Background

Primary progressive multiple sclerosis (PPMS) is a clinical subtype of MS characterized by the progressive accumulation of disability from onset. It is diagnosed in approximately 15% of people with multiple sclerosis (MS).

microRNAs (miRNAs) are small non-coding RNA molecules that participate in the regulation of gene expression. Their role in different diseases, including MS, is being studied.

Current disease-modifying therapies for MS as well as miRNA studies mainly focus on relapsing-remitting MS (RRMS), the most common subtype.

Objectives

The aim of this study was to identify and validate a differential profile of circulating miRNAs in PPMS patients compared to RRMS and controls with other neurological disease (OND) subjects in order to increase our knowledge of the biological processes involved in the different forms of the disease.

Methods

miRNAs were extracted from serum and cerebrospinal fluid (CSF) from a cohort of 111 patients (49 PPMS, 35 RRMS and 27 OND). In the identification phase, samples were analyzed using TaqMan OpenArray Human Advanced MicroRNA panels and in the validation phase, the quantification of the miRNAs was performed by qPCR. Differential expression was analyzed using the Kruskal-Wallis test with the normalized value of miRNAs.

Results

In the identification phase, 10 miRNAs showed differential expression in serum between some of the groups; while in CSF, miR-143-3p presented differential expression in PPMS group (p= 0.009), and let-7b-5p and miR-451a showed a tendency to be deregulated.

In serum samples, the validation phase showed miR-20a-5p overexpression in PPMS compared to controls, and miR-26a-5p among the forms of MS (p= 0.002 and p= 0.036, respectively). On the other hand, miR-142-5p was differentially expressed in RRMS compared to OND (p= 0.036).

In CSF, let-7b-5p and miR-143-3p presented significantly reduced levels in PPMS forms compared to OND (p= 0.029 and p= 0.039, respectively).

Conclusions

miR-20a-5p, miR-26a-5p, let-7b-5p and miR-143-3p present deregulation in PPMS versus RRMS and OND, indicating that they are involved in the pathophysiological mechanisms of PPMS forms. Further studies will be necessary to determine the role of these miRNAs in the development of the different forms of the disease.

Background

Some studies have shown a more aggressive clinical course in multiple sclerosis (MS) patients of North African origin residing in Europe. It has been established that some genetic and environmental factors interact in a complex way by means of epigenetics to produce the pathology and the symptoms in MS. One of these epigenetic mechanisms is microRNAs (miRNAs), small non-coding RNA molecules that participate in the regulation of gene expression.

Objectives

The objective of this study was to identify the existence of a differential profile of circulating cerebrospinal fluid (CSF) miRNAs between individuals with MS based on their ethnic origin.

Methods

A cohort of 20 individuals was studied: 10 European origin (MS-E) and 10 North African origin individuals (MS-NA). MS-NA individuals were subclassified according to migration age (before or after 15 years old).

216 miRNAs were analyzed in CSF using TaqMan OpenArray Human Advanced MicroRNA panels. Differential expression of the normalized value of each miRNA was studied using the U Mann-Whitney test.

Results

When comparing the expression of miRNAs in CSF between MS-E and MS-NA, overexpression of miR-335-5p and miR-653-3p was observed in MS-NA (p= 0.008 and p= 0.027, respectively). Furthermore, two other miRNAs (miR-143-3p and miR-20a-5p) showed a tendency to be deregulated.

A sub-analysis was performed in which MS-NA was divided according to the age of migration. miR-145-5p, miR-150-5p and miR-653-3p showed significant differences between some of the 3 groups. Specifically, miR-150-5p, previously related to inflammation and MS in CSF, showed very low levels in MS-NA that migrated older than 15 years of age.

Conclusions

The results show the presence of a differential expression in miRNAs between MS patients according to their ethnic origin. In patients of North African origin who migrated at an early age, an overexpression of miRNAs clearly related to inflammation is observed.

Background

Memory impairment affects more than 50% of patients with multiple sclerosis (MS), strongly impacting their life quality. Previous studies have suggested a correlation between functional hippocampal alterations and episodic memory impairments in MS. Nevertheless, these studies are rarely focused on preclinical nor initial stages of the disease, essential to develop targeted interventions to prevent or delay memory impairment in MS.

Objectives

To investigate episodic memory performance and hippocampal functional connectivity abnormalities in the preclinical and initial stages of MS.

Methods

Cross-sectional study of 50 subjects: 30 healthy controls and 20 patients with clinical and radiological isolated syndrome (CIS/RIS) (n=13 and 7, respectively). Episodic memory capabilities were assessed with a modified version of Rey Auditory Verbal Learning Test (RAVLTm): introduction of two recognition trials in the five learning trials. Moreover, participants underwent a magnetic resonance imaging session on which resting-state sequences were acquired. Regression models were used to evaluate between-group differences in memory capabilities. Two-sample t-tests models were used to assess whole-brain differences in the seed-based functional connectivity (FC) of the bilateral hippocampus. All analysis were controlled for gender, age, educational level and presence of anxiety and/or depressive symptoms.

Results

No between-group differences emerged in the sum of the words of the learning trials (p=0.164), the delayed recall trial (p=0.193) nor the three recognition trials as measured by discriminability index (d’) (p=0.775, p=0.954, p=0.395, respectively) and Criterion Level (C) (p=0.860, p=0.864, p=0.858, respectively). Nevertheless, compared to controls, CIS/RIS showed higher FC in the hippocampi-right angular gyrus network (t= 5.18, p<0.001).

Conclusions

Prior any sign of episodic memory dysfunction in preclinical and initial stages of MS, higher FC in the hippocampi-right angular gyrus are detected. These findings could be explained as compensatory mechanism used by CIS/RIS to achieve the same performance in episodic memory task as healthy controls. At the same time, such FC increase could be an early sign of future episodic memory problems.