The Val66Met polymorphism of the brain-derived neurotrophic factor gene affects age-related brain morphology

We investigated the effects of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on age-associated changes of brain morphology in 109 Japanese healthy subjects using MRI with optimized voxel-based morphometry technique. A significant age-related volume reduction was found in the dorsolateral prefrontal cortices (DLPFC), anterior cingulate cortices, and temporal and parietal cortices in all subjects. Further analysis revealed a significantly negative correlation between age and the volume of the bilateral DLPFC only in the Met-BDNF carriers, and a significant interaction between the polymorphism and age-associated volume changes in the bilateral DLPFC. Furthermore, Met-carriers showed a significant interaction (p<0.0001) between the gender and the genotype on the gray matter volume in the DLPFC, and female Met-carriers showed more widespread age-associated volume reduction in DLPFC than male Met-carriers. Our data suggest that the Val66Met polymorphism may impact on age-related changes of the brain, which might be associated with the functional variance of neuroprotective effects of the BDNF. Furthermore, we suggest that genotype effects of the BDNF gene on brain morphology might differ in female from in male.

[1]  A. Apkarian,et al.  Aging alters the multichemical networking profile of the human brain: an in vivo1H‐MRS study of young versus middle‐aged subjects , 2001, Journal of neurochemistry.

[2]  Thomas E. Nichols,et al.  Thresholding of Statistical Maps in Functional Neuroimaging Using the False Discovery Rate , 2002, NeuroImage.

[3]  E. Huang,et al.  Neurotrophins: roles in neuronal development and function. , 2001, Annual review of neuroscience.

[4]  Richard S. J. Frackowiak,et al.  Navigation-related structural change in the hippocampi of taxi drivers. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[5]  G. Cosnard,et al.  Comparison of regional cerebral blood flow and glucose metabolism in the normal brain: effect of aging , 2000, Journal of the Neurological Sciences.

[6]  Karl J. Friston,et al.  A Voxel-Based Morphometric Study of Ageing in 465 Normal Adult Human Brains , 2001, NeuroImage.

[7]  Paul J. Laurienti,et al.  An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets , 2003, NeuroImage.

[8]  Carlo Miniussi,et al.  The Role of Prefrontal Cortex in Verbal Episodic Memory: rTMS Evidence , 2003, Journal of Cognitive Neuroscience.

[9]  S. Gabriel,et al.  Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus , 2002, Molecular Psychiatry.

[10]  R. Hashimoto,et al.  No association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder in a Japanese population: A multicenter study , 2004, Biological Psychiatry.

[11]  J. Conner,et al.  Anterograde transport of brain-derived neurotrophic factor and its role in the brain , 1997, Nature.

[12]  A. Meyer-Lindenberg,et al.  The Brain-derived Neurotrophic Factor Val66met Polymorphism and Variation in Human Cortical Morphology , 2022 .

[13]  Karl J. Friston,et al.  Nonlinear Regression in Parametric Activation Studies , 1996, NeuroImage.

[14]  H. Nelson,et al.  Dementia: The Estimation of Premorbid Intelligence Levels Using the New Adult Reading Test , 1978, Cortex.

[15]  M. Hayashi,et al.  Changes in BDNF-immunoreactive structures in the hippocampal formation of the aged macaque monkey , 2001, Brain Research.

[16]  M. Egan,et al.  Brain-Derived Neurotrophic Factor val66met Polymorphism Affects Human Memory-Related Hippocampal Activity and Predicts Memory Performance , 2003, The Journal of Neuroscience.

[17]  O. Lindvall,et al.  Rapid Alterations of BDNF Protein Levels in the Rat Brain after Focal Ischemia: Evidence for Increased Synthesis and Anterograde Axonal Transport , 1998, Experimental Neurology.

[18]  G. Ratcliff,et al.  Sex differences in brain aging: a quantitative magnetic resonance imaging study. , 1998, Archives of neurology.

[19]  Faith M. Gunning-Dixon,et al.  Aging, sexual dimorphism, and hemispheric asymmetry of the cerebral cortex: replicability of regional differences in volume , 2004, Neurobiology of Aging.

[20]  D Robinson,et al.  Brain-derived neurotrophic factor Val66met polymorphism and volume of the hippocampal formation , 2005, Molecular Psychiatry.

[21]  H. Sakai,et al.  Infarct tolerance induced by intra-cerebral infusion of recombinant brain-derived neurotrophic factor , 2000, Brain Research.

[22]  M. Egan,et al.  The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function , 2003, Cell.

[23]  Nick C Fox,et al.  A longitudinal study of brain volume changes in normal aging using serial registered magnetic resonance imaging. , 2003, Archives of neurology.

[24]  C. Altar,et al.  Brain-derived neurotrophic factor (BDNF) prevents the degeneration of medial septal cholinergic neurons following fimbria transection , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[25]  Paresh D Patel,et al.  Variant Brain-Derived Neurotrophic Factor (BDNF) (Met66) Alters the Intracellular Trafficking and Activity-Dependent Secretion of Wild-Type BDNF in Neurosecretory Cells and Cortical Neurons , 2004, The Journal of Neuroscience.

[26]  Karl J. Friston,et al.  Voxel-Based Morphometry—The Methods , 2000, NeuroImage.

[27]  Hiroshi Kunugi,et al.  The Breakpoint Cluster Region Gene on Chromosome 22q11 is Associated with Bipolar Disorder , 2005, Biological Psychiatry.

[28]  J. Gorski,et al.  Early Striatal Dendrite Deficits followed by Neuron Loss with Advanced Age in the Absence of Anterograde Cortical Brain-Derived Neurotrophic Factor , 2004, The Journal of Neuroscience.