An imbalance between excitatory and inhibitory neurotransmitters in amyotrophic lateral sclerosis revealed by use of 3-T proton magnetic resonance spectroscopy

Abstract

Importance: A lack of neuroinhibitory function may result in unopposed excitotoxic neuronal damage in amyotrophic lateral sclerosis (ALS).

Objective: To determine whether there are reductions in γ-aminobutyric acid (GABA) levels and elevations in glutamate-glutamine (Glx) levels in selected brain regions of patients with ALS by use of proton magnetic resonance spectroscopy.

Design: Case-control study using short echo time and GABA-edited proton magnetic resonance spectroscopy at 3 T with regions of interest in the left motor cortex, left subcortical white matter, and pons; data analyzed using logistic regression, t tests, and Pearson correlations; and post hoc analyses performed to investigate differences between riluzole-naive and riluzole-treated patients with ALS.

Setting: Tertiary referral center.

Participants: Twenty-nine patients with ALS and 30 age- and sex-matched healthy controls.

Exposure: Fifteen patients were taking 50 mg of riluzole twice a day as part of their routine clinical care for ALS.

Main outcomes and measures: Levels of GABA, Glx, choline (a marker of cell membrane turnover), creatine (a marker of energy metabolism), myo-inositol (a marker of glial cells), and N-acetylaspartate (a marker of neuronal integrity).

Results: Patients with ALS had significantly lower levels of GABA in the motor cortex than did healthy controls (P < .01). Patients with ALS also had significantly lower levels of N-acetylaspartate in the motor cortex (P < .01), subcortical white matter (P < .05), and pons (P < .01) and higher levels of myo-inositol in the motor cortex (P < .001) and subcortical white matter (P < .01) than did healthy controls. Riluzole-naive patients with ALS had higher levels of Glx than did riluzole-treated patients with ALS (P < .05 for pons and motor cortex) and healthy controls (P < .05 for pons and motor cortex). Riluzole-naive patients with ALS had higher levels of creatine in the motor cortex (P < .001 for both comparisons) and subcortical white matter (P ≤ .05 for both comparisons) than did riluzole-treated patients with ALS and healthy controls. Riluzole-naive patients with ALS had higher levels of N-acetylaspartate in the motor cortex than did riluzole-treated patients with ALS (P < .01).

Conclusions and relevance: There are reduced levels of GABA in the motor cortex of patients with ALS. There are elevated levels of Glx in riluzole-naive patients with ALS compared with riluzole-treated patients with ALS and healthy controls. These results point to an imbalance between excitatory and inhibitory neurotransmitters as being important in the pathogenesis of ALS and an antiglutamatergic basis for the effects of riluzole, although additional research efforts are needed.

Figure 1

Voxel placement and MEGA-PRESS spectrum. T1-weighted images showing single voxel placement centered on pons in the sagittal (A) and axial projections (B); the left motor cortex in the sagittal (C) and axial projections (D) and on the left subcortical white matter located caudal to the motor cortex in the sagittal (E) and axial projections (F). Representative magnetic resonance spectroscopy spectrum from the pons using conventional PRESS technique (G). Representative magnetic resonance spectroscopy spectrum from the left motor cortex using MEGA-PRESS editing technique (H). Combined measure of glutamine and glutamate (Glx) is resolved at 3.8 ppm, γ-aminobutyric acid (GABA) at 3.0 ppm with an inverted N-acetylaspartate (NAA) peak at 2.0 ppm.

Figure 2

Decreased γ-aminobutyric acid (GABA) levels in the motor cortex (MC) of amyotrophic lateral sclerosis (ALS) patients. Circles represent GABA levels in the left motor cortex (A) and subcortical white matter (SWCM) located caudal to the motor cortex (B) for individual healthy controls (HC) and ALS patients. Horizontal bars indicate the mean. ALS patients have reduced levels of GABA in the left motor cortex compared to healthy controls. There is no difference between ALS patient and healthy control GABA levels in the left subcortical white matter. IU = institutional units.

Figure 3

MRS PRESS results of left motor cortex (MC) metabolite levels for riluzole-naïve (⊖riluzole) and riluzole-treated (⊕riluzole) ALS patients. Circles represent respective brain metabolites for Cr (A), Glx (B) and NAA (C). Riluzole-naïve ALS patients have elevated levels of Cr, Glx and NAA in the left motor cortex compared to riluzole-treated ALS patients. Glx = glutamine + glutamate, Cr = Creatine, NAA = N-acetylaspartate, IU = institutional units.