this hypothesis. In this 16-week open-label clinical trial, we tested the predictive role of BDNF Val66Met polymorphism on serum BDNF levels and the relationship of serum BDNF and clinical response in people with bipolar disorder during an acute illness episode. METHOD: Sixty-four people with bipolar disorder who were medication-free at baseline and in an acute mood episode were recruited. They were matched with 64 healthy controls. Clinical evaluation, serum BDNF, and BDNF Val66Met polymorphism were determined at baseline, and change in serum BDNF was assessed in patients at weeks 2, 4, 8 and 16. RESULTS: There were no differences between patients and controls in serum BDNF or in frequencies of the BDNF Val66Met polymorphism genotype at baseline. The multivariable model showed that Met carriers had a significantly different change in BDNF levels compared with Val homozygotes. Not achieving a complete remission was also associated with lower prospectively assessed BDNF levels. CONCLUSION: This study provides the first longitudinal evidence that both the BDNF Val66Met polymorphism and remission status predict change in circulating BDNF levels.

BACE1-Deficient Mice Exhibit Alterations in Immune System Pathways.

BACE1 encodes for the beta-site amyloid precursor protein cleaving enzyme 1 or ß-secretase. Genetic deletion of Bace1 leads to behavioral alterations and affects midbrain dopaminergic signaling and memory processes. In order to further understand the role of BACE1 in brain function and behavior, we performed microarray transcriptome profiling and gene pathway analysis in the hippocampus of BACE1-deficient mice compared to wild type. We identified a total of 91 differentially expressed genes (DEGs), mostly enriched in pathways related to the immune and inflammation systems, particularly IL-9 and NF-κB activation pathways. Serum levels of IL-9 were elevated in BACE1-deficient mice. Our network analysis supports an intimate connection between immune response via NF-κB and BACE1 signaling through the NRG1/Akt1 pathway. Our findings warrant future mechanistic studies to determine if BACE1 signaling and the IL-9 pathway interact to alter behavior and brain function. This study opens new avenues in the investigation of hippocampus-related neuroimmunological and neuroinflammation-associated disorders.

The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders.

Psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia, affect a significant percentage of the world population. These disorders are associated with educational difficulties, decreased productivity and reduced quality of life, but their underlying pathophysiological mechanisms are not fully elucidated. Recently, studies have suggested that psychiatric disorders could be considered as inflammatory disorders, even though the exact mechanisms underlying this association are not known. An increase in inflammatory response and oxidative stress may lead to inflammation, which in turn can stimulate microglia in the brain. Microglial activation is roused by the M1 phenotype, which is associated with an increase in interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). On the contrary, M2 phenotype is associated with a release of anti-inflammatory cytokines. Thus, it is possible that the inflammatory response from microglial activation can contribute to brain pathology, as well as influence treatment responses. This review will highlight the role of inflammation in the pathophysiology of psychiatric disorders, such as MDD, BD, schizophrenia, and autism. More specifically, the role of microglial activation and associated molecular cascades will also be discussed as a means by which these neuroinflammatory mechanisms take place, when appropriate.

Interaction between SLC6A4 promoter variants and childhood trauma on the age at onset of bipolar disorders.

Age at onset (AAO) of bipolar disorders (BD) could be influenced both by a repeat length polymorphism (5HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) and exposure to childhood trauma. We assessed 308 euthymic patients with BD for the AAO of their first mood episode and childhood trauma. Patients were genotyped for the 5HTTLPR (long/short variant) and the rs25531. Genotypes were classified on functional significance (LL, LS, SS). A sample of 126 Brazilian euthymic patients with BD was used for replication. In the French sample, the correlation between AAO and trauma score was observed only among 'SS' homozygotes (p = 0.002) but not among 'L' allele carriers. A history of at least one trauma decreased the AAO only in 'SS' homozygotes (p = 0.001). These results remained significant after correction using FDR. Regression models suggested an interaction between emotional neglect and 'SS' genotype on the AAO (p = 0.009) and no further interaction with other trauma subtypes. Partial replication was obtained in the Brazilian sample, showing an interaction between emotional abuse and 'LS' genotype on the AAO (p = 0.02). In conclusion, an effect of childhood trauma on AAO of BD was observed only in patients who carry a specific stress responsiveness-related SLC6A4 promoter genotype.

Increased annexin-V and decreased TNF-α serum levels in chronic-medicated patients with schizophrenia.

Schizophrenia (SZ) is a chronic severe mental disorder. Increased inflammatory processes have been shown in acute and chronic SZ. Apoptotic processes may alter the neuronal network and are involved in the pathogenesis of several neurodegenerative diseases, such as SZ. Annexin-V seems to have a role on inhibition of pro-inflammatory activities during apoptosis. Tumor necrosis factor (TNF-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines which stimulate acute phase reactions. A chronic immune activation in SZ has been shown. The aim of this study was to compare annexin-V and TNF-alpha serum levels in chronic medicated patients with SZ and healthy controls. Thirty-eight outpatients from the HCPA Schizophrenia Program and 38 healthy controls were enrolled to this study protocol. Annexin-V and TNF-alpha serum levels were measured with ELISA. Serum annexin-V levels were significantly higher in patients with SZ than in controls (p<0.001) and TNF-alpha significantly lower (p<0.001). The present result of increased annexin-V and decreased serum levels of TNF-alpha compared to controls may be a result of the stabilization phase of psychosis and a reduction in metabolic brain aggression. In this complex picture, increased levels of annexin-V and decreased levels of TNF-alpha in our sample would be explained by illness stability and chronic treatment. Our findings support the hypothesis of a state dependant process of inflammation in SZ. Further prospective studies to clarify the findings described in this paper are needed.

Effects of increased opportunity for physical exercise and learning experiences on recognition memory and brain-derived neurotrophic factor levels in brain and serum of rats.

Studies with animal models showed that cellular, structural, and behavioral changes induced by environmental enrichment are related to increased levels of brain-derived neurotrophic factor (BDNF) in the brain. These evidence suggest that BDNF could be an interesting biomarker of the effects of lifestyle on cognition and other behavioral parameters in humans, mainly if the BDNF alterations in brain are accompanied by correspondent peripheral modifications, since human studies depend basically on the evaluation of this neurotrophin in serum or plasma. To test this hypothesis, we analyzed the effects of environmental enrichment on long-term memory for object recognition and on BDNF levels of hippocampus, frontal cortex, and serum of rats exposed to an experimental protocol that could be more easily translated to human intervention studies. Animals were maintained for 10 weeks in a social (standard laboratory conditions) or enriched (increased opportunity for physical exercise and learning experiences) condition. In the 7th week, they were submitted to behavioral testing (open field and novel object memory task), and at the end of the 10th week, they were killed and BDNF levels were analyzed. Animals maintained in the enriched condition showed enhanced performance on the memory task in the absence of any significant alteration in central or peripheral BDNF levels. The results of this study are important to highlight the need to develop experimental protocols using animal models that more closely resemble the characteristics of studies with humans and motivate more investigations to determine the conditions under which BDNF could be a biomarker of the effects of environment enrichment.