Cognitive Performance in Multiple Sclerosis: Role of Gamma-Aminobutyric Acid System
Abstract
Objective: Explore the relationship between glutamatergic and GABAergic changes and cognitive functioning in multiple sclerosis (MS).
Participants: 60 people with MS (mean age 45.5) and 22 healthy controls.
Method: Neuropsychological testing and MRI used; GABA-receptor density was assessed with [11 C]flumazenil PET.
Findings: 33% of MS participants showed cognitive impairment (CI). No significant differences in glutamate or GABA concentrations were found. Increased GABA-receptor density was noted in deep grey matter in cognitively preserved (CP) MS patients.
Introduction
Prevalence of CI: 40–65% in MS, negatively impacts daily life.
Importance of Thalamus and Hippocampus: Key regions affected in MS.
Role of Neurotransmission: Glutamatergic and GABAergic systems potentially explain CI in MS.
Molecular Imaging Techniques: MRS and PET used to study neurotransmitter systems in vivo.
Methods
Participants
Recruited from Amsterdam UMC and online advertisements.
Inclusion: Diagnosed with MS, with motor function and visual acuity intact.
Exclusion: Other neurological/psychiatric illnesses, MRI contraindications, corticosteroid use within 4 weeks.
Clinical and Neuropsychological Examination
Adjusted neuropsychological test battery to classify CI.
Cognitive tests corrected for age, sex, and education; Z-scores calculated.
MRI and MRS
MRI scanning for white and grey matter volumes.
MRS measured glutamate and GABA concentrations in the hippocampus and thalamus.
PET Imaging
Used [11 C]flumazenil to assess GABA-receptor density.
Dynamic PET scanning for 60 minutes.
Statistical Analysis
Compared demographic, clinical, and imaging data using Welchs t-tests and ANOVA.
Results
Demographic and Volumetric Data
CI associated with reduced grey matter volume.
CP group exhibited increased GABA-receptor density.
MRS and PET Results
No significant differences in neurotransmitter concentrations between groups.
CP group showed higher GABA-receptor density in deep grey matter and hippocampus.
Positive correlation between GABA-receptor density and information processing speed (IPS) in MS.
Discussion
GABA-Receptor Density: Suggests temporary upregulation in CP phase of MS; disappears as CI progresses.
Functional Reorganization: Increased receptor density may represent adaptive changes.
Neurotransmission Balance: Possible simultaneous upregulation of inhibition and excitation.
Limitations: Cross-sectional study, need for longitudinal data to confirm findings.
Conclusion
GABA-receptor density plays a crucial role in preserving cognitive function in MS, particularly in CP individuals.
Increased receptor density may offer protective benefits against CI in MS.
Supplementary Material
Data available upon request from corresponding author.
Acknowledgements
Created graphical abstract using BioRender.
Funding and Conflicts of Interest
Supported by Dutch MS Research Foundation and others.
Some authors received research support from pharmaceutical companies.