Role of gamma-amino-butyric acid in the dorsal anterior cingulate in age-associated changes in cognition

Abstract

<p class="first" id="Par1">GABAergic mechanisms have been shown to contribute to cognitive aging in animal models, but there is currently limited in vivo evidence to support this relationship in humans. It is also unclear whether aging is associated with changes in GABA levels measured with proton magnetic resonance spectroscopy (MRS). Spectral-editing MRS at 3 T was used to measure GABA in the dorsal anterior cingulate cortex (dACC) for a large sample of healthy volunteers ( <i>N</i> = 229) aged 18–55. In a subset of 171 participants, age effects on several cognitive tasks were studied. We formally tested whether the MRS measures mediated the relationship between age and cognition. Robust associations of age with performance were found for the Wisconsin Card Sorting Test ([WCST], <i>p</i> &lt; 0.0001). Age was also significantly associated with declining levels of GABA in the dACC ( <i>p</i> &lt; 0.001), and GABA levels significantly predicted WCST performance ( <i>p</i> &lt; 0.0004). Mediation analysis revealed that GABA in the dACC mediated the effect of age on WCST performance ( <i>p</i> &lt; 0.01). Other metabolites were similarly associated with age, but only GABA and creatine levels were significantly associated with WCST performance. No association with age or cognitive performance was found in a frontal white matter control region in a subset of participants. The association of GABA with WCST performance was not related to the amount of brain atrophy associated with aging as measured by the proportion of CSF, gray, and white matter in the MRS voxel. These results implicate GABAergic and possibly energetic metabolism in the dACC as mechanisms of age effects in executive function. </p>