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. 2023 May 3;5(3):fcad140.
doi: 10.1093/braincomms/fcad140. eCollection 2023.

Cognitive performance in multiple sclerosis: what is the role of the gamma-aminobutyric acid system?

Marijn Huiskamp  1 , Maqsood Yaqub  2 , Marike R van Lingen  1 , Petra J W Pouwels  2 , Lodewijk R J de Ruiter  3 , Joep Killestein  3 , Lothar A Schwarte  4 , Sandeep S V Golla  2 , Bart N M van Berckel  2 , Ronald Boellaard  2 , Jeroen J G Geurts  1 , Hanneke E Hulst  1   5
Affiliations

Cognitive performance in multiple sclerosis: what is the role of the gamma-aminobutyric acid system?

Marijn Huiskamp et al. Brain Commun. .

Abstract

Cognitive impairment occurs in 40-65% of persons with multiple sclerosis and may be related to alterations in glutamatergic and GABAergic neurotransmission. Therefore, the aim of this study was to determine how glutamatergic and GABAergic changes relate to cognitive functioning in multiple sclerosis in vivo. Sixty persons with multiple sclerosis (mean age 45.5 ± 9.6 years, 48 females, 51 relapsing-remitting multiple sclerosis) and 22 age-matched healthy controls (45.6 ± 22.0 years, 17 females) underwent neuropsychological testing and MRI. Persons with multiple sclerosis were classified as cognitively impaired when scoring at least 1.5 standard deviations below normative scores on ≥30% of tests. Glutamate and GABA concentrations were determined in the right hippocampus and bilateral thalamus using magnetic resonance spectroscopy. GABA-receptor density was assessed using quantitative [11C]flumazenil positron emission tomography in a subset of participants. Positron emission tomography outcome measures were the influx rate constant (a measure predominantly reflecting perfusion) and volume of distribution, which is a measure of GABA-receptor density. Twenty persons with multiple sclerosis (33%) fulfilled the criteria for cognitive impairment. No differences were observed in glutamate or GABA concentrations between persons with multiple sclerosis and healthy controls, or between cognitively preserved, impaired and healthy control groups. Twenty-two persons with multiple sclerosis (12 cognitively preserved and 10 impaired) and 10 healthy controls successfully underwent [11C]flumazenil positron emission tomography. Persons with multiple sclerosis showed a lower influx rate constant in the thalamus, indicating lower perfusion. For the volume of distribution, persons with multiple sclerosis showed higher values than controls in deep grey matter, reflecting increased GABA-receptor density. When comparing cognitively impaired and preserved patients to controls, the preserved group showed a significantly higher volume of distribution in cortical and deep grey matter and hippocampus. Positive correlations were observed between both positron emission tomography measures and information processing speed in the multiple sclerosis group only. Whereas concentrations of glutamate and GABA did not differ between multiple sclerosis and control nor between cognitively impaired, preserved and control groups, increased GABA-receptor density was observed in preserved persons with multiple sclerosis that was not seen in cognitively impaired patients. In addition, GABA-receptor density correlated to cognition, in particular with information processing speed. This could indicate that GABA-receptor density is upregulated in the cognitively preserved phase of multiple sclerosis as a means to regulate neurotransmission and potentially preserve cognitive functioning.

Keywords: GABA-receptor; cognition; magnetic resonance spectroscopy; multiple sclerosis; positron emission tomography.

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Conflict of interest statement

M. Huiskamp receives research support from the Dutch MS Research Foundation. Prof. Dr. Killestein reports speaker and consulting fees and grants from Biogen, Celgene, Genzyme, Immunic, Merck, Novartis, Roche, Sanofi and Teva. Prof. Dr. van Berckel has received research support from EU-FP7, CTMM, ZonMw, NWO and Alzheimer Nederland. BvB has performed contract research for Rodin, IONIS, AVID, Eli Lilly, UCB, DIAN-TUI and Janssen. BvB was a speaker at a symposium organized by Springer Healthcare. BvB has a consultancy agreement with IXICO for the reading of PET scans. BvB is a trainer for GE. BvB only receives financial compensation from Amsterdam UMC. Prof. Dr. Geurts has served as a consultant for Merck-Serono, Biogen, Novartis, Genzyme and Teva Pharmaceuticals; he has received research support from the Dutch MS Research Foundation, Ammodo, Eurostars-EUREKA, Biogen, Celgene/BMS, Merck, MedDay and Novartis. Prof. Dr. Hulst receives research support from Dutch MS Research Foundation, ZonMW, NWO, ATARA, Biogen, Celgene/BMS, Merck and Medday, serves as a consultant for Sanofi Genzyme, Merck BV, Biogen Idec, Roche and Novartis and is on the editorial board of Multiple Sclerosis Journal. Other authors report no conflicts of interest.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Cortical GM volume of distribution (VT) differences between HC and multiple sclerosis groups. Figures are violin plots with boxplots and distribution of data. Statistical comparisons of multiple sclerosis versus HC are shown in A using Welch’s t-test (twelch) while comparisons between HC, CP and CI PwMS are shown in B using Welch’s ANOVA (Fwelch). HC = healthy control; MS = multiple sclerosis; CP = cognitively preserved multiple sclerosis; CI = cognitively impaired multiple sclerosis.
Figure 2
Figure 2
Deep GM volume of distribution (VT) differences between HC and multiple sclerosis groups. Figures are violin plots with boxplots and distribution of data. Statistical comparisons of multiple sclerosis versus HC are shown in A using Welch’s t-test (twelch) while comparisons between HC, CP and CI PwMS are shown in B using Welch’s ANOVA (Fwelch). HC = healthy control; MS = multiple sclerosis; CP = cognitively preserved multiple sclerosis; CI = cognitively impaired multiple sclerosis.
Figure 3
Figure 3
Hippocampal volume of distribution (VT) differences between HC and multiple sclerosis groups. Figures are violin plots with boxplots and distribution of data. Statistical comparisons of multiple sclerosis versus HC are shown in A using Welch’s t-test (twelch) while comparisons between HC, CP and CI PwMS are shown in B using Welch’s ANOVA (Fwelch). HC = healthy control; MS = multiple sclerosis; CP = cognitively preserved multiple sclerosis; CI = cognitively impaired multiple sclerosis.
Figure 4
Figure 4
Relationship between thalamic glutamate and IPS in multiple sclerosis. Pearson’s correlation with scatterplot and fit line including 95% confidence interval (grey area).
Figure 5
Figure 5
Pearson’s correlation matrices showing positive correlations of cognition z-scores with influx rate constant and volume of distribution. Correlation coefficients of PET measures and cognition are indicated with a bold border. MS = multiple sclerosis; IPS = information processing speed; GM = grey matter.
See this image and copyright information in PMC

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