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Effects of BDNF polymorphisms on brain function and behavior in health and disease
Abstract
Brain-derived neurotrophic factor (BDNF), the most abundant neurotrophin in the brain, serves an important role during brain development and in synaptic plasticity. Given its pleiotropic effects in the central nervous system, BDNF has been implicated in cognitive function and personality development as well as the pathogenesis of various psychiatric disorders. Thus, BDNF is considered an attractive candidate gene for the study of healthy and diseased brain function and behaviors. Over the past decade, many studies have tested BDNF genetic association, particularly its functional Val66Met polymorphism, with psychiatric diseases, personality disorders, and cognitive function. Although many reports indicated a possible role for BDNF genetic effects in mental problems or brain function, other reports were unable to replicate the findings. The conflicting results in BDNF genetic studies may result from confounding factors such as age, gender, other environmental factors, sample size, ethnicity and phenotype assessment. Future studies with more homogenous populations, well-controlled confounding factors, and well-defined phenotypes are needed to clarify the BDNF genetic effects on mental diseases and human behaviors.
... A single nucleotide polymorphism (SNP) producing a valine-to-methionine substitution at codon 66 (Val66Met; rs6265) in the BDNF gene is associated with reduced activity-dependent secretion of BDNF (Egan et al., 2003). While findings have been somewhat mixed (Harrisberger et al., 2014;Hong, Liou, & Tsai, 2011;Notaras, Hill, & Van Den Buuse, 2015), Val66Met allele status, and especially possession of the Met allele, has been associated with variation in brain structure and function, including smaller brain volumes (Kawasaki et al., 2021;Nemoto et al., 2006;Pezawas et al., 2004;Szeszko et al., 2005) and lower connectivity (Park et al., 2017;Ueda et al., 2020), poorer neuropsychological functioning (Kambeitz et al., 2012;Toh, Ng, Tan, Tan, & Chan, 2018), and greater risk for a multitude of psychiatric and neurological conditions, in non-brain-injured individuals (Brown, Vickers, Stuart, Cechova, & Ward, 2020;Notaras et al., 2015). ...
... The present results are consistent with our prior report in this cohort (Treble-Barna et al., 2021), suggesting that the Met allele (associated with reduced activity-dependent secretion of BDNF) may confer risk for poorer neuroplasticity and repair mechanisms after TBI, affecting both longitudinal behavioral adjustment and neuropsychological functioning. These inconsistent findings regarding risk versus protection of the Met allele are not unique to TBI, with similar complex and conflicting findings in other clinical conditions (Hong et al., 2011;Notaras et al., 2015), perhaps most relevantly in stroke (Rezaei, Asgari Mobarake, & Saberi, 2020; Rezaei, Mobarake, Saberi, & Keshavarz, 2020). Reviews of the effect of Val66Met in other populations have cited heterogeneity in confounders such age, sex, environmental factors, sample size, ethnicity, and phenotype assessment as likely accounting for some of the mixed findings (Hong et al., 2011;Notaras et al., 2015). ...
... These inconsistent findings regarding risk versus protection of the Met allele are not unique to TBI, with similar complex and conflicting findings in other clinical conditions (Hong et al., 2011;Notaras et al., 2015), perhaps most relevantly in stroke (Rezaei, Asgari Mobarake, & Saberi, 2020; Rezaei, Mobarake, Saberi, & Keshavarz, 2020). Reviews of the effect of Val66Met in other populations have cited heterogeneity in confounders such age, sex, environmental factors, sample size, ethnicity, and phenotype assessment as likely accounting for some of the mixed findings (Hong et al., 2011;Notaras et al., 2015). In stroke, Val66Met status has shown significant interactions with age, dominant hemisphere lesions, degree of cerebral atrophy, number of lesions, recovery stage, and family history of dementia in predicting neuropsychological outcomes (Balkaya & Cho, 2019;Rezaei, Asgari Mobarake, et al., 2020;. ...
Objective
The present study examined the differential effect of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on neuropsychological functioning in children with traumatic brain injury (TBI) relative to orthopedic injury (OI).
Methods
Participants were drawn from a prospective, longitudinal study of children who sustained a TBI ( n = 69) or OI ( n = 72) between 3 and 7 years of age. Children completed a battery of neuropsychological measures targeting attention, memory, and executive functions at four timepoints spanning the immediate post-acute period to 18 months post-injury. Children also completed a comparable age-appropriate battery of measures approximately 7 years post-injury. Parents rated children’s dysexecutive behaviors at all timepoints.
Results
Longitudinal mixed models revealed a significant allele status × injury group interaction with a medium effect size for verbal fluency. Cross-sectional models at 7 years post-injury revealed non-significant but medium effect sizes for the allele status x injury group interaction for fluid reasoning and immediate and delayed verbal memory. Post hoc stratified analyses revealed a consistent pattern of poorer neuropsychological functioning in Met carriers relative to Val/Val homozygotes in the TBI group, with small effect sizes; the opposite trend or no appreciable effect was observed in the OI group.
Conclusions
The results suggest a differential effect of the BDNF Val66Met polymorphism on verbal fluency, and possibly fluid reasoning and immediate and delayed verbal memory, in children with early TBI relative to OI. The Met allele—associated with reduced activity-dependent secretion of BDNF—may confer risk for poorer neuropsychological functioning in children with TBI.
... Actions of BDNF are mediated through binding to two receptors -a specific and high-affinity receptor and a tyrosine kinase B receptor, as well as a nonspecific low-affinity receptor, p75 [1]. BDNF plays an important rôle in neuronal differentiation and survival during embryonic development, as well as in the maintenance of neuron viability in adulthood, in both the central and peripheral nervous systems [2,3]. Furthermore, BDNF can modulate synaptic plasticity and its molecular mediators across multiple neurotransmitter systems [1]. ...
... Substitution of Val66 with Met66 disrupts cellular processing, trafficking, and activity-dependent secretion of BDNF [15]. Previous studies found that this polymorphism is associated with various neuropsychiatric diseases or their therapeutic responses including major depression, schizophrenia, Alzheimer's disease (AD), violent behaviors, suicide behaviors, personality traits, and substance abuse [2,3,[16][17][18][19][20][21][22][23][24][25][26] although not all studies have similar findings [3]. Some information from other BDNF SNPs is overlooked because that investigating a single BDNF polymorphism (i.e., the Val66Met polymorphism) might only reveal some of the BDNF genetic variability [3]. ...
... Regarding negative findings in those two studies, we suggested that the BDNF Val66Met polymorphism is not a major contributing factor to depression susceptibility. The negative findings are supported by the following studies in Korean population, Japanese population, Belgian population, Spanish population (that used eight BDNF polymorphisms), British population, and Chinese population [2,3]. However, haplotype analysis with three BDNF polymorphisms in a German population has produced nominally association for major depression [34]. ...
Background: Brain-derived neurotrophic factor (BDNF), the most abundant and widely expressed neurotrophin in the brain, is believed to play an important role in depression and anxiety. In this study, we hypothesized that single-nucleotide polymorphisms (SNPs) within the BDNF gene should be linked with depression and anxiety through complex interactions in the general population. Methods: We analyzed 7,098 Taiwanese participants from the Taiwan Biobank. Measures of anxiety and depression were evaluated using the Patient Health Questionnaire-4 (PHQ-4). We used 43 BDNF polymorphisms in the genetic analysis. Results: We found a nominal association between nine BDNF genetic variants and depression state, after having adjusted for the factors of age and gender. Furthermore, three BDNF SNPs showed evidence of nominal association with PHQ-4 scores. In addition, an interaction significantly existed between the BDNF rs73430670 and BDNF rs4923461 in influencing depression state (p < 0.05). Finally, we found that influence of interaction significantly existed between BDNF rs12418745 and physical activity (p < 0.05) in depression state. Conclusion: Those results suggest that the BDNF genetic variants may contribute to psychological distress independently as well as through SNP-SNP and gene-physical activity interactions in the general population.
... Compared with the Val66 allele, the Met66 allele is associated with a decrease in activity-dependent secretion of BDNF . BDNF has received attention due to its evident role in anxiety and mood disorders (Angelucci et al., 2014;Hemmings et al., 2008;Li, Chang, & Xiao, 2016;Martinowich et al., 2007;Molendijk et al., 2014;Suliman, Hemmings, & Seedat, 2013), although findings have been inconsistent across studies (Frustaci, Pozzi, Gianfagna, Manzoli, & Boccia, 2008;Hong, Liou, & Tsai, 2012;Lam, Cheng, Hong, & Tsai, 2004;Minelli et al., 2011;Notaras et al., 2015;Surtees et al., 2007;Wang et al., 2015). ...
... These findings suggest that the BDNF Val66Met polymorphism does not have a direct effect on AS. This finding is in line with studies that have found no significant direct association between BDNF Val66Met polymorphism and personality traits such as neuroticism or harm avoidance and anxiety disorders or mood disorders, including OCD, panic disorder, PTSD and depression (Arias et al., 2012;Chen et al., 2013;Frustaci et al., 2008;Hong et al., 2012;Minelli et al., 2011;Surtees et al., 2007;Terracciano et al., 2010), despite some studies reporting such associations (Frustaci et al., 2008;Lang et al., 2005;Min et al., 2013;Montag et al., 2010;Sen et al., 2003;Terracciano et al., 2010). Firstly, the grouping of Met66 allele carriers (i.e. ...
... Met66Met and Val66Met genotypes), as is frequently carried out in studies in which the rate of the Met66Met genotype is relatively low, such as in Caucasian samples (Gatt et al., 2009;Lehto, Maestu, Kiive, Veidebaum, & Harro, 2016;Nedic et al., 2013;Pivac et al., 2009), may introduce a bias in which a main effect of genotype is not detected due to the exclusion of Notaras et al., 2015). Secondly, the Val66Met and Met66Met genotypes, respectively, may have dissimilar effects (Hong et al., 2012). Nevertheless, the main effect of CM on AS determined in this study provides support for the positive association between CM, including stressful life events, and AS in adolescents (McLaughlin & Hatzenbuehler, 2009;Tollenaar, Molendijk, Penninx, Milaneschi, & Antypa, 2017), a well-established cognitive risk factor for the development of anxiety disorders and associated symptoms in youth (Hishinuma et al., 2001;McLaughlin et al., 2007;Muris et al., 2001). ...
Background: Anxiety disorders in youth are attributable to multiple causal mechanisms, comprising biological vulnerabilities, such as genetics and temperament, and unfavourable environmental influences, such as childhood maltreatment (CM).
Objective: A gene-environment (G x E) interaction study was conducted to determine the interactive effect of the BDNF Val66Met polymorphism and CM to increase susceptibility to anxiety sensitivity (AS) in a sample of mixed race adolescents.
Method: Participants (n = 308, mean age = 15.8 years) who were all secondary school students and who completed measures for AS and CM were genotyped for the BDNF Val66Met polymorphism. Hierarchical multiple regression analysis was conducted to assess G x E influences on AS. Age and gender were included in the models as covariates as age was significantly associated with AS total score (p < .05), and females had significantly higher AS scores than males (p < .05).
Results: A main effect of CM on AS was evident (p < .05), however, no main effect of BDNF genotype on AS was observed (p > .05). A non-significant G x E effect on AS was revealed (p < .05).
Conclusions: Our results suggest that CM does not have a moderating role in the relationship between the BDNF Val66Met genotype and the increased risk of anxiety-related phenotypes, such as AS. Given the exploratory nature of this study, findings require replication in larger samples and adjustment for population stratification to further explore the role of BDNF Val66Met and CM on AS in mixed race adolescents.
... Neurotrophins are a group of proteins that aid the process of neurogenesis (i.e., the growth of new neurons from neuronal stem cells) and, more broadly, are essential in the facilitation of brain plasticity, particularly use-dependent plasticity (see Cotman & Berchtold, 2002). One of the more commonly studied neurotrophins is BDNF, which is the most abundant neurotrophin in the human brain (Hong, Liou, & Tsai, 2011) and the most broadly abundant neurotrophin in the adult forebrain and the hippocampus (Spitzer & Hollmann, 2013). BDNF is manufactured and released by glutamatergic neurons and has a number of functions, with one of the most important being the survival, proliferation, and plasticity of the dopaminergic and serotonergic systems (see Berton et al., 2006). ...
... A dysfunctional BDNF system has the potential to result in a number of neuropsychiatric disadvantages, including reduced cognitive abilities (Yamada, Mizuno, & Nabeshima, 2002) and problems with executive functioning (Rybakowski, Borkowska, Czerski, Skibińska, & Hauser, 2003). Although BDNF activity can be stimulated or suppressed by various environmental factors, genetic mechanisms also play an important role in the manufacture of BDNF proteins (Hong et al., 2011). Because the impact of BDNF is relevant to numerous brain structures and neurotransmitter systems, a deficiency in BDNF has the potential to lead to conduct problems through a variety of neurological pathways (see Archer & Kostrzewa, 2012). ...
... BDNF also appears to differentiate and aid the survival of dopaminergic neurons in the midbrain (e.g., the ventral striatum). Some scholars have posited that the likely result of BDNF deficits in the ventral striatum are symptoms of reward deficiency (see Hong et al., 2011). Such deficiencies would be expected to incite stimulation-seeking behaviors and ADHD-like symptoms, which would in turn increase the risk of delinquent behavior (see Pratt et al., 2002). ...
This chapter examines some of the literature that has explored the links among physical exercise, brain structure and functioning, and antisocial phenotypes. It analyses the relationship between executive dysfunction and antisocial behavior in conjunction with the benefits of physical exercise on executive functioning. The chapter reviews the hippocampal abnormalities and dysfunction as an explanation of offending, together with research demonstrating the structural and functional improvements to the hippocampus that can result from exercise. It outlines the role of monoamines in the production of antisocial behavior along with the effect of exercise on the production and synthesis of monoamines. The chapter discusses the relationship between diminished brain-derived neurotrophic factor (BDNF) and criminogenic traits. It also discusses the feasibility of physical exercise as a core feature of offender treatment. The chapter expresses that an exercise training program can serve as a potential option to reduce antisocial phenotypes.
... Further, role of sex hormones and various other genetic, hormonal and environmental factors have been implicated in modulating BDNF function [25,29,[31][32][33][34][35]. Despite a higher risk of depression in Asian and Indian populations [25,36], extensive studies targeting polymorphisms in BDNF have never been executed in these populations so far. ...
... BDNF G196A polymorphism reduces the expression of the gene and activates apoptotic pathway [48,49] and in other populations as US Caucasians, American Indian, African American, Chinese a significant association of this polymorphism was shown with depression cases [50][51][52] and several psychiatric disorders such as anxiety, obsessive compulsive disorder, depression, schizophrenia, psychosis and eating disorder [36,53]. BDNF G196A, "A" (minor allele) has been considered as the risk factor because this minor allele carriers have a reduced activity dependent secretion of BDNF [29,54]. ...
Background:
Adolescence is a distinctive stage of various changes and is noted as peak age for onset of many psychiatric disorders, especially linked to stress and depression. Several genetic variations are being increasingly known to be linked with stress and depression. The polymorphisms in two such genes, the BDNF and SLC1A3, have been reported to be linked with either depression/stress or with suicidal behaviour. These genes have not been validated in Indian population, and therefore there is a need to investigate these genes in Indian population. The present study was undertaken to test whether the known polymorphisms SLC1A3 C3590T, SLC1A3 C869G and BDNF G196A are associated or not with stress or depression in an eastern Indian population.
Methods:
A case-control association study was performed with 108 cases having variable levels of stress and depression and 205 matched controls. Detection of stress and depression was done by using standard instruments as PSS and CES-D, respectively and demographic profile was obtained for each individual on the basis of personal data sheet. Genotyping for the selected polymorphisms was performed by PCR followed by restriction digestion.
Results:
The SNP SLC1A3 C3590T was found to be associated with stress and depression (p = 0.0042, OR = 2.072). Therefore, the T allele increases the risk by more than two folds for stress and depression in the present population. The other allele of SLC1A3, G869C, as well as BDNF G196A were not associated with stress or depression in the population studied.
Conclusion:
SLC1A3 C3590T is a predisposition factor for stress and depression in an eastern Indian population, whereas SLC1A3 G869C and BDNF G196A were not found to be a risk factor. Therefore, presence of T allele of SLC1A3 C3590T, may predict the development of stress and depression in an individual. This may also help in the understanding of pathophysiology of the disease. However, these findings warrant a wider study in Indian populations and would be of significance in understanding the predisposition of stress and depression in this population.
... The genetic model for the analysis of an single-nucleotide polymorphism (SNP), such as the BDNF Val66Met polymorphism, may be dominant (Met carriers vs. Val/Val), codominant (Met/Met vs. Val/Met vs. Val/Val), or recessive (Met/Met vs. Val carriers). The BDNF Met allelic frequency is often reported to be high in Asian populations but low in Caucasian, Central and South American, and African populations Hong et al., 2011;Gonzalez-Castro et al., 2017). Many studies in non-Asian populations have grouped carriers of BDNF Val/Met and Met/Met genotypes together as Met carriers because of the small number of Met homozygotes. ...
... Cognitive impairment has been reported in a mouse model of the BDNF Met allele (Chen et al., 2006;Dincheva et al., 2012). Conflicting findings have been obtained for the genetic effect of BDNF Val66Met on human cognitive function (Tsai et al., , 2008aHong et al., 2011). A meta-analysis including 7,095 individuals failed to support significant genetic associations between the Val66Met polymorphism and any of the cognitive phenotypes (Mandelman and Grigorenko, 2012). ...
Neurotrophins have been implicated in the pathophysiology of many neuropsychiatric diseases. Brain-derived neurotrophic factor (BDNF) is the most abundant and widely distributed neurotrophin in the brain. Its Val66Met polymorphism (refSNP Cluster Report: rs6265) is a common and functional single-nucleotide polymorphism (SNP) affecting the activity-dependent release of BDNF. BDNF Val66Met transgenic mice have been generated, which may provide further insight into the functional impact of this polymorphism in the brain. Considering the important role of BDNF in brain function, more than 1,100 genetic studies have investigated this polymorphism in the past 15 years. Although these studies have reported some encouraging positive findings initially, most of the findings cannot be replicated in following studies. These inconsistencies in BDNF Val66Met genetic studies may be attributed to many factors such as age, sex, environmental factors, ethnicity, genetic model used for analysis, and gene–gene interaction, which are discussed in this review. We also discuss the results of recent studies that have reported the novel functions of this polymorphism. Because many BDNF polymorphisms and non-genetic factors have been implicated in the complex traits of neuropsychiatric diseases, the conventional genetic association-based method is limited to address these complex interactions. Future studies should apply data mining and machine learning techniques to determine the genetic role of BDNF in neuropsychiatric diseases.
... Studies of candidate genes have produced inconsistent results often due to insufficent sample sizes leading to false postive and false negative assocations. Two of the most widely studied such genes are COMT, which encodes the neurotransmiter catechol-O-methyl transferase, and BDNF, which encodes the neurotrophin brainderived neurotrophic factor [104,436,475]. The COMT VAL158MET and BDNF VAL66MET polymorphisms have been assoicated with excutive function, episodic memory and working memory, though the results are inconsistent between studies (reviewed in [104,436,475]). ...
... Two of the most widely studied such genes are COMT, which encodes the neurotransmiter catechol-O-methyl transferase, and BDNF, which encodes the neurotrophin brainderived neurotrophic factor [104,436,475]. The COMT VAL158MET and BDNF VAL66MET polymorphisms have been assoicated with excutive function, episodic memory and working memory, though the results are inconsistent between studies (reviewed in [104,436,475]). In this work, the BDNF MET allele was associated with worse working memory performance at baseline and the COMT MET allele was assoicated with a faster rate of decline in episodic memory. ...
With advancing age individuals experience a deterioration in cognitive abilities that is characterized by substantial inter-individual variation in the observed trajectories of cognitive decline. Late onset Alzheimer’s disease (LOAD) susceptibility genes and environmental risk factors are good candidates for association with cognitive decline, as the pathological features of LOAD progress to varying degrees in individuals without dementia or cognitive impairment and are associated with nonclinical cognitive decline.
This thesis investigates whether Alzheimer’s disease risk factors and genetic variants previously associated with cognitive function are also associated with cognitive decline. Data collected from the 60+ cohort of the Personality and Total Health (PATH) through life project was used, in which 2,551 participants were assessed at 4-year intervals for a total of 12 years on a comprehensive battery of cognitive tests.
The publications in this thesis investigate the following. First, whether APOE*4 moderates the association between high blood pressure and cognitive function in late life. It was observed that a APOE–hypertension interaction was associated with a small but statistically significant increase in the rate of decline of episodic memory, verbal ability and global cognition. In contrast, the interaction between APOE and mean arterial pressure interaction had no effect on rate of decline.
Second, the role of 25 LOAD risk loci in non-linear cognitive change was examined, both individually and collectively as a genetic risk score (GRS). Twelve LOAD risk loci were associated with baseline cognitive performance (ABCA7, MS4A4E, SORL1), linear rate of change (APOE, ABCA7, EPHA1, INPP5D, ZCWPW1, CELF1) or quadratic rate of change (APOE, CLU, FERMT2). In addition, a weighted GRS was associated with linear rate of change in episodic memory and information processing speed.
Third, the role of 9 single nucleotide polymorphisms that have been previously associated with cognitive performance was further examined, with 6 SNPs observed to be associated with baseline cognitive performance (BDNF, PDE7A, AKAP6), linear rate of change (COMT, CTNNBL1, PDE7A) or quadratic rate of change (MIR2113).
Finally, it was examined whether a risk score comprised of lifestyle, medical and demographic factors (the Australian National University Alzheimer’s disease Risk Index; ANU-ADRI) and a LOAD GRS were predictors of progression to Mild Cognitive Impairment (MCI). A higher ANU-ADRI score was associated with a higher probability of transitioning from normal cognition to cognitive impairment, while the GRS was associated with an increased risk of transitioning from normal cognition to dementia.
These results suggest that a subset of LOAD related SNPs may be associated with cognitive decline. However, the effect size of each locus is small and when demographic and lifestyle factors are taken into account, neither individual SNPs nor GRS explain a significant proportion of the variance in cognitive decline in our sample. Further research is required to verify these results and to examine the effect of preclinical LOAD in genetic association studies of cognitive decline. The identification of LOAD risk loci associated with cognitive performance may help in screening for individuals at greater risk of cognitive decline.
... Despite several studies, the specific mechanisms by which BDNF and serotonin interact to influence mood disorders remain incompletely understood [14,15]. Prior studies have largely investigated BDNF and serotonin separately, with limited exploration of their combined effects [15,16]. Thus, there is a need for more comprehensive assessments that clarify the direct relationships between these neurobiological components and the severity of mood disorders. ...
Background
Mood disorders like major depressive disorder (MDD) and bipolar disorder (BD) involve complex interactions between brain-derived neurotrophic factor (BDNF) and serotonin. While extensive research has explored these factors individually, their combined effects and interactions in these disorders are less understood. This study uniquely addresses this gap by examining how BDNF and serotonin interact and relate to mood disorder severity, providing new insights into their joint role in MDD and BD.
Objectives
The objective of this study was to examine the correlation between serum BDNF and plasma serotonin levels and to assess how these correlations relate to the severity of symptoms and overall disease severity in MDD and BD.
Methodology
This cross-sectional study, conducted at the Khyber Medical University, Peshawar, from January to September 2023, examined the correlation between BDNF and serotonin in individuals with MDD and BD. Participants (n = 63) aged 18-65 were recruited based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, excluding those with neurological disorders, substance abuse, or severe medical illness. A control group of 21 healthy individuals was matched by age and gender. Data collection involved demographic details, clinical history, and comorbid diagnoses assessed using the Mini International Neuropsychiatric Interview (MINI). Mood disorder severity was measured using the Hamilton Depression Rating Scale (HAM-D) for MDD and the Young Mania Rating Scale (YMRS) for BD, along with additional assessments (Beck Depression Inventory, Global Assessment of Functioning). Serum BDNF and serotonin levels were analyzed using enzyme-linked immunosorbent assay (ELISA) kits. Statistical analyses included t-tests, Mann-Whitney U tests, Pearson correlations, and subgroup analyses to assess relationships between biomarkers, mood disorder severity, and influencing factors.
Results
BDNF levels were found to be 20.1 ± 5.3 ng/mL in MDD, 18.5 ± 4.7 ng/mL in BD, and 25.9 ± 6.2 ng/mL in controls. Serotonin levels were 45.8 ± 12.6 ng/mL in MDD, 43.2 ± 11.4 ng/mL in BD, and 52.1 ± 14.3 ng/mL in controls. In the MDD group, significant negative correlations were observed between BDNF levels and mood disorder severity (r = -0.32, p = 0.045), whereas serotonin levels did not show significant correlations (r = -0.21, p = 0.23). In the BD group, BDNF levels also showed a significant negative correlation with manic symptoms (r = -0.28, p = 0.048), but serotonin levels showed no significant correlation. Subgroup analyses revealed that participants under 40 years had higher BDNF levels (22.8 ± 5.6 ng/mL) compared to those aged 40 and above (19.7 ± 4.3 ng/mL). Females showed higher BDNF levels (24.5 ± 6.3 ng/mL) than males (19.3 ± 3.8 ng/mL). Participants not on medication had higher BDNF levels (23.6 ± 5.1 ng/mL) compared to those on medication (17.9 ± 4.2 ng/mL). Those without comorbidities also had higher BDNF levels (23.8 ± 5.9 ng/mL) than those with comorbidities (18.2 ± 4.5 ng/mL), while serotonin levels varied similarly across these subgroups.
Conclusion
Lower BDNF levels are associated with mood disorders and symptom severity, indicating their potential as a biomarker.
... The rs6265 polymorphism is a common functional nonsynonymous SNP, a coding mutation that changes the protein sequence, in which the amino acid valine (Val) is replaced with methionine (Met) in the BDNF protein, resulting in a less efficient BDNF secretion. Due to the important role played by BDNF in the nervous system, this SNP has been extensively studied in the pathogenesis of several psychiatric disorders, including mood disorders [33,34]. ...
Brain-derived neurotrophic factor (BDNF) plays a key role in brain development, contributing to neuronal survival and neuroplasticity. Previous works have found that BDNF is involved in several neurological or psychiatric diseases. In this review, we aimed to collect all available data on BDNF and bipolar disorder (BD) and assess if BDNF could be considered a biomarker for BD. We searched the most relevant medical databases and included studies reporting original data on BDNF circulating levels or Val66Met polymorphism. Only articles including a direct comparison with healthy controls (HC) and patients diagnosed with BD according to international classification systems were included. Of the 2430 identified articles, 29 were included in the present review. Results of the present review show a reduction in BDNF circulating levels during acute phases of BD compared to HC, which increase after effective therapy of the disorders. The Val66Met polymorphism was related to features usually associated with worse outcomes. High heterogeneity has been observed regarding sample size, clinical differences of included patients, and data analysis approaches, reducing comparisons among studies. Although more studies are needed, BDNF seems to be a promising biomarker for BD.
... The molecular and cellular mechanisms involved in these reorganizations include the synthesis of neurotrophins such as the brain-derived F o r P e e r R e v i e w O n l y neurotrophic factor (BDNF). BDNF plays an essential role in synaptic plasticity and is reportedly involved in mechanisms of drug addiction (Hong et al. 2011). Serum BDNF levels are lower in people with AUD than in healthy controls (Joe et al. 2007). ...
Objectives:
Brain-derived neurotrophic factor (BDNF) levels vary in various conditions including alcohol use disorder (AUD). We aimed to identify drivers of these variations.
Methods:
Twelve patients with AUD were assessed at hospitalisation for alcohol withdrawal and four months later. We looked for associations between the change in serum BDNF levels and (1) length of abstinence, (2) anxiety (Hamilton Anxiety Scale) and depression (Beck-Depression Inventory), (3) one functional BDNF genotype (rs6265) and (4) methylation levels of twelve CpG sites within the BDNF gene (located in exons I, IV and IX).
Results:
While abstinence remained, serum BDNF level increased. This increase correlated with the variation of methylation levels of the BDNF gene, and more specifically of exon I. We found no significant effect of length of abstinence, rs6265, depression or anxiety on serum BDNF level.
Conclusions:
Epigenetic regulation of the BDNF gene may be involved in variations of BDNF blood level associated with alcohol abstinence.
... Studies have suggested that longitudinal PA may enhance neural connections [72]. A longer period of PA can produce better cognitive changes [73], raise the levels of brain-derived neurotrophic factor (BDNF) [74], and enhance the release of dopamine [75]. Relevant metaanalysis also suggested that longitudinal sports activities may promote nerve growth and development, and the impact may exist for a long time. ...
This systematic review and meta-analysis aimed to systematically evaluate the effect of physical activity (PA) on inhibitory function in children with ADHD. Experimental studies on the effect of PA on the inhibitory function of children with ADHD were retrieved. The data were obtained from PubMed, The Cochrane Library, Web of Science, EBSCO (MEDLINE, APA Psyclnfo, ERIC), Embase, Scopus, and ProQuest. The search period was from the date of inception of the respective databases to 4 May 2022, and Reviewer Manager software (version 5.3) was used for analysis. Eleven articles and 713 samples were included in the meta-analysis. Results revealed that PA can significantly improve the inhibitory function of children with ADHD (SMD = 0.78, 95% CI: 0.45–1.10, p < 0.001). Subgroup analysis showed that the effectiveness of PA as an intervention in improving the inhibitory function of children with ADHD was moderated by the frequency, intensity, duration, type, and length of intervention. Based on the findings, PA can effectively improve interference suppression inhibitory function in children with ADHD. Longitudinal open-skill exercise for 60 min or more, two times/week has the best effect on improving inhibitory function in children with ADHD.
... One of the most well studied is the Val66Met polymorphism, where valine (Val) is substituted by methionine (Met) at codon 66 resulting in protein misfolding and reduced binding of the protein to its receptor, TrkB (Egan et al., 2003). The BDNF Val66Met polymorphism has a reported association with many psychiatric disorders, such as major depressive disorder, obsessive compulsive disorder, schizophrenia, and anxiety (Hong et al., 2011). In addition, it has been shown to influence hippocampal volume, memory, and PTSD risk (Brooks et al., 2014;Zhang et al., 2006Zhang et al., , 2014. ...
Mild traumatic brain injury (mTBI) increases the risk of posttraumatic stress disorder (PTSD) in military populations. Utilizing translationally relevant animal models is imperative for establishing a platform to delineate neurobehavioral deficits common to clinical PTSD that emerge in the months to years following mTBI. Such platforms are required to facilitate preclinical development of novel therapeutics. First, this mini review provides an overview of the incidence of PTSD following mTBI in military service members. Secondly, the translational relevance of fear conditioning paradigms used in conjunction with mTBI in preclinical studies is evaluated. Next, this review addresses an important gap in the current preclinical literature; while incubation of fear has been studied in other areas of research, there are relatively few studies pertaining to the enhancement of cued and contextual fear memory over time following mTBI. Incubation of fear paradigms in conjunction with mTBI are proposed as a novel behavioral approach to advance this critical area of research. Lastly, this review discusses potential neurobiological substrates implicated in altered fear memory post mTBI.
... Levels of BDNF in brain tissue decrease with increasing age in humans, especially in the hippocampus (Hattiangady, Rao, Shetty, & Shetty, 2005) which could be linked to age-related cognitive impairment (Mattson & Magnus, 2006). These findings have led to the hypothesis that BDNF plays a role in directing growth, differentiation and survival of neurons, especially of peripheral sensory and brain neurons (Hong, Liou, & Tsai, 2011;Jones, Fariñas, Backus, & Reichardt, 1994;Webster et al., 2006). ...
This thesis studied the interaction of neural stimulation and genotype on functional connectivity in 67 healthy subjects. Neural stimulation was performed using repetitive transcranial magnetic stimulation (rTMS) of the right dorsolateral prefrontal cortex (DLPFC). The effect of genotype was studied for a well-known polymorphism in the brain-derived neurotrophic factor (BDNF), which is implicated in neuronal plasticity. Functional connectivity was assessed as the degree of correlation between well-established functional networks during resting-state. In short, this thesis investigated the effect of rTMS and the genotype for a polymorphism in the BDNF on the connectivity between resting-state functional connectivity networks in 67 healthy subjects. Functional connectivity networks represent reproducible patterns of temporally correlated hemodynamic signal fluctuations in the human brain, which are involved in fundamental neurocognitive processes and show alterations in psychiatric disorders such as schizophrenia and depression. rTMS of the right DLPFC has been shown to produce lasting effects on functional connectivity and has emerged as an effective treatment in these disorders. Another mechanism affecting functional connectivity is the valine66methionine (val66met) polymorphism in the gene for the BDNF. Both mechanisms have been linked to neuronal plasticity. However, the combined effect of BDNF genotype and rTMS on functional connectivity is not known. To fill this gap, this thesis studied the interaction of rTMS and genotype on functional connectivity in a sample of 67 healthy subjects. Subjects received 5Hz stimulation of the right DLPFC during one data collection session and sham stimulation of the identical stimulation site during the other session. Following both true and sham stimulation, a resting-state functional magnetic resonance imaging scan was performed. Subjects were genotyped for the val66met single-nucleotide polymorphism (rs6265) in the 5’ proregion of the gene for the BDNF. Met66met homozygotes and val66met heterozygotes were grouped as met66 carriers for further analysis, due to the low number of homozygotes. The sample population consisted of 26 met66 allele carriers and 41 val66 homozygotes. Independent component analysis was used to generate independent components from the resting-state functional magnetic resonance imaging data. These independent components were spatially correlated with canonical samples of resting-state networks to determine best matches for the default-mode network (DMN), executive control network (ECN) and salience network (SLN). The DMN was represented by three independent components, comprising predominantly superior posterior, inferior posterior and anterior nodes respectively. The ECN was split into two components, corresponding to left-hemispheric and right-hemispheric network nodes, respectively. The SLN was covered by a single independent component. Functional connectivity between the networks was measured by the correlation of their voxel time series. Statistical analysis of the networks’ Fisher r-to-z-transformed correlation coefficients was performed using a mixed analysis of variance approach. The results of this study are as follows: rTMS did not result in significant changes in inter-network connectivity compared to sham stimulation. This concurs with published studies, which also reported a lack of effect of repetitive transcranial stimulation of the right DLPFC on inter-network connectivity. There was also no effect of the BDNF polymorphism on connectivity between the networks of interest, which contrasts with a publication, utilizing a different approach to functional connectivity analysis, that reported altered connectivity between nodes of two networks in met66 carriers. However, an interaction effect emerged which suggests that rTMS effects are influenced by the BDNF genotype. Following stimulation, met66 allele carriers showed stronger connectivity between superior posterior parts of the DMN and left-hemispheric parts of the ECN compared to the sham condition. This finding remained significant after correction for multiple comparisons and the effect was not observed in val66 homozygote individuals. This is the first study to demonstrate that the BDNF val66met genotype modulates rTMS effects on inter-network functional connectivity. A tentative interpretation could be that the observed stimulation effect may be implicated in previously observed adverse effects of rTMS in patients with schizophrenia involving increased severity of hallucinations, as it mirrors functional connectivity abnormalities observed in schizophrenic patients that correlate with symptom intensity. Variations in the therapeutic effectiveness of rTMS in major depressive disorder could also conceivably be associated to genotype-associated differences in functional connectivity modulation, although the observed effects did not align with published findings concerning the influence of this genotype on presumed therapeutic mechanisms of action of rTMS involving functional connectivity. The results from this investigation should be used to guide further research into the mechanisms of action underlying the therapeutic, and adverse, effects of rTMS and into the genotype for BDNF as a potential cause for interindividual differences in therapeutic response. These results also suggest that the BDNF val66met genotype of subjects should be routinely determined in rTMS studies, especially in those observing therapeutic effects of rTMS in patients suffering from major depressive disorder and schizophrenia.
... Met (Frustaci et al., 2008). L'allèle Met serait donc lié à une susceptibilité accrue envers certains troubles neuropsychiatriques, mais pas à un diagnostic psychiatrique (Gratacòs et al., 2007;Hong et al., 2011). ...
Le facteur neurotrophique dérivé du cerveau (BDNF, Brain-Derived Neurotrophic Factor) est une protéine qui joue un rôle essentiel dans la survie et la différenciation des neurones, ainsi que dans l'induction et l'expression de la plasticité synaptique (Deinhardt and Chao, 2014; Lu et al., 2005). Le BDNF est très exprimé à l'âge adulte et la réduction de son expression est impliquée dans de nombreuses maladies neurodégénératives et troubles psychologiques (Anastasia and Hempstead, 2014). Son action sur la plasticité synaptique est majeure pour la mise en place de fonctions cognitives et pour la mise en place de la mémoire (Bekinschtein et al., 2008; Egan et al., 2003).Le BDNF existant sous deux formes ayant des fonctions opposées, on peut parler d'effet Yin et Yang du BDNF (Lu et al., 2005). En effet, le BDNF est synthétisé en tant que molécule précurseur, le proBDNF, qui a des effets négatifs " Yin ". Par sa liaison au récepteur p75NTR, le proBDNF favorise l'apoptose, la rétraction dendritique et la dépression à long-terme. Au contraire, la forme clivée, le BDNF mature (mBDNF), se lie préférentiellement au récepteur TrkB qui active les voies de signalisation de survie cellulaire, de différentiation et de potentialisation à long terme. On parle alors d'effets positifs ou " Yang ". Le clivage de BDNF joue donc un rôle capital dans la régulation de sa balance fonctionnelle vers l'une ou l'autre voie. Il est généralement admis que le proBDNF est clivé en mBDNF par la furine dans le Golgi ou par la pro-protéine convertase 1/3 dans les vésicules de sécrétion (Mowla et al., 2001; Seidah et al., 1996). Le proBDNF restant n'ayant pas été clivé dans la cellule peut être sécrété et être rapidement clivé par la plasmine ou les métalloprotéases de matrice (MMP7) dans l'espace extracellulaire (Lee et al., 2001). Cependant, si les enzymes de conversion du BDNF sont bien connues, les mécanismes de régulation du clivage ne sont pas encore compris.Nous montrons ici un nouveau mécanisme de régulation de la maturation de BDNF via une phosphorylation qui impacte directement la balance fonctionnelle. En effet, nous montrons que la phosphorylation du résidu S130, localisé à l'interface entre le pro-domaine et le domaine mature, diminue l'efficacité du clivage du BDNF par la furine, régulant ainsi l'équilibre entre les formes immature et mature. Cette phosphorylation au site S130 est catalysée par les ectokinases FJX1 et FAM69B qui sont localisées dans l'appareil de Golgi avec BDNF. De plus, grâce à l'utilisation de souris transgéniques knock-in phospho-mutantes, nous montrons que la phosphorylation de BDNF, en favorisant la forme proBDNF, inhibe la potentialisation à long-terme et diminue la dynamique de plasticité des épines dendritiques après stimulation neuronale. Ces résultats suggèrent ainsi une nouvelle voie de régulation de la balance fonctionnelle de BDNF et suggèrent un rôle critique de la phosphorylation S130 dans les processus d'apprentissage et de la mémoire.En parallèle, la recherche de kinases potentielles de BDNF nous a amenés à identifier une exoPKA, localisée dans le Golgi et qui interagit directement avec BDNF. Cette exoPKA atypique phosphoryle BDNF au niveau de la sérine S130 et régule sa maturation et donc l'équilibre entre les formes pro et matures de BDNF. Cette exoPKA est différente de la PKA cytosolique ce qui suggère l'existence d'un nouveau mécanisme de régulation de la plasticité par PKA via BDNF. Enfin, nous sommes en train de tester le rôle de l'exoPKA sur la régulation négative de la plasticité synaptique via la régulation du clivage de BDNF. Ces résultats permettront de déterminer l'existence d'une dichotomie d'action de PKA sur la plasticité en fonction de la forme activée, cytosolique ou golgienne/sécrétée.
... Brain-derived neurotrophic factor (BDNF), the most abundant neurotrophic factor in the brain, serves as an important role in neurogenesis, neuronal survival and synaptic plasticity. Decreased BDNF has been implicated in many neuropsychiatric diseases such as major depression and dementia [1,2]. Therefore, up-regulation of BDNF signaling represents an intriguing opportunity to treat BDNF-implicated neuropsychiatric disorders. ...
... Brain-derived neurotrophic factor (BDNF) is a member of a family of neurotrophic factors that includes nerve growth factor, neurotrophin-3, and neurotrophin-4/5, which activate various isoforms of tropomyosin kinase (Trk) receptors. BDNF supports neuronal growth, synaptic transmission and plasticity as well as pathogenesis of psychiatric disorders [96]. It exists at high levels in hippocampal neurons, and its expression is controlled by neural activity. ...
We have developed a novel rat model that correlates with seemingly normal individuals who are predisposed (at-risk) to developing Alzheimer’s disease (AD). This work summarizes the findings we have reported on the effect of chronic psychosocial stress in this at-risk rat model of AD. Behavioral (learning and memory tests), electrophysiological (evoked LTP) and molecular (determining protein levels of signaling molecules) studies suggest that even mild chronic psychosocial stress can converts this seemingly normal rat into one showing clear AD phenotype. It is well known that vast individual variations exist in the time of onset and severity of the sporadic type of AD. Therefore, a patient-related external factor must be assumed to play a significant role in the development of the sporadic type of the disease. Since stress is increasingly recognized as an external factor in the development of AD, we tested the effect of mild psychosocial stress on our at-risk model.
... Brain-derived neurotropic factor (BDNF) is a neurotrophic polypeptide expressed heavily in the hippocampus and cerebral cortex. 66 BDNF is involved in synapse development, synaptic plasticity, neuronal connectivity, and enhanced survival of adult neurons. 67 A common, single-nucleotide polymorphism of BDNF, Val66Met, has been associated with lower hippocampal volumes and various neuropsychiatric disorders. ...
Context:
Multiple forms of behavioral therapies have been developed to treat alcohol abuse disorders (AUDs). Despite positive outcomes during and immediately after behavioral treatment, 60% to 90% of patients relapse in the year after treatment. Combined approaches have also been developed, but similar high relapse rates have occurred. Aerobic exercise may be an appropriate complimentary treatment for behavioral therapy in AUDs. However, it is critical to identify the appropriate dose of exercise to gain maximal benefit.
Objective:
This literature review intended to explore the neural components of alcohol addiction, identify the mechanisms by which exercise might influence brain function, characterize the appropriate exercise intervention for AUDs, and ascertain strategies for implementing exercise into behavioral therapy treatment.
Design:
The research team searched the literature for systematic reviews, descriptive studies, case reports, cross-sectional, along with experimental design studies (both randomized controlled trials and nonrandomized single group). Mechanisms of AUD, neurophysiological adaptations to physical exercise, and exercise interventions in AUD treatment were the primary areas of interest. PubMed, ScienceDirect, Cochrane Library, and Google Scholar databases were searched between 1970 and 2019.
Results:
Neural mechanisms of AUD identified included abnormal neurotransmission, prefrontal cortex function, and neurogenic processes. Exercise may serve the underlying neurophysiological mechanisms of AUD, and this has been demonstrated in a handful of exercise therapies studied among alcohol abusers.
Conclusions:
Given the current reviews findings on the neural mechanisms of alcohol addiction, the neurophysiological basis of exercise treatment, and the results of exercise interventions during alcohol treatment the current research team has developed a novel approach to treatment of alcohol addiction by incorporating aerobic interval exercise into traditional, evidence-based, cognitive behavioral therapy. The benefits of exercise may promote and compliment CBT treatment and lead to reduced drinking outcomes.
... Progressive debilitating neurodegeneration follows these pathological changes. Brain-derived neurotrophic factor (BDNF), a chief member of the neurotrophin family, is important for neuronal growth, development, differentiation and survival, and has been implicated in many neuropsychiatric diseases [23,24]. Gradual dysregulation of neurotrophic factors like BDNF play an important role in the neurodegenerative process thus intensifying further research in targeting these factors as neurodegenerative disease modifying therapies [25]. ...
Chronic traumatic encephalopathy (CTE), a disease process well-recognized in boxers, American football players and military personnel, is a progressive neurodegenerative disease caused by repetitive blows to the head. Subjects with CTE can have a wide range of emotional, cognitive and physical symptoms. The cognitive group patients had a significantly higher probability of developing dementia in later years. Currently, there are no disease modifying regimen for CTE. Timely intervention of head blow could diminish the development of CTE. Low-intensity pulsed ultrasound (LIPUS) is a common adjunct used to promote bone healing for fresh fracture. Recent reports suggest that LIPUS can noninvasively modulate the cortical function and have neuroprotective effect in various animal models of traumatic brain injury, stroke, Alzheimer's disease and major depressive disorder. The multifunctional mechanisms of LIPUS neuroprotective effect include several trophic factor stimulations, anti-inflammatory properties and reduction of brain edema. From the above evidence, LIPUS intervention could be a strategy for the prevention of the clinical CTE sequelae of repetitive head blows. We hypothesized that due to its neuroprotective effects, the non-invasive and easy-to-use method of LIPUS brain stimulation could have a preventive effect on players who have head blows during the match. The development of a time sensitive protocol, resembling the therapeutic algorithm for traumatic brain injury, would potentially prevent the development of subsequent CTE adverse outcome. Further long-term longitudinal studies of LIPUS stimulation are warranted to verify the prevention efficacy of this intervention for CTE.
... Genetic association studies have shown that the Val66Met polymorphism may be a risk factor for the development of neuropsychiatric disorders (Hong et al., 2011), and that there is evidence that the polymorphism modulates aspects of neurocognitive function in otherwise healthy adults (Dincheva et al. 2012). Since 2003, the year in which the Val66Met polymorphism was first described as a functional variant (Egan et al. 2003), the number of studies evaluating the effects of this evolutionarily recent genetic aberration has progressively increased, especially in psychiatric disorders. ...
Background:
Brain-derived neurotrophic factor (BDNF) polymorphism plays an important role in neural survival and was proposed to be related to obsessive-compulsive disorder (OCD). Genetic association studies of the BDNF Val66Met polymorphism (rs6265) in OCD have produced inconsistent results. A meta-analysis of studies was conducted to compare the frequency of the BDNF Val66Met variant between cases with OCD and age-matched controls.
Subjects and methods:
Electronic databases were searched for eligible articles in English and ten studies on the association of the BDNF Val66Met polymorphism with OCD were analysed.
Results:
A total of ten studies involving 2306 cases with OCD and 4968 healthy controls were included. Findings indicated that the BDNF Val66Met polymorphism was not associated with OCD. But there was a marginally significant effect of the BDNF Val66Met variant on OCD in different ethnicity.
Conclusion:
Findings from this meta-analytic investigation of published literature provide little support for the Val66Met variant of BDNF as a predictor of OCD. Future well-powered agnostic genome-wide association studies with more refined phenotype are needed to clarify genetic influences on OCD.
... On the other hand, it was not possible to find that association of the Val66Met polymorphism and the risk of schizophrenia on other meta-analytic study (Kawashima et al., 2009). Furthermore, recent studies are providing growing evidence about positive associations between the BDNF Val66Met polymorphism and some crucial aspects of schizophrenia condition ranging from clinical symptoms and brain morphology to cognitive function (Hong et al., 2011). Not only the BDNF gene but also the BDNF protein itself, as determined in plasma or serum, has been proposed as a marker of cognitive recovery (Penadés et al., 2013). ...
The role of genetics in cognitive remediation therapies in schizophrenia has not been completely understood yet. Different genes involved in neurotrophic, dopaminergic and serotonin systems have reported to influence cognitive functioning in schizophrenia. These genetic factors could also be contributing to the variability in responsiveness to cognitive treatments. No comprehensive synthesis of the literature of the role of genetics in the context of cognitive remediation has been conducted until now. We aimed to systematically review the published works through three electronic database searches: PubMed, Scopus, and the Cochrane Library. Eligible studies revealed a rising interest in the field although the number of published studies was rather small (n = 10). Eventually, promising results showing a relationship between some phenotypic variations based on different polymorphisms and different levels of responsivity to cognitive remediation therapies have been described although results are still inconclusive. In case those findings will be replicated, they could be guiding future research and informing clinical decision-making in the next future.
... Niciu et al. further revealed that the combination of thalamic volume and BDNF polymorphism may predict the treatment response of ketamine infusion (Niciu et al., 2017). The replacement of Val by Met in the coding exon of the BDNF gene at position 66 (Val66Met) disrupts neuronal processing, trafficking, and activity-dependent secretion of BDNF, which plays a crucial role in neuronal growth, neuronal survival, synaptogenesis, and synaptic plasticity (Hong et al., 2011). BDNF-related synaptogenesis is responsible for the rapid antidepressant effect of low-dose ketamine infusion (Kavalali and Monteggia, 2012;Zanos and Gould, 2018). ...
Background:
Growing evidence suggests a rapid antisuicidal effect of low-dose ketamine infusion in Caucasian patients with treatment-resistant depression (TRD). However, the antisuicidal effects of ketamine on Taiwanese patients with TRD remains unknown.
Methods:
Seventy-one patients with TRD were randomly classified into three treatment groups: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, or normal saline (placebo) infusion. The Hamilton Depression Rating Scale (HAMD) and Montgomery-Åsberg Depression Rating Scale (MADRS) were applied prior to initiation of test infusions, at 40, 80, 120, and 240 min postinfusion, and sequentially on Days 2, 3, 4, 5, 6, 7, and 14 after ketamine or placebo infusion. Item 3 (suicide) of the HAMD and item 10 (suicidal thoughts) of the MADRS were extracted for generalized estimating equation (GEE) model analyses to investigate the antisuicidal effects of ketamine infusion. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism was genotyped.
Results:
The GEE model revealed significant group (p = 0.007) and time (p = 0.004) effects on suicidal symptoms over times (prior to infusion to day 14 postinfusion). The group that received 0.5 mg/kg ketamine infusion exhibited a significantly lower score in item 3 of the HAMD and item 10 of the MADRS compared with the groups that received 0.2 mg/kg ketamine or placebo infusion. Among those carrying any Val allele of BDNF, both 0.5 and 0.2 mg/kg ketamine infusions were effective in reducing suicidal thoughts; however, among those with Met/Met of BDNF, only 0.5 mg/kg ketamine infusion was effective in reducing suicidal thoughts.
Discussion:
A single low-dose ketamine infusion was effective in reducing suicidal ideation among Taiwanese patients with TRD. BDNF Val66Met polymorphism may play a crucial role in the antisuicidal effects of ketamine infusion.
... The most abundant neurotrophin in the central nervous system is brain-derived neurotrophic factor (BDNF) and it modulates neuronal differentiation, synapse formation, survival, support and function of neurons, brain neurotransmission, proliferation, long-term potentiation, and synaptic growth in the central nervous system (18). Due to its localization and expression in the limbic system, brain regions that are involved in the regulation of fear and stress responses, and its modulatory role in dopaminergic, serotonergic and glutamatergic synthesis, metabolism, neuronal activity and release (18,19), it is not surprising that BDNF is involved in the development of different neuropsychiatric disorders, including PTSD (19)(20)(21). ...
Posttraumatic stress disorder (PTSD) is a trauma and stressor related disorder that may develop after exposure to an event that involved the actual or possible threat of death, violence or serious injury. Its molecular underpinning is still not clear. Brain-derived neurotrophic factor (BDNF) modulates neuronal processes such as the response to stress, but also weight control, energy and glucose homeostasis. Plasma BDNF levels and a functional BDNF Val66Met (rs6265) polymorphism were reported to be associated with PTSD, as well as with increased body mass index (BMI) and dyslipidaemia in healthy subjects and patients with cardio-metabolic diseases, but these results are controversial. The other frequently studied BDNF polymorphism, C270T (rs56164415), has been associated with the development of different neuropsychiatric symptoms/disorders. As far as we are aware, there are no data on the association of BDNF Val66Met and C270T polymorphisms with metabolic indices in PTSD. Due to high rates of obesity and dyslipidaemia in PTSD, the aim of this study was to elucidate the association of BDNF Val66Met and C270T polymorphisms with BMI and lipid levels in veterans with PTSD. We hypothesized that BDNF variants contribute to susceptibility to metabolic disturbances in PTSD. The study included 333 Caucasian males with combat related PTSD, diagnosed according to DSM-5 criteria. Genotyping of the BDNF Val66Met and C270T polymorphisms was performed using the real-time PCR method. Results were analyzed using hierarchical multiple linear regression and the Mann–Whitney test, with p-value corrected to 0.005. The results showed that BDNF Val66Met and BDNF C270T polymorphisms were not significantly associated with BMI, total cholesterol, LDL-cholesterol, HDL-cholesterol or triglycerides. Although the BDNF C270T polymorphism was nominally associated only with HDL-cholesterol in veterans with PTSD, this significance disappeared after controlling for the effect of age. Namely, slightly higher plasma HDL values in T allele carriers, compared to CC homozygotes, were associated with differences in age. Our results, controlled for the critical covariates, revealed that BDNF Val66Met and C270T were not significantly associated with metabolic indices in veterans with PTSD and that these genetic variants do not contribute to susceptibility to metabolic disturbances in PTSD.
... We recognized that BDNF genetic polymorphism and BDNF protein have complex actions/regulations in the brain that could not be simplified to a single or unifying explanation based on our resting-state brain complexity study at this stage. Other confounding factors, such as age, gender (Stefani et al., 2012), environmental factors, sample size, ethnicity, and phenotype assessment, might also result in controversial findings in BDNF genetic studies (Hong et al., 2011;Notaras et al., 2015;Tsai, 2018). Moreover, it is still an ongoing debate whether the Met allele of BDNF Val66Met might serve as a deleterious role on brain structures, performances, or health (Autry and Monteggia, 2012;Tingting et al., 2014;Benarroch, 2015;Notaras et al., 2015). ...
The irregularity and uncertainty of neurophysiologic signals across different time scales can be regarded as neural complexity, which is related to the adaptability of the nervous system and the information processing between neurons. We recently reported general loss of brain complexity, as measured by multiscale sample entropy (MSE), at pain-related regions in females with primary dysmenorrhea (PDM). However, it is unclear whether this loss of brain complexity is associated with inter-subject genetic variations. Brain-derived neurotrophic factor (BDNF) is a widely expressed neurotrophin in the brain and is crucial to neural plasticity. The BDNF Val66Met single-nucleotide polymorphism (SNP) is associated with mood, stress, and pain conditions. Therefore, we aimed to examine the interactions of BDNF Val66Met polymorphism and long-term menstrual pain experience on brain complexity. We genotyped BDNF Val66Met SNP in 80 PDM females (20 Val/Val, 31 Val/Met, 29 Met/Met) and 76 healthy female controls (25 Val/Val, 36 Val/Met, 15 Met/Met). MSE analysis was applied to neural source activity estimated from resting-state magnetoencephalography (MEG) signals during pain-free state. We found that brain complexity alterations were associated with the interactions of BDNF Val66Met polymorphism and menstrual pain experience. In healthy female controls, Met carriers (Val/Met and Met/Met) demonstrated lower brain complexity than Val/Val homozygotes in extensive brain regions, suggesting a possible protective role of Val/Val homozygosity in brain complexity. However, after experiencing long-term menstrual pain, the complexity differences between different genotypes in healthy controls were greatly diminished in PDM females, especially in the limbic system, including the hippocampus and amygdala. Our results suggest that pain experience preponderantly affects the effect of BDNF Val66Met polymorphism on brain complexity. The results of the present study also highlight the potential utilization of resting-state brain complexity for the development of new therapeutic strategies in patients with chronic pain.
... Both receptors elicit contradictory biological function in the brain [12]. With its pleiotropic effects in the brain, BDNF has been implicated in causing various neuropsychiatric disorders [13][14][15][16]. ...
Overview Major depressive disorder (MDD) is a common mental disorder accounting for signifi cant morbidity and an increase in mortality worldwide. Antidepressants are often recommended as fi rst-line treatment options in MDD patients. But the clinical management of depression with antidepressants remains a major concern for psychiatrists, and there is a need for more effective and quick onset antidepres-sants beyond the monoaminergic modulation. Studies in recent two decades have provided strong evidence for the neurotrophic hypothesis of MDD, suggesting that stress and antidepressant treatments exert opposing infl uences on the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. BDNF-mediated changes in adult hippocampal neurogenesis is critical for the therapeutic actions of antidepressant treatments. Therefore, up-regulation of BDNF signaling represents an intriguing opportunity to enhance response rates, and to have faster therapeutic onset in MDD. Those drugs that have received preclinical testing include agents that increase BDNF levels (cysteamine, deltamethrin, zinc, hydrogen sulfi de, magnesium , S 47445, TC G-1008, sodium butyrate, inosine, curcumin, riluzole, and harmine), agents that activate BDNF receptors (7,8-dihydroxyfl avone, and isofl u-rane), and agents that increase BDNF/proBDNF ratio (atorvastatin, and zileuton). The neurotrophic hypothesis of MDD may provide opportunity to develop faster and more effi cient antidepressant drugs with higher response rates.
... It is an evolutionarily recent variation observed only in humans (Anastasia et al., 2013) with a frequency reaching up to 40-50 % in Asian and 25-32% in Caucasian populations (Verhagen et al., 2010). Val66met SNP appears to be implicated in a number of psychiatric conditions including anxiety, major depression, bipolar disorder, schizophrenia and eating disorders (Hong et al., 2011;Verhagen et al., 2010) and confers risk of sporadic Alzheimer's disease (Ventriglia et al., 2002). ...
Stroke leads to long term sensory, motor and cognitive impairments. Most patients experience some degree of spontaneous recovery which is mostly incomplete and varying greatly among individuals. The variation in recovery outcomes has been attributed to numerous factors including lesion size, corticospinal tract integrity, age, gender and race. It is well accepted that genetics play a crucial role in stroke incidence and accumulating evidence suggests that it is also a significant determinant in recovery. Among the number of genes and variations implicated in stroke recovery the val66met single nucleotide polymorphism (SNP) in the BDNF gene influences post-stroke plasticity in the most significant ways. Val66met is the most well characterized BDNF SNP and is common (40-50 % in Asian and 25-32% in Caucasian populations) in humans. It reduces activity-dependent BDNF release, dampens cortical plasticity and is implicated in numerous diseases. Earlier studies on the effects of val66met on stroke outcome and recovery presented primarily a maladaptive role. Novel findings however indicate a much more intricate interaction between val66met and stroke recovery which appears to be influenced by lesion location, post-stroke stage and age. This review will focus on the role of BDNF and val66met SNP in relation to stroke recovery and try to identify potential pathophysiologic mechanisms involved. The effects of age on val66met associated alterations in plasticity and potential consequences in terms of stroke are also discussed.
... Furthermore, a growing number of studies have demonstrated the modulating role of the polymorphism on the association between social environmental stress and PE (Alemany et al., 2011;de Castro-Catala et al., 2016;Simons et al., 2009). In addition, BDNF-Val66Met polymorphism has also been associated with a range of common mental disorders including mood, eating, and some anxiety disorders (Gratacos et al., 2007;Hong, Liou, & Tsai, 2011;Notaras, Hill, & van den Buuse, 2015a). There is robust evidence that the risk of PE is significantly higher in individuals who have common mental disorders in comparison with individuals who do not (Kaymaz et al., 2012;McGrath et al., 2016;van Os & Reininghaus, 2016 ...
There is little research on genetic risk for the extended psychosis phenotype ranging from psychotic experiences (PEs) to psychotic disorders (PDs). In this general population‐based prospective cohort study, the longitudinal associations between BDNF‐Val66Met polymorphism and the different levels of the extended psychosis phenotype were investigated. Addresses were contacted in a multistage clustered probability sampling frame covering 11 districts and 302 neighborhoods at baseline (n = 4011). A nested case‐control study (n = 366) recruited individuals with PEs and PDs as well as individuals with no psychotic symptoms. In this subgroup, blood sampling for genetic analysis and assessment of environmental exposures were carried out, followed by clinical re‐appraisal at follow‐up 6 years later (n = 254). The BDNF‐Val66Met polymorphism was significantly associated with the extended psychosis phenotype. The pattern of the association was that the BDNF‐Val66Met polymorphism impacted in a dose‐response but extra‐linear fashion, with stronger impact at the PD end of the extended psychosis phenotype. Associations were still significant after adjusting for sociodemographic factors and environmental exposures including life events, childhood adversity, socioeconomic status, urbanicity, and cannabis use. The BDNF‐Val66Met polymorphism may index susceptibility to expression of psychosis along a spectrum.
... Taken together, our data corroborate these findings in alcohol dependence in the sense that an increase in BDNF levels appears to modulate the memory acquisition for drug cues (Shen et al., 2006). Thus, we can hypothesize that increased BDNF levels in healthy individuals, which is advantageous for learning and memory (Hong et al., 2011), could be a vulnerability factor for drug dependence. Additionally, elevated BDNF plays an important role in the enhancement of mesolimbic dopaminergic neuronal function, which is related to increased drug seeking behavior, drug memories related to craving, and reward drug effects (McGinty et al., 2010). ...
BACKGROUND
Genetic association studies can reveal biology and treatment targets but have received limited attention for stroke recovery. STRONG (Stroke, Stress, Rehabilitation, and Genetics) was a prospective, longitudinal (1-year), genetic study in adults with stroke at 28 US stroke centers. The primary aim was to examine the association that candidate genetic variants have with (1) motor/functional outcomes and (2) stress-related outcomes.
METHODS
For motor/functional end points, 3 candidate gene variants (ApoE ε4, BDNF [brain-derived neurotrophic factor], and a dopamine polygenic score) were analyzed for associations with change in grip strength (3 months-baseline), function (3-month Stroke Impact Scale-Activities of Daily Living), mood (3-month Patient Health Questionnaire-8), and cognition (12-month telephone-Montreal Cognitive Assessment). For stress-related outcomes, 7 variants (serotonin transporter gene–linked promoter region, ACE [angiotensin-converting enzyme], oxytocin receptor, FKBP5 [FKBP prolyl isomerase 5], FAAH [fatty acid amide hydrolase], BDNF, and COMT [catechol-O-methyltransferase]) were assessed for associations with posttraumatic stress disorder ([PTSD]; PTSD Primary Care Scale) and depression (Patient Health Questionnaire-8) at 6 and 12 months; stress-related genes were examined as a function of poststroke stress level. Statistical models (linear, negative binomial, or Poisson regression) were based on response variable distribution; all included stroke severity, age, sex, and ancestry as covariates. Stroke subtype was explored secondarily. Data were Holm-Bonferroni corrected. A secondary replication analysis tested whether the rs1842681 polymorphism (identified in the GISCOME study [Genetics of Ischaemic Stroke Functional Outcome]) was related to 3-month modified Rankin Scale score in STRONG.
RESULTS
The 763 enrollees were 63.1±14.9 (mean±SD) years of age, with a median initial National Institutes of Health Stroke Scale score of 4 (interquartile range, 2–9); outcome data were available in n=515 at 3 months, n=500 at 6 months, and n=489 at 12 months. At 1 year poststroke, the rs6265 (BDNF) variant was associated with poorer cognition (0.9-point lower telephone-Montreal Cognitive Assessment score, P =1×10 ⁻⁵ ). For stress-related outcomes, rs4291 (ACE) and rs324420 (FAAH) were risk factors linking increased poststroke stress with higher 1-year depression and PTSD symptoms ( P <0.05), while rs4680 (COMT) linked poststroke stress with lower 1-year depression and PTSD. Findings were unchanged when considering stroke subtype. STRONG replicated GISCOME: rs1842681 was associated with lower 3-month modified Rankin Scale score ( P =3.2×10 ⁻⁵ ).
CONCLUSIONS
This study identified genetic associations with cognitive function, depression, and PTSD 1 year poststroke. Genetic susceptibility to PTSD and depressive symptoms varied according to the amount of poststroke stress, underscoring the critical role of lived experiences in recovery. Together, the results suggest that genetic association studies provide insights into the biology of stroke recovery in humans.
Ischemic stroke, which accounts for 87% of cerebrovascular accidents, is responsible for massive global burden both in terms of economic cost and personal hardship. Many stroke survivors face long-term disability—a phenotype associated with an increasing number of genetic variants. While clinical variables such as stroke severity greatly impact recovery, genetic polymorphisms linked to functional outcome may offer physicians a unique opportunity to deliver personalized care based on their patient’s genetic makeup, leading to improved outcomes. A comprehensive catalogue of the variants at play is required for such an approach. In this review, we compile and describe the polymorphisms associated with outcome scores such as modified Rankin Scale and Barthel Index. Our search identified 74 known genetic polymorphisms spread across 48 features associated with various poststroke disability metrics. The known variants span diverse biological systems and are related to inflammation, vascular homeostasis, growth factors, metabolism, the p53 regulatory pathway, and mitochondrial variation. Understanding how these variants influence functional outcome may be helpful in maximizing poststroke recovery.
Cognitive abilities tend to decline with aging, with variation between individuals, and many studies seek to identify genetic biomarkers that more accurately anticipate risks related to pathological aging. We investigated the influence of BDNF, NTRK2, and FNDC5 single nucleotide polymorphisms (SNPs) on the cognitive performance of young and older adults with contrasting educational backgrounds. We addressed three questions: (1) Is education associated with reduced age-related cognitive decline? (2) Does the presence of SNPs explain the variation in cognitive performance observed late in life? (3) Is education differentially associated with cognition based on the presence of BDNF, NTRK2, or FNDC5 polymorphisms? We measured the cognitive functions of young and older participants, with lower and higher education, using specific and sensitive tests of the Cambridge Automated Neuropsychological Test Assessment Battery. A three-way ANOVA revealed that SNPs were associated with differential performances in executive functions, episodic memory, sustained attention, mental and motor response speed, and visual recognition memory and that higher educational levels improved the affected cognitive functions. The results revealed that distinct SNPs affect cognition late in life differentially, suggesting their utility as potential biomarkers and emphasizing the importance of cognitive stimulation that advanced education early in life provides.
Les patients souffrant de dépression suicidaire répondent moins bien aux traitements antidépresseurs conventionnels que ceux qui n’ont pas d’idées suicidaires. Une avancée prometteuse dans ce domaine est l’utilisation de la kétamine, qui a montré une efficacité significative et rapide dans la réduction de l’intensité des idées suicidaires chez les patients déprimés. Des études ont montré qu’une seule perfusion intraveineuse de kétamine à faible dose pouva3it réduire de manière significative et durable les idées de suicide. De plus, la kétamine semble également réduire l’anhédonie, un symptôme associé aux idées suicidaires. Les mécanismes d’action de la kétamine sont multiples. Elle stimule la neuroplasticité via l’activation de la voie du BDNF (facteur neurotrophique du cerveau) et réduit l’inflammation. De plus, la kétamine semble agir sur le système opioïdergique, qui est impliqué dans les conduites suicidaires. En conclusion, la kétamine présente un intérêt dans la réduction des idées suicidaires chez les patients déprimés. Cependant, il est nécessaire de déterminer si son administration permet de prévenir les actes suicidaires. De plus amples recherches sont nécessaires pour mieux comprendre les mécanismes d’action de la kétamine et développer des stratégies thérapeutiques ciblées pour prévenir les conduites suicidaires.
The burden of neurological illnesses on global health is significant. Our perception of the molecular and biological mechanisms underlying intellectual processing and behavior has significantly advanced over the last few decades, laying the groundwork for potential therapies for various neurodegenerative diseases. A growing body of literature reveals that most neurodegenerative diseases could be due to the gradual failure of neurons in the brain's neocortex, hippocampus, and various subcortical areas. Research on various experimental models has uncovered several gene components to understand the pathogenesis of neurodegenerative disorders. One among them is the brain-derived neurotrophic factor (BDNF), which performs several vital functions, enhancing synaptic plasticity and assisting in the emergence of long-term thoughts. The pathophysiology of some neurodegenerative diseases, including Alzheimer's, Parkinson's, Schizophrenia, and Huntington's, has been linked to BDNF. According to numerous research, high levels of BDNF are connected to a lower risk of developing a neurodegenerative disease. As a result, we want to concentrate on BDNF in this article and outline its protective role against neurological disorders.
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Epigenomic modifications of the brain-derived neurotrophic factor (BDNF) gene have been postulated to underlie the pathogenesis of neurodevelopmental, psychiatric, and neurological conditions. This systematic review summarizes current evidence investigating the association of BDNF epigenomic modifications (DNA methylation, non-coding RNA, histone modifications) with brain-related phenotypes in humans. A novel contribution is our creation of an open access web-based application, the BDNF DNA Methylation Map, to interactively visualize specific positions of CpG sites investigated across all studies for which relevant data were available. Our literature search of four databases through September 27, 2021 returned 1,701 articles, of which 153 met inclusion criteria. Our review revealed exceptional heterogeneity in methodological approaches, hindering the identification of clear patterns of robust and/or replicated results. We summarize key findings and provide recommendations for future epigenomic research. The existing literature appears to remain in its infancy and requires additional rigorous research to fulfill its potential to explain BDNF-linked risk for brain-related conditions and improve our understanding of the molecular mechanisms underlying their pathogenesis.
Perinatal depression is the most common psychiatric complication of pregnancy, with its detrimental effects on maternal and infant health grossly underrated. There is a pressing need for specific molecular biomarkers, with a pregnancy-related decline in brain-derived neurotrophic factor (BDNF) in the blood and downregulation of TrkB receptor in the brain reported in both clinical and preclinical studies. In this review, we highlight the emerging role of BDNF in reproductive biology and discuss evidence suggesting its deficiency as a risk factor for perinatal depression. With the increasing evidence for the restoration of serum BDNF levels by antidepressant therapy, the growing association of perinatal depression with deficiency of BDNF support its potential as a surrogate endpoint for preclinical and clinical studies.
Brain-derived neurotrophic factor (BDNF) is abundantly expressed in brain regions involved in both homeostatic and hedonic feeding, and it circulates at reduced levels in patients with anorexia nervosa (AN). A single nucleotide polymorphism in the gene encoding for BDNF (Val66Met) has been associated with worse outcomes in patients with AN, and it is shown to promote anorectic behaviour in a mouse model of caloric restriction paired with social isolation stress. Previous animal models of the Val66Met polymorphism have been in mice because of the greater ease in modification of the mouse genome, however, the most widely-accepted animal model of AN, known as activity-based anorexia (ABA), is most commonly conducted in rats. Here, we examine ABA outcomes in a novel rat model of the BDNF Val66Met allelic variation (Val68Met), and we investigate the role of this polymorphism in feeding, food choice and sucrose preference, and energy expenditure. We demonstrate that the BDNF Val68Met polymorphism does not influence susceptibility to ABA or any aspect of feeding behaviour. The discrepancy between these results and previous reports in mice may relate to species–specific differences in stress reactivity.
The Met allele of the Val66Met SNP of the BDNF gene (rs6265) is associated with impaired activity-dependent release of brain-derived neurotrophic factor (BDNF), resulting in reduced synaptic plasticity, impaired glutamatergic neurotransmission, and morphological changes. While previous work has demonstrated Val66Met effects on magnetic resonance spectroscopy (MRS) markers of either glutamatergic metabolism (Glx) or neuronal integrity (NAA), no study has investigated Val66Met effects on these related processes simultaneously. As these metabolites share a metabolic pathway, the Glx/NAA ratio may be a more sensitive marker of changes associated with the Val66Met SNP. This ratio is increased in psychiatric disorders linked to decreased functioning in the anterior cingulate cortex (ACC). In this study, we investigated the correlation of the Val66Met polymorphism of the BDNF gene with Glx/NAA in the pregenual anterior cingulate cortex (pgACC) using MRS at 3 Tesla (T) (n = 30, all males) and 7 T (n = 98, 40 females). In both cohorts, Met carriers had lower Glx/NAA compared to Val homozygotes. Follow-up analyses using absolute quantification revealed that the Met carriers do not show decreased pgACC glutamate or glutamine levels, but instead show increased NAA compared to the Val homozygotes. This finding may in part explain conflicting evidence for Val66Met as a risk factor for developing psychiatric illnesses.
The Val66Met is a polymorphism of the brain-derived neurotrophic factor (BDNF) gene that encodes a substitution of a valine (Val) to methionine (Met) amino acid. Carrying this polymorphism reduces the activity-dependent secretion of the BDNF protein, which can potentially affect brain plasticity and cognition. We reviewed the biology of Val66Met and surveyed 26 studies (11,417 participants) that examined the role of this polymorphism in moderating the cognitive response to physical activity (PA) and exercise. Nine observational studies confirmed a moderating effect of Val66Met on the cognitive response to PA but differences between Val and Met carriers were inconsistent and only significant in some cognitive domains. Only five interventional studies found a moderating effect of Val66Met on the cognitive response to exercise, which was also inconsistent in its direction. Two studies showed a superior cognitive response in Val carriers and three studies showed a better response in Met carriers. These results do not support a general and consistent effect of Val66Met in moderating the cognitive response to PA or exercise. Both Val and Met carriers can improve specific aspects of cognition by increasing PA and engaging in exercise. Causes for discrepancies among studies, effect moderators, and future directions are discussed.
The Val66Met is a polymorphism of the brain-derived neurotrophic factor (BDNF) gene that encodes a substitution of a valine (Val) to methionine (Met) amino acid. Carrying this polymorphism reduces the activity-dependent secretion of the BDNF protein, which can potentially affect brain plasticity and cognition. We reviewed the biology of Val66Met and surveyed 26 studies (11,417 participants) that examined the role of this polymorphism in moderating the cognitive response to physical activity (PA) and exercise. Nine observational studies confirmed a moderating effect of Val66Met on the cognitive response to PA but differences between Val and Met carriers were inconsistent and only significant in some cognitive domains. Only five interventional studies found a moderating effect of Val66Met on the cognitive response to exercise, which was also inconsistent in its direction. Two studies showed a superior cognitive response in Val carriers and three studies showed a better response in Met carriers. These results do not support a general and consistent effect of Val66Met in moderating the cognitive response to PA or exercise. Both Val and Met carriers can improve specific aspects of cognition by increasing PA and engaging in exercise. Causes for discrepancies among studies, effect moderators, and future directions are discussed.
Schizophrenia is a highly heritable disorder characterized by disruptions on the molecular, cellular, and neural circuit level that lead to the behaviors and cognitive impairments associated with the illness. This chapter evaluates how combining neuroimaging methods with genetic approaches such as studying single genes and polygenic risk scores, to genome-wide association study (GWAS) variants and gene expression networks, can provide valuable insight into both biomarkers of schizophrenia and underlying neural mechanisms. Discussions begin with the evolving focus on smaller studies and a few genetic variants to larger scale multi-variant initiatives, and the benefits and challenges of both. The implications of recent findings are explored from bottom-up studies investigating brain abnormalities associated with candidate and GWAS identified variants individually, as well as the utility of examining aggregated risk in the form of polygenic risk scores. Advancements with large collaborative efforts such as ENIGMA hold promise with their top-down work identifying genetic variants underlying variation in brain structure, function, and connectivity. However, further work is needed to clarify how this builds upon our knowledge of intermediate phenotypes and insight into schizophrenia pathology. Moving forward, this chapter highlights emerging work examining relationships between imaging phenotypes and gene expression patterns that take into account spatial variation across the brain. It also evaluates the importance and increasing prevalence of studies investigating schizophrenia from a neurodevelopmental standpoint, and provides a dimensional point of view by examining early and prodromal stages of psychosis. Finally, the overall limitations in imaging genetic research, including challenges, and the progress to overcome them are discussed.
The addition of genetic factors to prognostic models of neurobehavioral recovery following pediatric traumatic brain injury (TBI) may account for unexplained heterogeneity in outcomes. The present study examined the cumulative influence of candidate genes involved in the inflammatory response on long-term neurobehavioral recovery in children with early childhood TBI relative to children with orthopedic injuries (OI). Participants were drawn from a prospective, longitudinal study evaluating outcomes of children who sustained TBI (n = 67) or OI (n = 68) between age 3-7 years. Parents completed ratings of child executive function and behavior at an average of 6.8 years after injury. Exploratory unweighted and weighted polygenic risk scores (PRS) were constructed from single nucleotide polymorphisms (SNPs) across candidate inflammatory response genes (i.e., ACE, BDNF, IL1RN, and NT5E) that showed nominal (p ≤ .20) associations with outcomes in the TBI group. Linear regression models tested the PRS x injury group (TBI vs OI) interaction term and post hoc analyses examined the effect of PRS within each injury group. Higher inflammatory response PRS were associated with more executive dysfunction and behavior problems in children with TBI but not in children with OI. The cumulative influence of inflammatory response genes as measured by PRS explained additional variance in long-term neurobehavioral outcomes, over and above well-established predictors and single candidate SNPs tested individually. The results suggest that some of the unexplained heterogeneity in long-term neurobehavioral outcomes following pediatric TBI may be attributable to a child's genetic predisposition for a greater or lesser inflammatory response to TBI.
Background: Vascular endothelial growth factor A (VEGFA) and brain-derived neurotrophic factor (BDNF), the most abundant and widely expressed neurotrophic factors in the brain, are believed to play an important rôle in depression and anxiety. In this study, we hypothesized that single-nucleotide polymorphisms (SNPs) within the VEGFA and BDNF genes would be linked with psychological distress through complex interactions in the general population. Methods: We analyzed 7,098 Taiwanese subjects from the Taiwan Biobank. Measures of anxiety and depression were evaluated using the Patient Health Questionnaire-4 (PHQ-4). Totally, 15 VEGFA and 43 BDNF polymorphisms were used in the genetic analysis. Results: In our analysis, an interaction was found between the VEGFA rs10434 and BDNF rs12418745 in significantly influencing depression state (p < 0.01). In addition, we found that influence of interaction existed between physical activity and VEGFA genetic variants including rs3025000, rs699947, rs833068, rs833069, rs3024998, and rs3025006 in depression state. But we found no association between 15 VEGFA genetic variants and depression state, after adjusting for age and gender. Furthermore, no VEGFA SNPs showed evidence of association with PHQ-4 scores. Conclusion: These results suggest that the VEGFA and BDNF genetic variants may contribute to psychological distress through gene-gene and gene-physical activity interactions in the general population.
Recent studies demonstrate that brain-derived neurotrophic factor (BDNF) might be associated with nicotine addiction, and circulating BDNF is a biomarker of memory and general cognitive function. Moreover, studies suggest that a functional polymorphism of the BDNF Val66Met may mediate hippocampal-dependent cognitive functions. We aimed to explore the relationships between smoking, cognitive performance and BDNF in a normal Chinese Han population. We recruited 628 male healthy subjects, inducing 322 smokers and 306 nonsmokers, and genotyped them the BDNF Val66Met polymorphism. Of these, we assessed 114 smokers and 98 nonsmokers on the repeatable battery for the assessment of neuropsychological status (RBANS), and 103 smokers and 89 nonsmokers on serum BDNF levels. Smokers scored lower than the nonsmokers on RBANS total score (p = 0.002), immediate memory (p = 0.003) and delayed memory (p = 0.021). BDNF levels among the smokers who were Val allele carriers were correlated with the degree of cognitive impairments, especially attention, as well as with the carbon monoxide concentrations. Our findings suggest that smoking is associated with cognitive impairment in a male Chinese Han population. The association between higher BDNF levels and cognitive impairment, mainly attention in smokers appears to be dependent on the BDNF Val66Met polymorphism.
Objectives:
To test the hypothesis that higher blood levels of neurotrophic proteins (proteins that support neuronal survival and function) in the first 2 weeks of life are associated with a lower risk of cognitive impairment at 10 years.
Study design:
We evaluated 812 10-year-old children with neonatal blood specimens enrolled in the multicenter prospective Extremely Low Gestational Age Newborn Study, assessing 22 blood proteins collected on 3 days over the first 2 weeks of life. Using latent profile analysis, we derived a cognitive function level based on standardized cognitive and executive function tests. We defined high exposure as the top quartile neurotrophic protein blood level on ≥2 days either for ≥4 proteins or for a specific cluster of neurotrophic proteins (defined by latent class analysis). Multinomial logistic regression analyzed associations between high exposures and cognitive impairment.
Results:
Controlling for the effects of inflammatory proteins, persistently elevated blood levels of ≥4 neurotrophic proteins were associated with reduced risk of moderate (OR, 0.35; 95% CI, 0.18-0.67) and severe cognitive impairment (OR, 0.22; 95% CI, 0.09-0.53). Children with a cluster of elevated proteins including angiopoietin 1, brain-derived neurotrophic factor, and regulated upon activation, normal T-cell expressed, and secreted had a reduced risk of adverse cognitive outcomes (OR range, 0.31-0.6). The risk for moderate to severe cognitive impairment was least with 0-1 inflammatory and >4 neurotrophic proteins.
Conclusions:
Persisting elevations of circulating neurotrophic proteins during the first 2 weeks of life are associated with lowered risk of impaired cognition at 10 years of age, controlling for increases in inflammatory proteins.
It is well established that brain-derived neurotrophic factor (BDNF) signaling pathway plays a key role in the pathophysiology of major depressive disorder (MDD) and in therapeutic mechanisms of antidepressants. We aim to identify genetic vairiants related to MDD susceptibility and antidepressant therapeutic response by using gene-based association analysis with genes related to the neurotrophic pathway. The present study investigated the role of genetic variants in the 10 neurotrophic-related genes (BDNF, NGFR, NTRK2, MTOR, VEGFA, S100A10, SERPINE1, ARHGAP33, GSK3B, CREB1) in MDD susceptibility through a case-control (455 MDD patients and 2,998 healthy controls) study and in antidepressant efficacy (n = 455). Measures of antidepressant therapeutic efficacy were evaluated using the 21-item Hamilton Rating Scale for Depression. Our single-marker and gene-based analyses with ten genes related to the neurotrophic pathway identified 6 polymorphisms that reached a significant level (p-value < 5.0 × 10⁻³) in both meta- and mega-analyses in antidepressant therapeutic response. One polymorphism was mapped to BDNF and 5 other polymorphisms were mapped to VEGFA. For case-control association study, we found that all of these reported polymorphisms and genes did not reach a suggestive level. The present study supported a role of BDNF and VEGFA variants in MDD therapeutic response.
Aim:
To identify the antecedents and very early correlates of low concentrations of neurotrophic growth factors in the blood of extremely preterm newborns during the first postnatal month.
Methods:
Using an immunobead assay, we measured the concentrations of neurotrophin 4 (NT4), brain-derived neurotrophic factor (BDNF), and basic fibroblast growth factor (bFGF) in blood spots collected on postnatal days 1 (N=1062), 7 (N=1087), 14 (N=989), 21 (N=940) and 28 (N=880) from infants born before the 28th week of gestation. We then sought the correlates of measurements in the top and bottom quartiles for gestational age and day the specimen was collected.
Results:
The concentrations of 2 neurotrophic proteins, NT4 and BDNF, were low among children delivered for medical (maternal or fetal) indications, and among those who were growth restricted. Children who had top quartile concentrations of NT4, BDNF, and bFGF tended to have elevated concentrations of inflammation-related proteins that day. This pattern persisted for much of the first postnatal month.
Conclusions:
Delivery for medical indications and fetal growth restriction are associated with a relative paucity of NT4 and BDNF concentrations during the first 24 h after very preterm birth. Elevated blood concentrations of NT4, BDNF, and bFGF tended to co-occur with indicators of systemic inflammation on the same day.
A deficit in amygdala habituation to repeated emotional stimuli may be an endophenotype of disorders characterized by emotion dysregulation, such as borderline personality disorder (BPD). Amygdala reactivity to emotional stimuli is genetically modulated by brain-derived neurotrophic factor (BDNF) variants. Whether amygdala habituation itself is also modulated by BDNF genotypes remains unknown. We used imaging-genetics to examine the effect of BDNF Val66Met genotypes on amygdala habituation to repeated emotional stimuli. We used functional magnetic resonance imaging (fMRI) in 57 subjects (19 BPD patients, 18 patients with schizotypal personality disorder [SPD] and 20 healthy controls [HC]) during a task involving viewing of unpleasant, neutral, and pleasant pictures, each presented twice to measure habituation. Amygdala responses across genotypes (Val66Met SNP Met allele-carriers vs. Non-Met carriers) and diagnoses (HC, BPD, SPD) were examined with ANOVA. The BDNF 66Met allele was significantly associated with a deficit in amygdala habituation, particularly for emotional pictures. The association of the 66Met allele with a deficit in habituation to unpleasant emotional pictures remained significant in the subsample of BPD patients. Using imaging-genetics, we found preliminary evidence that deficient amygdala habituation may be modulated by BDNF genotype.
Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the central nervous system.
However, the role of endogenous BDNF in the development and function of these neurons has not been established in vivo because of the early postnatal lethality of BDNF null mice. In the present study, we use heterozygous BDNF+/− mice that have a normal life span and show that these animals develop enhanced intermale aggressiveness and hyperphagia accompanied
by significant weight gain in early adulthood; these behavioral abnormalities are known to correlate with 5-HT dysfunction.
Forebrain 5-HT levels and fiber density in BDNF+/− mice are normal at an early age but undergo premature age-associated decrements. However, young adult BDNF+/− mice show a blunted c-fos induction by the specific serotonin releaser-uptake inhibitor dexfenfluramine and alterations in the expression of several
5-HT receptors in the cortex, hippocampus, and hypothalamus. The heightened aggressiveness can be ameliorated by the selective
serotonin reuptake inhibitor fluoxetine. Our results indicate that endogenous BDNF is critical for the normal development
and function of central 5-HT neurons and for the elaboration of behaviors that depend on these nerve cells. Therefore, BDNF+/− mice may provide a useful model to study human psychiatric disorders attributed to dysfunction of serotonergic neurons.
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin growth factor family, has been implicated in both mood disorders and suicidal behavior. This study has examined the association between the BDNF gene Val66Met polymorphism and mood disorders, age of onset and suicidal behavior in a Chinese sample population. The genotype and allele frequencies for the BDNF gene Val66Met polymorphism did not differ comparing depression groups (total, bipolar disorder or major depression) and control subjects. Furthermore, it was not demonstrated that this BDNF polymorphism was associated with age of onset or suicidal history in our mood disorder patients. Based on these results, it seems reasonable to suggest that this polymorphism is unlikely to play a major role in the genetic susceptibility to mood disorders. Given the fact that the positive association between BDNF gene Val66Met polymorphism and bipolar disorder has only been demonstrated for a Caucasian population but not for a Japanese analog or our Chinese sample, it appears likely that this association is ethnicity dependent.
Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic,
but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway–specific knockdown of brain-derived
neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion.
Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated
aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant.
These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to
aversive social experiences.
Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the central nervous system. However, the role of endogenous BDNF in the development and function of these neurons has not been established in vivo because of the early postnatal lethality of BDNF null mice. In the present study, we use heterozygous BDNF(+/-) mice that have a normal life span and show that these animals develop enhanced intermale aggressiveness and hyperphagia accompanied by significant weight gain in early adulthood; these behavioral abnormalities are known to correlate with 5-HT dysfunction. Forebrain 5-HT levels and fiber density in BDNF(+/-) mice are normal at an early age but undergo premature age-associated decrements. However, young adult BDNF(+/-) mice show a blunted c-fos induction by the specific serotonin releaser-uptake inhibitor dexfenfluramine and alterations in the expression of several 5-HT receptors in the cortex, hippocampus, and hypothalamus. The heightened aggressiveness can be ameliorated by the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that endogenous BDNF is critical for the normal development and function of central 5-HT neurons and for the elaboration of behaviors that depend on these nerve cells. Therefore, BDNF(+/-) mice may provide a useful model to study human psychiatric disorders attributed to dysfunction of serotonergic neurons.
Attention-deficit/hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder with a strong genetic component. Brain-derived neurotrophic factor (BDNF), which participates in the differentiation and survival of dopaminergic and noradrenergic neurons, could play a role in ADHD development. We aimed to explore the relationships between ADHD and BDNF gene polymorphism.
We conducted a case-control analysis of 202 ADHD subjects and 159 controls, performed a transmission disequilibrium test on 151 trios, and compared the results of a continuous performance test (CPT) according to the genotype of the three single nucleotide polymorphisms (rs11030101, rs6265, rs16917204) in the BDNF gene.
In the case-control analysis, the AA genotype of the BDNF rs11030101 polymorphism was significantly associated with ADHD only in girls (p=0.024, odds ratio=3.00). The T-G-G haplotype was significantly less frequent (p=0.005) and A-G-G was more frequent (p=0.048) in girls with ADHD than in control girls (global p=0.027). A multivariate analysis of variance for commission errors on the CPT showed a significant main effect for the rs11030101 genotype (p=0.026) and an interaction effect of the rs11030101 genotype and gender (p=0.032) in ADHD probands.
These results provide preliminary evidence for a gender-specific association between BDNF and ADHD in the Korean population.
Evidence suggests that the down-regulation of the signaling pathway involving brain-derived neurotrophic factor (BDNF), a molecular element known to regulate neuronal plasticity and survival, plays an important role in the pathogenesis of major depression. The restoration of BDNF activity induced by antidepressant treatment has been implicated in the antidepressant therapeutic mechanism. Because there is variability among patients with major depressive disorder in terms of response to antidepressant treatment and since genetic factors may contribute to this inter-individual variability in antidepressant response, pharmacogenetic studies have tested the associations between genetic polymorphisms in candidate genes related to antidepressant therapeutic action. In human BDNF gene, there is a common functional polymorphism (Val66Met) in the pro-region of BDNF, which affects the intracellular trafficking of proBDNF. Because of the potentially important role of BDNF in the antidepressant mechanism, many pharmacogenetic studies have tested the association between this polymorphism and the antidepressant therapeutic response, but they have produced inconsistent results. A recent meta-analysis of eight studies, which included data from 1,115 subjects, suggested that the Val/Met carriers have increased antidepressant response in comparison to Val/Val homozygotes, particularly in the Asian population. The positive molecular heterosis effect (subjects heterozygous for a specific genetic polymorphism show a significantly greater effect) is compatible with animal studies showing that, although BDNF exerts an antidepressant effect, too much BDNF may have a detrimental effect on mood. Several recommendations are proposed for future antidepressant pharmacogenetic studies of BDNF, including the consideration of multiple polymorphisms and a haplotype approach, gene-gene interaction, a single antidepressant regimen, controlling for age and gender interactions, and pharmacogenetic effects on specific depressive symptom-clusters.
Decreased brain-derived neurotrophic factor (BDNF) has been demonstrated in animal models and patients with depression. However, little is known about changes in BDNF in post-stroke depression (PSD). This study investigated the changes in serum BDNF in patients with PSD, and evaluated whether serum concentrations of BDNF were associated with BDNF gene Val66Met polymorphism.
PSD patients were diagnosed in accordance with DSM-IV criteria, and the severity of depression was evaluated with the Hamilton Rating Scale for depression. Serum BDNF was measured twice, first at 7 days after the onset of stroke and then at 3-6 months after stroke. Val66Met polymorphisms of the BDNF gene were determined using the polymerase chain reaction-restriction fragment length polymorphism method. BDNF concentrations and Val66Met polymorphisms were also measured in 30 healthly controls.
A total of 93 patients admitted as a result of first time acute ischemic stroke were included. During the 6-month follow-up, 35 patients (37.6%) were diagnosed with PSD. Serum BDNF concentrations were decreased in PSD patients at 3-6 months after stroke (p < 0.05). The serum BDNF concentrations were not associated with BDNF gene Val66Met polymorphisms in either patients or healthy controls.
Serum concentrations of BDNF decrease in PSD patients and BDNF may play an important role in the pathogenesis of PSD. However, Val66Met polymorphisms are not associated with serum concentrations of BDNF. The mechanism of decreased serum BDNF requires further study.
Brain-derived neurotrophic factor (BDNF) is needed to support neuronal survival and differentiation. It also promotes synaptic remodeling and modulates the function of many other neurotransmitters. BDNF is implicated in major depression (MD), and to a lesser extent, in schizophrenia. In the current study, we examined BDNF polymorphisms (G-712A, C270T and Val66Met) in 202 patients with MD and 323 patients with schizophrenia. Results were compared to 346 healthy individuals. The analysis revealed a strong association between the G-712A genotype distribution and MD (p=0.0005). The frequency of the -712A allele was significantly higher in MD patients than in the healthy controls (p=0.0007). The -712AG heterozygote was associated with higher Hamilton score in MD patients. No association was found between schizophrenia and the three BDNF variants. These findings support an important role of G-712A polymorphism of BDNF in MD, and may guide future studies to identify genetic risk factors for MD.
Brain-derived neurotrophic factor (BDNF) belongs to a family of proteins related to the nerve growth factor family, which are responsible for the proliferation, survival and differentiation of neurons. BDNF is thought to be involved in the pathogenesis of bipolar disorder, schizophrenia, eating disorders and addiction. We hypothesize that a functionally relevant polymorphism of the BDNF gene promoter may be associated with the pathogenesis of alcohol dependence. We performed an association study of 141 families with alcohol dependence. One hundred and thirty-eight healthy control subjects were matched based on ethnicity and gender. An association between the BDNF Val66Met gene polymorphism and alcoholism was not found.
Symptoms of attention-deficit hyperactivity disorder (ADHD) have been found in several studies of children with intellectual disabilities (ID) but the two diseases are not always associated. Several lines of evidence implicate the involvement of brain-derived neurotrophic factor (BDNF) in ADHD, and it may also be relevant in ID due to its known involvement in the development of the central nervous system (CNS) and in learning/memory functions. We genotyped paediatric patients with ADHD and ID for the Val66Met and 270 C/T polymorphisms in BDNF. Diagnosis of ADHD and ID was confirmed by the clinicians in accordance with DSM-IV criteria. The G/A genotype of the Val66Met SNP was associated with both ADHD and ID, and the G allele was significantly associated with ADHD. The C/C genotype of the C270T SNP was significantly overrepresented in both ADHD and ID groups compared with the controls. Data suggest that both BDNF polymorphisms could play a role in the etiology of ADHD. In addition, we present the first results suggesting that these BDNF SNPs are significantly associated with ID.
Although not observed in younger adult cohorts, in older individuals the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with major depressive disorder (MDD) risk. It is further associated with subjective social support and magnetic resonance imaging (MRI) hyperintense lesions, clinical features independently related to MDD. We examined the relationship between this polymorphism and antidepressant remission rates in an elderly sample with MDD, while also testing for mediation effects of social support and hyperintensities. A total of 229 elderly Caucasian subjects with MDD completed baseline assessments, 1.5 T MRI, and BDNF genotyping. They received antidepressant medication under a structured treatment algorithm and were evaluated for remission at 3 and 6 months. At the 3-month evaluation, BDNF Val66Met genotype was not associated with remission (Wald's χ²=2.51, P=0.1131). When not controlling for multiple comparisons, Met66 allele carriers were more likely to be remitted at 6 months (χ²=4.32, P=0.0377) with an odds ratio of 1.82 (95% CI: 1.04, 3.22). This effect persisted after controlling for lesion volume and social support, neither of which mediated this relationship. Thus in this exploratory analysis, the Met66 allele may be associated with increased odds of remission in older subjects, but also with increased time to remission as there was no 3-month effect.
Postpartum depression disorder (PPD) is a severe illness affecting around 15% of deliveries. Several evidences suggest that PPD is, at least, partially genetic determined. The gene encoding BDNF is a strong candidate for pathogenesis of PPD since that it has been observed decrease of serum BDNF in patients suffering from PPD. The gene encoding BDNF has a polymorphism (Val66Met) that alters the regulated protein secretion; the methionine variant being associated with insufficient secretion compared with the Valine variant. We hypothesized that BDNF gene Val66Met polymorphism could be associated with PPD. We assessed 227 subjects randomly selected who had delivery at a maternity hospital using EPDS. Differences in genotype frequency were calculated by χ
2 test. Logistic Regression Analyses was performed to verify the existence of interaction between biological, psychiatric and environmental variables and PPD. Difference between groups was tested with Student’s t test. Tests were two-tailed and results significant when p ≤ 0.05. No difference in BDNF genotype distribution was observed between the depressed and non-depressed women. Educational level, stress during pregnancy, bipolar disorder and anxiety was strongly associated with PPD. We were not able to show an association between BDNF polymorphisms and PPD. Further studies are necessary to both of confirm our results and improve validity of PPD diagnosis.
Risperidone is a widely used atypical antipsychotic agent that produces considerable interindividual differences in patient response. We investigated the pharmacogenetic relationship between the brain-derived neurotrophic factor (BDNF) gene and response to risperidone in 127 Han Chinese schizophrenic patients. Three functional polymorphisms, (GT)(n) dinucleotide repeat polymorphism, C-270T, and the rs6265G/A single-nucleotide polymorphism (SNP), were genotyped and analyzed for association, with reduction of Brief Psychiatric Rating Scale (BPRS) scores following an 8-week period of risperidone monotherapy. For individual polymorphic analysis, we found that the frequency of the 230-bp allele of the (GT)(n) polymorphism was much higher in responders (47.95%) than in nonresponders (32.41%) and the difference was statistically significant even after Bonferroni's adjustment (for the 230-bp allele: adjusted P=0.039). For haplotype-based analyses of the three polymorphisms, no positive finding was observed in the global test, but in specific haplotype tests, two haplotypes were also significantly related to response to risperidone (for haplotype 230-bp/C-270/rs6265G: P=0.0009; for haplotype 234-bp/C-270/rs6265A: P=0.043), indicating that patients with the 230-bp allele of the (GT)(n) polymorphism or the 230-bp/C-270/rs6265G haplotype responded better to risperidone than those with other alleles or haplotypes, and that the positive effect of the individual haplotype 230-bp/C-270/rs6265G was mainly driven by the 230-bp allele. These findings demonstrate that the individual and combinatorial genetic variants in the BDNF gene might have a role in the therapeutic response to risperidone in the Han Chinese population.
Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. In this study, we examine the links between BDNF and personality traits, assessed using the Revised NEO Personality Inventory (NEO-PI-R), in a sample from SardiNIA (n=1560) and the Baltimore Longitudinal Study of Aging (BLSA; n=1131). Consistent with GWA results, we found that BDNF Met carriers were more introverted. By contrast, in both samples and in a meta-analysis inclusive of published data (n=15251), we found no evidence for a main effect of BDNF Val66Met on neuroticism. Finally, on the basis of recent reports of an epistatic effect between BDNF and the serotonin transporter, we explored a Val66Met x 5-HTTLPR interaction in a larger SardiNIA sample (n=2333). We found that 5-HTTLPR LL carriers scored lower on neuroticism in the presence of the BDNF Val variant, but scored higher on neuroticism in the presence of the BDNF Met variant. Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism.
Brain-derived neurotrophic-factor (BDNF) and its receptor neurotrophic tyrosine kinase receptor 2 (NTRK2) have been implicated in both major depression and cognitive function. This study examines the main effects of single loci and multilocus interactions to test the hypothesis that the BDNF and NTRK2 genes may contribute to the etiology of geriatric depression independently and/or through complex interactions. We genotyped the BDNF gene Val66Met (rs6265) polymorphism and four single-nucleotide polymorphisms (SNPs) (including rs1187323, rs1187329, rs1778929, and rs1545285) in the NTRK2 gene in 155 elderly inpatients diagnosed with major depression and 195 age- and sex-similar control subjects. All patients were assessed with the Hamilton Rating Scale for Depression (HAM-D) for depression severity and the Mini-Mental Status Examination (MMSE) for cognitive function after admission. The genotype distributions of all five SNPs tested were significantly different between depressed patients and control subjects. BDNF rs6265, NTRK2 rs1187323, and NTRK2 rs1778929 (p = 0.0031, 0.002, and 0.0014, respectively) also displayed statistically significant differences in the genotypic tests after Bonferroni correction (p < 0.05/5 = 0.01). In addition, the 2-marker haplotype derived from the rs1187323 and rs1187329 polymorphisms demonstrated a significant difference between geriatric depression and control groups according to haplotype distribution (global p = 0.003). Furthermore, BDNF and NTRK2 interactions were found in the significant 2-locus, 3-locus, 4-locus, and 5-locus gene-gene interaction models (p = 0.014, <0.001, 0.007, and 0.032, respectively) using a generalized multifactor dimensionality reduction (GMDR) method. Analyses using logistic regression models confirmed the gene-gene interactions. The results suggest that the BDNF and NTRK2 genes may contribute to the risk of geriatric depression independently and in an interactive manner.
Attention-deficit hyperactivity disorder (ADHD) is an important psychiatric condition in terms of its prevalence and impact on quality of life. It has one of the highest heritabilities found in psychiatric disorders. A number of association studies exploring several candidate genes in different populations around the world have been carried out. The objective of the present study was to carry out a meta-analysis for 8 common variants located in 5 top candidate genes for ADHD (BDNF, HTR1B, SLC6A2, SLC6A4 and SNAP25); these genes are known to be involved in synaptic transmission and plasticity.
We performed a search for published genetic association studies that analyzed the candidate polymorphisms in different populations, and we applied state-of-the-art meta-analytical procedures to obtain pooled odds ratios (ORs) and to evaluate potential basis of heterogeneity. We included 75 genetic association studies in these meta-analyses.
A major part of the previously postulated associations were nonconsistent in the pooled odds ratios. We observed a weak significant association with a single nucleotide polymorphism (SNP) located in the 3' UTR region of the SNAP25 gene (rs3746544, T allele, OR 1.15, 95% confidence interval 1.01-1.31, p = 0.028, I(2) = 0%). In addition to the low coverage of genetic variability given by these variants, phenotypic heterogeneity between samples (ADHD subtypes, comorbidities) and genetic background may explain these differences.
Limitations of our study include the retrospective nature of our meta-analysis with the incorporation of study-level data from published articles.
To our knowledge, the present study is the largest meta-analysis carried out for ADHD genetics; previously proposed cumulative associations with common polymorphisms in SLC6A4 and HTR1B genes were not supported. We identified a weak consistent association with a common SNP in the SNAP25 gene, a molecule that is known to be central for synaptic transmission and plasticity mechanisms.
The gene encoding the brain-derived neurotrophic factor (BDNF) has been demonstrated as a candidate for Alzheimer's disease-related depression (AD-D) susceptibility. Additionally, an association between AD-D and the functional valine to methionine (Val66Met) polymorphism has been reported. The aim of this study was to assess the genetic contribution of other BDNF variants to AD-D. Two-hundred forty-five AD patients were divided into two subgroups according to the presence (AD-D) or the absence (AD-nD) of depressive symptoms. Four single-nucleotide polymorphisms within BDNF gene were considered, i.e., C270T, rs2049045 C/G, G196A (Val66Met), and G11757C. In our sample, 35.5% of patients (n = 87) reported AD-related depressive symptoms. The individual SNP analysis showed an association between G196A and G11757C genotypes and AD-D. Accordingly, considering the allele frequencies, BDNF 196*A allele was significantly overrepresented in AD-D compared to AD-nD (OR = 1.80, 95% CI = 1.19-2.72), as well as BDNF 11757*C allele (OR = 1.90, 95% CI = 1.25-2.90). Haplotype analyses revealed that the alleles at four loci (C270T, rs2049045 C/G, G196A, G11757C) interacted to further increase the risk of AD-D. Compared to the most common not-at-risk C-C-G-G haplotype, C-G-A-C (OR = 3.55, 95% CI = 1.44-8.76, P = 0.006) and C-C-A-C haplotypes (OR = 1.72, 95% CI = 1.03-2.87, P = 0.037) were overrepresented in AD-D. This study suggests that BDNF genetic variations play a role in the susceptibility to AD-related depression.
Single nucleotide polymorphisms (SNPs) are important markers which can be used in association studies searching for susceptible genes of complex diseases. High-throughput methods are needed for SNP genotyping in a large number of samples. In this study, we applied polyacrylamide gel-based microarray combined with dual-color hybridization for association study of four BDNF polymorphisms with autism. All the SNPs in both patients and controls could be analyzed quickly and correctly. Among four SNPs, only C270T polymorphism showed significant differences in the frequency of the allele (chi(2) = 7.809, p = 0.005) and genotype (chi(2) = 7.800, p = 0.020). In the haplotype association analysis, there was significant difference in global haplotype distribution between the groups (chi(2) = 28.19, p = 3.44e-005). We suggest that BDNF has a possible role in the pathogenesis of autism. The study also show that the polyacrylamide gel-based microarray combined with dual-color hybridization is a rapid, simple and high-throughput method for SNPs genotyping, and can be used for association study of susceptible gene with disorders in large samples.
Panic disorder (PD) is a severe and chronic psychiatric disorder, with significant genetic components in the etiology. Brain-derived neurotrophic factor (BDNF) gene, which has regulatory effects on neurotransmitter systems such as serotonin and dopamine, is a candidate for susceptibility locus of PD. This study investigated three single-nucleotide polymorphisms (SNPs) of BDNF (rs6265 (Val66Met), rs11030104 and rs7103411) in Japanese patients with PD and controls. No significant association was observed between the three SNPs and PD. No association of the Val66Met was consistent with two small studies in Japanese and Chinese populations. We therefore conclude that the BDNF polymorphism may not play a major role in PD in the East Asian populations.
Brain-derived neurotrophic factor (BDNF) has been proposed as a risk factor for schizophrenia, but no consistent association between BDNF Val66Met polymorphism and schizophrenia has been established. Therefore, analyses with larger sample sizes and better methodology are needed. To examine whether BDNF Val66Met polymorphism is associated with schizophrenia, schizophrenia patients (n=251) and healthy volunteers (n=284) were recruited for a case-control analysis. Pretreatment psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) in a subset of 125 hospitalized schizophrenia patients who were drug-free or drug-naive. Genotyping was performed using polymerase chain reaction, restriction fragment length polymorphism (RFLP), and direct screening techniques. With the exception of nominally significant associations between BDNF Val66Met variation and PANSS total, negative, or general scores, no association between the BDNF Val66Met polymorphism and schizophrenia was found. However, this polymorphism may reduce psychopathology, in particular negative symptoms, in schizophrenia.
Brain‐derived neurotrophic factor (BDNF) is a protein that allows the survival of specific neuronal populations. This study reports on the distribution of the BDNF mRNA in the adult mouse brain, where the BDNF gene is strongly expressed, using quantitative Northern blot analysis and in situ hybridization. All brain regions examined were found to contain substantial amounts of BDNF mRNA, the highest levels being found in the hippocampus followed by the cerebral cortex. In the hippocampus, which is also the site of highest nerve growth factor (NGF) gene expression in the central nervous system (CNS), there is approximately 50‐fold more BDNF mRNA than NGF mRNA. In other brain regions, such as the granule cell layer of the cerebellum, the differences between the levels of BDNF and NGF mRNAs are even more pronounced. The BDNF mRNA was localized by in situ hybridization in hippocampal neurons (pyramidal and granule cells). These data suggest that BDNF may play an important role in the CNS for a wide variety of adult neurons.
BDNF plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus. A frequent single nucleotide polymorphism in the targeting region of the human BDNF gene (val ⁶⁶ met) has been associated with abnormal intracellular trafficking and regulated secretion of BDNF in cultured hippocampal neurons transfected with the met allele. In addition, the met allele has been associated with abnormal hippocampal neuronal function as well as impaired episodic memory in human subjects, but a direct effect of BDNF alleles on hippocampal processing of memory has not been demonstrated. We studied the relationship of the BDNF val ⁶⁶ met genotype and hippocampal activity during episodic memory processing using blood oxygenation level-dependent functional magnetic resonance imaging and a declarative memory task in healthy individuals. Met carriers exhibited relatively diminished hippocampal engagement in comparison with val homozygotes during both encoding and retrieval processes. Remarkably, the interaction between the BDNF val ⁶⁶ met genotype and the hippocampal response during encoding accounted for 25% of the total variation in recognition memory performance. These data implicate a specific genetic mechanism for substantial normal variation in human declarative memory and suggest that the basic effects of BDNF signaling on hippocampal function in experimental animals are important in humans.
The brain-derived neurotrophic factor (BDNF) promotes survival, differentiation and maintenance of neurons in the central nervous system. BDNF 196G>A and 270C>T polymorphisms have previously been associated with Alzheimer's disease (AD) and with Parkinson's disease (PD). To study the role of BDNF 196G>A and 270C>T polymorphisms in Finnish AD and PD patients we genotyped BDNF 196G>A and 270C>T polymorphisms in 97 sporadic AD patients, 52 PD patients and 101 control subjects with polymerase chain reaction. No associations were found between the genotypes studied and AD or PD in Finnish patients. Moreover, no interaction between either BDNF polymorphism and the ε4 allele of apolipoprotein E was found. In conclusion, it seems that the BDNF gene does not contribute significantly to the risk of AD or PD in Finnish patients.
Recent studies have begun to characterize the actions of stress and antidepressant treatments beyond the neurotransmitter and receptor level. This work has demonstrated that long-term antidepressant treatments result in the sustained activation of the cyclic adenosine 3', 5'-monophosphate system in specific brain regions, including the increased function and expression of the transcription factor cyclic adenosine monophosphate response element-binding protein. The activated cyclic adenosine 3', 5'-monophosphate system leads to the regulation of specific target genes, including the increased expression of brain-derived neurotrophic factor in certain populations of neurons in the hippocampus and cerebral cortex. The importance of these changes is highlighted by the discovery that stress can decrease the expression of brain-derived neurotrophic factor and lead to atrophy of these same populations of stressvulnerable hippocampal neurons. The possibility that the decreased size and impaired function of these neurons may be involved in depression is supported by recent clinical imaging studies, which demonstrate a decreased volume of certain brain structures. These findings constitute the framework for an updated molecular and cellular hypothesis of depression, which posits that stressinduced vulnerability and the therapeutic action of antidepressant treatments occur via intracellular mechanisms that decrease or increase, respectively, neurotrophic factors necessary for the survival and function of particular neurons. This hypothesis also explains how stress and other types of neuronal insult can lead to depression in vulnerable individuals and it outlines novel targets for the rational design of fundamentally new therapeutic agents.
Published online 18 February 2007
Despite considerable evidence that neuronal activity influences the organization and function of circuits in the developing and adult brain, the molecular signals that translate activity into structural and functional changes in connections remain largely obscure. This review discusses the evidence implicating neurotrophins as molecular mediators of synaptic and morphological plasticity. Neurotrophins are attractive candidates for these roles because they and their receptors are expressed in areas of the brain that undergo plasticity, activity can regulate their levels and secretion, and they regulate both synaptic transmission and neuronal growth. Although numerous experiments show demonstrable effects of neurotrophins on synaptic plasticity, the rules and mechanisms by which they exert their effects remain intriguingly elusive.