Multimodal investigation of neuropathology and neurometabolites in mild cognitive impairment and late-life depression with 11C-PiB beta-amyloid PET and 7T magnetic resonance spectroscopy

Abstract

Positron emission tomography (PET) and magnetic resonance spectroscopy (¹H-MRS) are complementary techniques that can be applied to study how proteinopathy and neurometabolism relate to cognitive deficits in preclinical stages of Alzheimer's disease (AD)-mild cognitive impairment (MCI) and late-life depression (LLD). We acquired beta-amyloid (Aβ) PET and 7 T ¹H-MRS measures of GABA, glutamate, glutathione, N-acetylaspartate, N-acetylaspartylglutamate, myo-inositol, choline, and lactate in the anterior and posterior cingulate cortices (ACC, PCC) in 13 MCI and 9 LLD patients, and 13 controls. We used linear regression to examine associations between metabolites, Aβ, and cognitive scores, and whether metabolites and Aβ explained cognitive scores better than Aβ alone. In the ACC, higher Aβ was associated with lower GABA in controls but not MCI or LLD patients, but results depended upon MRS data quality control criteria. Greater variance in California Verbal Learning Test scores was better explained by a model that combined ACC glutamate and Aβ deposition than by models that only included one of these variables. These findings identify preliminary associations between Aβ, neurometabolites, and cognition.

Keywords: GABA; beta-amyloid; glutamate; late-life depression; magnetic resonance spectroscopy; mild cognitive impairment.

Figure 1:

(A) Example voxel placement in one participant for the ACC (green) and PCC (blue) voxels overlaid on their T1-weighted image. (B) Example MR spectra for ACC (green) and PCC (blue) from one participant. (C) Multiple slices of a single subject’s T1-weighted structural scan with distribution volume ratio (DVR) image intensities overlaid. The two MRS voxels are shown in blue and green. (D) Localized PET image intensity histograms with 5-parameter Gaussian fit (distribution center, amplitude, full-width at half-maximum, linear baseline). The center of the fit to the DVR distribution is used as the Aβ deposition metric for further analysis.

Figure 2

(A) Individual MR spectra (light grey) for both ACC and PCC, mean spectra per group (solid-colored lines), and standard deviation across group (color-shaded ribbons). Visualizations are color-coded for controls (red), MCI (green), and LLD (blue). (B) Example LCModel fit (orange) of a processed MR spectrum (black) with model residual in the top row. The individual metabolite constituent contributions are plotted

Figure 3:

Higher Aβ deposition in the ACC and PCC MRS volumes in MCI, but not LLD, compared with controls. Distribution plots of the Aβ distribution volume ratio (DVR) within the MRS volumes are shown for each region. (A) ACC data (B) PCC data. Each panel shows individual data points, whisker plots (representing mean +/− within-group standard deviation), and raincloud plots visualizing the distributions. All visualizations are color-coded for controls (red), LLD (blue), and MCI (green).

Figure 4:

Group-specific associations between Glu/tCr and Aβ in the PCC, displayed as predicted metabolite values (conditional effects). The association between Glu/tCr and Aβ deposition suggests a different Glu-Aβ relationship for the LLD group compared with the control and MCI groups. Color-coding: controls (red), LLD (blue), and MCI (green). Shaded regions indicate 95% confidence intervals. The region- and group-specific adjusted-R² and p-values for the Aβ deposition correlations are similarly colored, noted with an asterisk when statistically significant.

Figure 5:

Group-specific associations between GABA/tCr and Aβ in the ACC, displayed as predicted metabolite values (conditional effects). (A) Without individual CRLB exclusions: Differences between groups and relationships within group are not significant (B) With individual CRLB exclusions: A significant control-specific correlation between GABA and Aβ is found and is not present in MCI. Color-coding: controls (red), LLD (blue), and MCI (green). Shaded regions indicate 95% confidence intervals. The region- and group-specific adjusted-R² and p-values for the Aβ deposition correlations are similarly colored, noted with an asterisk when statistically significant.