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

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

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

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

Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers

CONTEXT: Relatively little is known about genetic determinants of cognitive dysfunction in schizophrenia. Recent studies suggest that a brain-derived neurotrophic factor (BDNF) prodomain single nucleotide polymorphism resulting in a valine (Val)-to-methionine (Met) substitution is associated with impaired declarative memory in healthy volunteers and patients with schizophrenia. These studies indicate that the BDNF(Met) variant may mediate hippocampal cognitive functions by modulating intracellular trafficking and activity-dependent BDNF release. To our knowledge, the way in which this functional single nucleotide polymorphism affects other neurocognitive measures has not been examined. Its role in determining cognitive deficits in schizophrenia has also not been systematically studied. OBJECTIVES: To characterize the neurocognitive and brain morphometric phenotypic correlates of the BDNF Val66Met polymorphism and to test the specificity of the BDNF(Met) variant on cognitive dysfunction in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: A comprehensive battery of standardized neuropsychological tests was administered to 144 healthy volunteers and 293 patients with schizophrenia spectrum disorder at a tertiary care university hospital. Approximately two thirds of the sample also underwent high-resolution magnetic resonance imaging brain scans. MAIN OUTCOME MEASURES: Genotype effects (in Met allele carriers vs Val homozygotes) on 5 cognitive domain z scores and magnetic resonance imaging gray matter brain volume measures (Talairach atlas-based cerebral lobes and optimized voxel-based morphometry) were examined using general linear models. RESULTS: On verbal memory, there was a significant genotype effect but no genotype x diagnosis effects. In both patients with schizophrenia and healthy volunteers, Met allele carriers had poorer verbal memory performance than their Val-homozygous counterparts. On visuospatial abilities, there were significant genotype and genotype x diagnosis effects. Met allele-associated visuospatial impairment was specific to patients with schizophrenia but not healthy volunteers. There were significant genotype effects on gray matter volumes within brain regions known to subserve these 2 cognitive domains, with Met allele carriers having smaller temporal and occipital lobar gray matter volumes. Optimized voxel-based morphometry further suggests that parietal heteromodal cortical gray matter deficits may underlie visuospatial impairment in patients with schizophrenia carrying the Met allele. CONCLUSIONS: We replicated the association between the BDNF(Met) variant and poor medial temporal lobe-related memory performance. The consonance of our cognitive and brain morphology findings further suggests that the BDNF(Met) variant may have a specific role in conferring visuospatial dysfunction in schizophrenia.     

Brain‐derived neurotrophic factor val66met polymorphism and hippocampal activation during episodic encoding and retrieval tasks

Brain‐derived neurotrophic factor (BDNF) is a neurotrophin which has been shown to regulate cell survival and proliferation, as well as synaptic growth and hippocampal long‐term potentiation. A naturally occurring single nucleotide polymorphism in the human BDNF gene (val66met) has been associated with altered intercellular trafficking and regulated secretion of BDNF in met compared to val carriers. Additionally, previous studies have found a relationship between the BDNF val66met genotype and functional activity in the hippocampus during episodic and working memory tasks in healthy young adults. Specifically, studies have found that met carriers exhibit both poorer performance and reduced neural activity within the medial temporal lobe (MTL) when performing episodic memory tasks. However, these studies have not been well replicated and have not considered the role of behavioral differences in the interpretation of neural differences. The current study sought to control for cognitive performance in investigating the role of the BDNF val66met genotype on neural activity associated with episodic memory. Across item and relational memory tests, met carriers exhibited increased MTL activation during both encoding and retrieval stages, compared to noncarriers. The results suggest that met carriers are able to recruit MTL activity to support successful memory processes, and reductions in cognitive performance observed in prior studies are not a ubiquitous effect associated with variants of the BDNF val66met genotype. © 2010 Wiley‐Liss, Inc.     

The brain-derived neurotrophic factor Val66Met polymorphism is associated with reduced functional magnetic resonance imaging activity in the hippocampus and increased use of caudate nucleus-dependent strategies in a human virtual navigation task

Multiple memory systems are involved in parallel processing of spatial information during navigation. A series of studies have distinguished between hippocampus-dependent 'spatial' navigation, which relies on knowledge of the relationship between landmarks in one's environment to build a cognitive map, and habit-based 'response' learning, which requires the memorization of a series of actions and is mediated by the caudate nucleus. Studies have demonstrated that people spontaneously use one of these two alternative navigational strategies with almost equal frequency to solve a given navigation task, and that strategy correlates with functional magnetic resonance imaging (fMRI) activity and grey matter density. Although there is evidence for experience modulating grey matter in the hippocampus, genetic contributions may also play an important role in the hippocampus and caudate nucleus. Recently, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene has emerged as a possible inhibitor of hippocampal function. We have investigated the role of the BDNF Val66Met polymorphism on virtual navigation behaviour and brain activation during an fMRI navigation task. Our results demonstrate a genetic contribution to spontaneous strategies, where 'Met' carriers use a response strategy more frequently than individuals homozygous for the 'Val' allele. Additionally, we found increased hippocampal activation in the Val group relative to the Met group during performance of a virtual navigation task. Our results support the idea that the BDNF gene with the Val66Met polymorphism is a novel candidate gene involved in determining spontaneous strategies during navigation behaviour.     

Executive attention in schizophrenic males and the impact of COMT Val108/158Met genotype on performance on the attention network test

Background: Executive control of attention in schizophrenia has recently been assessed by means of the Attention Network Test (ANT). In the past, for tasks assessing executive attention, findings in schizophrenia have been contradictory, among others suggesting a lack of increased stimulus interference effects. Attention and executive functioning are substantially influenced by candidate genes of schizophrenia, including the functional single-nucleotide polymorphism catechol-o-methyltransferase (COMT) Val^108/158Met, with task-dependent, specific effects of Met allele load on cognitive function. Therefore, we aimed at investigating executive attention in schizophrenic patients (SZP) as compared with healthy controls (HC), and to assess the specific impact of COMT Val^108/158Met on executive attention, using ANT. Methods: We applied ANT to 63 SZP and 40 HC. We calculated a general linear model to investigate the influence of affection status and the COMT Val^108/158Met genotype on executive attention as assessed by the ANT. Results: Multivariate analysis of variance revealed a significant effect of group on executive attention. SZP exhibited smaller conflict effects in the ANT. Met allele load significantly modulated executive attention efficiency, with homozygous Met individuals showing low overall reaction time but increased effects conflicting stimulus information in executive attention. Conclusions: Our data suggest a disease-related dissociation of executive attention with reduced conflict effects in SZP. Furthermore, they support the hypothesis of differential tonic-phasic dopamine activation and specific dopamine level effects in different cognitive tasks, which helps interpreting contradictory findings of Met allele load on cognitive performance. Disease status seems to modulate the impact of COMT Val^108/158Met on cognitive performance.     

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

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

BDNF val66met affects hippocampal volume and emotion-related hippocampal memory activity

The val⁶⁶met polymorphism on the BDNF gene has been reported to explain individual differences in hippocampal volume and memory-related activity. These findings, however, have not been replicated consistently and no studies to date controlled for the potentially confounding impact of early life stress, such as childhood abuse, and psychiatric status. Using structural and functional MRI, we therefore investigated in 126 depressed and/or anxious patients and 31 healthy control subjects the effects of val⁶⁶met on hippocampal volume and encoding activity of neutral, positive and negative words, while taking into account childhood abuse and psychiatric status. Our results show slightly lower hippocampal volumes in carriers of a met allele (n=54) relative to val/val homozygotes (n=103) (P=0.02, effect size (Cohen''s d)=0.37), which appeared to be independent of childhood abuse and psychiatric status. For hippocampal encoding activity, we found a val⁶⁶met–word valence interaction (P=0.02) such that carriers of a met allele showed increased levels of activation in response to negative words relative to activation in the neutral word condition and relative to val/val homozygotes. This, however, was only evident in the absence of childhood abuse, as abused val/val homozygotes showed hippocampal encoding activity for negative words that was comparable to that of carriers of a met allele. Neither psychiatric status nor memory accuracy did account for these associations. In conclusion, BDNF val⁶⁶met has a significant impact on hippocampal volume independently of childhood abuse and psychiatric status. Furthermore, early adverse experiences such as childhood abuse account for individual differences in hippocampal encoding activity of negative stimuli but this effect manifests differently as a function of val⁶⁶met.     

Effect of the BDNF Val66Met Polymorphism on Regional Gray Matter Volumes and Cognitive Function in the Chinese Population

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is common and influences the activity-dependent secretion of BDNF, which is critical for neuronal plasticity and survival. This study investigated the genetic effect of the BDNF Val66Met polymorphism on cognitive function and regional gray matter (GM) volume in a healthy Chinese population (n = 330). Voxel-based morphometry (VBM)-optimized analysis was used. There was no significant difference in the neuropsychological performances among the three BDNF genotypic groups. VBM analyses demonstrated that Met homozygotes had greater GM volumes than Val homozygotes in the left medial frontal gyrus, the left middle temporal gyrus, the left cerebellum, and the right middle temporal gyrus, and had larger GM volumes than Val/Met heterozygotes in the left middle temporal gyrus, the left inferior temporal gyrus, and the right superior frontal gyrus. Our findings suggest that the presence of two Met alleles has a protective effect on regional GM volumes in the Chinese population.     

Prefrontal dopamine and the dynamic control of human long-term memory

Dopaminergic projections to the prefrontal cortex support higher-order cognitive functions, and are critically involved in many psychiatric disorders that involve memory deficits, including schizophrenia. The role of prefrontal dopamine in long-term memory, however, is still unclear. We used an imaging genetics approach to examine the hypothesis that dopamine availability in the prefrontal cortex selectively affects the ability to suppress interfering memories. Human participants were scanned via functional magnetic resonance imaging while practicing retrieval of previously studied target information in the face of interference from previously studied non-target information. This retrieval practice (RP) rendered the non-target information less retrievable on a later final test—a phenomenon known as retrieval-induced forgetting (RIF). In total, 54 participants were genotyped for the catechol-O-methyltransferase (COMT) Val^108/158Met polymorphism. The COMT Val^108/158Met genotype showed a selective and linear gene-dose effect on RIF, with the Met allele, which leads to higher prefrontal dopamine availability, being associated with greater RIF. Mirroring the behavioral pattern, the functional magnetic resonance imaging data revealed that Met allele carriers, compared with Val allele carriers, showed a greater response reduction in inhibitory control areas of the right inferior frontal cortex during RP, suggesting that they more efficiently reduced interference. These data support the hypothesis that the cortical dopaminergic system is centrally involved in the dynamic control of human long-term memory, supporting efficient remembering via the adaptive suppression of interfering memories.     

The flexible mind is associated with the catechol-O-methyltransferase (COMT) ValMet polymorphism: Evidence for a role of dopamine in the control of task-switching

Genetic variability related to the catechol-O-methyltransferase (COMT) gene (Val¹⁵⁸Met polymorphism) has received increasing attention as a possible modulator of cognitive control functions. Recent evidence suggests that the Val¹⁵⁸Met genotype may differentially affect cognitive stability and flexibility, in such a way that Val/Val homozygous individuals (who possess low prefrontal dopamine levels) may show more pronounced cognitive flexibility than Met/-carriers (who possess high prefrontal dopamine levels). To test this, healthy humans (n = 87), genotyped for the Val¹⁵⁸Met polymorphism at the COMT gene, performed a task-switching paradigm, which provides a relatively diagnostic index of cognitive flexibility. As predicted, Met/-carriers showed larger switching costs (i.e., less cognitive flexibility), F(1,85) = 4.28, p < 0.05, than Val/Val homozygous individuals. Our findings support the idea that low prefrontal dopamine levels promote cognitive flexibility.     

Distinct medial temporal contributions to different forms of recognition in amnestic mild cognitive impairment and Alzheimer's disease

The simplest expression of episodic memory is the experience of familiarity, the isolated recognition that something has been encountered previously. Brain structures of the medial temporal lobe (MTL) make essential contributions to episodic memory, but the distinct contributions from each MTL structure to familiarity are debatable. Here we used specialized tests to assess recognition impairments and their relationship to MTL integrity in people with amnestic mild cognitive impairment (aMCI, n=19), people with probable Alzheimer's disease (AD; n=10), and age-matched individuals without any neurological disorder (n=20). Recognition of previously presented silhouette objects was tested in two formats—forced-choice recognition with four concurrent choices (one target and three foils) and yes/no recognition with individually presented targets and foils. Every foil was extremely similar to a corresponding target, such that forced-choice recognition could be based on differential familiarity among the choices, whereas yes/no recognition necessitated additional memory and decision factors. Only yes/no recognition was impaired in the aMCI group, whereas both forced-choice and yes/no recognition were impaired in the AD group. Magnetic resonance imaging showed differential brain atrophy, as MTL volume was reduced in the AD group but not in the aMCI group. Pulsed arterial spin-labeled scans demonstrated that MTL blood flow was abnormally increased in aMCI, which could indicate physiological dysfunction prior to the emergence of significant atrophy. Regression analyses with data from all patients revealed that regional patterns of MTL integrity were differentially related to forced-choice and yes/no recognition. Smaller perirhinal cortex volume was associated with lower forced-choice recognition accuracy, but not with lower yes/no recognition accuracy. Instead, smaller hippocampal volumes were associated with lower yes/no recognition accuracy. In sum, familiarity memory can be specifically assessed using the forced-choice recognition test, it declines later than other MTL-dependent memory functions as AD progresses, and it has distinct anatomical substrates.     

The role of BDNF methylation and Val66Met in amygdala reactivity during emotion processing

Epigenetic alterations of the brain‐derived neurotrophic factor (BDNF) gene have been associated with psychiatric disorders in humans and with differences in amygdala BDNF mRNA levels in rodents. This human study aimed to investigate the relationship between the functional BDNF‐Val⁶⁶Met polymorphism, its surrounding DNA methylation in BDNF exon IX, amygdala reactivity to emotional faces, and personality traits. Healthy controls (HC, n = 189) underwent functional MRI during an emotional face‐matching task. Harm avoidance, novelty seeking and reward dependence were measured using the Tridimensional Personality Questionnaire (TPQ). Individual BDNF methylation profiles were ascertained and associated with several BDNF single nucleotide polymorphisms surrounding the BDNF‐Val⁶⁶Met, amygdala reactivity, novelty seeking and harm avoidance. Higher BDNF methylation was associated with higher amygdala reactivity (x = 34, y = 0, z = ?26, t₍₁₆₆₎ = 3.00, TFCE = 42.39, p_(FWE) = .045), whereby the BDNF‐Val⁶⁶Met genotype per se did not show any significant association with brain function. Furthermore, novelty seeking was negatively associated with BDNF methylation (r = ?.19, p = .015) and amygdala reactivity (r = ?.17, p = .028), while harm avoidance showed a trend for a positive association with BDNF methylation (r = .14, p = .066). The study provides first insights into the relationship among BDNF methylation, BDNF genotype, amygdala reactivity and personality traits in humans, highlighting the multidimensional relations among genetics, epigenetics, and neuronal functions. The present study suggests a possible involvement of epigenetic BDNF modifications in psychiatric disorders and related brain functions, whereby high BDNF methylation might reduce BDNF mRNA expression and upregulate amygdala reactivity.     

BDNF and COMT polymorphisms

Recent investigations in several species have suggested a role for brain-derived neurotrophic factor (BDNF) in memory, which may be mediated by the influence of BDNF on neuronal plasticity in the hippocampus. BDNF polymorphisms have also been associated with mood disorders. Catechol-O-methyltransferase (COMT) metabolizes dopamine and has been implicated in prefrontal function, another area of the brain relevant for memory. In a sample of 63 young adults with a history of childhood-onset mood disorder, we typed three BDNF polymorphisms, including the BDNF Val66Met single nucleotide polymorphism (SNP), and the COMT Val108/158Met SNP. Multivariate analysis of variance was used to test the association between BDNF and COMT markers and measures of declarative memory. Variants at the three BDNF markers and one COMT marker were not associated with declarative memory function—p-values ranged from 0.25 to 0.98. Higher IQ (F=6.18, df=4, 58, p=0.0003) and female gender (F=4.41, df=4, 58, p=0.0035) were associated with more optimal performance on the memory tasks. This study did not provide evidence supporting an association between BDNF and COMT genes and declarative memory phenotypes.     

The brain-derived neurotrophic factor Val66Met polymorphism and rate of decline in Alzheimer's disease

It is largely unknown why some patients with Alzheimer's disease (AD) decline cognitively more rapidly than others. Genetic differences among patients could influence rate of decline. Brain-derived neurotrophic factor (BDNF) is a neurotrophin important in the survival neurons and in memory function. BDNF levels are reduced in the brain in AD. The Val66Met polymorphism in the BDNF gene modifies neuronal BDNF secretion, and affects hippocampal function and memory performance. We tested the hypothesis that the BDNF Val66Met polymorphism influences rate of cognitive decline in AD. In a sample of 149 AD patients followed for an average of 3.9 years, we found no effect of BDNF Val66Met genotype on rate of change in the Mini Mental State Examination. Results were similar when we excluded patients taking an acetylcholinesterase inhibitor, those placed in a nursing home during the study, or those with a neuropathological diagnosis that included AD plus an entity other than AD. We also found no evidence that the effects of the BDNF Val66Met genotype depend on APOE genotype, which itself had no effect on rate of cognitive change. These findings suggest that the functional BDNF Val66Met variant is not a major determinant of rate of cognitive decline in AD.     

Influence of brain-derived neurotrophic-factor and apolipoprotein E genetic variants on hippocampal volume and memory performance in healthy young adults

Unravelling the impact of genetic variants on clinical phenotypes is a challenging task. Apolipoprotein E (ApoE) and brain-derived neurotrophic factor (BDNF) play an important role in cell growth, regeneration, synaptic plasticity, learning and memory processes. The aim of the present study was to examine the impact of BDNF Val66Met- and ApoE-polymorphisms and their interactions on hippocampal morphology and memory functions in healthy young adults. Hippocampal volume and memory performance of 135 healthy individuals, aged 24.6 ± 3.2 years, were assessed, using magnetic resonance imaging and the Inventory for Memory diagnostics. The performance of BDNF-Met66 carriers was significantly lower in working memory (P = 0.03) compared with non carriers, whereas no further differences were observed either in cognitive performance or in hippocampal volumes between the groups. Age, BDNF Val66 Met polymorphism and the interaction factor BDNF genotype x age were significantly associated with the variation of working memory scores (P = 0.01, 0.01, 0.02 respectively). No statistically significant differences were detected in the volumes of hippocampi and in memory phenotypes between individuals carrying the ApoE E4 allele and those without it. The analysis did not reveal an impact of gene-gene interaction between BDNF and ApoE genes on hippocampal volumes or memory performance. BDNF Val66Met polymorphism seems to influence working memory function and modulate the effects of ageing on working memory in healthy young adults.     

Genetics of serum BDNF: Meta-analysis of the Val66Met and genome-wide association study

Abstract

Objectives. Lower levels of serum brain derived neurotrophic factor (BDNF) is one of the best known biomarkers of depression. To identify genetic variants associated with serum BDNF, we tested the Val66Met (rs6265) functional variant and conducted a genome-wide association scan (GWAS). Methods. In a community-based sample (N = 2054; aged 19–101, M = 51, SD = 15) from Sardinia, Italy, we measured serum BDNF concentration and conducted a GWAS. Results. We estimated the heritability of serum BDNF to be 0.48 from sib-pairs. There was no association between serum BDNF and Val66Met in the SardiNIA sample and in a meta-analysis of published studies (k = 13 studies, total n = 4727, P = 0.92). Although no genome-wide significant associations were identified, some evidence of association was found in the BDNF gene (rs11030102, P = 0.001) and at two loci (rs7170215, P = 4.8 × 10^–5 and rs11073742 P = 1.2 × 10^–5) near and within NTRK3 gene, a neurotrophic tyrosine kinase receptor. Conclusions. Our study and meta-analysis of the literature indicate that the BDNF Val66Met variant is not associated with serum BDNF, but other variants in the BDNF and NTRK3 genes might regulate the level of serum BDNF.     

Impact of the BDNF Val66Met Polymorphism on Regional Brain Gray Matter Volumes: Relevance to the Stress Response

Objective

Genetic imaging is used to investigate the mechanism by which genetic variants influence brain structure. In a previous study, a structural change of the dorsolateral prefrontal cortex was associated with symptom modulation in post-traumatic stress disorder patients. This study examined the effect of a polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF) on regional gray matter (GM) volumes and the correlations between the dorsolateral prefrontal GM volume and the stress level in healthy volunteers.

Methods

Sixty-one volunteers underwent genotyping for the BDNF Val66Met single nucleotide polymorphism (SNP) and completed the Stress Response Inventory (SRI). Magnetic resonance images were also acquired, and the effect of each subject''s BDNF genotype and SRI subscore on his or her dorsolateral prefrontal GM volume was evaluated.

Results

The Val/Val homozygotes had significantly larger GM volumes in the prefrontal cortex and the precuneus, the uncus, and the superior temporal and occipital cortices than Met carriers. The Met homozygotes demonstrated a higher stress response in depression domain than Val/Val and Val/Met groups. A negative correlation between the middle frontal cortex GM volume and the SRI depression subscore was found.

Conclusion

These findings indicate an interaction between genes and brain structure, and they suggest that differences in dorsolateral prefrontal GM volume related to the BDNF Val66Met SNP are associated with resilience to stressful life events, particularly in the dimension of emotion.     

Brain derived neurotrophic factor Val66Met polymorphism and psychotic symptoms in Alzheimer's disease

Objective

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder with a high prevalence. Since behavioral disturbances, such as psychotic symptoms, represent a key feature of AD, genes related to dopamine, serotonin and brain derived neurotrophic factor (BDNF), are considered as candidate genes for AD. BDNF is a neurotrophin that regulates neurodevelopment, neuroplasticity, and neuronal functions. BDNF is involved in the etiopathogenesis of psychiatric and neurodegenerative disorders. A single base pair polymorphism (BDNF Val66Met) was reported to be associated with AD and/or schizophrenia, as well as other psychoses, although some studies failed to replicate these findings. The aim of the study was to evaluate the association between BDNF Val66Met variants and AD, as well as onset of AD or presence of psychotic symptoms in AD.

Method

BDNF Val66Met was analyzed in 211 patients with AD and in 402 aged healthy control subjects. All subjects were ethnically homogenous Caucasians from Croatia, and were subdivided according to the gender, onset of AD, and presence of psychotic symptoms. A χ² test, with Bonferroni correction and standardized residuals were used to evaluate the data.

Results

Distribution of the BDNF Val66Met genotypes differed significantly between male and female AD patients with or without psychotic symptoms. This difference was due to the significant contribution of the Met/Val genotype and the combined Met/Met and Met/Val genotypes between psychotic and non-psychotic symptoms in male, but not in female patients with AD. The frequency of the gene variants of the BDNF Val66Met did not differ significantly among male and female patients with AD and control subjects, or between male and female patients with early or late onset AD. There were significant sex related differences in age, duration of illness and scores of dementia between patients with AD.

Conclusion

Our male patients were younger, had shorter duration of illness, and had less severe dementia and higher cognitive performance than female AD patients. The gene variants of the BDNF Val66Met polymorphism were significantly associated with the presence of psychotic symptoms in male, but not in female patients with AD. The results had adequate statistical power to suggest that BDNF Val66Met was not related to susceptibility to AD or the onset of AD, but that presence of one or two Met alleles of BDNF Val66Met polymorphism might present a risk factor for psychosis in AD.     

COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of 'switching on' hallucinations in the flow of daily life

Objective: A functional polymorphism in the catechol‐o‐methyltransferase gene (COMT Val¹⁵⁸Met) may moderate the psychosis‐inducing effects of cannabis. In order to extend this finding to dynamic effects in the flow of daily life, a momentary assessment study of psychotic symptoms in response to cannabis use was conducted. Method: The experience sampling technique was used to collect data on cannabis use and occurrence of symptoms in daily life in patients with a psychotic disorder (n = 31) and healthy controls (n = 25). Results: Carriers of the COMT Val¹⁵⁸Met Val allele, but not subjects with the Met/Met genotype, showed an increase in hallucinations after cannabis exposure, conditional on prior evidence of psychometric psychosis liability. Conclusion: The findings confirm that in people with psychometric evidence of psychosis liability, COMT Val¹⁵⁸Met genotype moderates the association between cannabis and psychotic phenomena in the flow of daily life.