Linking cortical lesions to metabolic changes in multiple sclerosis using 7T proton MR spectroscopy

Abstract Importance Cortical lesions contribute to disability in multiple sclerosis (MS) but their impact on regional neurotransmitter levels remains to be clarified. Objective To test the hypothesis that cortical lesions in MS alter the regional concentrations of the main excitatory and inhibitory neurotransmitters, glutamate and gamma-aminobutyric acid (GABA), in the affected cortex. Design Prospective, cross-sectional, observational proton MR-spectroscopy ( 1 H-MRS) and structural MRI study at 7T. Setting Data were collected at a single center between August 2018 and September 2020. Participants A volunteer sample of 57 MS patients and 38 healthy participants were screened for participation in the study. 50 MS patients and 28 healthy participants were included. In the final cohort, three patients and five healthy participants were excluded due to drop out (n=6) or insufficient data-quality (n=2). Exposures Two-voxel 7T 1 H-MRS covering the right and left sensorimotor hand areas (SM1-HAND) and high-resolution structural brain 7T MRI. Main outcome Regional concentrations of glutamate and GABA in SM1-HAND and their relation to cortical lesion volume within the MRS voxel. Results Data from 34 relapsing remitting (RR) and 13 secondary progressive (SP)MS patients (mean +/− standard deviation, 45.1 +/− 12.5 years, 31 female) along with 23 age- and sex-matched healthy participants (44.4 +/− 13 years, 15 female) entered data-analyses. Patient data were pooled to assess the relationship between cortical lesion volume and neurotransmitter levels. Larger cortical lesion volume within SM1-HAND was associated with higher regional glutamate (0.61 +/− 0.21 log(mm 3 ), P=0.005) and lower regional GABA (−0.71 +/− 0.27 log(mm 3 ), P=0.01) concentration. Between-group comparison showed that glutamate concentration within the SM1-voxel was reduced in SPMS patients compared to healthy participants (−0.75 +/− 0.24 mM, P=0.004) and RRMS patients (−0.55 +/− 0.22 mM, P=0.04), while regional GABA levels did not differ among groups. Conclusion Our results link cortical lesion load in SM1-HAND with regional glutamate and GABA levels in patients with RRMS and SPMS, showing a shift in balance between regional excitatory and inhibitory neurotransmitters towards increased excitation with increasing cortical lesion volume. Between-group comparisons provide preliminary evidence that a progressive disease course may be associated with a decrease in cortical glutamate levels. Key points Question: How do cortical lesions change the regional metabolic profile in multiple sclerosis? Findings: This observational cross-sectional study employed voxel-based proton MR-spectroscopy ( 1 H-MRS) of the primary sensorimotor hand areas (SM1-HAND) at ultra-high field (7T) to show that cortical lesions alter regional concentrations of glutamate and gamma-aminobutyric acid (GABA) in patients with multiple sclerosis. We found that higher regional glutamate concentrations were associated with larger regional cortical lesion volume, whereas higher GABA concentrations were associated with lower regional cortical lesion volume. Meaning: These findings suggest that cortical lesions shift the regional excitation-inhibition balance towards excitation.