Correspondence Among Gray Matter Damage and Neurotransmitter Maps Is Clinically Relevant in Multiple Sclerosis
Paolo Preziosa1, Alessia Fiore3, Nicolò Tedone3, Monica Margoni4, Carmen Vizzino3, Damiano Mistri3, Mor Gueye4, Maria Rocca1, Massimo Filippi2
1Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, 2Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, IRCCS San Raffaele Scientific Institute; Vita-Salute San Raffaele University, 3Neuroimaging Research Unit, Division of Neuroscience, 4Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, IRCCS San Raffaele Scientific Institute
Objective:

To investigate the associations among regional gray matter (GM) atrophy, neurotransmitter distributions and clinical manifestations in a large group of patients with multiple sclerosis (PwMS).

Background:

In multiple sclerosis (MS), clinically-relevant GM atrophy progresses in a non-random manner, possibly due to the preferential involvement of specific neurotransmitter networks, which has not been fully evaluated yet.

Design/Methods:

Brain 3.0 T MRI scans were acquired from 286 PwMS and 172 healthy controls (HC). Regional GM volume differences, cross-correlations between regional GM atrophy and nuclear imaging-derived neurotransmitter maps and their associations with disease duration, clinical disability, cognitive impairment, fatigue and depression were investigated using voxel-based morphometry and Juspace toolbox.

Results:

Compared to HC, PwMS showed a widespread cortico-subcortical GM atrophy being spatially correlated with serotonergic, dopaminergic, opioid, noradrenergic, cholinergic and glutamatergic maps (false discovery rate, [FDR]-p≤0.004). PwMS with a disease duration ≥5 vs <5 years had a significant GM atrophy in several deep GM, cortical and cerebellar regions being spatially correlated with a higher distribution of serotoninergic and dopaminergic receptors (FDR-p≤0.03). Compared to mildly-disabled PwMS, those with Expanded Disability Status Scale (EDSS)≥3.0 or ≥4.0 had significant cortical, subcortical and cerebellar atrophy, which was associated with serotonergic and dopaminergic maps (FDR-p≤0.04). A significant spatial correspondence with opioid and cholinergic maps was also found for PwMS with EDSS≥4.0 vs <4.0 (FDR-p≤0.04). Cognitively-impaired vs cognitively-preserved PwMS had a widespread GM atrophy being spatially correlated with serotonergic, dopaminergic, noradrenergic, cholinergic and glutamatergic maps (FDR-p≤0.04). PwMS with vs without fatigue had significant cortical, subcortical and cerebellar atrophy, which were associated with serotonergic, dopaminergic, opioid and glutamatergic maps (FDR-p≥0.07). No significant GM atrophy and associations with neurotransmitter maps were found according to depression.

Conclusions:

GM atrophy in regions belonging to specific neurotransmitter systems may contribute to explain part of MS clinical manifestations, including locomotor disability, cognitive impairment and fatigue.

10.1212/WNL.0000000000202276