Magnetic resonance imaging detection of deep gray matter iron deposition in multiple sclerosis: A systematic review

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease involving immune-mediated damage. Iron deposition in deep gray matter (DGM) structures like the thalamus and basal ganglia have been suggested to play a role in MS pathogenesis. Magnetic Resonance Imaging (MRI) imaging methods like T2 and T2* imaging, susceptibility-weighted imaging, and quantitative susceptibility mapping can track iron deposition storage in the brain primarily from ferritin and hemosiderin (paramagnetic iron storage proteins) with varying levels of tissue contrast and sensitivity. In this systematic review, we evaluated the role of DGM iron deposition as detected by MRI techniques in relation to MS-related neuroinflammation and its potential as a novel therapeutic target. We searched through PubMed, Embase, and Web of Science databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, against predetermined inclusion and exclusion criteria. We included 89 articles (n = 6630 patients), and then grouped them into different categories: i) methodological techniques to measure DGM iron, ii) cross-sectional and group comparison of DGM iron content, iii) longitudinal comparisons of DGM iron, iv) associations between DGM iron and other imaging and neurobiological markers, v) associations with disability, and vi) associations with cognitive impairment. The review revealed that iron deposition in DGM is independent yet concurrent with demyelination, and that these iron deposits contribute to MS-related cognitive impairment and disability. Variability in iron distributions appears to rely on a positive feedback loop between inflammation, and release of iron by oligodendrocytes. DGM iron seems to be a promising prognostic biomarker for MS pathophysiology.