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Chronic active lesions: a new MRI biomarker to monitor treatment effect in multiple sclerosis?

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS) characterized by the accumulation of focal white matter (WM) lesions that can be classified as active, chronic active (also referred to as mixed active/inactive lesions), inactive, and remyelinated, according to the presence and topography of ongoing demyelination and active inflammation or remyelination [1–3]. In pathological studies, chronic active lesions represent up to 57% of all focal WM lesions, being more frequently described in patients with progressive (P) MS [1–3]. Chronic active lesions typically show a peripheral ‘rim’ of iron-laden activated microglia/macrophages associated with ongoing demyelination and axonal loss, around an inactive core without blood-brain barrier damage, thus reflecting a compartmentalized chronic inflammatory pathological process [1–4]. Pathology represents the gold standard to identify chronic active lesions [5]. However, promising neuroimaging strategies have been proposed to detect in vivo these lesions. First, chronic active lesions have been evaluated by looking at susceptibility-based magnetic resonance imaging (MRI) scans at highand ultra-high field. On these sequences, chronic active lesions show a paramagnetic hypointense rim (i.e. ‘iron rim lesions’) that corresponds pathologically to peripheral iron-laden microglia [3,4,6] (Figure 1(a)). Moreover, by combining susceptibility-based MRI scans and serial post-contrast T1weighted sequences rapidly acquired after gadolinium injection (i.e. dynamic contrast enhancement [DCE]), chronic active lesions, ~9.4% of all chronic lesions, showed no contrastenhancement, thus they lack substantially abnormal bloodbrain barrier permeability that typically characterizes acute lesions [7]. Iron rim lesions are also characterized by a more limited lesional repair and have been described in all MS phenotypes although with heterogeneous reported rates: clinically isolated syndrome/relapsing-remitting (RR) MS from 6% to 53%, PMS from 7% to 62% [3,4,8,9]. By evaluating the longitudinal evolution of iron rim lesions over up to 7 years, a recent study with the longest follow-up currently available showed that such lesions are characterized by a slow rate of increase in size in the first years after their formation and then stabilize. Moreover iron rim lesions persist for years, although they gradually diminish over time, likely reflecting a reduction of peripheral chronic activity [4]. Quantitative susceptibility mapping (QSM) has also been recently applied to quantify and localize brain iron more accurately, with iron rim lesions being reported with rates from 4.2% to 10.6% [10–12]. Second, since chronic active lesions slowly increase in size over time (i.e. slowly evolving lesions [SEL]), such lesions have been identified among those WM lesions showing a linear and progressive longitudinal expansion over long-enough periods of time on conventional T1and T2-weighted sequences [13–15] (Figure 1(b)). Third, chronic active lesions have been studied with positron emission tomography (PET) using radiotracers specific to microglia/macrophages [16–18] (Figure 1(c)). More recently, sodium (Na) MRI has been also proposed to identify chronic active lesions [19]; however it has not yet been evaluated to study treatment effects. Chronic active lesions seem to represent one of the most relevant pathological substrates associated with more severe clinical disability, progressive disease course, and brain atrophy and contributing to disability progression in MS, also in the absence of overt inflammatory activity [6,9]. Accordingly, the investigation of the potential beneficial effects of disease-modifying treatments (DMTs) on the occurrence, accumulation and microstructural features of chronic active lesions may represent a rewarding strategy to understand whether specific therapeutic interventions may limit this compartmentalized chronic inflammation in MS.