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

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.

Along with atrophy,¹ several pathologic variations have been demonstrated in the deep gray matter (DGM) of MS patients by means of advanced MRI techniques.² Among these, recent quantitative susceptibility mapping (QSM) studies explored magnetic susceptibility alterations of subcortical GM,^3-5 because such changes might reflect iron accumulation and depletion, which play an important role in MS pathophysiology⁶ and seem to relate to motor and cognitive disability.^4,5Nonetheless, when drawing inferences on the relevance of DGM iron modifications in MS as measured by QSM, some considerations are needed. Indeed, brain magnetic susceptibility is also influenced by other molecules (primarily myelin, quantitatively assessable through the estimation of the longitudinal relaxation rate [R1]^7,8) whose spatial distribution remarkably overlaps with iron patterns.^9,10 Furthermore, susceptibility changes can differ across distinct subregions of DGM nuclei, which show intrinsic structural heterogeneity.¹¹ Finally, the observed modifications may partially reflect atrophy-related epiphenomena rather than actual increases of iron load.¹²Here we performed a multimodal (QSM and R1 relaxometry) investigation of DGM, computing in vivo iron- and myelin-specific maps to disentangle the contribution of atrophy and iron and myelin (concentration and content) abnormalities to subcortical GM damage in patients with MS at both global (bulk analysis) and regional (voxel-based and thalamic subnuclei ROI analyses) levels, simultaneously exploring their relationship with clinical disability.We hypothesized that: 1) modifications of DGM iron and myelin in MS would be partially accounted for by the presence of atrophy; 2) subregional analyses would show a heterogeneous spatial distribution of iron and myelin changes; 3) these alterations would predict clinical disability independent of atrophy.