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Correspondence among gray matter atrophy and atlas-based neurotransmitter maps is clinically relevant in multiple sclerosis

Molecular Psychiatry volume 28, pages 1770–1782 (2023)Cite this article

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Abstract

In multiple sclerosis (MS), gray matter (GM) atrophy progresses in a non-random manner, possibly in regions with a high distribution of specific neurotransmitters involved in several relevant central nervous system functions. We investigated the associations among regional GM atrophy, atlas-based neurotransmitter distributions and clinical manifestations in a large MS patients’ group. Brain 3 T MRI scans, neurological examinations and neuropsychological evaluations were obtained from 286 MS patients and 172 healthy controls (HC). Spatial correlations among regional GM volume differences and atlas-based nuclear imaging-derived neurotransmitter maps, and their associations with MS clinical features were investigated using voxel-based morphometry and JuSpace toolbox. Compared to HC, MS patients showed widespread GM atrophy being spatially correlated with the majority of neurotransmitter maps (false discovery rate [FDR]-p ≤ 0.004). Patients with a disease duration ≥ 5 vs < 5 years had significant cortical, subcortical and cerebellar atrophy, being spatially correlated with a higher distribution of serotoninergic and dopaminergic receptors (FDR-p ≤ 0.03). Compared to mildly-disabled patients, those with Expanded Disability Status Scale ≥ 3.0 or ≥ 4.0 had significant cortical, subcortical and cerebellar atrophy being associated with serotonergic, dopaminergic, opioid and cholinergic maps (FDR-p ≤ 0.04). Cognitively impaired vs cognitively preserved patients had widespread GM atrophy being spatially associated with serotonergic, dopaminergic, noradrenergic, cholinergic and glutamatergic maps (FDR-p ≤ 0.04). Fatigued vs non-fatigued MS patients had significant cortical, subcortical and cerebellar atrophy, not associated with neurotransmitter maps. No significant association between GM atrophy and neurotransmitter maps was found for depression. Regional GM atrophy with specific neurotransmitter systems may explain part of MS clinical manifestations, including locomotor disability, cognitive impairment and fatigue.

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Fig. 1: Between-group differences in regional GM atrophy and spatial correlations between GM atrophy and neurotransmitter distribution maps in MS patients vs HC and according to their clinical phenotype and disease duration.
Fig. 2: Heatmap.
Fig. 3: Between-group differences in regional GM atrophy and spatial correlations between GM atrophy and neurotransmitter distribution maps in MS patients according their disability.
Fig. 4: Between-group differences in regional GM atrophy and spatial correlations between GM atrophy and neurotransmitter distribution maps in MS patients according the presence of cognitive impairment and fatigue.

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Data availability

The dataset used and analyzed during the current study is available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Alessia Fiore, Paolo Preziosa, Nicolò Tedone, Monica Margoni, Carmen Vizzino, Damiano Mistri, Mor Gueye, Maria A. Rocca & Massimo Filippi

  2. Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Paolo Preziosa, Monica Margoni, Mor Gueye, Maria A. Rocca & Massimo Filippi

  3. Vita-Salute San Raffaele University, Milan, Italy

    Paolo Preziosa, Maria A. Rocca & Massimo Filippi

  4. Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Massimo Filippi

  5. Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Massimo Filippi

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Contributions

AF contributed to analysis and interpretation of clinical and MRI data, drafting and revising the text, and preparing the figures. PP contributed to the conception of the study, acquisition, analysis and interpretation of clinical and MRI data, drafting and revising the text, and preparing the figures. NT, MM, CV, DM, MG contributed to the acquisition, analysis and interpretation of MRI data and revising the manuscript. MAR and MF contributed to the conception of the study, drafting and revising the text, acting as the study supervisors. All the authors gave their approval to the current version of the manuscript.

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Correspondence to Massimo Filippi.

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Competing interests

AF, NT, CV, DM, MG report no competing interests. PP received speaker honoraria from Roche, Biogen, Novartis, Merck Serono, Bristol Myers Squibb and Genzyme. He has received research support from Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. M. Margoni reports grants and personal fees from Sanofi Genzyme, Merck Serono, Novartis and Almiral. She was awarded a MAGNIMS-ECTRIMS fellowship in 2020. MAR received speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva, and receives research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla. MF is Editor-in-Chief of the Journal of Neurology and Associate Editor of Radiology, Human Brain Mapping and Neurological Sciences, received compensation for consulting services and/or speaking activities from Almiral, Alexion, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, and Teva Pharmaceutical Industries, and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi, Almiral, Eli Lilly, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

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Fiore, A., Preziosa, P., Tedone, N. et al. Correspondence among gray matter atrophy and atlas-based neurotransmitter maps is clinically relevant in multiple sclerosis. Mol Psychiatry 28, 1770–1782 (2023). https://doi.org/10.1038/s41380-023-01943-1

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