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Original Investigation |

An Imbalance Between Excitatory and Inhibitory Neurotransmitters in Amyotrophic Lateral Sclerosis Revealed by Use of 3-T Proton Magnetic Resonance Spectroscopy

Bradley R. Foerster, MD1,4,5; Martin G. Pomper, MD, PhD5; Brian C. Callaghan, MD, MS2; Myria Petrou, MA, MBChB, MS1,5; Richard A. E. Edden, PhD5,6; Mona A. Mohamed, MD, PhD, MPH5,6; Robert C. Welsh, PhD1,3; Ruth C. Carlos, MD, MS1; Peter B. Barker, DPhil5,6; Eva L. Feldman, MD, PhD2
[+] Author Affiliations
1Department of Radiology, University of Michigan, Ann Arbor
2Department of Neurology, University of Michigan, Ann Arbor
3Department of Psychiatry, University of Michigan, Ann Arbor
4Department of Veterans Affairs Ann Arbor Healthcare System, Michigan
5Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland
6F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland
JAMA Neurol. 2013;70(8):1009-1016. doi:10.1001/jamaneurol.2013.234.
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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.

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Figures

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Figure 1.
Voxel Placement and Mescher-Garwood Point-Resolved Spectroscopy (MEGA-PRESS) Spectrum

The box in each T1-weighted image shows the single-voxel placement centered on the pons in the sagittal (A) and axial projections (B), on 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). A representative proton magnetic resonance spectroscopy spectrum was obtained from the pons using the conventional PRESS technique (G). A representative proton magnetic resonance spectroscopy spectrum was obtained from the left motor cortex using the MEGA-PRESS editing technique (H). The combined measure of glutamine and glutamate (Glx) is resolved at 3.8 ppm, and γ-aminobutyric acid (GABA) is resolved at 3.0 ppm with an inverted N-acetylaspartate (NAA) peak at 2.0 ppm. Cho indicates choline; Cr, creatine; mI, myo-inositol.

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Figure 2.
Decreased γ-Aminobutyric Acid (GABA) Levels in the Motor Cortex of Patients With Amyotrophic Lateral Sclerosis (ALS)

The diamonds represent GABA levels in the left motor cortex (A) and subcortical white matter located caudal to the motor cortex (B) for individual healthy controls (open diamonds) and patients with ALS (filled diamonds). The horizontal bars indicate the mean. Patients with ALS have reduced levels of GABA in the left motor cortex compared with healthy controls. There is no difference in GABA levels in the left subcortical white matter between patients with ALS and healthy controls.

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Figure 3.
Metabolite Levels in the Left Motor Cortex for Riluzole-Naive Patients With Amyotrophic Lateral Sclerosis (ALS) and Riluzole-Treated Patients With ALS

The diamonds represent the respective brain metabolites of creatine (Cr [A]), glutamate and glutamine (Glx [B]), and N-acetylaspartate (NAA [C]). Riluzole-naive patients with ALS have elevated levels of Cr, Glx, and NAA in the left motor cortex compared with riluzole-treated patients with ALS.

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