Frontal Gamma-Aminobutyric Acid Concentrations Are Associated With Cognitive Performance in Older Adults

Abstract

BACKGROUND Gamma-aminobutyric acid (GABA), the brain’s principal inhibitory neurotransmitter, has been associated with perceptual and attentional functioning. Recent application of magnetic resonance spectroscopy (MRS) provides in vivo evidence for decreasing GABA concentrations during adulthood. It is unclear, however, how age-related decrements in cerebral GABA concentrations contribute to cognitive decline, or whether previously reported declines in cerebral GABA concentrations persist during healthy aging. We hypothesized that participants with higher GABA concentrations in the frontal cortex would exhibit superior cognitive function and that previously reported age-related decreases in cortical GABA concentrations continue into old age. METHODS We measured GABA concentrations in frontal and posterior midline cerebral regions using a Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) 1H-MRS approach in 94 older adults without history or clinical evidence of mild cognitive impairment or dementia (mean age, 73 years). We administered the Montreal Cognitive Assessment to assess cognitive functioning. RESULTS Greater frontal GABA concentrations were associated with superior cognitive performance. This relation remained significant after controlling for age, years of education, and brain atrophy. GABA concentrations in both frontal and posterior regions decreased as a function of age. CONCLUSIONS These novel findings from a large, healthy, older population indicate that cognitive function is sensitive to cerebral GABA concentrations in the frontal cortex, and GABA concentration in frontal and posterior regions continue to decline in later age. These effects suggest that proton MRS may provide a clinically useful method for the assessment of normal and abnormal age-related cognitive changes and the associated physiological contributors.

Impact of tissue correction strategy on GABA-edited MRS findings

“…Specifically, GABA+/Cr levels in frontal and parietal brain regions have been shown to decrease with age (2). This finding was subsequently replicated in comparable voxel locations (3) and was associated with age-related changes in cognitive performance. Cognitive performance was strongly correlated with frontal GABA+ concentrations, even after accounting for age, the fraction of cerebral spinal fluid (CSF) in the MRS voxel (a coarse measure of brain atrophy) and behavioral factors such as education or age related normative performance.…”

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…During brain aging, the fidelity of neuronal network activity within and between brain regions is perturbed, in some individuals relatively subtly and in others pathologically. Excitatory imbalances occur in the aging brain as a result of impaired GABAergic signaling, particularly reduced signaling via GABA-A receptors (Heise et al, 2013; Richardson et al, 2013; McQuail et al, 2015; Porges et al, 2017). Several hallmarks of brain aging can render neuronal circuits vulnerable to hyperexcitability and excitotoxic damage, including oxidative stress, mitochondrial dysfunction, impaired adaptive stress responses, and inflammation (Camandola and Mattson, 2011).…”

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

“…Recent studies showed that such reductions of GABA levels in the human brain are associated with cognitive impairments in an age-dependent manner [8] and are further worsened during older age [9]. …”