Family-based association study between brain-derived neurotrophic factor gene polymorphisms and attention deficit hyperactivity disorder in UK and Taiwanese samples.

Brain-derived neurotrophic factor (BDNF) plays an important role in normal neuronal development. Several lines of evidence implicate the involvement of BDNF in attention-deficit hyperactivity disorder (ADHD). This study investigated the role of two common BDNF variants (Val66Met, C270T) in two samples of ADHD probands from the United Kingdom (n = 180) and Taiwan (n = 212). We found evidence of increased transmission of the C allele of the C270T in Taiwanese samples (TDT: chi(2) = 6.78, P = 0.009) and the two samples pooled together (TDT: chi(2) = 7.24, P = 0.007). No association was found between the Val66Met polymorphism and ADHD in either of the two populations. Analysis of haplotypes demonstrated a significant decreased transmission of haplotypes containing the Val66 allele and the 270T allele in the Taiwanese samples (TDT: chi(2) = 4.57, P = 0.032) and the pooled sample set (TDT: chi(2) = 5.82, P = 0.016). This study provides evidence for the possible involvement of BDNF in susceptibility to ADHD.     

High concentrations of plasma brain-derived neurotrophic factor in methamphetamine users

Methamphetamine is a highly addictive drug that has a neurotoxic effect on the brain. A growing body of evidence suggests that brain-derived neurotrophic factor (BDNF) is associated with addictive behavior. The present study investigated the changes in plasma BDNF concentration that were induced by chronic methamphetamine use. Using an enzyme-linked immunosorbent assay (ELISA), we measured peripheral BDNF levels in methamphetamine users and in a control group. The plasma BDNF concentrations of methamphetamine users were significantly higher compared with those of controls (2536.3 pg/ml versus 1352.6 pg/ml). This finding suggests that BDNF plays some role in the neurotoxicity of methamphetamine.     

Association between the glutathione S-transferase M1 gene deletion and female methamphetamine abusers.

Several lines of evidence suggest that increased generation of auto-oxidized dopamine (DA) o-quinone is associated with the neurotoxicity of methamphetamine (MAP) in the brain, and that, as a cellular defenses against DA-derived quinines, glutathione S-transferase (GST) detoxifies auto-oxidized DA o-quinone in the brain. Glutathione S-transferase M1 (GSTM1) of the mu-class of GSTs catalyzes reaction between glutathione and catecholamine o-quinones under physiological conditions. This study was undertaken to investigate the role of the GSTM1 gene deletion polymorphism in the neuropathology of MAP abuse. One hundred fifty-seven MAP abusers and 200 healthy comparison subjects were tested for a genetic polymorphism of GSTM1. The difference in the frequency of deletion (D)/non-deletion (N) alleles between the female abusers and female controls was close to statistical significance (P = 0.071), although there was no statistical difference (P = 0.651) between male abusers and male controls. Furthermore, the number of female abusers with deletion alleles was significantly (P = 0.007, odds ratio: 2.77, 95% CI 1.30-5.89) higher than that of male abusers with deletion alleles. These findings suggest that GSTM1 gene deletion may contribute to a vulnerability to MAP abuse in female subjects, but not in male subjects.     

Association between the brain-derived neurotrophic factor (BDNF) gene and schizophrenia in the Chinese population

Brain-derived neurotrophic factor (BDNF) belongs to a family of the neurotrophin which plays important roles in the development of the brain. BDNF has been suggested as a factor that increases the risk of schizophrenia. In this study, we genotyped three single nucleotide polymorphisms (SNPs) in the BDNF gene using a set sample of Han Chinese subjects consisting of 560 schizophrenes and 576 controls. No significant differences were found for either the genotype or allele distribution of analyzed polymorphisms, nor was any gender-specific association found. Thus, our data suggest that the BDNF gene may not be an important factor in susceptibility to schizophrenia.     

Association study of brain-derived neurotrophic factor and apolipoprotein E polymorphisms and cognitive function in aged males without dementia

Genetic factors for inter-individual variation in cognition have been arousing great interest among researchers. Among the many associated genes, brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE), as two of the most frequently studied, might be good prospects for cognitive genetics. Thus, the aim of this study was to investigate both the isolated and cooperative effect of BDNF and APOE on normal cognitive ageing. A homogeneous population of Chinese aged males (N=161) were genotyped for functional genetic variants of BDNF (BDNF-G196A) and APOE (APOE-epsilon4) and assessed by a comprehensive neuropsychological measurement (Cognitive Abilities Screening Instrument Chinese version; CASI C-2.0). Thereafter genotypic group differences of BDNF and APOE in CASI cognitive profiles were tested. Results from the present study suggest the possible influence of APOE on specific cognitive domains (CASI orientation and language domains; p=0.010 and 0.028, respectively), whereas there was no significant role of BDNF, either solely or with APOE, in cognition in the elderly. Our findings suggest a possible association between APOE-epsilon4 and specific cognitive domains in the aged male, whereas the functional genetic variant of BDNF (BDNF-G196A) played no significant role in normal cognitive ageing.     

Association of the brain-derived neurotrophic factor gene G196A rs6265 polymorphisms and the cognitive function and clinical symptoms of schizophrenia

This study aimed to explore the association between BDNF G196A gene rs6265 polymorphisms and the cognitive function and clinical symptoms of schizophrenia. Methods: BDNF G196A rs6265 genotype and allele frequency were measured using Polymerase Chain Reaction (PCR) methods in 224 drug-free patients with schizophrenia and 220 controls. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), and cognitive functioning was assessed using the Wisconsin Card Sorting Test (WCST) and the Trail Making Test (TMT). In the patient group, differences in severity of symptoms across the three genotypes (i.e., G/G, G/A and A/A) of G196A were assessed using one-way analysis of variance. Results G/A genotype had higher frequencies than GG or AA genotype in both patients and controls. There was no significant difference in G/G, G/A, A/A genotype frequency between patients and controls (P > 0.05). The allele G had higher frequencies than allele A in both patients and controls. There was no significant difference in G or A allele frequency between patients and controls (P > 0.05). There was significant difference in A/A genotype frequency between positive group patients and negative group patients. There was no significant difference in cognitive performance between patients with G/G, G/A and A/A genotype (all P > 0.05). Conclusion BDNF G196A gene rs6265 polymorphism is not associated with the cognitive function but with the clinical symptoms of schizophrenia.     

Implication of brain-derived neurotrophic factor in the release of dopamine and dopamine-related behaviors induced by methamphetamine

It is widely recognized that methamphetamine enhances the release of dopamine at dopaminergic neuron terminals of the mesolimbic system, which induces dopamine-related behaviors. Brain-derived neurotrophic factor (BDNF), a neurotrophin, binds to and activates its specific receptor tyrosine kinase, TrkB. BDNF has been shown to influence the release of dopamine in the mesolimbic dopamine system. The present study was designed to investigate roles of BDNF and TrkB in the expression of methamphetamine-induced dopamine release in the nucleus accumbens and dopamine-related behaviors induced by methamphetamine in rats. Methamphetamine (1 mg/kg, s.c.) produced a substantial increase in the extracellular levels of dopamine and induced a progressive augmentation of dopamine-related behaviors such as rearing and sniffing. In contrast, both the stimulation of dopamine release and induction of dopamine-related behaviors by methamphetamine were significantly suppressed by pretreatment with intra-nucleus accumbens injection of either BDNF (2.0 microl/rat, 1:1000, 1:300 and 1:100) or TrkB (2.0 microl/rat, 1:1000 and 1:100) antibody. Furthermore, the basal level of dopamine in the nucleus accumbens was not affected by treatment with both BDNF and TrkB antibodies. These findings provide further evidence that BDNF/TrkB pathway is implicated in the methamphetamine-induced release of dopamine and the induction of dopamine-related behaviors.     

Association analysis between polymorphisms in the conserved dopamine neurotrophic factor (CDNF) gene and cocaine dependence

Cocaine-induced neuroplasticity changes in the mesocorticolimbic dopamine systems are thought to be involved in the pathophysiology of cocaine dependence. Since neurotrophic factors have been observed to prevent/reverse and mimic cocaine-induced neurobiological changes in the brain, related genes are plausible candidates for susceptibility to cocaine dependence. The novel conserved dopamine neurotrophic factor protein (CDNF) promotes the survival, growth, and function of dopamine-specific neurons and is expressed in brain regions that undergo cocaine-induced neuroplasticity. In this study, we hypothesize that polymorphisms in the CDNF gene (CDNF/ARMETL1) contribute to increased risk for cocaine dependence. Cocaine dependent individuals (n = 351) and unaffected controls (n = 257) of African descent were genotyped for four single nucleotide polymorphisms (SNPs) in the CDNF gene (rs11259365, rs7094179, rs7900873, rs2278871). We observed no significant differences in allele, genotype, or haplotype frequencies between cases and controls for any of the tested SNPs. Our study suggests that there is no association between variants in the CDNF gene and cocaine dependence. However, additional studies using larger sample sizes, comprehensive SNP coverage, and clinically homogenous populations are necessary before confidently excluding CDNF as a significant genetic risk factor for cocaine dependence.     

Relationship between learning, stress and hippocampal brain-derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF) expression in the hippocampus is reduced in response to acute, as well as repeated immobilization stress. This effect might be mediated by corticosterone, because corticosterone administration is known to reduce hippocampal BDNF. However, rats subjected to a learning paradigm showed an increased BDNF expression in the hippocampus despite the high corticosterone levels found during the test. To dissect the relative contributions of learning and stress to the overall changes in BDNF levels we set up an experimental model in which two groups of rats received the same amount of stress, but only one group had the possibility to learn how to avoid it. Using this model, we now report that learning and stress exert an opposite modulation on BDNF levels in the hippocampus, and that the increasing effect of learning predominates over the decreasing effect of stress.     

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.     

Association analysis of delta-opioid receptor gene polymorphisms in methamphetamine dependence/psychosis.

The role of the delta-opioid receptor (OPRD1) in methamphetamine (MAP) addiction was investigated using association analysis between OPRD1 gene polymorphisms and MAP dependence/psychosis. DNA samples from Japanese patients with MAP dependence/psychosis were analyzed to find polymorphisms in OPRD1 gene exons and exon-intron boundaries. One novel single nucleotide polymorphism (SNP) in intron 1 and two SNPs in exon 3 were identified. The two SNPs in exon 3 were in linkage disequilibrium. No significant difference was observed in either genotypic or allelic frequencies of these SNPs between controls (n = 260) and MAP dependent/psychotic patients (n = 170). Global analyses using the three SNPs and subcategory analyses on clinical parameters also showed no significant differences. These results suggest that the OPRD1 gene variants may not be a factor in vulnerability to MAP dependence/psychosis.     

抑郁症患者脑源性神经营养因子蛋白及基因表达水平与自杀行为的关联分析

目的:探讨抑郁症患者外周血脑源性神经营养因子(BDNF)蛋白和mRNA表达水平与自杀行为、抑郁症状的关联。方法:共纳入符合中国精神障碍分类与诊断标准第3版诊断标准的抑郁症患者65例,按有无自杀未遂行为分为自杀未遂组(n=31)、无自杀行为组(n=34),健康对照30名。采用汉密顿抑郁量表(HAMD)、Beck绝望量表(BHS)、自杀意念自评量表(SIOSS)评估病例组的抑郁、绝望与自杀意念;采用酶联免疫吸附法测定血清BDNF蛋白浓度,实时荧光定量聚合酶链式反应(PCR)法测定BDNF mRNA相对表达量。结果:自杀未遂组与无自杀行为组的BDNF蛋白浓度[(57.3±9.2)ng/mL,(76.0±25.7)ng/mL vs.(113.8±44.4)ng/mL,均P0.05]与BDNF mRNA相对表达量[(0.2±0.0),(0.5±0.0)vs.(1.0±0.1),均P0.05]均低于正常对照组,自杀未遂组的血清BDNF蛋白浓度和mRNA相对表达量低于无自杀组(P0.05)。病例组(n=65)血清BDNF蛋白浓度与SIOSS总分(r=-0.24,P0.01)呈负相关,与BDNF mRNA相对表达量(r=0.28,P0.01)呈正相关;BDNF mR-NA相对表达量与HAM D总分(r=-0.46,P0.01)、BHS总分(r=-0.42,P0.01)、SIOSS总分(r=-0.43,P0.01)呈负相关,与病程(r=0.19,P0.05)呈正相关。结论:研究提示外周血BDNF蛋白和mRNA水平低可能是抑郁发作患者出现自杀行为的危险因素之一。     

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.     

脑源性神经营养因子转基因成纤维细胞的构建与检测

目的:构建大鼠脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)基因修饰的成纤维细胞(fibroblasts FBs).方法:真核表达载体pcDNA3/BDNF由昆明医学院神经科学研究所提供.FBs取自胎鼠.pcDNA3/BDNF重组质粒载体以阳离子脂质体Lipofect...     

Brain-derived neurotrophic factor gene polymorphisms and schizophrenia: a meta-analysis

OBJECTIVES: To evaluate whether the G196A and C270T polymorphisms of the brain-derived neurotrophic factor gene are associated with increased risk of schizophrenia. METHODS: A meta-analysis of nine genetic association studies was carried out. The meta-analysis included genotype data on 1404/1597 schizophrenics/controls for G196A and 877/989 schizophrenics/controls for C270T. RESULTS: The overall analysis for investigating the association of the G196A allele G and the risk of developing schizophrenia relative to the allele A, showed significant evidence of heterogeneity (P=0.05, I(2)=58%) between the studies and nonsignificant association [random effects odds ratio 1.08 and 95% confidence interval (0.88-1.32)]. In Caucasians, there was a trend towards heterogeneity (P=0.19, I(2)=40%), then, the random and fixed effects odds ratios were 1.24 (0.96-1.60) and 1.27 (1.06-1.53), respectively. For the C270T polymorphism, overall, there was significant evidence of heterogeneity between studies (P=0.07, I(2)=55%) and the allele T was associated with a 63% increased risk of schizophrenia compared with C allele [random effects odds ratio 1.63 (1.01-2.65)]. The dominant model for allele T produced significant association [random effects odds ratio 1.68 (1.02-2.79)]. No source of bias was seen in the selected studies and the differential magnitude of effect in large versus small studies was not significant. CONCLUSIONS: The meta-analysis results provided a weak evidence of association between C270T polymorphism and schizophrenia, and large heterogeneity between studies, whereas there was no evidence of association for G196A polymorphism. The above findings reinforce the need for large and more rigorous association studies.     

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.