Regular article3T hippocampal glutamate-glutamine complex reflects verbal memory decline in aging
Introduction
One of the key concerns of older adults is the experience of memory loss, both in the normal course of aging and as it is associated with neural degenerative disease. Many of the types of memory that demonstrate age-related decline are mediated by the hippocampus and surrounding medial temporal lobe structures (Morrison and Baxter, 2012; Small, 2001, Yassa et al., 2011a). While there are many laboratory tasks that are designed to tax-specific aspects of hippocampal function, standardized neuropsychological tests are broadly available and extensively used in both research and clinical settings. The Rey Auditory Verbal Memory Task (RAVLT; Rey, 1941) has been shown to be highly effective at detecting age-related memory decline (Mitrushina et al., 1991, Schoenberg et al., 2006). In this task, memory is assessed based on the acquisition of a list of 15 unrelated words, followed by free recall, and repeated over the course of 5 presentations. Participants are then given an interference list of 15 new words, followed by free recall of the original list and another free recall 15 minutes later. Age-related decline has been observed on all recall trials (Mitrushina et al., 1991), with performance on delayed recall correlating with functional scales of memory in those with subjective memory complaints (Estevez-Gonzalez et al., 2003). It is currently used by a number of research groups to identify healthy agers who are particularly “successful” (Mapstone et al., 2014), “super” (Rogalski et al., 2013), or “unimpaired” (Stark et al., 2013) in their memory performance relative to other, healthy participants. Likewise, a delayed word-recall performance on a related task is particularly sensitive to early decline associated with Alzheimer's disease (Albert, 1996).
Although the aging brain has been associated with declines in hippocampal volume (Raz et al., 2005), there is strong evidence that this neuronal loss is not simply due to fewer neurons (Burke and Barnes, 2006). Instead, there are evidence of synaptic alterations (Nicholson et al., 2004) and decreases in gene expression (Berchtold et al., 2013) in aging. Likewise, there are neuromodulatory changes in the hippocampus, including decreased cholinergic input to the hippocampus (Sugaya et al., 1998) and a reduction in dopamine that correlates with memory performance (Stemmelin et al., 2000). While these findings have been reported in rodents, we now have the technology to investigate some of these neurotransmitters in humans using magnetic resonance spectroscopy (MRS). Instead of looking at MRS related to disease, the goal of this work is to link it to behavioral performance.
MRS quantifies the concentration of various metabolites (intermediary and byproducts of metabolism) in the brain, with many of these accessible via conventional proton (1H) imaging. Numerous studies have utilized the efficiency of MRS in providing biological information on cellular/metabolic changes in the aging brain or diseased brain (see Wang et al., 2015 for a review). Specifically, our focus is on Glutamate (Glu), the most abundant metabolite in the brain, a dominant excitatory neurotransmitter. Glutamate is released during neuronal excitation and converted to Glutamine (Gln) with the Glu-Gln cycle requiring high energy demands. Alterations in concentrations of Glu and Gln have been reported in numerous neurological and psychiatric diseases, such as depression and mood disorders, epilepsy, alcohol and drug abuse, schizophrenia, and neurodegenerative disorders (see Ramadan et al., 2013 for a review).
MRS studies have shown reduced Glu levels in a mouse model of Alzheimer's disease (AD; Chen et al., 2012b) and in humans with AD (Rupsingh et al., 2011). They have also shown a decrease in combined Glu and Gln (referred to as Glx) in the cingulate cortices and posterior cingulate gyrus of AD patients (Antuono et al., 2001, Hattori et al., 2002). Little is known about any such alterations in healthy aging or in the hippocampus per se, despite the clear potential for age-related changes in hippocampal activity (Miller et al., 2008, Wilson et al., 2006, Yassa et al., 2011b). In one report, Wagner et al. (2016) investigated the relationship between hippocampal Glx, functional connectivity with the hippocampus, and verbal memory performance (on a different task) in healthy young males. They reported that lower Glx levels were associated with higher functional connectivity of the hippocampus to prefrontal cortex and anterior cingulate. In addition, they found that Glx concentration in the posterior hippocampus predicted verbal memory performance. These relationships emphasize the utility of MRS as a functional measure of neuronal activity, related to both behavior and brain connectivity.
Given the relationship of Glx to aging and AD, and the possible link to memory performance, the purpose of this study was to investigate age-related changes in Glx levels in the hippocampus using short echo time MRS in young and older adults. We hypothesized that Glx levels would correlate with age-related decline on the RAVLT. Following the findings of Wagner et al. (2016), we also investigated the relationship between Glx and resting-state functional connectivity (rs-fMRI) in a subset of our sample for which we were fortunate enough to also have rs-fMRI scans. We hypothesized that we would replicate the negative relationship found between the resting-state functional connectivity (RSFC) anterior hippocampus to regions in the prefrontal cortex and Glx levels in the right anterior hippocampus. These findings would significantly extend those of Wagner et al. (2016) by showing the behavioral relevance of Glx in the hippocampus to healthy aging and link them to the highly-used RAVLT.
Section snippets
Participant recruitment
Forty-one participants, consisting of 21 older (ages 59–84) and 20 younger adults (ages 20–38) were recruited for this study from the community surrounding the University of California in Irvine (UCI). Two participants were removed from the analysis: 1 young adult was excluded because one of their MRS voxels contained only 20% overlap with the hippocampus (motion between scan preparation and acquisition) and one older adult was excluded for RAVLT scores that fell outside the age-thresholded
Age-related differences in RAVLT performance
One older adult performed more than 2 standard deviations below standardized normative values for his age. As this may represent either exceptionally inattentive performance or potential early clinical impairment, this individual was excluded from further analysis. All other young and older participants performed within 1 standard deviation of the standardized norms for their age.
In the resulting data set, we examined the effect of aging on the RAVLT using planned independent samples t tests.
Discussion
In this study, we measured Glx (a combined measure of glutamate and glutamine) in the anterior hippocampus of young and older adults. We found that greater Glx concentration in older adults was correlated with higher memory performance in a word recall on the RAVLT, both at encoding and retrieval. Moreso, we showed that this effect was observed in both the left and the right hippocampus, providing an internal replication of this relationship. Interestingly, this relationship was not evident in
Conclusions
We report that decreases in Glx in the anterior hippocampus were accompanied by decreased performance in verbal memory in aged adults. These preliminary findings suggest a potential age-related modulatory role of Glu and/or Glu in the hippocampal regulation of memory. Future studies are needed to focus on how a dysregulation of the excitation-inhibition balance in the hippocampus may contribute to age-related memory decline.
Disclosure statement
The authors have no conflicts of interest to disclose.
Acknowledgements
The authors would like to thank Samantha Rutledge for her assistance with data collection and Derek Huffman and Veronique Boucquey for assistance with preprocessing the resting state functional connectivity data. Funding for this project was provided in part by a grant from the National Institutes on Aging R01-AG034613 and R21-AG053040.
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