The aging hippocampus: interactions between exercise, depression, and BDNF

Abstract

Late adulthood is associated with increased hippocampal atrophy and dysfunction. Although there are multiple paths by which hippocampal deterioration occurs in late life, the authors discuss the evidence that a single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene and age-related changes in BDNF protein or receptor expression contribute to hippocampal atrophy. The authors conclude that few studies have tested whether BDNF mediates age-related hippocampal atrophy and memory impairment. However, there is strong evidence that decreased BDNF is associated with age-related hippocampal dysfunction, memory impairment, and increased risk for depression, whereas increasing BDNF by aerobic exercise appears to ameliorate hippocampal atrophy, improve memory function, and reduce depression. Importantly, the most consistent associations between BDNF and hippocampal dysfunction have emerged from research on BDNF protein expression in rodents and serum and plasma concentrations of BDNF in humans. Current research suggests that the BDNF val66met polymorphism may be only weakly associated with hippocampal atrophy in late adulthood. These conclusions are interpreted in relation to age-related memory impairment and preventions for hippocampal atrophy.

Figure 1

The mean hippocampal volume (for both left and right hemispheres) atrophies in late adulthood. These data were collected using a high-resolution magnetic resonance imaging scan and the hippocampus demarcated using an automated segmentation algorithm (data adapted from Erickson, Prakash, and others 2010).

Figure 2

There is significant variation in brain atrophy with advancing age, such that some older adults show little atrophy whereas others show considerable atrophy. In this array of nine brains, we demonstrate that some of the variation can be easily detected by the naked eye. (A) Brain images from young subjects at an average age of 22 years. (B) Brain images from older adult subjects at an average age of 72 years. (C) Brain images from older adult subjects at an average age of 72 years. The average age of (B) and (C) are identical yet the morphology and amount of atrophy are quite disparate between these subjects. For example, the ventricles and sulci are enlarged in (B) compared with (C) or (A). These data showing differential trajectories of brain atrophy support the idea that brain decay might be slowed or prevented.

Figure 3

Evidence for a shift in the brain-derived neurotrophic factor genotype-phenotype association in executive function over a 10-year span in older adults. Participants in this study performed a switching task, a common measure of executive function twice over a 10-year period. There were two conditions: a repeat condition in which two tasks of the same type follow each other and switch conditions when the tasks switch from one trial to the next. There was a main effect of condition such that all participants were slower on the switch condition than repeat. Although Val/Val carriers performed faster at time 1, they were the only group to show a decline in performance over a 10-year span (data adapted from Erickson and others 2008).

Figure 4

Mediation models for how (A) reductions in hippocampal volume mediate age-related decline in memory function and (B) reductions in brain-derived neurotrophic factor (BDNF) signaling result in reduced hippocampal volume (e.g., dendritic branching and cell proliferation), which in turn results in poorer memory function. Note that in both of these models, there are additional direct paths between age and memory function because hippocampal volume most likely only makes up one node in a network of brain structures that are leading to memory impairment. Furthermore, in (B), a direct path is modeled between age and hippocampal volume because changes in many different molecules besides BDNF are probably contributing to decreased hippocampal volume and function.

Figure 5

Serum brain-derived neurotrophic factor levels decline with advancing age (P < 0.05; data adapted from Erickson, Prakash, and others 2010).

Figure 6

Serum brain-derived neurotrophic factor is positively correlated with hippocampus volume in older adults. Although this association is a relatively small effect, it is significant (P < 0.05) and remains so after controlling for potentially confounding factors such as sex and years of education (data adapted from Erickson, Prakash, and others 2010).

Figure 7

Hypothetical mediation models for (A) the association between brain-derived neurotrophic factor (BDNF) signaling, serotonin fibers and neurotransmission, hippocampal volume, and depressive symptoms. Depressive symptoms are modeled here as a latent cluster of symptoms. In this model, BDNF signaling has a reciprocal relationship with serotonin such that reductions in both lead to decreased hippocampal volume. There is a circular path between decreased hippocampal volume, increased depressive symptoms, and decreased serotonin fibers and neurotransmission. Thus, in this model, it appears as if decreased hippocampal volume precedes depressive symptoms, but increased depressive symptoms might have compounding effects on decreased hippocampal volume by magnifying the loss of serotonergic fibers. In model (B), we hypothesize that increased aerobic exercise leads to increased production of BDNF, which in turn leads to increased hippocampal volume (e.g., dendritic branching and cell proliferation) and improved memory function. However, similar to model (A), we predict that exercise influences hippocampal volume through several pathways, BDNF being only one of them. Furthermore, exercise could also improve memory function by influencing several different molecules and brain networks in addition to the hippocampus.

Figure 8

Greater mean hippocampus volume (across left and right hemispheres) is associated with higher cardiorespiratory fitness levels as quantified by VO₂ peak, the gold standard measure of aerobic fitness, in 165 older adults without dementia (data adapted from Erickson and others 2009).

Figure 9

(A) Over a nine-year period, greater amounts of physical activity in the form of walking are associated with greater gray matter volume in several regions including prefrontal, temporal, and hippocampal areas. (B) The effect of walking on greater gray matter volume was dependent on the amount of walking. Those individuals walking at least 72 blocks or roughly 6 to 9 miles per week showed the greatest amount of gray matter volume. Given the association between exercise and brain-derived neurotrophic factor (BDNF), it is possible that these effects are at least partially mediated by BDNF (data adapted from Erickson, Raji, and others 2010).

Figure 10

Hypothetical biomarker models of brain-derived neurotrophic factor (BDNF) signaling, hippocampal volume, and memory function. In model (A), increased age is associated with decreased BDNF signaling and decreased hippocampal volume, but these paths run parallel with each other such that reductions in BDNF signaling are viewed as a liability for decreased hippocampal volume but not a mechanistic pathway. Similarly, in model (B), reciprocal connections between BDNF and serotonin exist, and reductions in BDNF signaling only indirectly influence the risk for depressive symptoms. In this model, changes in BDNF and hippocampal volume would be correlated with depressive symptoms but would not by themselves be sufficient for causing depressive symptoms. In model (C), an increase in the amount of exercise results in improvements in memory but does so independently of changes in BDNF or hippocampal volume. Again, BDNF and hippocampal volume might be correlated with exercise-related improvements in memory function but would not be causally related.