Lead scientist: Jaume Sastre-Garriga / Deborah Pareto

Brain volumetry is about to take a central role in the management of patients with MS. Recent evidence suggests that the neurodegenerative process can be reliably estimated in vivo with the help of MRI and appropriate software tools, and that such measurements are clinically relevant both for prognosis as well as in monitoring of treatment response. In the Clinical Neuroimmunology Group, brain volumetry estimates have been already obtained using well-tested methodologies in selected cohorts and its clinical relevance has been confirmed. New, more sophisticated software tools to obtain in-depth measuring of brain and spinal cord areas are now being tested for clinical relevance. This has been achieved through collaboration with the MRI Unit at the Institut de Diagnòstic per la Imatge.

5.1 Bone morphogenetic proteins (BMP) antagonism as a target to enhance neuroregeneration in multiple sclerosis

Lead scientist: Carmen Espejo

Because MS therapies are mainly conducted to modulate the immune response, in the last years new research lines have been established in order to better understand the mechanisms that regulate and/or mediate the neurodegenerative and neuroregenerative processes. Although neuroregeneration occurs in the adult central nervous system (CNS), several negative signals impede the restore of the damaged CNS. Some of these signals could be mediated by BMPs, since these proteins have a key role in the developing CNS and in the adult CNS neurogenesis. BMPs also have a prominent role in the development of the thymus as well as in the differentiation of T-cells. We aim to characterize the expression of BMPs, receptors and antagonists in MS lesions, quantify them in the CSF of MS patients and evaluate its prognostic value. We also aim to test the therapeutic potential of the administration of BMP4 and an antagonist of BMPs, noggin, in experimental autoimmune encephalomyelitis (EAE), an experimental model of MS.

5.2. Role of semaphorins 3A and 7A in neuroregeneration and immune regulation in EAE model

Lead scientist: Carmen Espejo

As BMPs, Semaphorins could also be involved in neurodegeneration in MS, as negative signals impeding the restoration of the damaged CNS. This project aims to study the role of semaphorin 3A (sema3A) and sema7A, two axonal guidance molecules also involved in the regulation of immune responses, in EAE pathogenesis as well as their therapeutic implications.

5.3 Microbiota as a therapeutic target in multiple sclerosis: preclinical trial of two probiotics and butyrate in two experimental models of multiple sclerosis

Lead scientist: Carmen Espejo

A series of recent studies reveal that gut microbiome can influence immune responses distant from mucosal surfaces. Immunological dysregulation is the cause of numerous human disorders such as autoimmune diseases. Aberrant central nervous system (CNS) autoimmunity arises as a consequence of the lost of the normal immune tolerance to CNS self-antigens. Commensal microbiota affects the autoreactivity of peripheral immune cells to the CNS.

The main objective of this project is to test whether the administration of two probiotics and butyrate has a beneficial effect in MS experimental model.

5.4. Tolerance induction in experimental autoimmune encephalomyelitis using gene therapy

Lead scientists: Jordi Barquinero / Carmen Espejo

Previous collaboration works with the group of Gene and Cell Therapy of our institution resulted in the development of a therapeutic strategy in which bone marrow cells were genetically modified to express a self-antigen with the aim to induce antigen-specific tolerance. We could see a therapeutic effect even in the absence of myeloablation, thus suggesting that a concrete population of cells generated in the cell culture, but not cells with a repopulating capacity, were responsible for the therapeutic effect seen in these mice. We have identified a candidate population, called myeloid derived suppressor cells that might be mediating the antigen-specific effect.

5.5. Genomic signature-based small molecule screening of neural stem cells to identify novel compounds to enhance oligodendrogenesis

Lead scientist: Carme Costa

Genomic signatures will be defined in the different stages of differentiation from neural stem cells to mature oligodendrocyte. The signatures will be used to identify new drugs that could induce oligodendrogenesis. In vitro validation will be performed to confirm that the addition of these compounds to cells under different stages of lineage commitment produces the desired gene expression signature. The selected compounds will be finally tested in vivo, in an experimental autoimmune encephalomyelitis mouse model.

5.6. Neurodegeneration and neuroregeneration in multiple sclerosis: search of biomarkers and potential new therapies

Lead scientist: Nicolás Fissolo

MS is a disease with two components: an inflammatory component that prevails in the initial stages (relapsing-remitting), and a neurodegenerative component that is more prominent in the advanced stages of the disease (progressive). Currently, therapeutic strategies in MS are highly effective to reduce or even suppress the inflammatory component of the disease; however, current treatments have proven to be totally ineffective in those patients in whom the neurodegenerative component predominates. Despite numerous studies in this field, the mechanisms of neurodegeneration that take place during the course of the disease are not well understood. We aim to identify biomarkers and potential therapeutic targets in the neurodegeneracion and neuroregeneration events taking place during the course of the EAE, the animal model of MS.

5.7 Targeting astrocytes to prevent neurodegeneration in patients with multiple sclerosis

Lead scientist: Manuel Comabella

The main objective of this proposal is a pharmacological modulation of astrocyte function in order to influence and modify neurodegeneration in MS patients.

3.1. Clinical, radiological and biological prognostic factors of response to treatment with interferon-beta

Lead scientist: Jordi Río / Manuel Comabella

Cohort study to establish outcome measures for clinical trials with clinical validity and clinical and radiological indicators associated with poor response to interferon-beta treatment.

Study to identify gene signatures that may predict the good or bad response to interferon-beta in patients with MS before initiating treatment or in the first months of treatment and to identify gene expression signatures that may help to predict patients who will develop neutralizing antibodies against interferon-beta.

2.1. Search for casual variants of genes associated with MS 

Lead scientist: Manuel Comabella

This line of research seeks to identify causal variants responsible for the MS risk of genes found to be associated with the disease in GWAS by means if deep sequencing.

2.2. To develop dynamic risk scores according to dynamic prognostic models for MS based on clinical, biological and radiological variables

Lead scientist: Mar Tintoré

In particular: 

1. Develop a dynamic risk score based on the evaluation of demographical, clinical, radiological, and biological factors that entail a higher risk of developing a second relapse after a clinically isolated syndrome (CIS), i.e. risk of CDMS, through building models of a dynamic nature.

2. Develop a dynamic risk score based on the evaluation of demographical, clinical, radiological, and biological factors entail a higher risk of progression of disability, as measured by the Expanded Disability Status Scale (EDSS) (Kurtzke Neurology 1983), in people who have suffered a CIS, also through building models of a dynamic nature.

Since 1995, patients presenting with a CIS or first attack suggestive of MS are included in a prospective cohort study. One thousand and one hundred CIS patients with a median follow-up of almost 10 years, have been included up to now. Clinical variables (age, gender, topography of the syndrome), radiological variables (number of lesions, number of Barkhof criteria, topography of the lesions, atrophy measures), as well as biological markers (IgG and IgM oligoclonal bands). In a subgroup of patients additional biomarkers (neurofilaments light and heavy chains, fetuin A, GFAP, anti-neurofascin antibodies, anti-glycan panel, chitinase, S1P, etc.) are studied as predictors of conversion to MS and as predictors of disability progression. Mathematical and marginal structural models with different combinations of the variables listed above are investigated.

2.3. Neuropsychological assessment of neurocognitive deficits in patients with multiple sclerosis

Lead scientist: Mª Jesús Arévalo

Unified neuropsychological assessment is considered necessary to make comparisons between different groups of patients and to draw general conclusions as well as to evolve in the knowledge of cognitive impairment of patients.

There is no consensus on protocols for neuropsychological assessment of people with MS in Catalonia and patient evaluations are performed disparately among different hospitals. Neurologists and neuropsychologists from 13 hospitals and patient foundations from Catalonia have held work meetings every two months since July 2012 to seek common work ground. Consensus has been reached as to a common neuropsychological protocol for the assessment of cognitive impairment in MS. We have set up a common database including clinical and neuropsychological variables recorded from interviews with patients introduced into one application.

Our work group has been incorporated into the Neuropsychology Section of the Official College of Psychology of Catalonia.

2.4. Upper limbs function and psychometric properties of outcome measures

Lead scientist: Núria Filló / Ingrid Galán

Upper limbs impairment impacts on daily activities and social participation of persons with MS. Under-recognition of upper limb dysfunction may result in part from limited availability of performance-based and patient self-report measures that are validated for use in MS and that can be readily incorporated into clinical practice for screening and regularly scheduled assessments This line of research seeks to study the psychometric properties of outcome measures for upper limb function in MS.

2.5 EpidEMcat

Lead scientist: Susana Otero

The Multiple Sclerosis Centre of Catalonia (Cemcat) coordinates a project that aims to characterize the epidemiology of MS in Catalonia. For this purpose, a prospective registry of new cases of MS in Catalonia was set up in 2009 with the participation of 21 hospitals throughout Catalonia. Prevalence and incidence studies based on this population-based registry are being performed. A new research line on co-morbidity and healthcare resource utilization in MS patients is now starting.

2.6 Search of genetic modifiers associated with aggressive and benign disease courses

Lead scientist: Manuel Comabella

We aim to identify genetic variants that influence the course of the disease by means of exome sequencing of MS patients with divergent clinical courses, i.e. aggressive and benign disease courses.

2.7 Search of biomarkers for multiple sclerosis by RNA, microRNA and exome sequencing approaches

Lead scientist: Manuel Comabella

Biomarkers are needed in MS to understand the complex and multifactorial heterogeneity of the disease, particularly disease activity biomarkers that may help to distinguish between different MS clinical courses or activity phases of the disease. Here, we aimed to identify disease activity biomarkers in MS by applying RNA, microRNA, and DNA sequencing approaches.