title: Reduced gamma-aminobutyric acid concentration is associated with physical disability in progressive multiple sclerosis.
abstract: Neurodegeneration is thought to be the major cause of ongoing, irreversible disability in progressive stages of multiple sclerosis. Gamma-aminobutyric acid is the principle inhibitory neurotransmitter in the brain. The aims of this study were to investigate if gamma-aminobutyric acid levels (i) are abnormal in patients with secondary progressive multiple sclerosis compared with healthy controls; and (ii) correlate with physical and cognitive performance in this patient population. Thirty patients with secondary progressive multiple sclerosis and 17 healthy control subjects underwent single-voxel MEGA-PRESS (MEscher-GArwood Point RESolved Spectroscopy) magnetic resonance spectroscopy at 3 T, to quantify gamma-aminobutyric acid levels in the prefrontal cortex, right hippocampus and left sensorimotor cortex. All subjects were assessed clinically and underwent a cognitive assessment. Multiple linear regression models were used to compare differences in gamma-aminobutyric acid concentrations between patients and controls adjusting for age, gender and tissue fractions within each spectroscopic voxel. Regression was used to examine the relationships between the cognitive function and physical disability scores specific for these regions with gamma-aminobuytric acid levels, adjusting for age, gender, and total N-acetyl-aspartate and glutamine-glutamate complex levels. When compared with controls, patients performed significantly worse on all motor and sensory tests, and were cognitively impaired in processing speed and verbal memory. Patients had significantly lower gamma-aminobutyric acid levels in the hippocampus (adjusted difference = -0.403 mM, 95% confidence intervals -0.792, -0.014, P = 0.043) and sensorimotor cortex (adjusted difference = -0.385 mM, 95% confidence intervals -0.667, -0.104, P = 0.009) compared with controls. In patients, reduced motor function in the right upper and lower limb was associated with lower gamma-aminobutyric acid concentration in the sensorimotor cortex. Specifically for each unit decrease in gamma-aminobutyric acid levels (in mM), there was a predicted -10.86 (95% confidence intervals -16.786 to -4.482) decrease in grip strength (kg force) (P < 0.001) and -8.74 (95% confidence intervals -13.943 to -3.015) decrease in muscle strength (P < 0.006). This study suggests that reduced gamma-aminobutyric acid levels reflect pathological abnormalities that may play a role in determining physical disability. These abnormalities may include decreases in the pre- and postsynaptic components of gamma-aminobutyric acid neurotransmission and in the density of inhibitory neurons. Additionally, the reduced gamma-aminobutyric acid concentration may contribute to the neurodegenerative process, resulting in increased firing of axons, with consequent increased energy demands, which may lead to neuroaxonal degeneration and loss of the compensatory mechanisms that maintain motor function. This study supports the idea that modulation of gamma-aminobutyric acid neurotransmission may be an important target for neuroprotection in multiple sclerosis.See De Stefano and Giorgio (doi:10.1093/brain/awv213) for a scientific commentary on this article.
authors: 1 NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, UK n.cawley@ucl.ac.uk.
authors: Niamh
authors: N
authors: Cawley
authors: 1 NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, UK.
authors: Bhavana S
authors: BS
authors: Solanky
authors: 1 NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, UK 2 School of Psychology and Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff, UK 3 School of Psychological Sciences, University of Manchester, Manchester, UK.
authors: Nils
authors: N
authors: Muhlert
authors: 1 NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, UK.
authors: Carmen
authors: C
authors: Tur
authors: 4 Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 5 FM Kirby Centre for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA.
authors: Richard A E
authors: RA
authors: Edden
authors: 1 NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, UK 6 Brain Connectivity Centre, C. Mondino National Neurological Institute, Pavia, Italy.
authors: Claudia A M
authors: CA
authors: Wheeler-Kingshott
authors: 1 NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, UK 7 National Institute of Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC), London, UK.
authors: David H
authors: DH
authors: Miller
authors: 1 NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, UK 7 National Institute of Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC), London, UK.
authors: Alan J
authors: AJ
authors: Thompson
authors: 1 NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, UK 7 National Institute of Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC), London, UK.
authors: Olga
authors: O
authors: Ciccarelli
mesh_terms: D000328:Adult; D001224:Aspartic Acid; D001921:Brain / Q000378:metabolism*; D004185:Disability Evaluation; D006233:Persons with Disabilities; D005260:Female; D018698:Glutamic Acid; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D009483:Neuropsychological Tests; D012720:Severity of Illness Index; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid
keywords: MRI; disability; disease progression; gamma-aminobutyric acid (GABA); multiple sclerosis