Dataset Information

Decreased motor cortex γ-aminobutyric acid in amyotrophic lateral sclerosis.

ABSTRACT:

Objectives

To determine if there are in vivo differences in γ-aminobutyric acid (GABA) in the motor cortex and subcortical white matter of patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls using proton magnetic resonance spectroscopy (1H-MRS).

Methods

In this cross-sectional study, 10 patients with ALS and 9 age- and sex-matched healthy controls (HCs) underwent 3T edited 1H-MRS to quantify GABA centered on the motor cortex and the subcortical white matter.

Results

Compared with healthy controls, patients with ALS had significantly lower levels of GABA in the left motor cortex (1.42 ± 0.27 arbitrary institutional units vs. 1.70 ± 0.24 arbitrary institutional units, p = 0.038). There was no significant difference in GABA levels between groups in the subcortical white matter (p > 0.05).

Conclusion

Decreased levels of GABA are present in the motor cortex of patients with ALS compared to HCs. Findings are consistent with prior reports of alterations in GABA receptors in the motor cortex as well as increased cortical excitability in the context of ALS. Larger, longitudinal studies are needed to confirm these findings and to further our understanding of the role of GABA in the pathogenesis of ALS.

SUBMITTER: Foerster BR

PROVIDER: S-EPMC3348851 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal disorder caused by the progressive degeneration of motoneurons in brain and spinal cord. Despite identification of disease-linked mutations, the diversity of processes involved and the ambiguity of their relative importance in ALS pathogenesis still represent a major impediment to disease models as a basis for effective therapies. Moreover, the human motor cortex, although critical to ALS pathology and physiologically altered in most forms of the disease, has not been screened systematically for therapeutic targets. RESULTS: By whole-genome expression profiling and stringent significance tests we identify genes and gene groups de-regulated in the motor cortex of patients with sporadic ALS, and interpret the role of individual candidate genes in a framework of differentially expressed pathways. Our findings emphasize the importance of defense responses and cytoskeletal, mitochondrial and proteasomal dysfunction, reflect reduced neuronal maintenance and vesicle trafficking, and implicate impaired ion homeostasis and glycolysis in ALS pathogenesis. Additionally, we compared our dataset with publicly available data for the SALS spinal cord, and show a high correlation of changes linked to the diseased state in the SALS motor cortex. In an analogous comparison with data for the Alzheimer's disease hippocampus we demonstrate a low correlation of global changes and a moderate correlation for changes specifically linked to the SALS diseased state. CONCLUSION: Gene and sample numbers investigated allow pathway- and gene-based analyses by established error-correction methods, drawing a molecular portrait of the ALS motor cortex that faithfully represents many known disease features and uncovers several novel aspects of ALS pathology. Contrary to expectations for a tissue under oxidative stress, nuclear-encoded mitochondrial genes are uniformly down-regulated. Moreover, the down-regulation of mitochondrial and glycolytic genes implies a combined reduction of mitochondrial and cytoplasmic energy supply, with a possible role in the death of ALS motoneurons. Identifying candidate genes exclusively expressed in non-neuronal cells, we also highlight the importance of these cells in disease development in the motor cortex. Notably, some pathways and candidate genes identified by this study are direct or indirect targets of medication already applied to unrelated illnesses and point the way towards the rapid development of effective symptomatic ALS therapies.