Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume

Abstract

Hippocampal volume shrinks in late adulthood, but the neuromolecular factors that trigger hippocampal decay in aging humans remains a matter of speculation. In rodents, brain-derived neurotrophic factor (BDNF) promotes the growth and proliferation of cells in the hippocampus and is important in long-term potentiation and memory formation. In humans, circulating levels of BDNF decline with advancing age, and a genetic polymorphism for BDNF has been related to gray matter volume loss in old age. In this study, we tested whether age-related reductions in serum levels of BDNF would be related to shrinkage of the hippocampus and memory deficits in older adults. Hippocampal volume was acquired by automated segmentation of magnetic resonance images in 142 older adults without dementia. The caudate nucleus was also segmented and examined in relation to levels of serum BDNF. Spatial memory was tested using a paradigm in which memory load was parametrically increased. We found that increasing age was associated with smaller hippocampal volumes, reduced levels of serum BDNF, and poorer memory performance. Lower levels of BDNF were associated with smaller hippocampi and poorer memory, even when controlling for the variation related to age. In an exploratory mediation analysis, hippocampal volume mediated the age-related decline in spatial memory and BDNF mediated the age-related decline in hippocampal volume. Caudate nucleus volume was unrelated to BDNF levels or spatial memory performance. Our results identify serum BDNF as a significant factor related to hippocampal shrinkage and memory decline in late adulthood.

Figure 1.

The spatial memory task load was parametrically manipulated between one, two, or three items (2-item condition shown here). Participants were asked to remember the locations of one, two, or three black dots. After a brief delay, a red dot appeared, and participants were asked to respond whether the location of the red dot matched or did not match one of the locations of the previously shown black dots.

Figure 2.

A, Scatter plot showing the negative association between serum levels of BDNF and increasing age (p < 0.05). B, The proposed and tested mediation model. In this model, both BDNF and hippocampal volume mediate age-related spatial memory deficits, but BDNF also mediates age-related hippocampal decline.

Figure 3.

A, Example of hippocampal segmentation and scatter plots showing decline in volume of the left and right hippocampus between 59 and 81 years of age (significant at p < 0.001). B, Example of caudate nucleus segmentation and scatter plots showing no significant decline in volume of the caudate nucleus between 59 and 81 years of age.

Figure 4.

Scatter plots of the association between the volume of the left and right hippocampus and BDNF levels (left, significant at p < 0.05; right, marginally significant at p < 0.06).