Reduced Hippocampal GABA+ Is Associated With Poorer Episodic Memory in Healthy Older Women: A Pilot Study

Joan Jiménez-Balado, Alexandra Ycaza Herrera, Kay Igwe, Lynda Klem, Korhan Buyukturkoglu, Andrei Irimia, Liu Chen, Jia Guo, Adam M Brickman, Teal S Eich, Joan Jiménez-Balado, Alexandra Ycaza Herrera, Kay Igwe, Lynda Klem, Korhan Buyukturkoglu, Andrei Irimia, Liu Chen, Jia Guo, Adam M Brickman, Teal S Eich

Abstract

Background: The current pilot study was designed to examine the association between hippocampal γ-aminobutyric acid (GABA) concentration and episodic memory in older individuals, as well as the impact of two major risk factors for Alzheimer's disease (AD)-female sex and Apolipoprotein ε4 (ApoE ε4) genotype-on this relationship. Methods: Twenty healthy, community-dwelling individuals aged 50-71 (11 women) took part in the study. Episodic memory was evaluated using a Directed Forgetting task, and GABA+ was measured in the right hippocampus using a Mescher-Garwood point-resolved magnetic resonance spectroscopy (MRS) sequence. Multiple linear regression models were used to quantify the relationship between episodic memory, GABA+, ApoE ɛ4, and sex, controlling for age and education. Results: While GABA+ did not interact with ApoE ɛ4 carrier status to influence episodic memory (p = 0.757), the relationship between GABA+ and episodic memory was moderated by sex: lower GABA+ predicted worse memory in women such that, for each standard deviation decrease in GABA+ concentration, memory scores were reduced by 11% (p = 0.001). Conclusions: This pilot study suggests that sex, but not ApoE ɛ4 genotype, moderates the relationship between hippocampal GABA+ and episodic memory, such that women with lower GABA+ concentration show worse memory performance. These findings, which must be interpreted with caution given the small sample size, may serve as a starting point for larger studies using multimodal neuroimaging to understand the contributions of GABA metabolism to age-related memory decline.

Keywords: Alzheimer’s disease; GABA; apolipoprotein ε4; episodic memory; sex; γ-aminobutyric acid.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Jiménez-Balado, Ycaza Herrera, Igwe, Klem, Buyukturkoglu, Irimia, Liu, Guo, Brickman and Eich.

Figures

Figure 1
Figure 1
Localized images and representative MR spectra from a 2 × 2 × 4 cm3 voxel manually placed in the right hippocampus of a subject. (A) Axial and sagittal planes showing the hippocampal voxel, outlined in aqua, from one study participant’s MPRAGE T1-weighted image. (B) Loadings for the GABA edited difference spectrum. (C) Representative model fitting showing Glx (a combination of glutamate and glutamine) and GABA spectrum peaks, representing the GABA signal, from the same subject. The blue line represents the actual edited spectrum, whereas the overlaid pink line is the model of best fit. The residual is shown in the black curve below the modeling plot.
Figure 2
Figure 2
Association between episodic memory and GABA+ concentration by sex. GABA+ concentration was standardized into z-scores. Lines show the relation between GABA+ levels and episodic memory performance by (A) ApoE ε4 and (B) Sex. Linear regression models were constructed using the proportion of the TBR words (those words that participants were instructed to remember) as the dependent variable, and while accounting for the interactions of ApoE ε4 × GABA+ level and of sex × GABA+ level in separate models. Values represent regression coefficients β, their 95% confidence intervals (CIs), and the p-values of the standardized GABA main effects.
Figure 3
Figure 3
Quantile regression plot of GABA+ statistical effect on memory performance at each decile of TBR accuracy, by sex. The variation of GABA+ regression β coefficients (y axis) obtained from quantile regression models is represented at each decile (x axis). Colors represent males (black) and females (red). The red dashed line is set at 0, and thus error bars not crossing the red dashed line represent statistically significant associations.

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