Can Measuring Iron in MS Provide Insight into Disease?
Abstract & Commentary
By Susan Gauthier, DO, MS
Assistant Professor of Neurology, Weill Cornell Medical College
Dr. Gauthier reports she receives research support from EMD Serono, Biogen Idec, and Novartis Pharmaceuticals, and is on the speakers bureau for Biogen Idec and Teva Neurosciences.
Synopsis: In a large histopathological study, the distribution of nonheme iron and the expression of iron-related proteins in multiple sclerosis (MS) brains were compared to controls. There was an age-related increase in iron found in control white matter but not within the normal appearing white matter of MS patients with longer disease durations.
Source: Hametner S, et al. Iron and neurodegeneration in the multiple sclerosis brain. Ann Neurol 2013;74:848-861.
Iron, stored within the central nervous system primar-
ily as non-heme iron within oligodendrocytes and myelin, has the potential to contribute to oxidative damage, and its role in many neurodegenerative diseases is being investigated. In multiple sclerosis (MS), imaging studies have revealed a higher deposition of iron within the basal ganglia of patients as compared to controls and suggested that lesions may have high levels of iron. Utilizing quantitative susceptibility mapping, our group found changes in MS lesion susceptibility (presumed to be predominantly due to iron) that was dependent on the age of the lesion.1 In this study by Hemetner et al, the authors attempted to gain an improved understanding of the white matter iron dynamics occurring in MS.
Tissue from 33 MS brains and 30 control cases were analyzed for this study. Optical densitometry and cellular staining were used to measure the iron distribution within the brain samples. The patient population ranged from acute MS (clinical course leading to death within 1 year) to relapsing and progressive subtypes. Nonheme iron within the white matter of control cases had a strong correlation with age (r = 0.899, P < 0.001) whereas MS patients failed to show this association (r = 0.087, P = 0.659). Furthermore, there was a reduction in iron load in MS patients with increasing disease duration (r = -0.558, P < 0.001). Oligodendrocytes expressing membrane-bound, iron-exporting ferroxidases were decreased in MS normal-appearing white matter; however, they were increased closer to periplaque white matter. Among MS lesions, the highest iron load was appreciated at the edges of classic, active, slowly expanding, and some inactive plaques, but not present at the edges of remyelinated lesions. Across all lesions, 8% had more iron as compared to normal-appearing white matter, 27% contained a similar amount, and 65% contained less. In active lesions, demyelination and oligodendrocyte destruction were prominent within the periplaque white matter and decreased toward the lesion center. Active lesions were found to have iron-reactive granules in the extracellular space as well as within endosomes or lysosomes of microglia/macrophages. Toward the center of lesions, the number of iron-containing microglia/macrophages decreased and, if iron was present, it was seen most often within astrocytes, axons, and occasional macrophages. At the rim of inactive (or chronic) lesions, iron-containing microglia demonstrated dystrophic features indicating degeneration, and in contrast, these findings were rarely appreciated among remyelinated lesions. Lastly, axonal sphericals, indicating acute axonal injury linked to oxidative damage, were most abundant in actively demyelinating lesions.
Commentary
As patients with MS age, the normal-appearing white matter lacks the normal accumulation of non-heme iron and may be due to a loss of myelin and/or oligodendrocytes or a loss of oligodendrocytes that specifically contain iron. The higher population of oligodendrocytes with an upregulation of iron-exporting ferroxidases near the lesion edge suggests that inflammatory mediators might facilitate iron export from these cells. Given that oligodendrocytes require iron for active myelination, these observed alterations in glial iron homeostasis may represent one mechanism contributing to remyelination failure in MS. The authors imply there are two sequential waves of iron liberation in MS lesions: 1) release of iron from damaged oligodendrocytes (and myelin loss) in active lesions and 2) release of iron from degenerating microglia/macrophages in chronic lesions. The iron is eventually removed from chronic lesions, yet the duration of extracellular iron exposure is unknown and important to consider given its potential to propagate a continued inflammatory process and promote oxidative damage within lesions.
This study demonstrates an alteration of the normal iron homeostasis within the white matter of MS patients. We have yet to fully understand the significance of these observed dynamics and/or how to approach from a therapeutic standpoint. However, it is reasonable to assume that iron may impact normal tissue repair or remyelination as well as further contribute to oxidative stress and mitochondrial dysfunction, all of which leads to neuronal loss in MS.
Reference
- Chen W, et al. Quantitative susceptibility mapping of multiple sclerosis lesions at various ages. Radiology 2013; Nov 18. doi: http://dx.doi.org/10.1148/radiol.13130353.