A quantitative meta-analysis of brain glutamate metabolites in aging

Glutamate (Glu) is a key molecule in cellular metabolism, the most abundant excitatory neurotransmitter in the brain, and the principal neurotransmitter of cortical efferents. Glutamate dysfunction, on the other hand, is common in neurodegenerative disorders, and likely contributes to age-related declines in behavioral and cognitive functioning. Nonetheless, the extant literature measuring age-related changes in brain glutamate in vivo has yet to be comprehensively and quantitatively summarized. This meta-analysis examines proton spectroscopy (¹HMRS) measures of Glu-related brain metabolites across 589 healthy young and older adults. Glu (Cohen's d = -0.82) and Glu+glutamine (Cohen's d = -0.51) concentrations were significantly lower in older compared with younger adults, whereas the concentration of glutamine (d = 0.43) was significantly higher in older individuals. Notably, ¹HMRS methodological choices impacted effect sizes for age-related Glu differences. Glu metabolite change appears to be a robust marker of aging-related neurological change; however, additional studies are needed to elucidate age-related trajectories of glutamatergic alterations and their relationship to cognitive phenotypes.