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: 3.63). 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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    • "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.
    Full-text · Article · Feb 2015 · Neuropsychology Review
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    • "Recent studies have shown that a common single nucleotide polymorphism of the BDNF gene at codon 66 —BDNF Val66Met—present in approximately one-third of the American population (Shimizu et al. 2004) is associated with several alterations in BDNF function and differences in cortical morphology. For example, reduced activity-dependent BDNF release in response to neural stimulation, reduced NMDA and GABA receptor-mediated synaptic transmission (Ninan et al. 2010; Pattwell et al. 2012), altered white matter integrity in the corpus callosum (CC; Carballedo et al. 2012; Kennedy et al. 2009), and reduced hippocampal volumes (Pezawas 2004) have been reported in Val66Met carriers. Val66Met polymorphism is also associated with altered shortterm plasticity in the motor cortex and impaired short-term motor learning. "
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    ABSTRACT: Recent data suggest that the Val66Met polymorphism of the BDNF gene can alter cortical plasticity within the motor cortex of carriers, which exhibits abnormally low rates of cortical reorganization following repetitive motor tasks. To verify if long-term retention of a motor skill is also modulated by the presence of the polymorphism, 20 participants (10 Val66Val; 10 Val66Met) were tested twice at a one week interval. During each visit, excitability of the motor cortex was measured by transcranial magnetic stimulations (TMS) before and after performing a procedural motor learning task (Serial Reaction Time Task) designed to study sequence-specific learning of the right hand and sequence-specific transfer from the right to the left hand. Behavioral results showed a motor learning effect that persisted for at least a week and task-related increased in corticospinal excitability identical for both sessions and without distinction for genetic group. Sequence-specific transfer of the motor skill from the right hand to the left hand was greater in session 2 than session 1 only in the Val66Met genetic group. Further analysis revealed that the sequence-specific transfer occurred equally at both sessions in the Val66Val genotype group. In the Val66Met genotype group, sequence-specific transfer did not occur at session 1, but did at session 2. These data suggest a limited impact of Val66Met polymorphism on the learning and retention of a complex motor skill and its associated changes in corticospinal excitability over time, and a possible modulation of the interhemispheric transfer of procedural learning.
    Preview · Article · Feb 2014 · Journal of Neurophysiology
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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.
    Full-text · Article · Nov 2012 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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