title: GABA and glutamate levels correlate with MTR and clinical disability: Insights from multiple sclerosis.
abstract: Converging areas of research have implicated glutamate and γ-aminobutyric acid (GABA) as key players in neuronal signalling and other central functions. Further research is needed, however, to identify microstructural and behavioral links to regional variability in levels of these neurometabolites, particularly in the presence of demyelinating disease. Thus, we sought to investigate the extent to which regional glutamate and GABA levels are related to a neuroimaging marker of microstructural damage and to motor and cognitive performance. Twenty-one healthy volunteers and 47 people with multiple sclerosis (all right-handed) participated in this study. Motor and cognitive abilities were assessed with standard tests used in the study of multiple sclerosis. Proton magnetic resonance spectroscopy data were acquired from sensorimotor and parietal regions of the brains' left cerebral hemisphere using a MEGA-PRESS sequence. Our analysis protocol for the spectroscopy data was designed to account for confounding factors that could contaminate the measurement of neurometabolite levels due to disease, such as the macromolecule signal, partial volume effects, and relaxation effects. Glutamate levels in both regions of interest were lower in people with multiple sclerosis. In the sensorimotor (though not the parietal) region, GABA concentration was higher in the multiple sclerosis group compared to controls. Lower magnetization transfer ratio within grey and white matter regions from which spectroscopy data were acquired was linked to neurometabolite levels. When adjusting for age, normalized brain volume, MTR, total N-acetylaspartate level, and glutamate level, significant relationships were found between lower sensorimotor GABA level and worse performance on several tests, including one of upper limb motor function. This work highlights important methodological considerations relevant to analysis of spectroscopy data, particularly in the afflicted human brain. These findings support that regional neurotransmitter levels are linked to local microstructural integrity and specific behavioral abilities that can be affected in diseases such as multiple sclerosis.
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, 845 Rue Sherbrooke Ouest, Montréal, H3H 0G4 Québec, Canada; Research Institute of the McGill University Health Centre, 2155 Guy Street, 5th Floor, Montréal, H3H 2R9 Québec, Canada.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Nantes
authors.affiliation: Research Institute of the McGill University Health Centre, 2155 Guy Street, 5th Floor, Montréal, H3H 2R9 Québec, Canada; Montreal General Hospital, 1650 Avenue Cedar, Montréal, H3G 1A4 Québec, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Proulx
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, 845 Rue Sherbrooke Ouest, Montréal, H3H 0G4 Québec, Canada; Research Institute of the McGill University Health Centre, 2155 Guy Street, 5th Floor, Montréal, H3H 2R9 Québec, Canada.
authors.forename: Jidan
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, 845 Rue Sherbrooke Ouest, Montréal, H3H 0G4 Québec, Canada; Research Institute of the McGill University Health Centre, 2155 Guy Street, 5th Floor, Montréal, H3H 2R9 Québec, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Holmes
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, 845 Rue Sherbrooke Ouest, Montréal, H3H 0G4 Québec, Canada; Montreal Neurological Institute, McGill University, 3801 University Street, Montréal, H3A 2B4 Québec, Canada.
authors.forename: Sridar
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Montreal Neurological Institute, McGill University, 3801 University Street, Montréal, H3A 2B4 Québec, Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Brown
authors.affiliation: Montreal Neurological Institute, McGill University, 3801 University Street, Montréal, H3A 2B4 Québec, Canada.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Hoge
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, 845 Rue Sherbrooke Ouest, Montréal, H3H 0G4 Québec, Canada; Research Institute of the McGill University Health Centre, 2155 Guy Street, 5th Floor, Montréal, H3H 2R9 Québec, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Koski
mesh_terms: D000328:Adult; D006233:Persons with Disabilities; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D066128:Gray Matter / Q000000981:diagnostic imaging / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology*; D066244:Proton Magnetic Resonance Spectroscopy / Q000379:methods*; D012720:Severity of Illness Index; D066127:White Matter / Q000000981:diagnostic imaging / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid
keywords: GABA; Glutamate; Magnetization transfer ratio; Multiple sclerosis; Myelin; Proton magnetic resonance spectroscopy