Slow expansion of multiple sclerosis iron rim lesions: pathology and 7 T magnetic resonance imaging

• DOI: 10.1007/s00401-016-1636-z
• Publication Date: 2016-10-27T12:12:48Z
• Authors: Assunta Dal-Bianco; Günther Grabner; Claudia Kronnerwe...; Michael Weber; Romana Höftberger; Thomas Berger; Eduard Auff; Fritz Leutmezer; Siegfried Trattnig; Hans Lassmann; Francesca Bagnato; Simon Hametner
• Keywords: Adult; Aged, 80 and over; Male; Original Paper; Multiple Sclerosis; Iron; Macrophages; Clinical Neurology; Brain; Middle Aged; Immunohistochemistry; Magnetic Resonance Imaging; Pathology and Forensic Medicine; Cellular and Molecular Neuroscience; Young Adult; 03 medical and health sciences; 0302 clinical medicine; Disease Progression; Humans; Female; Microglia; Aged

In multiple sclerosis (MS), iron accumulates inside activated microglia/macrophages at edges of some chronic demyelinated lesions, forming rims. In susceptibility-based magnetic resonance imaging at 7 T, iron-laden microglia/macrophages induce a rim of decreased signal at lesion edges and have been associated with slowly expanding lesions. We aimed to determine (1) what lesion types and stages are associated with iron accumulation at their edges, (2) what cells at the lesion edges accumulate iron and what is their activation status, (3) how reliably can iron accumulation at the lesion edge be detected by 7 T magnetic resonance imaging (MRI), and (4) if lesions with rims enlarge over time in vivo, when compared to lesions without rims. Double-hemispheric brain sections of 28 MS cases were stained for iron, myelin, and microglia/macrophages. Prior to histology, 4 of these 28 cases were imaged at 7 T using post-mortem susceptibility-weighted imaging. In vivo, seven MS patients underwent annual neurological examinations and 7 T MRI for 3.5 years, using a fluid attenuated inversion recovery/susceptibility-weighted imaging fusion sequence. Pathologically, we found iron rims around slowly expanding and some inactive lesions but hardly around remyelinated shadow plaques. Iron in rims was mainly present in microglia/macrophages with a pro-inflammatory activation status, but only very rarely in astrocytes. Histological validation of post-mortem susceptibility-weighted imaging revealed a quantitative threshold of iron-laden microglia when a rim was visible. Slowly expanding lesions significantly exceeded this threshold, when compared with inactive lesions (p = 0.003). We show for the first time that rim lesions significantly expanded in vivo after 3.5 years, compared to lesions without rims (p = 0.003). Thus, slow expansion of MS lesions with rims, which reflects chronic lesion activity, may, in the future, become an MRI marker for disease activity in MS.