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.

Aging-related magnification of genetic effects on cognitive and brain integrity

“…Age magnification of the effects of BDNF has also been reported for other measures of brain integrity, emphasizing the role of BDNF in modulating myelin expression [40] and survival of neurons in the adult brain [41]. Specifically, Met carriers had lower hippocampal volumes than Val homozygotes after age 65, whereas no such differences were apparent at younger ages ( Figure 3C) [38]. Crucially, age was unrelated to hippocampal volume in Val homozygotes, supporting the idea that brain maintenance in old age may partly reflect genetic factors [4].…”

“…In addition, in line with the resource-modulation hypothesis, longitudinal data from a sample of older adults aged 70 to 103 years demonstrate exacerbated decline in perceptual speed across 13 years for Met carriers [37], an effect that remained after excluding prodromal dementia cases ( Figure 3A). Similarly, pilots carrying the Met allele (aged 40-69 years) declined disproportionately across 2 years in flight-simulator performance, presumably reflecting executive functioning [38]. At the neural level, BDNF Met carriers exhibited lower hippocampal activity during encoding and retrieval of episodic memories [35].…”

“…White-matter integrity is indicated by fractional anisotropy. Adapted from [39] and [38] with permission from Nature Publishing Group, and from [43] C homozygotes, demonstrating stronger genetic effects with advancing age (Figure 4C,D).…”

Genetics and Functional Imaging: Effects of APOE, BDNF, COMT, and KIBRA in Aging

“…Also in line with the resource modulation hypothesis, longitudinal data demonstrate exacerbated decline in perceptual speed across 13 years among BDNF Met carriers (Ghisletta et al 2014), an effect that remained after excluding prodromal dementia cases. Similarly, Sanchez et al (2011) reported that pilots carrying the Met allele (aged 40-69 years) declined disproportionately in flight-simulator performance, presumably reflecting executive functioning.…”

“…Cross-sectional imaging studies have shown age magnification of the effects of BDNF for grey-matter volumes (Sanchez et al 2011) and white-matter microstructure (Kennedy et al 2009). Specifically, Met carriers had lower hippocampal volumes than Val homozygotes after age 65, whereas no such differences were apparent before 65 years (Sanchez et al 2011). Critically, age was uncorrelated with hippocampal volume in Val homozygotes, supporting the idea that brain maintenance in old age may be partly due to genetic factors .…”