Unraveling Deep Gray Matter Atrophy and Iron and Myelin Changes in Multiple Sclerosis

Abstract

Background and purpose: Modifications of magnetic susceptibility have been consistently demonstrated in the subcortical gray matter of MS patients, but some uncertainties remain concerning the underlying neurobiological processes and their clinical relevance. We applied quantitative susceptibility mapping and longitudinal relaxation rate relaxometry to clarify the relative contribution of atrophy and iron and myelin changes to deep gray matter damage and disability in MS.

Materials and methods: Quantitative susceptibility mapping and longitudinal relaxation rate maps were computed for 91 patients and 55 healthy controls from MR images acquired at 3T. Applying an external model, we estimated iron and myelin concentration maps for all subjects. Subsequently, changes of deep gray matter iron and myelin concentration (atrophy-dependent) and content (atrophy-independent) were investigated globally (bulk analysis) and regionally (voxel-based and atlas-based thalamic subnuclei analyses). The clinical impact of the observed MRI modifications was evaluated via regression models.

Results: We identified reduced thalamic (P < .001) and increased pallidal (P < .001) mean iron concentrations in patients with MS versus controls. Global myelin and iron content in the basal ganglia did not differ between the two groups, while actual iron depletion was present in the thalamus (P < .001). Regionally, patients showed increased iron concentration in the basal ganglia (P ≤ .001) and reduced iron and myelin content in thalamic posterior-medial regions (P ≤ .004), particularly in the pulvinar (P ≤ .001). Disability was predicted by thalamic volume (B = -0.341, P = .02), iron concentration (B = -0.379, P = .005) and content (B = -0.406, P = .009), as well as pulvinar iron (B = -0.415, P = .003) and myelin (B = -0.415, P = .02) content, independent of atrophy.

Conclusions: Quantitative MRI suggests an atrophy-related iron increase within the basal ganglia of patients with MS, along with an atrophy-independent reduction of thalamic iron and myelin correlating with disability. Absolute depletions of thalamic iron and myelin may represent sensitive markers of subcortical GM damage, which add to the clinical impact of thalamic atrophy in MS.

FIG 1.

Image shows voxelwise analyses of iron maps. Clusters of significant between-group differences regarding unmodulated (top panel) and modulated (lower panel) iron maps for both the MS>HC (red-yellow, according to 1 - P value) and MS<HC (blue-light blue, according to 1 - P value) contrasts are presented, superimposed on the QSM template in the MNI space. Reprinted by permission from Springer Nature Customer Service Center GmbH: Springer Nature, Neuroradiology, European Society of Neuroradiology 2020, Copyright 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

FIG 2.

Image shows voxelwise analyses of myelin maps. Clusters of significant between-group difference regarding modulated myelin maps for the MSP value) contrast are presented, superimposed on the QSM template in the MNI space. No significant differences emerged for the MS>HC contrast or for unmodulated myelin maps. Reprinted by permission from Springer Nature Customer Service Center GmbH: Springer Nature, Neuroradiology, European Society of Neuroradiology 2020, Copyright 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

FIG 3.

Between-group comparisons of MRI features regarding thalamic subnuclei. Boxplots at the y-axis show z scores (adjusted for the effect of age and sex in HC) of iron concentration and content (upper panel), myelin concentration and content (middle panel), and normalized volume (lower panel) of the corresponding thalamic subregions shown at the x-axis for both the MS and HC groups. Red asterisks mark significant between-group differences.