Decreasing brain iron in multiple sclerosis: The difference between concentration and content in iron MRI

Abstract

Increased brain iron concentration is often reported concurrently with disease development in multiple sclerosis (MS) and other neurodegenerative diseases. However, it is unclear whether the higher iron concentration in patients stems from an influx of iron into the tissue or a relative reduction in tissue compartments without much iron. By taking into account structural volume, we investigated tissue iron content in the deep gray matter (DGM) over 2 years, and compared findings to previously reported changes in iron concentration. 120 MS patients and 40 age- and sex-matched healthy controls were included. Clinical testing and MRI were performed both at baseline and after 2 years. Overall, iron content was calculated from structural MRI and quantitative susceptibility mapping in the thalamus, caudate, putamen, and globus pallidus. MS patients had significantly lower iron content than controls in the thalamus, with progressive MS patients demonstrating lower iron content than relapsing-remitting patients. Over 2 years, iron content decreased in the DGM of patients with MS, while it tended to increase or remain stable among controls. In the thalamus, decreasing iron content over 2 years was associated with disability progression. Our study showed that temporally increasing magnetic susceptibility in MS should not be considered as evidence for iron influx because it may be explained, at least partially, by disease-related atrophy. Declining DGM iron content suggests that, contrary to the current understanding, iron is being removed from the DGM in patients with MS.

Keywords: QSM; iron content; longitudinal study; multiple sclerosis; quantitative susceptibility mapping.

FIGURE 1

Schematic illustration of different cellular realizations of regional atrophy. (a) Healthy tissue model with the same number of iron‐containing and iron‐free cells. Panels (b–e) show atrophied tissue models characterized by a reduction in the number of cells by one‐third. (b) Atrophic mechanism characterized by the removal of primarily iron‐laden cells. (c) Iron‐containing and iron‐free cells are similarly affected by atrophic mechanisms. (d) Primarily iron‐free cells are lost. (e) Only iron‐free cells are lost. This schematic does not include scenarios in which iron influx occurs, or iron is removed from iron‐containing cells (see Table 3). The schematic also does not include scenarios in which iron is transferred between cell‐types (e.g., released by iron‐containing cells and then taken up by iron‐free cells) because such an iron transfer would not affect the bulk tissue magnetic susceptibility (Taege et al., 2019). Furthermore, the conclusions about changes in iron concentration and content would be similar if the “iron‐free” cells in the schematic were not completely iron‐free but contained considerably less iron than the “iron‐containing” cells. In the deep gray matter (DGM), “iron‐containing” cells represent oligodendrocytes, and “iron‐free” cells represent all other cellular components including neurons and neuropil that have a considerably lower iron content than oligodendrocytes

FIGURE 2

Percent change of regional iron content relative to baseline iron content over 2 years for (a) multiple sclerosis patients (multiple sclerosis [MS]; gray) and normal controls (normal control [NC]; black), and (b) relapsing–remitting (RR) MS (black) and secondary progressive (SP) MS (gray) patients. *Unadjusted p < 0.05. **False discovery rate adjusted q < 0.05. Brackets refer to an interaction effect of the groups over 2 years at q < 0.05. Error bars represent the 95% confidence interval of the change