Brain-Derived Neurotrophic Factor Val66Met Polymorphism Affects Resting Regional Cerebral Blood Flow and Functional Connectivity Differentially in Women Versus Men

Section on Integrative Neuroimaging, National Institute of Mental Health Intramural Research Programs, National Institutes of Health, Bethesda, Maryland 20892, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2012; 32(20):7074-81. DOI: 10.1523/JNEUROSCI.5375-11.2012
Source: PubMed


The human Val⁶⁶Met single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene impacts BDNF signaling at the cellular level. At the neural-systems level, it is associated with differences in prefrontal cortex (PFC) and hippocampal function during performance of cognitive and affective tasks. Because the impact of this variant on basal prefrontal and hippocampal activity is not known but may be relevant to understanding the function of this gene in health and disease, we studied 94 healthy individuals with H₂ ¹⁵O PET to assess regional cerebral blood flow (rCBF) during rest and tested for between-genotype differences. Because BDNF and gonadal steroid hormones conjointly influence neuronal growth, survival, and plasticity in hippocampus and PFC, we also tested for sex × genotype interactions. Finally, in light of the known impact of BDNF on plasticity and dendritic arborization, we complimented direct rCBF comparisons with connectivity analyses to determine how activity in hippocampal and prefrontal regions showing between-genotype group differences covaries with rCBF in other nodes throughout the brain in a genotype- or sex-dependent manner. Compared with Val homozygotes, Met carriers had higher rCBF in prefrontal (BA25 extending into BA10) and hippocampal/parahippocampal regions. Moreover, there were significant sex × genotype interactions in regions (including frontal, parahippocampal, and lateral temporal cortex) in which Val homozygotes showed higher rCBF in females than males, but Met carriers showed the opposite relationship. Functional connectivity analysis demonstrated that correlations of BA25, hippocampus, and parahippocampus with frontal and temporal networks were positive for Val homozygotes and negative for Met carriers. In addition, sex × genotype analysis of functional connectivity revealed that genotype affected directionality of the inter-regional correlations differentially in men versus women. Our data indicate that BDNF allelic variation and sex interactively affect basal prefrontal and hippocampal function.

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Available from: Shau-Ming Wei, Jan 02, 2015
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    • "We controlled for BMI as weight may be a significant confound on cognition, particularly hippocampal-related memory performance [5], [12]. Furthermore, sex may significantly alter the size and structure of the brain [31] particularly in the hippocampus and other subcortical brain regions, and particularly in the elderly [15]. Additionally, level of education attainment during adolescence may impact on cerebral volume [32]. "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) links learning, memory and cognitive decline in elderly, but evidence linking BDNF allele variation, cognition and brain structural differences is lacking. 367 elderly Swedish men (n = 181) and women (n = 186) from Prospective Investigation of the Vasculature in Uppsala seniors (PIVUS) were genotyped and the BDNF functional rs6265 SNP was further examined in subjects who completed the Trail Making Task (TMT), verbal fluency task, and had a magnetic resonance imaging (MRI) scan. Voxel-based morphometry (VBM) examined brain structure, cognition and links with BDNF. The functional BDNF SNP (rs6265,) predicted better working memory performance on the TMT with positive association of the Met rs6265, and was linked with greater cerebellar, precuneus, left superior frontal gyrus and bilateral hippocampal volume, and reduced brainstem and bilateral posterior cingulate volumes. The functional BDNF polymorphism influences brain volume in regions associated with memory and regulation of sensorimotor control, with the Met rs6265 allele potentially being more beneficial to these functions in the elderly.
    PLoS ONE 01/2014; 9(1):e82707. DOI:10.1371/journal.pone.0082707 · 3.23 Impact Factor
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    • "In Val/Val homozygotes no analogous gender difference was found (Tukey HSD post hoc test p = .520, t(33)  = −1.330, p = .193) (See Figure 2). A similar genotype x gender interaction was found for the parahippocampal, right DLPFC, various left temporal and right caudate rCBF levels of female and male Val/Val and Val/Met carriers [10]: Val/Val females had higher activity than Val/Val males whereas Val/Met males had higher activity than Val/Met females. "
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    ABSTRACT: Mechanisms of visual perception should be robustly fast and provide veridical information about environmental objects in order to facilitate survival and successful coping. Because species-specific brain mechanisms for fast vision must have evolved under heavy pressure for efficiency, it has been held that different human individuals see the physical world in the same way and produce psychophysical functions of visual discrimination that are qualitatively the same. For many years, this assumption has been implicitly accepted in vision research studying extremely fast, basic visual processes, including studies of visual masking. However, in recent studies of metacontrast masking surprisingly robust individual differences in the qualitative aspects of subjects' performance have been found. As the basic species-specific visual functions very likely are based on universal brain mechanisms of vision, these differences probably are the outcome of variability in ontogenetic development (i.e., formation of idiosyncrasic skills of perception). Such developmental differences can be brought about by variants of genes that are differentially expressed in the course of CNS development. The objective of this study was to assess whether visual discrimination in metacontrast masking is related to three widely studied genetic polymorphisms implicated in brain function and used here as independent variables. The findings suggest no main effects of BDNF Val66Met, NRG1/rs6994992, or 5-HTTLPR polymorphisms on metacontrast performance, but several notable interactions of genetic variables with gender, stage of the sequence of experimental trials, perceptual strategies, and target/mask shape congruence were found. Thus, basic behavioral functions of fast vision may be influenced by common genetic variability. Also, when left uncontrolled, genetic factors may seriously confound variables in vision research using masking, obscure clear theoretical interpretation, lead to unexplicable inter-regional differences and create problems of replicability of formerly successful experiments.
    PLoS ONE 01/2013; 8(1):e55287. DOI:10.1371/journal.pone.0055287 · 3.23 Impact Factor
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    • "For instance , males and females were not matched on the distribution of genetic polymorphisms that are known to modulate prefrontal functions and – in addition to hormonal differences – may have also driven the present differential findings (e.g. Wei et al., 2012). Furthermore, as often reported, males and females differ substantially with respect to brain sizes and volumes (cf. "
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    ABSTRACT: Planning of behavior relies on the integrity of the mid-dorsolateral prefrontal cortex (mid-dlPFC). Yet, only indirect evidence exists on the association of protracted maturation of dlPFC and continuing gains in planning performance post adolescence. Here, gray matter density of mid-dlPFC in young, healthy adults (18-32years) was regressed onto performance on the Tower of London planning task while accounting for moderating effects of age and sex on this interrelation. Multiple regression analysis revealed an association of planning performance and mid-dlPFC gray matter density that was especially strong in late adolescence and early twenties. As expected, for males better planning performance was linked to reduced gray matter density of mid-dlPFC, possibly due to maturational processes such as synaptic pruning. Most surprisingly, females showed an inverted, positive interrelation of planning performance and mid-dlPFC gray matter density, indicating that sexually dimorphic development of dlPFC continues during early adulthood. Age and sex are hence important moderators of the link between planning performance and gray matter density in mid-dlPFC. Consequently, the assessment of moderator effects in regression designs can significantly enhance understanding of brain-behavior relationships.
    NeuroImage 08/2012; 63(3):1454-63. DOI:10.1016/j.neuroimage.2012.08.032 · 6.36 Impact Factor
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