Iron heterogeneity in early active multiple sclerosis lesions.

OBJECTIVE Multiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disease. Iron distribution is altered in MS patients' brains suggesting iron liberation within active lesions amplifies demyelination and neurodegeneration. Whether the amount and distribution of iron are similar or different among different MS immunopatterns is currently unknown. METHODS We used synchrotron X-ray fluorescence imaging, histology and immunohistochemistry to compare the iron quantity and distribution between immunopattern II and III early active MS lesions. We analyzed archival autopsy and biopsy tissue from 21 MS patients. RESULTS Immunopattern II early active lesions contain 64% more iron (95%CI: 17%, 127%; p=0.004) than immunopattern III lesions, and 30% more iron than the surrounding periplaque white matter (95%CI: 3%, 64%; p=0.03). Iron in immunopattern III lesions is 28% lower than in the periplaque white matter (95%CI: -40%, -14%; p<0.001). When normalizing the iron content of early active lesions to that of surrounding periplaque white matter, the ratio is significantly higher in immunopattern II (p<0.001). Micro-focused X-ray fluorescence imaging shows that iron in immunopattern II lesions localizes to macrophages, while macrophages in immunopattern III lesions contain little iron. INTERPRETATION Iron distribution and content are heterogeneous in early active MS lesions. Iron accumulates in macrophages in immunopattern II, but not immunopattern III lesions. This heterogeneity in the two most common MS immunopatterns may be explained by different macrophage polarization, origin or different demyelination mechanisms, and paves the way for developing new or using existing iron-sensitive MRI techniques to differentiate among immunopatterns in the general non-biopsied MS patient population. This article is protected by copyright. All rights reserved.