Cognitive and MRI Brain Morphometric Correlates of Brain-Derived Neurotrophic Factor Val66Met Gene Polymorphism in Schizophrenia and Healthy Volunteers

Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, USA.
Archives of General Psychiatry (Impact Factor: 14.48). 08/2006; 63(7):731-40. DOI: 10.1001/archpsyc.63.7.731
Source: PubMed


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.
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.
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.
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.
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.
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.

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Available from: Daniel S O'Leary, Sep 08, 2014
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    • "The Val66Met polymorphism in the BDNF gene has been shown to play an important role in structural and functional plasticity in schizophrenia (Buckley et al., 2011). Most studies exploring the influence of BDNF-gene on brain structure in schizophrenia have focused on cross-sectional brain anomalies in chronic (Dutt et al., 2009; Gruber et al., 2012; Ho et al., 2006), and first episode of psychosis (FEP) patients (Smith et al., 2012; Szeszko et al., 2005). To our knowledge, only three follow-up studies have also investigated the association between the BDNF polymorphism and brain volume changes across time. "
    European Psychiatry 12/2014; 29:1. DOI:10.1016/S0924-9338(14)78142-8 · 3.44 Impact Factor
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    • "The BDNF val66met polymorphism has thus also been investigated for its association with declarative memory performance. While several studies have not shown an association between BDNF polymorphism and declarative memory measures (Benjamin et al., 2010; Gong et al., 2009; Houlihan et al., 2009; Karnik et al., 2010; Strauss et al., 2004; Tsai et al., 2008), several studies found that in samples of young adults, the BDNF met carriers had poorer verbal memory for items than the BDNF val homozygotes (Dempster et al., 2005; Egan et al., 2003; Hariri et al., 2003; Ho et al., 2006; Tan et al., 2005). Recent meta-analyses indicate that most of these studies relied mainly on tasks of item memory, and almost exclusively tested verbal memory (Kambeitz et al., 2012; Mandelmann and Grigorenko, 2012). "
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    ABSTRACT: The BDNF val66met polymorphism (rs6265) influences activity-dependent secretion of brain-derived neurotrophic factor in the synapse, which is crucial for learning and memory. Individuals homozygous or heterozygous for the met allele have lower BDNF secretion than val homozygotes and may be at risk for reduced declarative memory performance, but it remains unclear which types of declarative memory may be affected and how aging of memory across the lifespan is impacted by the BDNF val66met polymorphism. This cross-sectional study investigated the effects of BDNF polymorphism on multiple indices of memory (item, associative, prospective, subjective complaints) in a lifespan sample of 116 healthy adults aged 20-93 years. Advancing age showed a negative effect on item, associative and prospective memory, but not on subjective memory complaints. For item and prospective memory, there were significant age x BDNF group interactions, indicating the adverse effect of age on memory performance across the lifespan was much stronger in the BDNF met carriers than for the val homozygotes. BDNF met carriers also endorsed significantly greater subjective memory complaints, regardless of age, and showed a trend (p<.07) toward poorer associative memory performance compared to val homozygotes. These results suggest that genetic predisposition to the availability of brain-derived neurotrophic factor, by way of the BDNF val66met polymorphism, exerts an influence on multiple indices of episodic memory - in some cases in all individuals regardless of age (subjective memory and perhaps associative memory), in others as an exacerbation of age-related differences in memory across the lifespan (item and prospective memory).
    Brain Research 09/2014; 1612. DOI:10.1016/j.brainres.2014.09.044 · 2.84 Impact Factor
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    • "Careful consideration of several factors is required when defining the specific genes incorporated into a particular genoset. Previous studies comparing neurodevelopmental outcomes in typically developing children compared to those with a history of institutional care have reported significant differences, particularly 2010), including working memory and spatial learning (Egan et al., 2003; Ho et al., 2006; Honea et al., 2009; Kuningas et al., 2007; Schulz-Heik et al., 2011; Sheldrick et al., 2008). "
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    ABSTRACT: An individual’s neurodevelopmental and cognitive sequelae to negative early experiences may, in part, be explained by genetic susceptibility. We examined whether extreme differences in the early caregiving environment, defined as exposure to severe psychosocial deprivation associated with institutional care compared to normative rearing, interacted with a biologically informed genoset comprising BDNF (rs6265), COMT (rs4680), and SIRT1 (rs3758391) to predict distinct outcomes of neurodevelopment at age 8 (N = 193, 97 males and 96 females). Ethnicity was categorized as Romanian (71%), Roma (21%), unknown (7%), or other (1%). We identified a significant interaction between early caregiving environment (i.e., institutionalized versus never institutionalized children) and the a priori defined genoset for full-scale IQ, two spatial working memory tasks, and prefrontal cortex gray matter volume. Model validation was performed using a bootstrap resampling procedure. Although we hypothesized that the effect of this genoset would operate in a manner consistent with differential susceptibility, our results demonstrate a complex interaction where vantage susceptibility, diathesis stress, and differential susceptibility are implicated.
    International Journal of Behavioral Development 06/2014; 39(2). DOI:10.1177/0165025414538557 · 1.58 Impact Factor
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