BDNF polymorphism predicts the rate of decline in skilled task performance and hippocampal volume in healthy individuals

Abstract

Numerous studies have indicated a link between the presence of polymorphism in brain-derived neurotrophic factor (BDNF) and cognitive and affective disorders. However, only a few have studied these effects longitudinally along with structural changes in the brain. This study was carried out to investigate whether valine-to-methionine substitution at position 66 (val66met) of pro-BDNF could be linked to alterations in the rate of decline in skilled task performance and structural changes in hippocampal volume. Participants consisted of 144 healthy Caucasian pilots (aged 40-69 years) who completed a minimum of 3 consecutive annual visits. Standardized flight simulator score (SFSS) was measured as a reliable and quantifiable indicator for skilled task performance. In addition, a subset of these individuals was assessed for hippocampal volume alterations using magnetic resonance imaging. We found that val66met substitution in BDNF correlated longitudinally with the rate of decline in SFSS. Structurally, age-dependent hippocampal volume changes were also significantly altered by this substitution. Our study suggests that val66met polymorphism in BDNF can be linked to the rate of decline in skilled task performance. Furthermore, this polymorphism could be used as a predictor of the effects of age on the structure of the hippocampus in healthy individuals. Such results have implications for understanding possible disabilities in older adults performing skilled tasks who are at a higher risk for cognitive and affective disorders.Translational Psychiatry (2011) 1, e51; doi:10.1038/tp.2011.47; published online 25 October 2011.

Figure 1

Schematic representation of possible mechanism by which val66met substitution in BDNF leads to failed activity-dependent release of BDNF or reduced intracellular transport. Val66met substitution changes the dynamics of interaction between BDNF and two important proteins: (1) Sortilin, is involved in intracellular sorting and pro-neurotrophin signaling. Val66met substitution leads to reduction of BDNF interaction with this protein, which results in mis-sorting into the constitutive secretory pathway instead of activity-dependent release. (2) Translin is a highly conserved protein involved in mRNA transport. An exon found in all BDNF mRNA splice variants contains a specific translin-binding region, which is essential for appropriate BDNF mRNA dendritic targeting. It has been shown that Val66met substitution diminishes BDNF mRNA interaction with translin, which leads to reduced translocation of BDNF mRNA to dendrites.

Figure 2

The slope of the SFSS in individuals with and without val66met substitution. As shown, we found a significant (ANOVA, F=7.696, P=0.0060) reduction in the slope of flight simulator score in met carriers (mean±s.d., slope=−0.110±0.135, n=55) compared with non-met carriers (slope=−0.036±0.165, n=89) during the first 2 years of follow-up.

Figure 3

The total volume of the hippocampus (both left and right) in individuals with and without val66met substitution. No significant differences were found in the size of the hippocampus, before and after 65 years in non-met carriers (before 65=100.0±9.63 and after 65=100.556±10.265: F=0.031, P-value=0.8610). However, there was a significant reduction in the size of the hippocampus in met carriers after the age of 65 years (before 65=104.654±9.938 and after 65=90.918±6.522, F=17.53, P-value=0.0001). As the result, we found a significant difference in the size of the hippocampus after the age of 65 years between met carriers and non-met carriers (F=7.207, P-value=0.014). The number of individuals in their sixth, seventh and eighth decades of life were 15, 15 and 6 among met carriers and 19, 26 and 5 among non-met carriers, respectively.

Figure 4

The relationship between the total volume of the hippocampus and the age and the effects of val66met substitution. Using a polynomial fitting curve, we found a (r=−0.447, P=0.0150) correlation between age and the volume of the hippocampus in met carriers. No such correlation was found in non-met carriers (r=−0.178, P=0.2639). Furthermore, the slope of the regression in met carriers (slope=−0.038) was twice the value of the slope of regression in non-met carriers (slope=−0.016).