Association Between Serum MicroRNAs and Magnetic Resonance Imaging Measures of Multiple Sclerosis Severity

Abstract

IMPORTANCE MicroRNAs (miRNAs) are promising multiple sclerosis (MS) biomarkers. Establishing the association between miRNAs and magnetic resonance imaging (MRI) measures of disease severity will help define their significance and potential impact. OBJECTIVE To correlate circulating miRNAs in the serum of patients with MS to brain and spinal MRI. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study comparing serum miRNA samples with MRI metrics was conducted at a tertiary MS referral center. Two independent cohorts (41 and 79 patients) were retrospectively identified from the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital. Expression of miRNA was determined by locked nucleic acid-based quantitative real-time polymerase chain reaction. Spearman correlation coefficients were used to test the association between miRNA and brain lesions (T2 hyperintense lesion volume [T2LV]), the ratio of T1 hypointense lesion volume [T1LV] to T2LV [T1:T2]), brain atrophy (whole brain and gray matter), and cervical spinal cord lesions (T2LV) and atrophy. The study was conducted from December 2013 to April 2016. MAIN OUTCOMES AND MEASURES miRNA expression. RESULTSOf the 120 patients included in the study, cohort 1 included 41 participants (7 [17.1%] men), with mean (SD) age of 47.7 (9.5) years; cohort 2 had 79 participants (26 [32.9%] men) with a mean (SD) age of 43.0 (7.5) years. Associations between miRNAs and MRIs were both protective and pathogenic. Regarding miRNA signatures, a topographic specificity differed for the brain vs the spinal cord, and the signature differed between T2LV and atrophy/destructive measures. Four miRNAs showed similar significant protective correlations with T1:T2 in both cohorts, with the highest for hsa.miR.143.3p

A two-year study using cerebral gray matter volume to assess the response to fingolimod therapy in multiple sclerosis

“…Lesion analysis was carried out in a blinded manner and researchers were not aware of clinical and demographic characteristics. The T2 dual-echo scans were applied to a fully automated pipeline in SPM (v.12; Wellcome Department of Cognitive Neurology, London, UK, http://www.fil.ion.ucl.ac.uk/spm/) to derive maps of GM, WM, and CSF compartments, for the calculation of intracranial volume and brain parenchymal fraction (BPF) [55][56][57] (Fig. 1).…”

“…Taken together, these results show the ability of DMTs to exert a partial but significant effect on limiting the rate of cerebral GM atrophy. Numerous mechanisms have been proposed regarding the pathophysiology of GM atrophy in patients with MS, including direct formation of demyelinating plaques, microglial proliferation, leptomeningeal inflammation, anti-lipid antibodies, micro-RNAs, oxidative stress, and Wallerian degeneration [27,44,56,57,[62][63][64][65][66]75]. Understanding fingolimod's proposed mechanism of action may provide some explanation as to how this DMT impacts GM atrophy.…”

Increased Circulating miR-10a Levels Associated with Multiple Sclerosis

“…[21,22] miRNA dysregulation has been reported in various immune cells of patients with MS; some studies have demonstrated changes in miRNA expression in the brain tissue and immune cells of patients with MS and associations between MS progression and miRNA expression. [23,24] Numerous studies have reported a correlation between miR-10a and different autoimmune diseases and T cells, [13,14] revealing that miR-10a is expressed at high levels in naturally occurring Treg cells and that Treg cell miR-10a expression is inversely correlated with susceptibility to autoimmune disease. [13] As mentioned previously, miR-10a probably contributes to other autoimmune diseases via a similar immune pathological mechanism; therefore, we examined the miR-10a targets HDAC4 and HOXA1 are involved in cell proliferation.…”

Inhibitory milieu at the multiple sclerosis lesion site and the challenges for remyelination

“…Multiple miR‐181 members are downregulated in active and chronic MS lesions and in demyelinated hippocampi (Dutta et al, ). Furthermore, miR‐181c was identified as higher in RRMS than progressive MS patient CSF (Haghikia et al, ), and serum miR‐181c expression is negatively correlated with T1:T2 MRI ratios in MS patients (Regev et al, ). This suggests that miR‐181c is important for protecting myelin or that it is simply a marker for maturing oligodendrocytes.…”