Sex-specific association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and plasma BDNF with attention-deficit/hyperactivity disorder in a drug-naïve Han Chinese sample

A functional polymorphism of the brain derived neurotrophic factor gene (BDNF) (Val66Met) has been suggested to be involved in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). It also has an impact on peripheral BDNF levels in psychiatric disorders. This study examined the association of Val66Met with plasma BDNF level of ADHD in Han Chinese children (170 medication – naïve ADHD patients and 155 unaffected controls, aged 6–16 years). The Val allele was showed a higher frequency in females with ADHD (n=84) than controls (P=0.029) from the case-control association study. The analysis of covariance (ANCOVA) indicated that the mean plasma BDNF levels of ADHD patients were significantly higher than that of controls (P=0.001). We performed both total sample and sex stratified analyses to investigate the effect of Val66Met genotype on the plasma BDNF levels, but only a trend of association was found in females with ADHD (n=84), with a tendency of lower plasma BDNF level in Val allele carriers than Met/Met genotype carriers (P=0.071). Our results suggested a sex-specific association between BDNF and ADHD. Furthermore, there was a possible sex-specific relationship between the BDNF Val66Met genotype and plasma BDNF levels. However, further studies are required to elucidate the role of BDNF in ADHD.     

BDNF Val66Met genotype interacts with childhood adversity and influences the formation of hippocampal subfields

Childhood stress and genetic factors like the Val66MET polymorphism of the brain derived neurotrophic factor (BDNF) gene are associated with a higher risk for developing major depressive disorder (MDD) and might also influence hippocampal changes. The aim of this study was to determine which hippocampal dentate gyrus and cornu ammonis subfields are altered in MDD compared to healthy controls and which subfields are affected by the BDNF Val66Met polymorphism and child adversity. Adult patients with MDD and healthy matched controls underwent high‐resolution magnetic resonance imaging. Automatic segmentation using the programme FreeSurfer was used to segment the hippocampal subfields dentate gyrus (DG/CA4), CA1 and CA2/3. The history of possible childhood adversity was assessed using the Childhood Trauma Questionnaire and the Val66Met BDNF SNP (rs6265) genotypes were obtained. Patients with MDD had significantly smaller CA4/DG and CA2/3 volumes compared to healthy controls. Furthermore, there was a significant interactive effect of BDNF allele and childhood adversity on CA2/3 and CA4/DG volumes. Met allele carriers without childhood adversity had larger and with childhood adversity smaller CA4/DG and CA2/3 volumes than Val‐allele homozygotes. Our results highlight stress by gene interactions as relevant for hippocampal volume reductions, in particular for the subfield CA2/3 and dentate gyrus. Hum Brain Mapp 35:5776–5783, 2014. © 2014 Wiley Periodicals, Inc .     

Smoking and BDNF Val66Met polymorphism in male schizophrenia: A case-control study

Some recent studies show an association between a functional polymorphism of BDNF gene (Val66Met) and the susceptibility to nicotine dependence and we hypothesized that this polymorphism was associated with smoking in both schizophrenia patients and healthy controls. The BDNF Val66Met gene polymorphism was genotyped in 690 chronic male schizophrenia patients (smoker/nonsmoker = 522/169) and 628 male controls (smoker/nonsmoker = 322/306) using a case-control design. Nicotine dependence (ND) was assessed by the cigarettes smoked per day (CPD), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). Patients also were rated on the Positive and Negative Syndrome Scale (PANSS). The results showed no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls or between smokers and nonsmokers in either patients or healthy controls alone. In patient groups, however, the smokers with the Met allele had significantly higher HSI scores (Met/Met: 2.8 ± 1.7 vs. Met/Val: 2.2 ± 1.7 vs. Val/Val: 2.0 ± 1.6, p < 0.01) and a trend toward a significantly higher FTND score (p = 0.09) than those with the Val/Val genotype. In addition, the smokers showed significantly lower PANSS negative symptom and total scores, longer duration of illness and more hospitalizations (all p < 0.05). In the control group, the smokers with the Met allele started smoking significantly earlier than those with the Val/Val genotype (both p < 0.05). These results suggest that the BDNF Val66Met polymorphism may affect a smoker's response to nicotine in both schizophrenia and healthy controls from a Chinese Han population, but with differential effects in different aspects of smoking behaviors.     

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.     

Variation in the BDNF Val66Met polymorphism and response to cognitive-behavior therapy in obsessive-compulsive disorder

BackgroundRecent research suggests that the brain-derived neurotrophic factor (BDNF) may play a role in extinction learning. The goal of this study was to test whether variation in the BDNF Val66Met polymorphism is related to treatment response to exposure-based cognitive-behavior therapy (CBT), a form of extinction learning, in obsessive-compulsive disorder (OCD).MethodsOne hundred and six OCD patients from a specialized clinic, who underwent a standardized CBT treatment after partial or non-response to a 12-week pharmacological trial, were genotyped for the BDNF Val66Met and the relationship between genotype and treatment response was analyzed.ResultsAmong 98 CBT completers, 36% of those carrying the BDNF Met allele were rated as CBT responders compared to 60% of nonMet allele carriers (P = 0.027). When analyzing the different obsessive-compulsive symptom dimensions, in patients with contamination/cleaning symptoms, the Met allele was associated with a significantly worse CBT response (P < 0.0001) and a lower obsessions severity decrease from pre- to posttreatment (P = 0.046).ConclusionGenetic variation in BDNF may be associated with treatment response in exposure-based CBT in OCD, especially in those patients exhibiting contamination/cleaning symptoms.     

Influence of the BDNF Val66Met polymorphism on coping response to stress in patients with advanced gastric cancer

Objective

Coping with cancer is an important determinant of psychological morbidity, quality of life, and treatment adherence in cancer patients. The aim of this study was to elucidate the association between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and coping response to stress in patients diagnosed with advanced gastric cancer.

Methods

Ninety-one subjects (60 males, 31 females) recently diagnosed with advanced gastric cancer were recruited. Coping style and distress level were examined using the Mini-Mental Adjustment to Cancer (Mini-MAC) scale and Hospital Anxiety and Depression Scale, and genotyping was evaluated. To examine the temporal stability of the Mini-MAC scores, a 6-week follow-up evaluation was conducted in 72 patients, after completion of two chemotherapy cycles.

Results

Coping style to cancer significantly differed between the Met carriers of BDNF Val66Met and the Val/Val homozygotes. The Met carriers were significantly more anxious than the Val/Val homozygotes.

Conclusion

The present findings suggest that the BDNF Val66Met polymorphism may be involved in individual coping responses to cancer. The Met allele of BDNF Val66Met may be predictive of an anxious coping style in patients with advanced cancer.     

Plasma BDNF levels are correlated with aggressiveness in patients with amnestic mild cognitive impairment or Alzheimer disease

In the present study, we examined whether neuropsychiatric symptoms were correlated with plasma brain-derived neurotrophic factor (BDNF) levels as a state marker or were associated with the BDNF polymorphism Val66Met in patients with amnestic mild cognitive impairment (A-MCI) or Alzheimer disease (AD). One hundred and seventy-six outpatients with AD (n = 129) or A-MCI (n = 47) were selected and their plasma BDNF concentrations measured. Next, we investigated the correlation between the plasma BDNF level and the Behavioral Pathology in Alzheimer Disease (Behave-AD) subscale scores, which reflect neuropsychiatric symptoms. We also compared the plasma BDNF level and the Behave-AD subscale scores among the BDNF Val66Met genotypic groups. Among the seven Behave-AD subscale scores, aggressiveness was positively correlated with the plasma BDNF level (ρ = 0.237, P < 0.005), but did not differ significantly among the three BDNF Val66Met genotypic groups. The Behave-AD total and other subscale scores did not differ significantly among the BDNF Val66Met genotypic groups and were not associated with the plasma BDNF level. Moreover, the plasma BDNF level did not differ significantly among the three BDNF Val66Met genotypic groups or between patients with A-MCI and those with AD. The plasma BDNF level was robustly correlated with aggressiveness, implying that the plasma BDNF level might be useful as a behavioral state marker in patients with AD or A-MCI.     

Gamma-transcranial alternating current stimulation and theta-burst stimulation: inter-subject variability and the role of BDNF

ObjectiveThe main limitation of neuromodulation techniques is inter-subject variability. Combining theta-burst stimulation (TBS) with gamma-transcranial alternating current stimulation (γ-tACS) allows to shape cortical plasticity. However, it is unknown whether γ-tACS modifies TBS-induced response variability. In this study, we measured the inter-subject variability of TBS-γ tACS and controlled the effect of the Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism.MethodsIntermittent TBS (iTBS)-sham tACS, iTBS-γ tACS, continuous TBS (cTBS)-sham tACS, and cTBS-γ tACS were applied in randomised sessions. Inter-subject variability was measured using grand average and clustering methods. TBS-γ tACS effects on motor evoked potentials (MEP) were compared between Val/Val and Met carriers.ResultsWe found that γ-tACS boosted iTBS-induced MEP facilitation and cancelled cTBS-induced MEP depression. Grand average analysis showed that γ-tACS prominently increased the percentage of iTBS responders and cTBS non-responders. The clustering method demonstrated that TBS-γ tACS response varied between subjects, a phenomenon unrelated to the BDNF genotype.ConclusionsEnhancing γ oscillations through tACS boosts iTBS-induced LTP-like plasticity and suppresses cTBS-induced LTD-like plasticity of the primary motor cortex in a reliable manner. The BDNF Val66Met polymorphism does not influence these effects.SignificanceSince γ-tACS significantly increases the number of iTBS responders, it may be used in clinical settings.     

Childhood trauma,BDNF Val66Met and subclinical psychotic experiences. Attempt at replication in two independent samples

Childhood trauma exposure is a robust environmental risk factor for psychosis. However, not all exposed individuals develop psychotic symptoms later in life. The Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) has been suggested to moderate the psychosis-inducing effects of childhood trauma in clinical and nonclinical samples. Our study aimed to explore the interaction effect between childhood trauma and the BDNF Val66Met polymorphism on subclinical psychotic experiences (PEs). This was explored in two nonclinical independent samples: an undergraduate and technical-training school student sample (n = 808, sample 1) and a female twin sample (n = 621, sample 2). Results showed that childhood trauma was strongly associated with positive and negative PEs in nonclinical individuals. A BDNF Val66Met x childhood trauma effect on positive PEs was observed in both samples. These results were discordant in terms of risk allele: while in sample 1 Val allele carriers, especially males, were more vulnerable to the effects of childhood trauma regarding PEs, in sample 2 Met carriers presented higher PEs scores when exposed to childhood trauma, compared with Val carriers. Moreover, in sample 2, a significant interaction was also found in relation to negative PEs. Our study partially replicates previous findings and suggests that some individuals are more prone to develop PEs following childhood trauma because of a complex combination of multiple factors. Further studies including genetic, environmental and epigenetic factors may provide insights in this field.     

Depression and Cognitive Dysfunction in Older U.S. Military Veterans: Moderating Effects of BDNF Val66Met Polymorphism and Physical Exercise

ObjectiveDepression is associated with increased risk for cognitive dysfunction, yet little is known about genetic and behavioral factors that may moderate this association. Using data from a nationally representative sample of older U.S. military veterans, we examined the direct and interactive effects of depression, brain-derived neurotropic factor (BDNF) Val66Met genotype, and physical exercise on cognitive functioning.MethodsOne thousand three hundred eighty-six older European-American U.S. military veterans (mean age = 63) completed a web-based survey and cognitive assessment. Analyses of covariance were conducted to evaluate the effects of depression, BDNF Met allele carrier status, and physical exercise on these measures.ResultsDepressed veterans scored worse than nondepressed veterans on subjective measures of cognitive functioning (Cohen d's = 0.34–0.57) and objective measures of visual learning (d = 0.39) and working memory (d = 0.28). Among depressed veterans, those who were Met allele carriers scored worse than Val/Val homozygotes on subjective cognitive measures (d's = 0.52–0.97) and an objective measure of visual learning (d = 0.36). Engagement in physical exercise moderated the association between depression and cognitive function, with depressed exercisers scoring better than depressed nonexercisers on a subjective measure of reasoning, and objective measures of processing speed, attention, and visual learning (d = 0.58–0.99): further, in depressed Met allele carriers, exercisers scored better than nonexercisers on subjective cognitive (d's = 0.80–1.92), and objective measures of visual learning (d = 0.8–1.31) and working memory (d = 0.67).ConclusionDepression is associated with moderate decrements in cognitive functioning in older U.S. military veterans, and this association is moderated by BDNF Val66Met genotype and physical exercise. Prevention and treatment efforts designed to promote physical exercise may help preserve cognitive functioning in at-risk veterans.     

Kynurenine pathway is altered in BDNF Val66Met knock-in mice: Effect of physical exercise

The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism has been correlated with increased predisposition to develop cognitive and psychiatric disorders, and with a reduced response to some therapeutic treatments. However, the mechanisms underlying these impairments are currently not completely understood. Remarkably, kynurenine pathway alterations have also been implicated in cognitive and psychiatric disorders. Moreover, recent evidence suggests that physical exercise may promote beneficial effects by controlling kynurenine metabolism in the muscle.The aim of the present study was to assess whether the kynurenine pathway was differentially regulated in sedentary and exercising wild-type (BDNF^Val/Val) and homozygous knock-in BDNF Val66Met (BDNF^Met/Met) mice. We found that plasma and hippocampal levels of kynurenic acid and the hippocampal mRNA levels of IDO1 and KAT2 protein levels were increased in BDNF^Met/Met mice and were not modulated by physical exercise. On the contrary, KAT1 protein levels in the gastrocnemius muscle were reduced, whereas MCP1 mRNA in the gastrocnemius muscle and GFAP protein in the hippocampus were increased in BDNF^Met/Met mice compared to BDNF^Val/Val mice, and reduced by physical exercise. Physical exercise increased plasmatic kynurenine levels only in BDNF^Met/Met mice, and protein levels of KAT1 and KAT4 in the gastrocnemius muscle and hippocampus respectively, regardless of the genotype. Finally, we found that physical exercise was able to enhance the hippocampal-dependent memory only in the BDNF^Val/Val mice. Overall our results showing an overactivation of the kynurenine pathway in the BDNF^Met/Met mice may suggest a possible mechanism underlying the cognitive deficits reported in the BDNF Val66Met carriers.     

BDNF plasma levels and genotype in depression and the response to electroconvulsive therapy

Background

Brain derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression and the antidepressant response. Electroconvulsive therapy (ECT) is reported to increase BDNF levels in blood, though only a small number of studies have been conducted to date.

Interaction of the DRD3 and BDNF gene variants in subtyped bipolar disorder

Objectives

Bipolar disorder is a severe mental disorder with prominent genetic etiologic factors. Dopaminergic dysfunction has been implicated in the pathogenesis of bipolar disorder, which suggests that the dopamine D3 receptor gene (DRD3) is a strong candidate gene. The brain-derived neurotrophic factor (BDNF) gene has been implicated in the etiology of bipolar disorder. We examined the association between the BDNF Val66Met and DRD3 Ser9Gly polymorphisms with two subtypes of bipolar disorder: bipolar-I and -II. Because BDNF regulates DRD3 expression (1), we also examined possible interactions between these genes.

Methods

We recruited 964 participants: 268 with bipolar-I, 436 with bipolar-II, and 260 healthy controls. The genotypes of the BDNF Val66Met and DRD3 Ser9Gly polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis.

Results

Logistic regression analysis showed a significant main effect for the Val/Val genotype of the BDNF Val66Met polymorphism (P = 0.020), which predicted bipolar-II patients. Significant interaction effects for the BDNF Val66Met Val/Val genotype and both DRD3 Ser9Gly Ser/Ser and Ser/Gly genotypes were found only in bipolar-II patients (P = 0.027 and 0.006, respectively).

Conclusion

We provide initial evidence that the BDNF Val66Met and DRD3 Ser9Gly genotypes interact only in bipolar-II disorder and that bipolar-I and bipolar-II may be genetically distinct.     

The val66met polymorphism of brain‐derived neurotrophic factor is associated with human esophageal hypersensitivity

Background Recent evidence implicates brain‐derived neurotrophic factor (BDNF) in visceral hypersensitivity and pain in functional gastrointestinal disorders. We hypothesized that presence of the val66met polymorphism in the BDNF gene would be linked to increased esophageal sensitivity to electrical stimulation. Methods A total of 39 healthy volunteers (20 males, mean age 30) compliant with inclusion criteria after screening procedures were genotyped for BDNF polymorphisms and completed an Hospital Anxiety and Depression Scale (HADS) questionnaire. Sensory (ST) and pain (PT) thresholds in the proximal (PE) and distal (DE) esophagus were determined using electrical stimuli to a swallowed intraluminal catheter with bipolar electrodes by an investigator blinded to the subjects’ genotype. For comparison, somatic ST and PT (hand and foot) were also tested. HADS scores together with esophageal and somatic thresholds were then correlated with BDNF polymorphism status. Key Results Eleven of 39 (28%) volunteers had at least one Met allele (Met carriers). When compared with Val/Val, Met carriers had lower esophageal PT (Median PT [mA]: Val/Val vs Met carriers, PE; 49.4 vs 44.3, P = 0.033, DE: 63.8 vs 55.4, P = 0.045) with higher proportion of Val/Val subjects in the upper quartile for PT in both PE (P = 0.021) and DE (P = 0.033), yet similar somatic PT (Median PT [mA] Hand; 33.6 vs 38.0, P = 0.22, Foot; 44.7 vs 44.0, P = 0.48). Sensitivity results were independent of anxiety (P = 0.66) and depression (P = 0.33) scores. Conclusions & Inferences val66met BDNF polymorphisms are associated with increased esophageal sensitivity to experimental electrical stimulation. Thus, BDNF genotype may be a useful biomarker for electrical sensitivity in the healthy human esophagus.     

BDNF Val66Met,stress, and positive mothering: Differential susceptibility model of adolescent trait anxiety

Etiological research has indicated the gene–environment interaction (G × E) on adolescent anxiety. This study aimed to examine how the BDNF Val66Met polymorphism interacted with stressful life events and positive mothering to influence youth trait anxiety. The study sample included 780 community adolescents of Chinese Han ethnicity (M = 13.6, 51.3% females). Participants’ trait anxiety, exposure to stressful life events, and mother's warmth-reasoning were assessed by self-reported questionnaires. We found that BDNF Val66Met polymorphism significantly moderated the influences of stressful life events and mother's warmth-reasoning on adolescent anxiety. The influences were significantly greater in adolescents carrying one or two Val allele than those with Met/Met genotype. Moreover, the G × E interactions were more consistent with the differential susceptibility than the diathesis–stress model. Adolescents carrying Val allele who were more susceptible to adversity were also more likely to benefit from supportive experiences. These findings provide novel evidence for the role of BDNF Val66Met as a genetic susceptibility modulating the influences of stressful life events and mother's warmth-reasoning on adolescent anxiety. We speculate that BDNF Val66Met may moderate anxious youths’ responses to mindfulness-based stress reduction program and family-based treatment targeting the enhancement of positive parenting.     

Influence of BDNF Val66Met polymorphism on excitatory-inhibitory balance and plasticity in human motor cortex

ObjectiveWhile previous studies showed that the single nucleotide polymorphism (Val66Met) of brain-derived neurotrophic factor (BDNF) can impact neuroplasticity, the influence of BDNF genotype on cortical circuitry and relationship to neuroplasticity remain relatively unexplored in human.MethodsUsing individualised transcranial magnetic stimulation (TMS) parameters, we explored the influence of the BDNF Val66Met polymorphism on excitatory and inhibitory neural circuitry, its relation to I-wave TMS (ITMS) plasticity and effect on the excitatory/inhibitory (E/I) balance in 18 healthy individuals.ResultsExcitatory and inhibitory indexes of neurotransmission were reduced in Met allele carriers. An E/I balance was evident, which was influenced by BDNF with higher E/I ratios in Val/Val homozygotes. Both long-term potentiation (LTP-) and depression (LTD-) like ITMS plasticity were greater in Val/Val homozygotes. LTP- but not LTD-like effects were restored in Met allele carriers by increasing stimulus intensity to compensate for reduced excitatory transmission.ConclusionsThe influence of BDNF genotype may extend beyond neuroplasticity to neurotransmission. The E/I balance was evident in human motor cortex, modulated by BDNF and measurable using TMS. Given the limited sample, these preliminary findings warrant further investigation.SignificanceThese novel findings suggest a broader role of BDNF genotype on neurocircuitry in human motor cortex.     

A common polymorphism in the brain-derived neurotrophic factor gene in patients with adult-onset primary focal and segmental dystonia

Brain-derived neurotrophic factor (BDNF) modulates neuroplasticity. A functional polymorphism [Val66Met (G196A)] in BDNF has been reported to modify cortical plasticity in humans. Physiologic investigations have revealed that dystonia might be a consequence of the pathologic plasticity of the sensorimotor cortex. We aimed to investigate the role of the Val66Met polymorphism in a cohort of Serbian patients with adult-onset primary focal and segmental dystonia (PTD). One hundred and forty-nine patients with primary adult-onset PTD, 194 patients with Parkinson’s disease (PD), and 366 healthy control subjects were recruited for the study. Patients with PTD and PD, as well as healthy controls had a similar distribution of genotypes and allele frequencies. There was no any significant difference in the allelic distribution at the Val66Met SNP of the BDNF gene among patients with adult-onset PTD, PD, and healthy volunteers from the same geographic areas. In addition, the presence of the Met allele did not influence the clinical characteristics of PTD patients. Patients with the Met variant did not differ by age at onset, number of affected regions, and efficacy of a sensory trick. Met66Met is not associated with an increased risk of dystonia.     

Val66Met polymorphism association with serum BDNF and inflammatory biomarkers in major depression

Objectives: Current evidence supports participation of neurotrophic and inflammatory factors in the pathogenesis of major depressive disorder (MDD). Some studies reported an association between the Val66Met polymorphism (rs6265) of brain-derived neurotrophic factor (BDNF) gene with MDD and peripheral BDNF levels. However, no previous studies have examined the association of this polymorphism with inflammation. The present study assessed the association of the Val66Met polymorphism with serum levels of BDNF and inflammatory markers among depressed outpatients.

Methods: All participants (n?=?73) met DSM-IV criteria for a unipolar depressive episode. The serum levels of BDNF and inflammatory biomarkers (IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ) were compared between individuals presenting with at least one Met allele (Met-carriers) and those homozygous for the Val allele.

Results: In our sample (84.9% female, mean age 52.4?±?10.3 years), 24.7% (n?=?18) were Met-carriers. After Bonferroni correction, the Met allele was significantly associated with higher BDNF and lower TNF-α. These associations persisted after adjusting for potential confounders.

Conclusions: The pattern of low BDNF and high inflammation in MDD may be influenced by the Val66Met polymorphism. The association of a polymorphism in the BDNF gene with inflammatory markers in addition to BDNF levels suggests an interaction between these systems.     

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.     

The association between brain-derived neurotrophic factor Val66Met variants and psychotic symptoms in posttraumatic stress disorder

Abstract

Objectives. Psychotic symptoms frequently occur in veterans with combat-related posttraumatic stress disorder (PTSD). Brain-derived neurotrophic factor (BDNF) plays a major role in neurodevelopment, neuro-regeneration, neurotransmission, learning, regulation of mood and stress responses. The Met allele of the functional polymorphism, BDNF Val66Met, is associated with psychotic disorders. This study intended to assess whether the Met allele is overrepresented in unrelated Caucasian male veterans with psychotic PTSD compared to veteran controls. Methods. The BDNF Val66Met variants were genotyped in 576 veterans: 206 veterans without PTSD and 370 veterans with PTSD subdivided into groups with or without psychotic features. Results. Veterans with psychotic PTSD were more frequently carriers of one or two Met alleles of the BDNF Val66Met polymorphism than veterans with PTSD without psychotic features and veterans without PTSD. Conclusions. The study shows that veterans with psychotic PTSD carried more Met alleles of the BDNF Val66Met than non-psychotic veterans with PTSD or veterans without PTSD. The results might add further support to the hypothesis that psychotic PTSD is a more severe subtype of PTSD.