The volume of the hippocampus shrinks in late adulthood (Kennedy et al., 2009
; Raz et al., 2005
), which increases the risk for cognitive impairment (Grundman et al., 2002
). However, the molecular factors contributing to hippocampal volume decline in humans has been a matter of speculation. BDNF is critical for memory formation and long-term potentiation (Korte et al., 1995
; Mu et al., 1999
) and is thought to regulate neurogenesis (Benraiss et al., 2001
; Katoh-Semba et al., 2002
; Lee et al., 2001
; Pencea et al., 2001
;). In humans, serum and plasma BDNF levels decline with advancing age (Lommatzsch et al., 2005
; Ziegenhorn et al., 2007
) and genetic studies have identified a single nucleotide polymorphism on the BDNF gene that moderates age-related cognitive decline over a 10-year period (Erickson et al., 2008
). Given this research, we reasoned that BDNF levels might be associated with age-related hippocampal volume loss. Consistent with this hypothesis, we found that increasing age was associated with reduced levels of BDNF, and reduced levels of BDNF were related to both decline in hippocampal volume and elevated memory deficits.
In rodents, BDNF moderates synaptic plasticity and neurogenesis in the dentate gyrus and has been directly related to learning rates in spatial memory paradigms (Hwang et al., 2006
; Rex et al., 2007
; Silhol et al., 2007
). By blocking either the release of BDNF or the binding of BDNF to its receptor (TrkB), long-term potentiation is effectively eliminated in the hippocampus (Pang et al., 2004
). Furthermore, inducing BDNF production and secretion in the hippocampus can rescue long-term potentiation and relieve spatial memory deficits in aged mice (Rex et al., 2006
; Simmons et al., 2009
). In a rodent model of successful aging in which the animals have longer lifespans and preserved memory capacities, BDNF levels were higher than in animals that experience normal age-related patterns of decline (Silhol et al., 2008
). BDNF also moderates tau formation (Elliott & Ginzburg, 2006
), beta-amyloid neurotoxicity (Arancibia et al., 2008
), and hippocampal-dependent memory performance in animal models of Alzheimer’s disease (Blurton-Jones et al., 2009
; Tapia-Arancibia et al., 2008
). In sum, BDNF has been convincingly demonstrated to relate to memory formation, neurogenesis, and Alzheimer’s disease pathology in aged animals.
In humans, post-mortem research has found reduced levels of BDNF in the hippocampus of older adults compared to younger adults and lower levels in individuals with Alzheimer’s and Parkinson’s diseases compared to age-matched controls (Hock et al., 2000
; Murer et al., 2001
). Given the challenges associated with measuring BDNF in post-mortem tissue, recent studies have examined circulating BDNF in living subjects. The functional significance of BDNF in the blood is a matter of debate, but our results, along with others (Gunstad et al., 2008
; Lommatzsch et al., 2005
; Ziegenhorn et al., 2007
), demonstrate that circulating BDNF levels decline with advancing age. However, the degree to which serum BDNF reflects BDNF levels in the brain (e.g. hippocampus) remains a matter of speculation. Several studies have now reported positive correlations (r=.81) between serum BDNF and BDNF in both the prefrontal cortex and hippocampus (Karege et al., 2002
; Elfving et al., 2009
; Sartorius et al., 2009
) suggesting there might be a link between peripheral and central sources of BDNF. BDNF is produced and secreted at several sites in the periphery (e.g. platelets) and therefore, the results from our study and previous studies could be due to parallel actions on peripheral sources and central sources of BDNF and not necessarily due to central levels influencing the concentration of BDNF in the periphery. Thus, prior studies on correlations between BDNF in the serum and brain cannot make inferences about the locus of its release (Pan et al., 1998
; Sartorius et al., 2009
). However, our results build on these prior studies and demonstrate that serum BDNF levels are correlated with measurements of hippocampal volume – an important link that suggests some association between BDNF in the blood and measures of brain integrity (Lang et al, 2007
). Future longitudinal studies should assess the possibility that declining BDNF could be a precursor to cognitive or cortical decay.
Several studies suggest that BDNF levels change rapidly with environmental stimulants such as acute (e.g. 30 minutes) periods of exercise (Gold et al., 2003
). Such fluctuation in circulating BDNF levels could influence reliability estimates of serum BDNF. Further, given that we collected blood approximately 2-weeks prior to the neuroimaging session it is possible that BDNF levels fluctuated across this period. However, our results suggest that any changes in BDNF concentrations across the two-week period are not enough to eliminate the association with hippocampal volume and memory. Nonetheless, increasing levels of BDNF with exercise suggests that BDNF levels are modifiable. Several studies have found that higher aerobic fitness levels are associated with larger hippocampal volumes (Erickson et al., 2009
) and greater volumes of prefrontal and temporal brain regions (Colcombe et al., 2003). It is possible that BDNF plays a critical role in the effects of exercise on the human brain (Kramer & Erickson, 2007).
We found evidence that declining levels of BDNF mediate age-related decline of the left and right hippocampus. Further, BDNF and hippocampal volume mediated spatial memory performance. Interestingly, the mediation results of the hippocampus on age-related memory decline were relatively specific to the left hippocampus, and not to the right. Other studies have reported asymmetries in the volume and function of the left and right hippocampus (Erickson et al., 2009
) and suggest that the left and right hemispheres might play different, but complementary roles, in memory tasks that emphasize speed. Our results suggest that the left hippocampus is related to measures of speed for all memory set sizes, and the right hippocampus only for the 3-item condition.
Although intriguing, these mediation analyses were conducted on cross-sectional data, so it is equally likely that shrinkage of the hippocampus results in lower BDNF levels in the blood. In fact, in another set of mediation analyses, we found that left hippocampal volume mediated the BDNF-spatial memory association. This finding highlights the difficulty of determining the direction of the effects on cross-sectional data. Besides the temporal constraints of interpreting the results from the mediation analysis, other unmeasured third variables correlated with both hippocampal volume and BDNF levels could also influence and explain the mediation results. The only way to formally test for mediation is through a longitudinal study that measures both circulating BDNF levels and hippocampal volumes at multiple time points. Nonetheless, our cross-sectional findings highlight the importance of BDNF as a factor associated with age-related hippocampal volume decay.
We found that circulating levels of BDNF were specific to the volume of the hippocampus and were unrelated to the volume of the caudate nucleus. BDNF is found in the striatum and interacts with the dopaminergic system to regulate parkinsonian symptoms in rodent models (Collier et al., 2005
; Murer et al., 2001
). Although we failed to find an association between blood levels of BDNF and caudate nucleus volume, we also failed to find any decline in volume of the caudate nucleus with increasing age. This was surprising given that several studies have identified the caudate nucleus as an important site of age-related volume loss (e.g. Raz et al., 2005
). Our failure to find an age-related decline in caudate nucleus volume might be due to the restricted age range of this sample as compared to other studies which have reported such effects. Nonetheless, the lack of an association between BDNF and caudate nucleus volume does not suggest that BDNF has no relation to the circuitry of the striatum. It is likely that many different molecules other than BDNF are contributing to age-related loss of tissue volume in both the caudate nucleus and the hippocampus. In fact, we found that BDNF only partially mediated the age-related decline in hippocampal volume, indicating that there are other factors besides declining levels of BDNF that contribute to hippocampal decay.
There are several important limitations of our study. First, future studies should examine the association between BDNF and age-related hippocampal volume loss in longitudinal or randomized designs. Longitudinal and randomized trials will help to determine mediation effects and directionality. In addition, our spatial memory findings were only partially related to BDNF levels, and only significantly so for response time measures. It will be important for future studies to examine BDNF levels in relation to other hippocampal-dependent tasks that are not as reliant on speeded responses as our task.
In sum, we found an important association between age-related hippocampal volume loss, decline in spatial memory performance, and reduced levels of circulating BDNF. Given the importance of determining the biomarkers and molecules associated with volume loss in late adulthood, our finding is clinically significant and suggests that interventions that elevate levels of BDNF might help to reduce age-related volume loss. Our mediation analyses, although intriguing, are inherently limited by the cross-sectional nature of the study and the interpretative difficulties with assigning causation to a correlational model. Further research is necessary to convincingly demonstrate a causal relation between declining levels of BDNF and age-related hippocampal decay. It is also critically important for future studies to identify the potential for healthy lifestyles (e.g. exercise) to moderate BDNF levels in an older adult cohort.