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.

Results: Of 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 (cohort 1: Spearman correlation coefficient rs = -0.452, P = .003; cohort 2: rs = -0.225, P = .046); the others included hsa.miR.142.5p (cohort 1: rs = -0.424, P = .006; cohort 2: rs = -0.226, P = .045), hsa.miR.181c.3p (cohort 1: rs = -0.383, P = .01; cohort 2: rs = -0.222, P = .049), and hsa.miR.181c.5p (cohort 1: rs = -0.433, P = .005; cohort 2: rs = -0.231, P = .04). In the 2 cohorts, hsa.miR.486.5p (cohort 1: rs = 0.348, P = .03; cohort 2: rs = 0.254, P = .02) and hsa.miR.92a.3p (cohort 1: rs = 0.392, P = .01; cohort 2: rs = 0.222, P = .049) showed similar significant pathogenic correlations with T1:T2; hsa.miR.375 (cohort 1: rs = -0.345, P = .03; cohort 2: rs = -0.257, P = .022) and hsa.miR.629.5p (cohort 1: rs = -0.350, P = .03; cohort 2: rs = -0.269, P = .02) showed significant pathogenic correlations with brain atrophy. Although we found several miRNAs associated with MRI outcomes, none of these associations remained significant when correcting for multiple comparisons, suggesting that further validation of our findings is needed.

Conclusions and relevance: Serum miRNAs may serve as MS biomarkers for monitoring disease progression and act as surrogate markers to identify underlying disease processes.

Figure 1. Magnetic Resonance Imaging (MRI) Segmentation Procedure to Derive Brain Volume (Atrophy) Measures in Cohort 1

Native axial dual-echo proton density (A) and T2-weighted (B) images were applied to a fully automated statistical parametric mapping pipeline (version 12), resulting in an intracranial volume segmented into brain vs cerebrospinal fluid (CSF) compartments used to derive brain parenchymal fraction (C) and gray vs white matter maps (D) used to derive global cerebral gray matter fraction. A patient with relapsing-remitting multiple sclerosis from cohort 1 is shown.

Figure 2. MicroRNA (miRNA) Correlation With Magnetic Resonance Imaging (MRI) Measures of Disease Severity

miRNAs showed significant correlations with MRI measures of disease severity in both cohort 1 and cohort 2. BPF indicates whole-brain parenchymal fraction; BPV, whole-brain parenchymal volume; and T1:T2, ratio of T1 hypointense to T2 hyperintense lesion volume.