Abstract
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.
Highlights
IntroductionSome lesions remyelinate early after the demyelinating event [16] and evolve into remyelinated shadow plaques, which protect against axonal degeneration [23]
Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) associated with focal inflammatory demyelinating lesions in the white and grey matter [14].Acta Neuropathol (2017) 133:25–42Some lesions remyelinate early after the demyelinating event [16] and evolve into remyelinated shadow plaques, which protect against axonal degeneration [23]
We examined whether lesions encircled by a rim-shaped signal in susceptibility-weighted imaging (SWI) are more likely to expand over a period of 3.5 years than those without rims in a prospective longitudinal study in seven patients with MS using a fluid attenuated inversion recovery/SWI fusion sequence (FLAIR–SWI) at 7 Tesla (7 T) [2, 11, 17]
Summary
Some lesions remyelinate early after the demyelinating event [16] and evolve into remyelinated shadow plaques, which protect against axonal degeneration [23]. Chronic demyelination fosters persistent low-degree neurodegeneration in the form of axonal transections [24]. A subset of lesions with inactive demyelinated centers maintains continuous myelin breakdown at the edge, which has led to the pathological concept of the slowly expanding lesion [36]. The edge of slowly expanding lesions is featured by a rim of activated microglia/macrophages harboring occasional myelin degradation products [15], few T cells [14, 36], and a considerable amount of axonal transections [15]
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