Thalamic energy dysfunction is associated with thalamo-cortical tract damage in multiple sclerosis: a diffusion spectroscopy study

Background: Diffusion-weighted 1H magnetic resonance spectroscopy (DW-MRS) allows to quantify creatine-phosphocreatine brain diffusivity (ADC(tCr)), whose reduction in multiple sclerosis (MS) has been proposed as a proxy of energy dysfunction. Objective: To investigate whether thalamic ADC(tCr) changes are associated with thalamo-cortical tract damage in MS. Methods: Twenty patients with MS and 13 healthy controls (HC) were enrolled in a DW-MRS and DW imaging (DWI) study. From DW-MRS, ADC(tCr) and total N-acetyl-aspartate diffusivity (ADC(tNAA)) were extracted in the thalami. Three thalamo-cortical tracts and one non-thalamic control tract were reconstructed from DWI. Fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivity (RD), reflecting microstructural integrity, were extracted for each tract. Associations between thalamic ADC(tCr) and tract metrics were assessed using linear regression models adjusting for age, sex, thalamic volume, thalamic ADC(tNAA), and tract-specific lesion load. Results: Lower thalamic ADC(tCr) was associated with higher MD and RD of thalamo-cortical projections in MS (MD: p = 0.029; RD: p = 0.017), but not in HC (MD: p = 0.625, interaction term between thalamic ADC(tCr) and group = 0.019; RD: p = 0.320, interaction term = 0.05). Thalamic ADC(tCr) was not associated with microstructural changes of the control tract. Conclusion: Reduced thalamic ADC(tCr) correlates with thalamo-cortical tract damage in MS, showing that pathologic changes in thalamic energy metabolism are associated with structural degeneration of connected fibers

Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis

Objective: To develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis. Design: Systematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions. We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action. Results: We identified a short list of fifty-two candidate interventions. After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation. Conclusions: We demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders

A "Candidate-Interactome" Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a “candidate interactome” (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms

Transciptome of B lymphocytes in multiple sclerosis

Objective: Over the past two decades B cells have increasingly moved into the spotlight in multiple sclerosis (MS) research. So far it has not been performed a detailed study of the B cells transcriptome in MS. This may be a prerequisite for identifying the elements that B cells use to carry out their pathogenic role. The primary aim of this project was to analyze the whole B cell-transcriptome (coding and non-coding RNA) in MS context. We studied the differences between MS patients and controls in B cell transcriptome: 1) mRNA including alternative splicing; 2) human microRNAs (miR). Methods: We studied peripheral CD19+ B cell subsets obtained from 10 MS patients, 10 healthy donors (HD), and 2 monozygotic twins discordant for MS. All affected individuals were treatment-naïve and all the investigations were performed at least three months after the last steroid therapy. Total RNA was extracted using miRNeasy Kit (Qiagen). Microarray data was performed using two Affymetrix’s platforms: GeneChip-Human Exon and GeneChip-miRNA. The statistical analysis was performed by means of two different software packages, whose output results have been compared: Partek Genomic Suite (version 6.6) and our own analysis pipe-line based on EasyExon tools. In order to discover and understand the connections among the genes obtained from the analysis, and their position in other biological processes, a pathway analysis was performed using Ingenuity Pathway Analysis (IPA). The miR Analysis was performed by IPA microRNA Target Filter. Results: Firstly, we found that EasyExon is much less permissive than Partek. So we focused on EasyExon results, in particular we selected 26 genes differentially expressed in MS compared HD (p=1.5). The list was then submitted to IPA and performed a pathway analysis that led us to choose seven, among the original 26 genes that were among those differentially expressed MS patients and HD. Furthermore, performing the miR analysis with IPA, it has emerged that 6 genes from our list are targeted by 9 miR differentially expressed in MS/HD groups. Conclusions: Peripheral B cell compartment seems to be promising for the identification of mRNA and miR signature. We have identified an MS-related pattern, in terms of miR and/or genes