Brain-derived Neurotrophic Factor Met Allele Carriers Research Articles

Variability in cTBS Aftereffects Attributed to the Interaction of Stimulus Intensity With BDNF Val66Met Polymorphism.

Objective: To evaluate whether a common polymorphism (Val66Met) in the gene for brain-derived neurotrophic factor (BDNF)—a gene thought to influence plasticity—contributes to inter-individual variability in responses to continuous theta-burst stimulation (cTBS), and explore whether variability in stimulation-induced plasticity among Val66Met carriers relates to differences in stimulation intensity (SI) used to probe plasticity.Methods: Motor evoked potentials (MEPs) were collected from 33 healthy individuals (11 Val66Met) prior to cTBS (baseline) and in 10 min intervals immediately following cTBS for a total of 30 min post-cTBS (0 min post-cTBS, 10 min post-cTBS, 20 min post cTBS, and 30 min post-cTBS) of the left primary motor cortex. Analyses assessed changes in cortical excitability as a function of BDNF (Val66Val vs. Val66Met) and SI.Results: For both BDNF groups, MEP-suppression from baseline to post-cTBS time points decreased as a function of increasing SI. However, the effect of SI on MEPs was more pronounced for Val66Met vs. Val66Val carriers, whereby individuals probed with higher vs. lower SIs resulted in paradoxical cTBS aftereffects (MEP-facilitation), which persisted at least 30 min post-cTBS administration.Conclusions: cTBS aftereffects among BDNF Met allele carriers are more variable depending on the SI used to probe cortical excitability when compared to homozygous Val allele carriers, which could, to some extent, account for the inconsistency of previously reported cTBS effects.Significance: These data provide insight into the sources of cTBS response variability, which can inform how best to stratify and optimize its use in investigational and clinical contexts.

Associations of plasma brain-derived neurotrophic factor (BDNF) and Val66Met polymorphism (rs6265) with long-term cancer-related cognitive impairment in survivors of breast cancer.

Brain-derived neurotrophic factor (BDNF) and the BDNF Val66Met polymorphism (rs6265) have been implicated in neurodegenerative conditions. This study aimed to investigate the associations of plasma BDNF and rs6265 with cancer-related cognitive impairment (CRCI) at the end of chemotherapy, and with persistent and delayed CRCI up to 24months post chemotherapy, among survivors of early-stage breast cancer. A multicenter, longitudinal study involving 174 breast cancer patients was conducted. CRCI was assessed using the FACT-Cog (V3) questionnaire and the CANTAB software. Plasma BDNF levels were quantified using an enzyme-linked immunosorbent assay at serial time points and genotyping was achieved using Sanger sequencing. The associations of BDNF and rs6265 with CRCI were analyzed using logistic regressions. A smaller magnitude of reduction in plasma BDNF between baseline and the end of chemotherapy was correlated with protection from overall subjective CRCI (OR 0.88; 95% CI 0.79-0.99). Furthermore, patients with higher plasma BDNF levels at the end of chemotherapy had lower odds of developing persistent overall subjective CRCI (OR 0.74; 95% CI 0.57-0.97) and persistent CRCI in the functional interference domain (OR 0.62; 95% CI 0.39-0.98). BDNF Met allele carriers were protected against subjective CRCI at the end of chemotherapy in the multitasking and memory domains, and against persistent subjective CRCI in the mental acuity and multitasking domains. BDNF plasma level or rs6265 genotype information may facilitate the identification of patients at higher risk of long-term CRCI during survivorship and enable the implementation of early intervention strategies that increase BDNF levels.

The brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism affects memory performance in older adults.

Objective:Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF) is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cognitive aging remains unclear. The purpose of this study was to investigate the effects of the BDNF Val66Met polymorphism on memory performance in a sample of elderly adults.Methods:Eighty-seven subjects aged > 55 years were recruited using a community-based convenience sampling strategy in Porto Alegre, Brazil. The logical memory subset of the Wechsler Memory Scale-Revised was used to assess immediate verbal recall (IVR), delayed verbal recall (DVR), and memory retention rate.Results: BDNF Met allele carriers had lower DVR scores (p = 0.004) and a decline in memory retention (p = 0.017) when compared to Val/Val homozygotes. However, we found no significant differences in IVR between the two groups (p = 0.088).Conclusion:These results support the hypothesis of the BDNF Val66Met polymorphism as a risk factor associated with cognitive impairment, corroborating previous findings in young and older adults.

BDNF val66met genotype shows distinct associations with the acoustic startle reflex and the cortisol stress response in young adults and children

Brain Derived Neurotrophic Factor (BDNF) is a crucial regulator of neuronal development, organization and function and the val66met polymorphism in the BDNF gene has been associated with several (endo-) phenotypes of cognitive and affective processing. The BDNF met allele is considered a risk factor for anxiety and fear related phenotypes although findings are not entirely consistent. Here, the impact of BDNF val66met on two parameters of anxiety and stress was investigated in a series of studies. Acoustic startle responses were assessed in three adult samples (N1=117, N2=104, N3=116) as well as a children sample (N4=123). Cortisol increase in response to the Trier Social Stress Test (TSST) was measured in one adult sample (N3) and in the children sample (N4). The BDNF met allele was associated with enhanced cortisol responses in young adults (p=0.039) and children (p=0.013). On the contrary, BDNF met allele carriers showed a reduced acoustic startle response which reached significance in most samples (N1: p=0.004; N2: p=0.045; N3: n.s., N4: p=0.043) pointing to differential effects of BDNF val66met on distinct endophenotypes of anxiety and stress-related responses. However, small effect sizes suggest substantial additional genetic as well as environmental contributors.

Effect of BDNF Val66Met and serotonin transporter 5-HTTLPR polymorphisms on psychopathological characteristics in a sample of university students

The aims of this study were to evaluate the impact of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on several psychological characteristics in a group of Greek University students and to explore putative interactions with the serotonin-transporter-linked polymorphic region (5-HTTLPR) and serious past adverse experiences. A total of 224 students were genotyped and classified as (a) carriers or noncarriers of the Met allele of the BDNF Val66Met polymorphism and (b) carriers or noncarriers of the S or Lg alleles (S') of the 5-HTTLPR polymorphism. Students were evaluated using a battery of standard psychological tests and answered questionnaires on serious past adverse experiences. The Val/Val BDNF genotype was associated with higher scores in several psychopathological dimensions. When the effect of the BDNF Met allele was examined in relation to 5-HTTLPR, it was restricted to S' noncarriers. Among these students, BDNF Met allele carriers had lower scores compared with noncarriers. The effects of the Met allele on the S' allele noncarriers in the anxiety and phobic anxiety dimensions were more pronounced among individuals who had reported no serious life adversities. There may be a protective role of the BDNF Met allele in several psychopathological features and it is suggested that some of these effects are moderated by 5-HTTLPR.

Brain-derived neurotrophic factor val66met genotype and early life stress effects upon bipolar course

BackgroundGene–environment interactions may contribute to bipolar disorder (BD) clinical course variability. We examined effects of brain-derived neurotrophic factor (BDNF) val66met genotype and early life stress (ELS) upon illness severity and chronicity in adult BD patients. Methods80 patients (43 BD I, 33 BD II, 4 BD not otherwise specified, mean ± SD age 46.4 ± 14.0 years, 63.7% female) receiving open evidence-based and measurement-based care in the Stanford Bipolar Disorders Clinic for at least 12 months underwent BDNF val66met genotyping and completed the Childhood Trauma Questionnaire. BDNF met allele carrier genotype and history of childhood sexual and physical abuse were evaluated in relation to mean prior-year Clinical Global Impressions-Bipolar Version-Overall Severity of Illness (MPY-CGI-BP-OS) score and clinical and demographic characteristics. ResultsBDNF met allele carriers (but not non-met allele carriers) with compared to without childhood sexual abuse had 21% higher MPY-CGI-BP-OS scores (3.5 ± 0.7 versus 2.9 ± 0.7, respectively, t = −2.4, df = 28, p = 0.025) and 35% earlier BD onset age (14.6 ± 5.7 versus 22.8 ± 7.9 years, respectively, t = 3.0, df = 27, p = 0.006). Regression analysis, however, was non-significant for a BDNF-childhood sexual abuse interaction. Limitationssmall sample of predominantly female Caucasian insured outpatients taking complex medication regimens; only one gene polymorphism considered. ConclusionsBetween group comparisons suggested BDNF met allele carrier genotype might amplify negative effects of ELS upon BD illness severity/chronicity, although with regression analysis, there was not a significant gene-environment interaction. Further studies with larger samples are warranted to assess whether BDNF met allele carriers with ELS are at risk for more severe/chronic BD illness course.

No effect of 5HTTLPR or BDNF Val66Met polymorphism on hippocampal morphology in major depression

Neuroimaging research implicates the hippocampus in the aetiology of major depressive disorder (MDD). Imaging genetics studies have investigated the influence of the serotonin transporter-linked polymorphic region (5HTTLPR) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on the hippocampus in healthy individuals and patients with depression (MDD). However, conflicting results have led to inconclusive evidence about the effect of 5HTTLPR or BDNF on hippocampal volume (HCV). We hypothesized that analysis methods based on three-dimensional (3D) hippocampal shape mapping could offer improved sensitivity to clarify these effects. Magnetic resonance imaging data were collected in parallel samples of 111 healthy individuals and 84 MDD patients. Manual hippocampal segmentation was conducted and the resulting data used to investigate the influence of 5HTTLPR and BDNF Val66Met genotypes on HCV and 3D shape within each sample. Hippocampal volume normalized by intracranial volume (ICV) showed no significant difference between 5HTTLPR S allele carriers and L/L homozygotes or between BDNF Met allele carriers and Val/Val homozygotes in the group of healthy individuals. Moreover, there was no significant difference in normalized HCV between 5HTTLPR diallelic and triallelic classifications or between the BDNF Val66Met genotypes in MDD patients, although there was a relationship between BDNF Val66Met and ICV. Shape analysis detected dispersed between-group differences, but these effects did not survive multiple testing correction. In this study, there was no evidence of a genetic effect for 5HTTLPR or BDNF Val66Met on hippocampal morphology in either healthy individuals or MDD patients despite the relatively large sample sizes and sensitive methodology.

BDNF Val66Met genotype modulates the effect of childhood adversity on subgenual anterior cingulate cortex volume in healthy subjects

According to the neurotrophic hypothesis of depression, stress can lead to brain atrophy by modifying brain-derived neurotrophic factor (BDNF) levels. Given that BDNF secretion is affected by a common polymorphism (rs6265, Val66Met), which also is associated with depression, we investigated whether this polymorphism modifies the effect of childhood adversity (CA) on local gray matter (GM) volume in depression-relevant brain regions, using data from two large cohorts of healthy subjects. We included 568 healthy volunteers (aged 18-50 years, 63% female) in our study, for whom complete data were available, with magnetic resonance imaging data at 1.5 Tesla (N=275) or 3 Tesla (N=293). We used a whole brain optimized voxel-based morphometry (VBM) approach assessing genotype-dependent GM differences, with focus on the amygdala, hippocampus and medial prefrontal cortex (PFC; including anterior cingulate cortex (ACC) and orbitomedial PFC). CA was assessed using a validated questionnaire. In both cohorts, we found that BDNF methionine (Met)-allele carriers with a history of CA had significantly less GM in subgenual ACC (P<0.05) compared with Met-allele carriers without CA and Val/Val homozygotes with CA. No differences were found in hippocampus, amygdala and orbitomedial PFC. On the basis of our findings, we conclude that BDNF Met-allele carriers are particularly sensitive to CA. Given the key role of the subgenual ACC in emotion regulation, this finding provides an important mechanistic link between stress and BDNF on one hand and mood impairments on the other hand.

P.1.e.008 Impact of genetic polymorphism on resting state functional connectivity in healthy subjects

Brain-derived neurotrophic factor (BDNF) regulates food intake and energy metabolism. It has also been suggested that mutations in the human BDNF gene and its receptor TrkB account for disturbed eating and obesity. The Met-allele of the BDNF Val66Met polymorphism has been associated with eating disorders, but the underlying mechanism of its contribution is not known. We report herewith that the effect of BDNF Val66Met polymorphism on binge eating in adolescent girls is dependent on severe food restriction. The scores on EDI-2 Bulimia subscale were significantly higher in BDNF Met-allele carriers who made attempts to regulate their body weight by reducing their meal frequency or by starving. This finding may help to explain why some people develop binge eating in response to dieting and others do not.

Food restriction leads to binge eating dependent upon the effect of the brain-derived neurotrophic factor Val66Met polymorphism

Brain-derived neurotrophic factor (BDNF) regulates food intake and energy metabolism. It has also been suggested that mutations in the human BDNF gene and its receptor TrkB account for disturbed eating and obesity. The Met-allele of the BDNF Val66Met polymorphism has been associated with eating disorders, but the underlying mechanism of its contribution is not known. We report herewith that the effect of BDNF Val66Met polymorphism on binge eating in adolescent girls is dependent on severe food restriction. The scores on EDI-2 Bulimia subscale were significantly higher in BDNF Met-allele carriers who made attempts to regulate their body weight by reducing their meal frequency or by starving. This finding may help to explain why some people develop binge eating in response to dieting and others do not.