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.

• Authors: Bradley R Foerster, Martin G Pomper, Brian C Callaghan, Myria Petrou, Richard A E Edden, Mona A Mohamed, Robert C Welsh, Ruth C Carlos, Peter B Barker, Eva L Feldman
• Journal: JAMA neurology (JAMA Neurol) Vol. 70 Issue 8 Pg. 1009-16 (Aug 2013) ISSN: 2168-6157 [Electronic] United States
• PMID: 23797905 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Excitatory Amino Acid Antagonists
• Glutamine
• Glutamic Acid
• gamma-Aminobutyric Acid
• Riluzole

Topics

• Adult
• Aged
• Amyotrophic Lateral Sclerosis (drug therapy, etiology, metabolism)
• Biomarkers (metabolism)
• Case-Control Studies
• Down-Regulation (drug effects, physiology)
• Excitatory Amino Acid Antagonists (administration & dosage)
• Female
• Glutamic Acid (biosynthesis, metabolism)
• Glutamine (biosynthesis, metabolism)
• Humans
• Magnetic Resonance Spectroscopy (instrumentation, methods)
• Male
• Middle Aged
• Motor Cortex (drug effects, metabolism)
• Neural Inhibition (physiology)
• Riluzole (therapeutic use)
• Up-Regulation (drug effects, physiology)
• gamma-Aminobutyric Acid (biosynthesis, metabolism)