The association between BDNF Val66Met polymorphism and emotional symptoms after mild traumatic brain injury.
ABSTRACT: BACKGROUND:Brain-derived neurotrophic factor (BDNF) is one of the most abundant neurotrophins in the adult brain, and it plays important roles in modulating synaptic plasticity and synaptogenesis. This study attempted to elucidate the role of the BDNF variant rs6265 in emotional symptoms following mild traumatic brain injury (mTBI). METHODS:To investigate the association between BDNF Val66Met polymorphism (rs6265) and emotional symptoms in mTBI patients, we recruited 192 mTBI patients and evaluated their Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) scores in the first and sixth week after mTBI. RESULTS:The patients carrying the T allele of rs6265 had significantly higher BAI scores in the first week following mTBI. In addition, the patients carrying the T allele also showed higher scores of BDI in the first week. In the gender-specific subgroup analysis, the male patients carrying the T allele of rs6265 had higher scores of both BAI and BDI in the first and sixth week. Meanwhile, female patients carrying the T allele also had significantly higher scores of BDI in the first week following mTBI. CONCLUSIONS:This study provides evidence for the association between the BDNF variant rs6265 and emotional symptoms following mTBI.
Project description:Brain-derived neurotrophic factor (BDNF) plays a role in cognition, as well as neural survival and plasticity. There are several common polymorphisms in the BDNF gene, one of which (rs6265) is an extensively studied non-synonymous coding polymorphism (Val66Met) which has been linked to cognitive performance in healthy controls and some clinical populations. We hypothesized that the Met allele of rs6265 would be associated with poorer cognitive performance in individuals with mild-to-moderate traumatic brain injury, and that other polymorphisms in the BDNF gene would also affect cognition. Genotype at 9 single-nucleotide polymorphisms (SNPs) in the BDNF gene, and measures of speed of information processing, learning, and memory were assessed in 75 patients with mTBI and 38 healthy subjects. Consistent with previous reports, the Met allele of rs6265 was associated with cognition (slower processing speed) in the entire group. Two other SNPs were associated with processing speed in the mTBI group, but both are in linkage disequilibrium with rs6265, and neither remained significant after adjustment for rs6265 status. Within the mTBI group, but not the controls, 4 SNPs, but not rs6265, were associated with memory measures. These associations were not affected by adjustment for rs6265 status. Polymorphisms in BDNF influence cognitive performance shortly after mTBI. The results raise the possibility that a functional polymorphism other than rs6265 may contribute to memory function after mTBI.
Project description:The detailed course of mental disorders at the acute and subacute stages of mild traumatic brain injury (mTBI), especially with regard to recovery from sleep disturbances, has not been well characterised. The aim of this study was to determine the course of depression, anxiety and sleep disturbance, following an mTBI.We recruited patients with mTBI from three university hospitals in Taipei and healthy participants as control group for this study.100 patients with mTBI (35 men) who were older than 20 years, with a Glasgow Coma Scale score of 13-15 and loss of consciousness for <30 min, completed the baseline and 6-week follow-up assessments. 137 controls (47 men) without TBI were recruited in the study. None of the participants had a history of cerebrovascular disease, mental retardation, previous TBI, epilepsy or severe systemic medical illness.The Beck Anxiety Inventory (BAI), the Beck Depression Inventory II (BDI), the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI) were assessed for the patients with mTBI at baseline and 6 weeks after mTBI and for the controls.The ESS scores were not significantly different between the mTBI at baseline or at 6 weeks after mTBI and controls. Although the BAI, BDI and PSQI scores of the mTBI group were significantly different than those of the control group at baseline, all had improved significantly 6 weeks later. However, only the PSQI score improved to a level that was not significantly different from that of the control group.Daytime sleepiness is not affected by mTBI. However, mTBI causes depression and anxiety and diminished sleep quality. Although all these conditions improve significantly within 6 weeks post-mTBI, only sleep quality improves to a pre-mTBI level. Thus, recovery from mTBI-induced sleep disturbance occurs more rapidly than that of mTBI-induced depression and anxiety.
Project description:Depression has been associated with inflammation, and inflammation may both influence and interact with growth factors such as brain-derived neurotrophic factor (BDNF). Both the functional Val66Met BDNF polymorphism (rs6265) and BDNF levels have been associated with depression. It is thus plausible that decreased BDNF could mediate and/or moderate cytokine-induced depression. We therefore prospectively employed the Beck Depression Inventory-II (BDI-II), the Hospital Anxiety and Depression Scale (HADS), and the Montgomery-Asberg Depression Rating Scale (MADRS) in 124 initially euthymic patients during treatment with interferon-alpha (IFN-?), assessing serum BDNF and rs6265. Using mixed-effect repeated measures, lower pretreatment BDNF was associated with higher depression symptoms during IFN-? treatment (F144,17.2=6.8; P<0.0001). However, although the Met allele was associated with lower BDNF levels (F1,83.0=5.0; P=0.03), it was only associated with increased MADRS scores (F4,8.9=20.3; P<0.001), and not the BDI-II or HADS. An exploratory comparison of individual BDI-II items indicated that the Met allele was associated with suicidal ideation, sadness, and worthlessness, but not neurovegetative symptoms. Conversely, the serotonin transporter promoter polymorphism (5-HTTLPR) short allele was associated with neurovegetative symptoms such as insomnia, poor appetite and fatigue, but not sadness, worthlessness, or suicidal ideation. IFN-? therapy further lowered BDNF serum levels (F4,37.7=5.0; P=0.003), but this decrease occurred regardless of depression development. The findings thus do not support the hypothesis that decreasing BDNF is the primary pathway by which IFN-? worsens depression. Nonetheless, the results support the hypothesis that BDNF levels influence resiliency against developing inflammatory cytokine-associated depression, and specifically to a subset of symptoms distinct from those influenced by 5-HTTLPR.
Project description:The negative long-term effects of mild traumatic brain injury (mTBI) have been a growing concern in recent years, with accumulating evidence suggesting that mTBI combined with additional vulnerability factors may induce neurodegenerative-type changes in the brain. However, the factors instantiating risk for neurodegenerative disease following mTBI are unknown. This study examined the link between mTBI and brain-derived neurotrophic factor (BDNF) genotype, which has previously been shown to regulate processes involved in neurodegeneration including synaptic plasticity and facilitation of neural survival through its expression. Specifically, we examined nine BDNF single-nucleotide polymorphisms (SNPs; rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850, rs11030107, rs7127507 and rs12273363) previously associated with brain atrophy or memory deficits in mTBI. Participants were 165 white, non-Hispanic Iraq and Afghanistan war veterans between the ages of 19 and 58, 110 of whom had at least one mTBI in their lifetime. Results showed that the BDNF SNP rs1157659 interacted with mTBI to predict hippocampal volume. Furthermore, exploratory analysis of functional resting state data showed that rs1157659 minor allele homozygotes with a history of mTBI had reduced functional connectivity in the default mode network compared to major allele homozygotes and heterozygotes. Apolipoprotein E (APOE) was not a significant predictor of hippocampal volume or functional connectivity. These results suggest that rs1157659 minor allele homozygotes may be at greater risk for neurodegeneration after exposure to mTBI and provide further evidence for a potential role for BDNF in regulating neural processes following mTBI.
Project description:The predictability of neurocognitive outcomes in patients with traumatic brain injury is not straightforward. The extent and nature of recovery in patients with mild traumatic brain injury (mTBI) are usually heterogeneous and not substantially explained by the commonly known demographic and injury-related prognostic factors despite having sustained similar injuries or injury severity. Hence, this study evaluated the effects and association of the Brain Derived Neurotrophic Factor (BDNF) missense mutations in relation to neurocognitive performance among patients with mTBI. 48 patients with mTBI were prospectively recruited and MRI scans of the brain were performed within an average 10.1 (SD 4.2) hours post trauma with assessment of their neuropsychological performance post full Glasgow Coma Scale (GCS) recovery. Neurocognitive assessments were repeated again at 6 months follow-up. The paired t-test, Cohen's d effect size and repeated measure ANOVA were performed to delineate statistically significant differences between the groups [wildtype G allele (Val homozygotes) vs. minor A allele (Met carriers)] and their neuropsychological performance across the time point (T1 = baseline/ admission vs. T2 = 6th month follow-up). Minor A allele carriers in this study generally performed more poorly on neuropsychological testing in comparison wildtype G allele group at both time points. Significant mean differences were observed among the wildtype group in the domains of memory (M = -11.44, SD = 10.0, p = .01, d = 1.22), executive function (M = -11.56, SD = 11.7, p = .02, d = 1.05) and overall performance (M = -6.89 SD = 5.3, p = .00, d = 1.39), while the minor A allele carriers showed significant mean differences in the domains of attention (M = -11.0, SD = 13.1, p = .00, d = .86) and overall cognitive performance (M = -5.25, SD = 8.1, p = .01, d = .66).The minor A allele carriers in comparison to the wildtype G allele group, showed considerably lower scores at admission and remained impaired in most domains across the timepoints, although delayed signs of recovery were noted to be significant in the domains attention and overall cognition. In conclusion, the current study has demonstrated the role of the BDNF rs6265 Val66Met polymorphism in influencing specific neurocognitive outcomes in patients with mTBI. Findings were more detrimentally profound among Met allele carriers.
Project description:Mild traumatic brain injury (mTBI) is one of the most common neurological disorders. Most patients diagnosed with mTBI could fully recover, but 15% of patients suffer from persistent symptoms. In recent studies, genetic factors were found to be associated with recovery and clinical outcomes after TBI. In addition, results from our previous research have demonstrated that the bone marrow tyrosine kinase gene in chromosome X (BMX), a member of the Tec family of kinases, is highly expressed in rats with TBI. Therefore, our aim in this study was to identify the association between genetic polymorphisms of BMX and clinical symptoms following mTBI. Four tagging single nucleotide polymorphisms (tSNPs) of BMX with minimum allele frequency (MAF) >1% were selected from the HapMap Han Chinese database. Among these polymorphisms, rs16979956 was found to be associated with the Beck anxiety inventory (BAI) and dizziness handicap inventory (DHI) scores within the first week after head injury. Additionally, another SNP, rs35697037, showed a significant correlation with dizziness symptoms. These findings suggested that polymorphisms of the BMX gene could be a potential predictor of clinical symptoms following mTBI.
Project description:To investigate the correlations of four genetic single nucleotide polymorphisms (SNPs) of brain-derived neurotrophic factor (BDNF) with posttraumatic stress disorder (PTSD).A total of 300 patients with sporadic PTSD and 150 healthy subjects (the control group) were selected according to the diagnostic criteria of PTSD (DSM-IV), and the genotypes of the BDNF SNPs G-712A, C270T, rs6265, and rs7103411 were detected by polymerase chain reaction and direct DNA sequencing to determine intergroup differences in the genotypes and allele frequencies; the p values were corrected with the permutation test.The genotypes and allele frequencies of the SNPs G-712A, rs6265, and rs7103411 of BDNF showed no significant intergroup differences (p>0.05). However, the genotype and allele frequencies of C270T showed significant differences between the PTSD group and the control group (p<0.05).The SNP C270T of BDNF may be associated with PTSD. Individuals carrying the polymorphic T allele of C270T may be more likely to suffer from PTSD.
Project description:Although genetic variants may play a key role in development of treatment-resistant depression (TRD), relevant research is scarce.To examine whether the polymorphisms of BDNF (rs6265) and NTRK2 (rs1387923, rs2769605 and rs1565445) genes confer risk for TRD in major depressive disorder (MDD), a total of 948 MDD patients were recruited in a 12-week, multicenter, prospective longitudinal study.Our study showed a significant allelic association between rs1565445 and TRD with an excess of the T allele in the TRD group, compared to non-TRD group (OR = 1.43, 95%CI: 1.16-1.76, p = 0.0008); while patients with genotype C/C and T/C in rs1565445 were less likely to develop TRD than those carrying T/T (OR = 0.52, 95%CI: 0.33-0.82; OR = 0.72, 95%CI: 0.54-0.97, respectively; p = 0.005). Haplotype T-T (rs1565445 and rs1387923) had 1.41-fold increased risk of TRD (p = 0.0014). Furthermore, significant four-locus (rs1387923-rs1565445-rs2769605-rs6265) gene-gene interactions were detected by the Multifactor-dimensionality reduction (MDR) method.These results suggest that the interactions of BDNF (rs6265) with NTRK2 (rs1387923, rs2769605 and rs1565445) gene polymorphisms likely play an essential role in the development of TRD in Han Chinese MDD patients.
Project description:Brain-Derived Neurotrophic Factor (BDNF) and its rs6265 single nucleotide polymorphism (SNP) play an important role in post-stroke recovery. We investigated the correlation between <i>BDNF</i> rs6265 SNP and recovery outcome, measured by the modified Barthel index, in 49 patients with stroke hospitalized in our rehabilitation center at baseline (T0) and after 30 sessions of rehabilitation treatment (T1); moreover, we analyzed the methylation level of the CpG site created or abolished into <i>BDNF</i> rs6265 SNP. In total, 11 patients (22.4%) were heterozygous GA, and 32 (65.3%) and 6 (12.2%) patients were homozygous GG and AA, respectively. The univariate analysis showed a significant relationship between the <i>BDNF</i> rs6265 SNP and the modified Barthel index cut-off (?<sup>2</sup>(1, N = 48) = 3.86, <i>p</i> = 0.049), considering patients divided for carrying (A+) or not carrying (A-) the A allele. A higher percentage of A- patients obtained a favorable outcome, as showed by the logistic regression model corrected by age and time since the stroke onset, compared with the A+ patients (OR: 5.59). At baseline (T0), the percentage of <i>BDNF</i> methylation was significantly different between GG (44.6 ± 1.1%), GA (39.5 ± 2.8%) and AA (28.5 ± 1.7%) alleles (<i>p</i> < 0.001). After rehabilitation (T1), only patients A- showed a significant increase in methylation percentages (mean change = 1.3, CI: 0.4-2.2, <i>p</i> = 0.007). This preliminary study deserves more investigation to confirm if <i>BDNF</i> rs6265 SNP and its methylation could be used as a biological marker of recovery in patients with stroke undergoing rehabilitation treatment.
Project description:Bone mineral density (BMD) is a major index for diagnosing osteoporosis. PhosSNPs are nonsynonymous SNPs that affect protein phosphorylation. The relevance and significance of phosSNPs to BMD and osteoporosis is unknown. This study aimed to identify and characterize phosSNPs significant for BMD in humans. We conducted a pilot genomewide phosSNP association study for BMD in three independent population samples, involving ?5000 unrelated individuals. We identified and replicated three phosSNPs associated with both spine BMD and hip BMD in Caucasians. Association with hip BMD for one of these phosSNPs, ie, rs6265 (major/minor allele: G/A) in BDNF gene, was also suggested in Chinese. Consistently in both ethnicities, individuals carrying the AA genotype have significantly lower hip BMD than carriers of the GA and GG genotypes. Through in vitro molecular and cellular studies, we found that compared to osteoblastic cells transfected with wild-type BDNF-Val66 (encoded with allele G at rs6265), transfection of variant BDNF-Met66 (encoded with allele A at rs6265) significantly decreased BDNF protein phosphorylation (at amino acid residue T62), expression of osteoblastic genes (OPN, BMP2, and ALP), and osteoblastic activity. The findings are consistent with and explain our prior observations in general human populations. We conclude that phosSNP rs6265, by regulating BDNF protein phosphorylation and osteoblast differentiation, influences hip BMD in humans. This study represents our first endeavor to dissect the functions of phosSNPs in bone, which might stimulate extended large-scale studies on bone or similar studies on other human complex traits and diseases.