State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: A meta-analytic study

Evidence has suggested a role of brain-derived neurotrophic factor (BDNF) in the pathogenesis of bipolar disorder (BD). Recent studies have examined BDNF levels in BD patients, but showed inconsistent results. In current study, meta-analyses by random-effects model were performed to compare blood BDNF levels between BD patients and healthy controls, and examine patients based on different affective status (manic, depressed, or euthymic state). Fifteen studies from 10 citations were included into the analysis. Pooling of results from all studies indicated that, overall, patients with BD had a lower level of BDNF than healthy controls (p = 1 × 10⁻⁴). But when separating these studies based on different affective status, it showed that the significance existed only when comparing patients in manic (p = 0.0008) or depressed (p = 0.02) state with controls, but not in euthymic state (p = 0.25). In addition, BDNF level was significantly increased after pharmacological treatment of manic state (p = 0.01). These findings indicate that BDNF levels are abnormally reduced in manic and depressed states of BD, and the reduced level in manic state increases after treatment. They suggest a role of blood BDNF level as a state-dependent biomarker of bipolar disorder.     

Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes

Genetic and pharmacological studies have suggested that brain-derived neurotrophic factor (BDNF) may be associated with the pathophysiology of bipolar disorder (BD). The present study investigated serum BDNF levels in manic, depressed, euthymic BD patients and in matched healthy controls, using an enzyme-linked immunosorbent assay (sandwich-ELISA). Serum BDNF levels were decreased in manic (p = 0.019) and depressed (p = 0.027) BD patients, as compared with euthymic patients and controls. Serum BDNF levels were negatively correlated with the severity of manic (r = −0.37, p = 0.005) and depressive (r = −0.30, p = 0.033) symptoms. These findings further support the hypothesis that the BDNF signaling system may play a role in the pathophysiology of BD.     

Decreased serum brain-derived neurotrophic factor levels in schizophrenic patients with tardive dyskinesia

The pathogenesis of tardive dyskinesia (TD) may involve neurodegeneration and associated dysfunction of brain-derived neurotrophic factor (BDNF) for the survival and maintenance of function in neurons. We therefore compared serum BDNF levels in schizophrenic patients with (n = 129) and without TD (n = 235), and normal controls (n = 323). Assessments included the abnormal involuntary movement scale (AIMS) and the positive and negative syndrome scale (PANSS). Our results were that patients with TD had lower serum BDNF levels than those without TD and normals. Lower serum BDNF levels were correlated with greater PANSS negative subscores, but not correlated with the AIMS scores. Serum BDNF levels did not differ between patients on typical and atypical antipsychotics and were not correlated with antipsychotic doses or years of exposure. We concluded that decreased BDNF levels might be associated with TD pathophysiology and more negative symptoms of schizophrenia.     

Association of the brain-derived neurotrophic factor gene and bipolar disorder with early age of onset in mainland China

Several evidences have suggested that the brain-derived neurotrophic factor (BDNF) gene may be involved in the pathogenesis of bipolar disorder (BPD), but not all studies get the same result. The paper investigated two genetic polymorphisms of BDNF, C-270T and Val66Met, in a case–control design for their association with BPD. Sixty-seven patients of early age of onset and 130 patients of late age of onset were selected for study and 208 healthy individuals were used as controls. No significantly statistical differences of these two polymorphisms were found in genotypes or allele frequencies between either overall patients or late age of onset patients and normal control subjects. However, the frequency of the Val allele of the Val66Met polymorphism was found to have significantly increased in the subgroup patients with early age of onset as compared with the controls (genotype: χ² = 6.602, d.f. = 2, P = 0.037; allele: χ² = 6.223, d.f. = 1, P = 0.015). The study demonstrates that the BDNF C-270T and Val66Met polymorphisms are unlikely to contribute to the genetic predisposition to BPD as a whole. But Val66Met may be associated with susceptibility to the early age of onset subset of the disorder, further studies designed to explore the relationship in a larger population may be warranted.     

脑源性神经营养因子Val66Met基因多态性与首发精神分裂症临床特征的关联研究

目的 探讨脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)基因Val66Met多态性与首发精神分裂症临床特征的关联性.方法 应用TaqMan荧光探针技术对135例首发精神分裂症患者及483名正常对照者进行基因分型;采用阳性与阴性症状量表(positive and negative syndrome scale,PANSS)评估精神分裂症患者临床特征.结果 精神分裂症患者组与正常对照组BDNF Val66Met基因型及等位基因分布频率的差异具有统计学意义(P＜0.01);Met/Met基因型患者的PANSS总分、焦虑(抑郁)因子分及认知损害因子分均高于Val/Val和Val/Met基因型患者,差异有统计学意义(P＜0.01).结论 BDNF基因Val66Met多态性可能与精神分裂症的发病有关;首发精神分裂症患者中Met/Met基因型者临床症状可能更重.     

Tyrosine kinase B protein expression is reduced in the cerebellum of patients with bipolar disorder

Background

The role of the cerebellum in coordinating mental activity is supported by its connections with cerebral regions involved in cognitive/affective functioning, with decreased activities on functional neuroimaging observed in the cerebellum of schizophrenia patients performing mental tasks. Brain-derived neurotrophic factor (BDNF)-induced activation of tyrosine kinase B (TrkB) is essential to synaptic plasticity. We hypothesized that alterations in BDNF and TrkB expression in the cerebellum were associated with schizophrenia and affective disorders.

Methods

We employed immunohistochemistry and immunoblotting to quantify protein expression of BDNF and TrkB in the cerebellum of patients with schizophrenia, bipolar disorder, and major depression compared to controls (n = 15 each).

Results

While TrkB immunoreactivity in each of the molecular and granule-cell layers was reduced in all 3 disease groups (12-34%) compared to the control (P = 0.018 and 0.038, respectively, ANOVA), only the reduction in bipolar disorder remained statistically significant upon Tukey-Kramer post hoc analyses (P = 0.019 and 0.021, respectively). Apparent decreases in BDNF immunoreactivity in all 3 disease groups (12-30%) compared to the control were not statistically significant. TrkB immunoreactivity was not significantly associated with any of the demographic, clinical, and postmortem variables. Immunoblotting displayed an 85-kDa TrkB-immunoreactive band, consistent with a truncated isoform, in all 60 cases.

Limitations

On immunoblotting, apparent decreases in 85-kDa-TrkB levels in all 3 disease groups compared to the control were not statistically significant.

Conclusions

Our finding of reduced TrkB expression in bipolar disorder suggests that dysregulation of TrkB-mediated neurotrophin signaling in the cerebellum may play a role in the pathophysiology of this disease.     

Increased plasma levels of brain-derived neurotrophic factor in patients with long-term bipolar disorder

Recent data indicate that neurotrophins may play a role in the physiopathology of bipolar disorder (BD) and may be useful as biomarkers of the disease. The aim of this study was to evaluate the plasma concentrations of brain-derived neurotrophic factor (BDNF) in BD patients, and to correlate their levels with clinical parameters. BDNF was measured in plasma from 53 BD type I subjects (34 during mania and 19 during euthymia) and 38 healthy controls by enzyme-linked immuno-sorbent assay (ELISA). Patients were assessed by a structured clinical interview (Mini-plus), Young mania and Hamilton depression rating scales. Plasma BDNF levels were significantly increased in patients with mania (P ≤ 0.001) and euthymia (P ≤ 0.001) when compared with controls, but did not correlate with any clinical parameters. BDNF concentration was higher in BD patients with 10 or more years of disease. BDNF plasma levels were increased in BD patients, mainly in those with a longer course of disease. In line with previous studies, it is conceivable that BDNF may play a role in the pathophysiology of BD.     

Polymorphisms of brain-derived neurotrophic factor associated with heroin dependence

Brain-derived neurotrophic factor (BDNF) promotes synaptic remodeling and modulates the function of other neurotransmitters. It also plays a role in the reward response to many drugs, including heroin. To identify genetic variants associated with heroin dependence, we compared four single nucleotide polymorphisms (SNPs, rs13306221, rs6265, rs56164415, and rs16917204) of the BDNF gene in 487 subjects with heroin dependence and 492 healthy individuals. The analysis revealed the G allele of rs6265 was significantly more common in heroin-dependent subjects than in the healthy controls (P=0.001 after Bonferroni correction). Among heroin-dependent individuals, the onset of dependence was significantly earlier in individuals with GG or GA genotypes compared to AA individuals (P<0.01). Additionally, we found that the G allele of rs13306221 was significantly more frequent in heroin-dependent subjects than in controls (P=0.005 after Bonferroni correction). These findings support a role of BDNF rs6265 and rs13306221 polymorphisms in heroin dependence and may guide future studies to identify other genetic risk factors for heroin dependence.     

Role of brain-derived neurotrophic factor in Huntington's disease

Neurotrophic factors are essential contributors to the survival of peripheral and central nervous system (CNS) neurons, and demonstration of their reduced availability in diseased brains indicates that they play a role in various neurological disorders. This paper will concentrate on the role of brain-derived neurotrophic factor (BDNF) in the survival and activity of the neurons that die in Huntington's disease (HD) by reviewing the evidence indicating that it involves profound changes in BDNF levels and that attempts to restore these levels are therapeutically interesting.

BDNF is a small dimeric protein that is widely expressed in adult mammalian brain and has been shown to promote the survival of all major neuronal types affected in Alzheimer's disease (AD) and Parkinson's disease (PD). Furthermore, cortical BDNF production is required for the correct activity of the corticostriatal synapse and the survival of the GABA-ergic medium-sized spiny striatal neurons that die in HD. We will highlight the available data concerning changes in BDNF levels in HD cells, mice and human postmortem samples, describe the molecular evidence underlying this alteration, and review the data concerning the impact of the experimental manipulation of BDNF levels on HD progression. Such studies have revealed a major loss of BDNF protein in the striatum of HD patients which may contribute to the clinical manifestations of the disease. They have also opened up a molecular window into the underlying pathogenic mechanism and new therapeutic perspectives by raising the possibility that one of the mechanisms triggering the reduction in BDNF in HD may also affect the activity of many other neuronal proteins.     

Increased serum glial cell line-derived neurotrophic factor immunocontent during manic and depressive episodes in individuals with bipolar disorder

Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor from the transforming growth factor β family, which plays a role in the development and function of hippocampal cells. Preclinical studies suggest that changes in neurotrophic growth factor systems might be involved in the pathophysiology of mood disorders including bipolar disorder (BD) [E.J. Nestler, M. Barrot, R.J. DiLeone, A.J. Eisch, S.J. Gold, L.M. Monteggia, Neurobiology of depression, Neuron 34 (2002) 13–25]. This is the first study to analyze GDNF immunocontent in BD subjects across different mood states, including mania, depression, and remission (euthymia). Fourty-four bipolar patients (14 depressed, 15 manic, and 15 euthymic) and 14 healthy controls, diagnosed according to the Structural Clinical Interview for DSM-IV were studied. Serum GDNF immunocontent was measured using Western blotting. Serum GDNF immunocontent was increased in manic (F = 42.31; p = 0.001; one-way ANOVA) and depressed (F = 42.31; p = 0.004; one-way ANOVA) bipolar patients, but not in euthymic patients as compared with controls. Our results indicate that changes in GDNF immunocontent occur during acute major affective episodes in bipolar subjects. These results further support the role of neurotrophins in the pathophysiology of bipolar disorder. Whether the observed increase in GDNF immunocontent correspond to a pathological or an adaptive response remains to be determined.     

A prospective,longitudinal study of metabolic syndrome in patients with bipolar disorder and schizophrenia

Background

Although cross sectional studies have evaluated the prevalence of metabolic syndrome (MetS) in patients with bipolar patients (BPAD), data from longitudinal studies are limited.

Aim

To assess the prevalence of MetS in patients with BPAD, to observe the change in prevalence rate over a period of 6 months, to assess the prevalence of sub-threshold MetS (i.e., patients fulfilling one or two criteria of MetS) and to compare patients with BPAD and schizophrenia on the above mentioned parameters.

Methodology

Seventy five patients with BPAD and 53 patients with schizophrenia were initially evaluated for MetS and then followed up for a period of 6 months.

Results

According to consensus definition, prevalence of MetS at baseline was 40% in BPAD group and 32% in schizophrenia group. Over 6 months of follow-up the prevalence of MetS increased by 8% and 9.4% in the BPAD and the schizophrenia groups respectively. There was no significant difference between the two groups on any of the assessments. Another 28–32% of patients in the BPAD group also fulfilled two criteria and 13–17% fulfilled at least one criterion of MetS at different points of assessment. Similarly, 19–26% of the patients with schizophrenia met at least two and 23–26% of the patients fulfilled at least one criterion of MetS.

Limitation

The study was limited by small sample size, inclusion and the relatively short follow-up period.

Conclusion

40% patients with BPAD and 32% with schizophrenia have MetS and the prevalence of MetS increases by 8–9.4% over 6 months.     

Increased serum levels of brain-derived neurotrophic factor in chronic institutionalized patients with schizophrenia

There is a growing body of evidence implicating the neurotrophin brain-derived neurotrophic factor (BDNF) in the pathogenesis of schizophrenia. As circulating BDNF levels may reflect the BDNF levels in the brain, we assessed serum BDNF in 40 institutionalized schizophrenic patients and 20 healthy controls. Serum BNDF levels were significantly increased in schizophrenic patients when compared to control subjects (p<0.001). Interestingly, serum BDNF correlated positively with the clinical scores at the negative subscale of the positive and negative syndrome scale (PANSS) (r=0.41; p<0.01). Our results confirm the emergent literature on the involvement of BDNF in schizophrenia.     

Changes in plasma brain-derived neurotrophic factor levels in smokers after smoking cessation

Several studies have reported that brain-derived neurotrophic factor (BDNF) might be associated with nicotine dependence. However, there are few studies on BDNF levels in humans with nicotine dependence. In the present study, we compared the differences in plasma BDNF levels in patients with nicotine dependence and in healthy nonsmokers, and we investigated serial changes in plasma BDNF levels in patients with nicotine dependence following smoking cessation. Forty-five voluntary smokers and 66 nonsmokers were recruited in this study. Of the 45 smokers, 12 were taking varenicline, 21 were using a nicotine patch, and 12 were unaided in their cessation effort by their own choice. Plasma BDNF levels were measured at baseline using an enzyme-linked immunosorbent assay (both smokers and nonsmokers) and at weeks 4 and 12 after smoking cessation (abstinent smokers only). A total of 19 smokers were able to remain abstinent during the entire study period. Baseline plasma BDNF levels were significantly lower in smokers compared to nonsmokers (F = 4.410, p = 0.002). The plasma BDNF levels in the abstinent smokers significantly increased from baseline after 4 weeks of smoking cessation (z = −2.86, p = 0.004) but had a tendency of decrease in the period between weeks 4 and 12. We could not find differences in the plasma BDNF levels among the three smoker subgroups at week 12 following cessation. Changes in plasma BDNF levels might be related to the process of abstinence and the pathophysiology of nicotine dependence.     

Levels of neuregulin 1 and 3 proteins in Brodmann's area 46 from subjects with schizophrenia and bipolar disorder

Neuregulin (NRG) 1Iα and NRG3 proteins levels were measured in Brodmann's area 46 from 20 subjects with schizophrenia, 8 subjects with bipolar 1 disorder and 20 age-sex matched control subjects. Protein levels of both NRG1Iα and NRG3 were unchanged in both psychiatric illnesses. These data suggest any change in NRG1Iα and NRG3 expression in schizophrenia or bipolar 1 disorder do not result in changes levels in levels of those proteins Brodmann's area 46.     

Influence of exercise on serum brain-derived neurotrophic factor concentrations in healthy human subjects

The effect of short-term exercise (15 min step-exercise) on serum brain-derived neurotrophic factor (BDNF) levels was evaluated in healthy human subjects. Results showed a short-term, significant increase in serum BDNF levels after exercise. Intra-individual differences in serum BDNF levels were remarkably small on the rest day and also when compared to rest values on the day of the exercise test. Inter-individual differences, on the other hand, were larger by comparison. The result of this study supports the need for larger sample size in studies on BDNF changes in psychiatric disorders or psychiatric drug effects.     

Serum brain-derived neurotrophic factor (BDNF) is not associated with response to electroconvulsive therapy (ECT): A pilot study in drug resistant depressed patients

Refractory depression is a highly debilitating mental condition that originates major social and economic burden. About 50% of the patients experience a chronic course of illness and up to 20% show an insufficient response to drug treatments. Electroconvulsive therapy (ECT) is the most effective treatment method in refractory depression, although its mechanism of action is still unknown. Brain-derived neurotrophic factor (BDNF) is decreased in depressive episodes, and increases with antidepressant treatment, being suggested as a biomarker of response to ECT. We report the findings of a study on the effects of ECT on BDNF and clinical outcomes in a group of drug resistant depressive patients before and after ECT. The patients post-ECTs have shown an important improvement of depressive symptomatology on the HDRS (p = 0.001), of psychotic features on the BPRS (p = 0.001) and of the severity of illness on the CGI (p = 0.001). There were no changes in the serum BDNF before and after the ECT treatment (p = 0.89). These results do not support the hypothesis that the clinical improvement following ECT is due to changes in the BDNF.     

脑源性神经营养因子对细胞外蛋白水解酶激活作用的研究

 目的：研究脑源性神经营养因子 (BDNF) 对细胞外蛋白水解酶表达和激活作用的影响。 方法：体外分离并培养人脐静脉内皮细胞（HUVEC），RT-PCR法检测HUVEC基质金属蛋白酶MMP-2 、MMP-9 和基质金属蛋白酶组织抑制剂TIMP-1、TIMP-2 mRNA的表达，明胶酶谱检测MMP-2和MMP-9蛋白酶活性，纤维蛋白酶谱检测尿激酶型纤溶酶原激活剂（uPA）蛋白酶活性，Western blotting检测uPA、纤溶酶原激活剂抑制剂（PAI）、TIMP-1及TIMP-2表达。 结果：在对HUVEC增殖无明显促进作用的浓度范围内，BDNF可促进无血清培养的HUVEC MMP-2和MMP-9 mRNA表达,并可促进MMP-2和MMP-9酶原的激活产生活性明胶酶，BDNF对TIMP-1和TIMP-2的表达无明显影响。BDNF以浓度和时间依赖性方式上调HUVEC uPA和PAI-1的表达，并可促进uPA的活性。 结论：BDNF可激活MMPs和uPA/PAI相关的蛋白级联。     

Association between the brain-derived neurotrophic factor Val66Met polymorphism and brain morphology in a Japanese sample of schizophrenia and healthy comparisons

Magnetic resonance imaging was used to investigate the relation between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and volumetric measurements for the medial temporal lobe structures (amygdala, hippocampus, and parahippocampal gyrus) and prefrontal sub-regions (the superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, ventral medial prefrontal cortex, orbitofrontal cortex, and straight gyrus) in a Japanese sample of 33 schizophrenia patients and 29 healthy subjects. For the controls, the Met carriers had significantly smaller parahippocampal and left superior frontal gyri than the Val homozygotes. The schizophrenia patients carrying the Met allele had a significantly smaller right parahippocampal gyrus than those with the Val/Val genotype, but the genotype did not affect the prefrontal regions in schizophrenia patients. These findings might reflect different genotypic effects of BDNF on brain morphology in schizophrenia patients and healthy controls, implicating the possible role of the brain morphology as an endophenotype for future genetic studies in schizophrenia.     

Physiological variability in brain-derived neurotrophic factor expression predicts dendritic spine density in the mouse dentate gyrus

Dendritic spines are the predominant sites of excitatory neurotransmission in the adult brain, and brain-derived neurotrophic factor (BDNF) is a well-characterized determinant of dendritic spine number and morphology. The relationship between BDNF expression and dendritic spine number is particularly evident in the hippocampus, where environmental conditions that enhance hippocampal BDNF levels also promote local increases in dendritic spine density. However, the relationship between physiological variability in hippocampal BDNF expression and spine number has yet to be assessed. To determine whether natural variability in BDNF expression is associated with hippocampal dendritic spine number, correlations between BDNF protein levels and dendritic spine density among Golgi-impregnated neurons in the hippocampal dentate gyrus and CA1 subfields were assessed in adult male C57Bl/6J mice. In the dentate gyrus, but not in the apical oblique dendrites of CA1 pyramidal cells, BDNF protein expression was significantly correlated with dendritic spine density. This observation suggests that there may be a subregionally specific relationship between hippocampal BDNF expression and the density of spines.