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Effect of BDNF val66met polymorphism on age-related amygdala volume changes in healthy subjects.

ABSTRACT: Brain-derived neurotrophic factor (BDNF) has been implicated in the mechanism of age-related regional brain volumetric changes. Healthy volunteers with the valine to methionine polymorphism at codon 66 of the BDNF gene (val66met) exhibit decreased volume of a number of brain structures, including hippocampus, temporal and occipital lobar gray matter volumes, and a negative correlation between age and the volume of bilateral dorsolateral prefrontal cortices. We sought to characterize the relationship between age, BDNF and amygdala volumes among healthy volunteers. We measured amygdala volumes in 55 healthy, right-handed volunteers who underwent structural magnetic resonance imaging (MRI) and were also characterized demographically and genotyped with respect to BDNF. Using an ANCOVA model, we found that amygdala volumes were inversely correlated with age in BDNF val66met carriers but not in non-carriers. This is the first report of age-related BDNF val66met polymorphism effects on amygdala volume.

SUBMITTER: Sublette ME

PROVIDER: S-EPMC2674019 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Effect of BDNF val66met polymorphism on age-related amygdala volume changes in healthy subjects.

Sublette M E ME Baca-Garcia Enrique E Parsey Ramin V RV Oquendo Maria A MA Rodrigues Sarina M SM Galfalvy Hanga H Huang Yung-Yu YY Arango Victoria V Mann J J JJ

Progress in neuro-psychopharmacology & biological psychiatry 20080624 7

Brain-derived neurotrophic factor (BDNF) has been implicated in the mechanism of age-related regional brain volumetric changes. Healthy volunteers with the valine to methionine polymorphism at codon 66 of the BDNF gene (val66met) exhibit decreased volume of a number of brain structures, including hippocampus, temporal and occipital lobar gray matter volumes, and a negative correlation between age and the volume of bilateral dorsolateral prefrontal cortices. We sought to characterize the relation ...[more]

PMID: 18621091

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Project description:Increasing evidence suggests that synaptic dysfunction is a core pathophysiological hallmark of neurodegenerative disorders. Brain-derived neurotropic factor (BDNF) is key synaptogenic molecule and targeting synaptic repair through modulation of BDNF signalling has been suggested as a potential drug discovery strategy. The development of such "synaptogenic" therapies depend on the availability of BDNF sensitive markers of synaptic function that could be utilized as biomarkers for examining target engagement or drug efficacy in humans. Here we have utilized the BDNF Val66Met genetic polymorphism to examine the effect of the polymorphism and genetic load (i.e. Met allele load) on electrophysiological (EEG) markers of synaptic activity and their structural (MRI) correlates. Sixty healthy adults were prospectively recruited into the three genetic groups (Val/Val, Val/Met, Met/Met). Subjects also underwent fMRI, tDCS/TMS, and cognitive assessments as part of a larger study. Overall, some of the EEG markers of synaptic activity and brain structure measured with MRI were the most sensitive markers of the polymorphism. Met carriers showed decreased oscillatory activity and synchrony in the neural network subserving error-processing, as measured during a flanker task (ERN); and showed increased slow-wave activity during resting. There was no evidence for a Met load effect on the EEG measures and the polymorphism had no effects on MMN and P300. Met carriers also showed reduced grey matter volume in the anterior cingulate and in the (left) prefrontal cortex. Furthermore, anterior cingulate grey matter volume, and oscillatory EEG power during the flanker task predicted subsequent behavioural adaptation, indicating a BDNF dependent link between brain structure, function and behaviour associated with error processing and monitoring. These findings suggest that EEG markers such as ERN and resting EEG could be used as BDNF sensitive functional markers in early clinical development to examine target engagement or drug related efficacy of synaptic repair therapies in humans.

Project description:Poor inhibitory processing of negative emotional content is central to many psychiatric disorders, including depression and anxiety. Moreover, increasing evidence suggests that core aspects of emotion-inhibitory processing are largely inherited and as such may represent a key intermediate or risk-related phenotype for common affective diseases (e.g., unipolar depressive, anxiety disorders). The current study employed a candidate-gene approach in order to most effectively examine this complex behavioral phenotype. We examined the novel interaction between BDNF (Val66Met) and TPH2 (rs4570625) polymorphisms and their influence on behavioral inhibition of negative emotion in two independent investigations of healthy adults. BDNF Met carriers consistently report greater symptoms of affective disease and display corresponding behavioral rigidity, while TPH2 T carriers display poor inhibitory processing. These genotypes are traditionally perceived as 'risk' genotypes when compared to their respective major Val and G homozygous genotypes, but evidence is mixed. Recent studies in humans and mutant mouse models suggest biological epistasis between BDNF and genes involved in serotonin regulation. Moreover, polymorphisms in the TPH2 gene may have greater influence on serotonergic function than other more commonly studied polymorphisms (e.g., 5-HTTLPR). We observed consistent evidence across two different emotion-inhibition paradigms, one with high internal validity (Study 1, n = 119) and one with high ecological validity (Study 2, n = 115) that the combination of Val/Val and G/G genotypes was clearly associated with impaired inhibition of negative emotional content. This was followed by individuals carrying the BDNF-Met allele (including Met/Val and Met/Met) when combined with the TPH2-T allele (including T/G and T/T combinations). The consistency of these results across tasks and studies suggests that these two groups may be particularly vulnerable to the most common psychiatric disorders and should be targets for future clinical investigation.

Dataset Information

Effect of BDNF val66met polymorphism on age-related amygdala volume changes in healthy subjects.

Publications

Effect of BDNF val66met polymorphism on age-related amygdala volume changes in healthy subjects.

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