Altered glutamate-glutamine and amide proton transfer-weighted values in the hippocampus of patients with amnestic mild cognitive impairment: A novel combined imaging diagnostic marker

Abstract

Background and purpose: Early diagnosis of amnestic mild cognitive impairment (aMCI) and timely management to delay the onset of Alzheimer's disease (AD) would benefit patients. Pathological metabolic changes of excitatory/inhibitory neurotransmitters and abnormal protein deposition in the hippocampus of aMCI may provide a new clue to imaging diagnosis. However, the diagnostic performance using these hippocampal metabolite measurements is still unclear. We aimed to quantify right hippocampal glutamate-glutamine (Glx) and gamma-aminobutyric acid (GABA) levels as well as protein-based amide proton transfer-weighted (APTw) signals of patients with aMCI and investigate the diagnostic performance of these metabolites.

Methods: In this cross-sectional study, 20 patients with aMCI and 20 age- and gender-matched healthy controls (HCs) underwent MEGA Point Resolved Spectroscopy (MEGA-PRESS) and APTw MR imaging at 3 T. GABA+, Glx, and APTw signals were measured in the right hippocampus. The GABA+ levels, Glx levels, Glx/GABA+ ratios, and APTw values were compared between the HCs and aMCI groups using the Mann-Whitney U test. Binary logistic regression and receiver operating characteristic (ROC) curve analyses were used to evaluate MEGA-PRESS and APTw parameters' diagnostic performance.

Results: Compared with HCs, patients with aMCI had significantly lower Glx levels in the right hippocampus (7.02 ± 1.41 i.u. vs. 5.81 ± 1.33 i.u., P = 0.018). No significant changes in the GABA+ levels were observed in patients with aMCI (HCs vs. aMCI: 2.54 ± 0.28 i.u. vs. 2.47 ± 0.36 i.u., P = 0.620). In addition, Glx/GABA+ ratios between the two groups (HCs vs. aMCI: 2.79 ± 0.60 vs. 2.37 ± 0.55, P = 0.035) were significantly different. Compared with HCs, patients with aMCI showed higher APTw values in the right hippocampus (0.99 ± 0.26% vs. 1.26% ± 0.28, P = 0.006). The ROC curve analysis showed that Glx, GABA+, Glx/GABA+, and APTw values had an area under the curve (AUC) of 0.72, 0.55, 0.70, and 0.75, respectively, for diagnosing aMCI. In the ROC curve analysis, the AUC of the combination of the parameters increased to 0.88, which is much higher than that observed in the univariate analysis (P < 0.05).

Conclusion: The combination of right hippocampal Glx levels and APTw values improved the diagnostic performance for aMCI, indicating it as a promising combined imaging diagnostic marker. Our study provided a potential imaging diagnostic strategy of aMCI, which may promote early detection of aMCI and facilitate timely intervention to delay the pathological progress toward AD.

Keywords: MEGA-PRESS; amide proton transfer-weighted imaging; amnestic mild cognitive impairment; hippocampus; imaging diagnostic marker.

Figure 1

The position of voxels and segmentation data. Coronal and sagittal T1-weighted TFE images show single-voxel placements centered on the right hippocampus in a healthy participant [female, 64 years (A)] and a patient with amnestic mild cognitive impairment (aMCI) [women, 66 years (B)].

Figure 2

Representative regions of interest (ROIs) for APT analysis. Delineate ROI of the right hippocampus in the maximum cross-sectional layer of T₁-weighted image with APTw image overlay.

Figure 3

The mean (±standard deviation) GABA+ and Glx edited spectra acquired by the MEGA-PRESS sequence in the healthy controls (HCs) and patients with aMCI. The signal intensities of the aMCI group consistently plus a constant of 2.0 × 10⁻⁴ for more convenient signal display and comparison.

Figure 4

Box and whisker plots for the comparison of Glx levels, GABA+ levels, Glx/GABA+ ratios, and APTw values between the HCs group (n = 20) and the aMCI group (n = 20). (A) No significant difference in GABA+ levels was found between HCs and aMCI (P = 0.620). (B) Compared with the HCs group, Glx levels of the aMCI group were significantly decreased (P = 0.018). (C) The Glx/GABA+ ratios of the aMCI group are lower than the HCs, and a statistical difference was detected (P = 0.035). (D) Compared with HCs, patients with aMCI showed higher APTw values in the right hippocampus (P = 0.006).

Figure 5

Correlation analysis of right hippocampus metabolites. No significant correlation was found between APTw values and GABA+ levels of the right hippocampus [r = −0.39, P = 0.083, (A)]; similar results were found between APTw values and Glx levels [r = 0.074, P = 0.755, (B)]. There is a moderate positive correlation between Glx and GABA+ levels [r = 0.454, P = 0.045, (C)].

Figure 6

Diagnostic performance of Glx, GABA+, Glx/GABA+ ratios, and APTw and the combined parameters. The ROC curve analysis showed that GABA+ has the lowest AUC of 0.55; Glx, Glx/GABA+ ratios, and APTw values have similar areas under the curve (AUC) of 0.72, 0.70, and 0.75, respectively, for the diagnosis of aMCI; a combination of these parameters demonstrated an increased AUC value of 0.88.