Associations of Plasma Glutamatergic Metabolites with Alpha Desynchronization during Cognitive Interference and Working Memory Tasks in Asymptomatic Alzheimer's Disease

Abstract

Electroencephalogram (EEG) studies have suggested compensatory brain overactivation in cognitively healthy (CH) older adults with pathological beta-amyloid(Aβ₄₂)/tau ratios during working memory and interference processing. However, the association between glutamatergic metabolites and brain activation proxied by EEG signals has not been thoroughly investigated. We aim to determine the involvement of these metabolites in EEG signaling. We focused on CH older adults classified under (1) normal CSF Aβ₄₂/tau ratios (CH-NATs) and (2) pathological Aβ₄₂/tau ratios (CH-PATs). We measured plasma glutamine, glutamate, pyroglutamate, and γ-aminobutyric acid concentrations using tandem mass spectrometry and conducted a correlational analysis with alpha frequency event-related desynchronization (ERD). Under the N-back working memory paradigm, CH-NATs presented negative correlations (r = ~-0.74--0.96, p = 0.0001-0.0414) between pyroglutamate and alpha ERD but positive correlations (r = ~0.82-0.95, p = 0.0003-0.0119) between glutamine and alpha ERD. Under Stroop interference testing, CH-NATs generated negative correlations between glutamine and left temporal alpha ERD (r = -0.96, p = 0.037 and r = -0.97, p = 0.027). Our study demonstrated that glutamine and pyroglutamate levels were associated with EEG activity only in CH-NATs. These results suggest cognitively healthy adults with amyloid/tau pathology experience subtle metabolic dysfunction that may influence EEG signaling during cognitive challenge. A longitudinal follow-up study with a larger sample size is needed to validate these pilot studies.

Keywords: Alzheimer’s disease (AD); electroencephalogram (EEG); event-related alpha desynchronization (ERD); glutamate; glutamine; pyroglutamate.

Figure 1

Conversion between glutamatergic metabolites. Abbreviations: TCA, tricarboxylic acid cycle; NH₃, ammonia; CO₂, carbon dioxide; GABA, γ-aminobutyric acid; glutamine’s conversion to glutamate is catalyzed via deamidation by glutaminase. The reaction is reversible via amidation of glutamate by glutamine synthase. Glutaminyl cyclase (QC) performs ideally around physiological pH and produces pyroglutamine and pyroglutamate from glutamine and glutamate, respectively, with pyroglutamate being the dominant species. Cyclization and deamination of glutamine forms pyroglutamate. Cyclization and dehydration of glutamate produces pyroglutamate. Decarboxylation of glutamate via glutamate decarboxylase under acidic conditions produces GABA. GABA also produces α-ketoglutarate as a byproduct to feed into the TCA cycle and eventually replenish GABA. This figure was drawn using ChemDraw 23.1.1 64-bit.

Figure 2

Topoplots of correlations between Glu, Gln, PGlu, and alpha ERD by group. p-values (0 to 0.05) are based on a black/white scale, while Pearson correlation coefficients (−1 to 1) are based on the red/green/blue scale. Glutamine concentrations in (A) CH-NATs demonstrate prominent central, frontal, and temporal positive correlations (black and red) with alpha ERD, unlike (B) insignificant correlations (white) in CH-PATs. Pyroglutamate in (C) CH-NATs negatively correlated with frontal, central, and temporal alpha ERD (black and blue), while (D) CH-PATs maintained insignificant associations (white).