Kennedy KM, Rodrigue KM, Land SJ, Raz N. BDNF Val66Met polymorphism influences age differences in microstructure of the Corpus Callosum. Front Hum Neurosci 3: 19

Center for Brain Health, School of Behavioral and Brain Sciences, The University of Texas at Dallas Dallas, TX, USA.
Frontiers in Human Neuroscience (Impact Factor: 2.99). 02/2009; 3:19. DOI: 10.3389/neuro.09.019.2009
Source: PubMed


Brain-derived neurotrophic factor (BDNF) plays an important role in neuroplasticity and promotes axonal growth, but its secretion, regulated by a BDNF gene, declines with age. The low-activity (met) allele of common polymorphism BDNF val66met is associated with reduced production of BDNF. We examined whether age-related reduction in the integrity of cerebral white matter (WM) depends on the BDNF val66met genotype. Forty-one middle-aged and older adults participated in the study. Regional WM integrity was assessed by fractional anisotropy (FA) computed from manually drawn regions of interest in the genu and splenium of the corpus callosum on diffusion tensor imaging scans. After controlling for effects of sex and hypertension, we found that only the BDNF 66met carriers displayed age-related declines in the splenium FA, whereas no age-related declines were shown by BDNF val homozygotes. No genotype-related differences were observed in the genu of the corpus callosum. This finding is consistent with a view that genetic risk for reduced BDNF affects posterior regions that otherwise are considered relatively insensitive to normal aging. Those individuals with a genetic predisposition for decreased BDNF expression may not be able to fully benefit from BDNF-based plasticity and repair mechanisms.

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Available from: Karen M Rodrigue, Oct 06, 2015
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    • "Another study in individuals with prodromal AD reported that the Met allele was associated with increased memory decline, paralleled by more hippocampal atrophy, across three years (Lim et al. 2014). Similarly, agerelated decline in white-matter microstructure (i.e., lower fractional anisotropy), as measured with diffusion tensor imaging, were found for Met carriers in the splenium of the corpus callosum, although no age-related decline was evident for Val homozygotes (Kennedy et al. 2009). Taken together, increasing behavioral evidence as well as data from functional and structural imaging studies suggest magnified effects of BDNF on brain and cognition in aging, with greater decline in functioning for older Met carriers. "
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    ABSTRACT: Increasing evidence from cross-sectional and longitudinal molecular-genetic studies suggests that effects of common genetic variations on cognitive functioning increase with aging. We review the influence of candidate genes on brain functioning in old age, focusing on four genetic variations that have been extensively investigated: APOE, BDNF, COMT, and KIBRA. Similar to the behavioral evidence, there are reports from age-comparative studies documenting stronger genetic effects on measures of brain functioning in older adults compared to younger adults. This pattern suggests disproportionate impairments of neural processing among older individuals carrying disadvantageous genotypes. We discuss various factors, including gene-gene interactions, study population characteristics, lifestyle factors, and diseases, that need to be considered in future studies and may help understand inconsistent findings in the extant literature.
    Neuropsychology Review 02/2015; 25(1). DOI:10.1007/s11065-015-9279-8 · 4.59 Impact Factor
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    • "Notably, the low frequency of the BDNF Met allele (0.18) and the resulting small number of Met/Met homozygotes (n ¼ 3) precluded independent statistical analysis of this genotype group. Thus, analogous to previous DTI studies on this variant (Ho et al, 2006; Kennedy et al, 2009; Montag et al, 2010; Soliman et al, 2010), Val/Met and Met/Met individuals were merged in one group for all analyses. Subject demographics stratified by BDNF genotype are reported in "
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    ABSTRACT: The BDNF Val(66)Met polymorphism, a possible risk variant for mental disorders, is a potent modulator of neural plasticity in humans and has been linked to deficits in gray matter structure, function, and cognition. The impact of the variant on brain white matter structure, however, is controversial and remains poorly understood. Here, we used diffusion tensor imaging to examine the effects of BDNF Val(66)Met genotype on white matter microstructure in a sample of 85 healthy Caucasian adults. We demonstrate decreases of fractional anisotropy and widespread increases in radial diffusivity in Val/Val homozygotes compared with Met-allele carriers, particularly in prefrontal and occipital pathways. These data provide an independent confirmation of prior imaging genetics work, are consistent with complex effects of the BDNF Val(66)Met polymorphism on human brain structure, and may serve to generate hypotheses about variation in white matter microstructure in mental disorders associated with this variant.Neuropsychopharmacology advance online publication, 7 November 2012; doi:10.1038/npp.2012.214.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2012; 38(3). DOI:10.1038/npp.2012.214 · 7.05 Impact Factor
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    • "2008), a result that is inconsistent with studies of the BDNF gene on hippocampal volume in younger populations (Bueller and others 2006). However, several studies have reported that the BDNF Met allele might be associated with reduced volume in the prefrontal cortex (Nemoto and others 2006) and splenium (Kennedy and others 2009). In short, the research on the association between the BDNF gene, cognition, and hippocampal volume in late adulthood appears inconsistent with research on the BDNF polymorphism in other populations (e.g., younger adults, schizophrenics), suggesting an age-related change in the penetrance of the BDNF gene on cognitive and brain atrophy phenotypes (Table 1). "
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    ABSTRACT: Late adulthood is associated with increased hippocampal atrophy and dysfunction. Although there are multiple paths by which hippocampal deterioration occurs in late life, the authors discuss the evidence that a single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene and age-related changes in BDNF protein or receptor expression contribute to hippocampal atrophy. The authors conclude that few studies have tested whether BDNF mediates age-related hippocampal atrophy and memory impairment. However, there is strong evidence that decreased BDNF is associated with age-related hippocampal dysfunction, memory impairment, and increased risk for depression, whereas increasing BDNF by aerobic exercise appears to ameliorate hippocampal atrophy, improve memory function, and reduce depression. Importantly, the most consistent associations between BDNF and hippocampal dysfunction have emerged from research on BDNF protein expression in rodents and serum and plasma concentrations of BDNF in humans. Current research suggests that the BDNF val66met polymorphism may be only weakly associated with hippocampal atrophy in late adulthood. These conclusions are interpreted in relation to age-related memory impairment and preventions for hippocampal atrophy.
    The Neuroscientist 04/2011; 18(1):82-97. DOI:10.1177/1073858410397054 · 6.84 Impact Factor
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