Memantine decreases hippocampal glutamate levels: a magnetic resonance spectroscopy study

Abstract

Glutamate (Glu) is associated with excitotoxic cell damage. Memantine modulates the glutamate induced excitotoxicity in Alzheimer's disease (AD). No information is available as to the influence of memantine on in vivo brain glutamate levels. Hippocampal Glu levels were measured in cognitively impaired and normal individuals (n=10) before and after 6 months of memantine treatment, using three dimensional high spatial resolution (0.5 cm(3) voxels) proton magnetic resonance spectroscopy at 3 T. These measurements were also repeated in a non-treated cognitively normal group (n=6). Treatment with memantine decreased Glu/Cr (creatine) ratio in the left hippocampal region. Memantine reduced hippocampal glutamate levels, which may be consistent with its anti-excitotoxic property.

Figure 1

Sagittal (a) and coronal (b) and paraxial (c) T1-weighted images, along the hippocampus axis, depicting the position and angulation of the 16_AP×16_LR×2_IS cm³ FOV (dashed line) and 7_AP×9_LR×2_IS cm³ VOI (solid line) centered on the hippocampi (arrows). The red indicates the region of the hippocampus from where the spectra were sampled.

Figure 2

Top, a: Schematic description of the TE=39ms PRESS with WET water suppression. Localization along X and Y (LR×AP) was ×16 CSI. The ×4 partitions along Z (IS) were achieved by sequentially encoding two slabs each TR=1600 ms, with 2^nd order HSI, as shown in 2b, with the 5.12 ms PRESS 90° pulse. The two refocusing 180°s were 12.8 ms long numerically optimized Shinnar-LeRoux pulses under the selective-gradient strengths indicated. Bottom, left, b: The spatial excitation profiles of the two 2^nd order HSI slabs in the VOI. The goal was to reduce the B₁ demands and the inter-slice “bleed” (Goelman et al.2006b;Goelman et al.2006a). Bottom, right, c: The four slice profiles obtained by the two inverse 2^nd order Hadamard transforms, Ĥ₂⁻¹, indicated as i±j with i and j indicating the pulse numbers in 2b.

Figure 3

a. Real part of the 18×14 (LR×AP) axial matrix of ¹H spectra in the VOI of Fig. 1c (Solid frame) superimposed on the MRI of this slice for anatomical reference (right side of the figure corresponds to the left side of the head). Spectra representing (0.5 cm)³=0.125 cm³ interpolated voxels share the same 1.6 - 3.7 ppm and intensity scales. The linewidths in this slice were 12.1±1.4 Hz (mean ± standard deviation). b: Top: Voxels marked “1-4” from the left hippocampus in the matrix above; raw spectra (solid thin lines) overlaid with the metabolite fitted function (gray thick curves) with the residual (raw spectrum – fit) plotted below. Spectra and residuals are on the same horizontal and PPM scales. Note the SNR, spectral resolution and quality of the fit (reflected from the noise-only residual, from these small voxels acquired in 27 minutes. b: Bottom: Axial metabolic maps of the N-acetylaspartate (NAA), glutamate (Glu), glutamine (Gln), creatine (Cr), and choline (Cho) obtained from the fit of the above matrix. Note the excellent correspondence between the metabolic images and the morphology of the image above, reflecting the overall quality of the spectra, spatial resolution and localization. The metabolite maps presented are formed from the quantified amplitude of each metabolite.