Sao Bettencourt’s MSA Coalition Travel Award Report

Sao Bettencourt’s MSA Coalition Travel Award Report

Written By Sao Bettencourt – MSA Coalition Travel Award Winner

Thanks to the support of MSA Coalition, I have attended in September (1-4th) the “Synuclein Meeting 2019: Where we are and where we need to go” in Ofir, a city in the outskirts of Porto, Portugal.

This meeting brought together over 300 participants, including leading experts in the field of Synuclein and Synucleinopathies, from both academia and industry, as well as a broad community of junior scientists. This meeting was organized in an unusual format, consisting mostly of round-table discussions, with just a few oral presentations and keynote lectures, to create more opportunities to discuss the major questions in the field. There were also two poster sessions (over 130 posters in total), during which I have presented a poster with our recent research findings on MSA (summarize below).

Attending this meeting was beneficial for me and our research group at several levels:

  1. Being able to disseminate and discuss our exciting findings on epigenetics of MSA;
  2. Having the chance to hear from leading experts, learn extensively and update my knowledge about
    ongoing research on Synuclein and Synucleinopathies (including MSA);
  3. Having the chance to meet personally and engage with both senior and junior scientists in the field,
    and discuss science as well as career development;
  4. Having the chance to network with researchers I have met/worked with before as well as with
    potentially new collaborators.

During the conference, MSA was given relevant attention in multiple occasions:

On the first day of the conference, there was a main talk by Gregor Wenning, who gave an overview about MSA, from clinical aspects to highlighting several recent studies trying to develop drugs that can then be taken into clinical trials. He mentioned that at least 25 compounds are already being or about to be tested in MSA.

MSA was also given major attention on “Roundtable 10 – Spreading of alpha-synuclein – relevant or epiphenomenon?”, chaired by Glenda Halliday and having Jiayi Li, Jeff Kordower, Donato Di Monte, Glenda Halliday, Veerle Baekelandt, and Gregor Wenning as speakers. The major discussion point was whether in Synucleinopathies the spreading of alpha-synuclein occurs in a prion-like manner. There was no overall consensus in this matter.

There were also about 15 posters mentioning MSA, some of which having MSA as the main research focus while others would use MSA as a comparison group together with other neurodegenerative diseases. From those, I would like to highlight our own poster:

PO42 – by Conceição Bettencourt et al. (United Kingdom), “DNA METHYLOME ANALYSIS IN POST-MORTEM BRAIN TISSUE OF MULTIPLE SYSTEM ATROPHY PATIENTS”. In the poster we have presented our recent findings on epigenetics of MSA. Despite extensive research, the regional vulnerability of the brain to MSA pathology remains poorly understood. Genetic, epigenetic and environmental factors have been proposed to explain which brain regions are affected by MSA, and to what extent. We explored for the first time epigenetic changes in post-mortem brain tissue from MSA cases. We conducted a multi-phase case-control study, and profiled genome-wide DNA methylation (Illumina EPIC arrays) in white mater from three brain regions characterized by severe-to-mild pathology burden in the MSA mixed subtype (cerebellum, frontal lobe and occipital lobe). We observed that DNA methylation levels in HIP1, LMAN2, MOBP, among other loci were perturbed in MSA mixed subtype, and also to variable degrees in the other pathological subtypes (MSA OPCA and SND). We also identified several molecular signatures significantly associated with MSA (disease status and pathological subtypes), and with neurodegeneration in the cerebellum. Importantly, the

DNA methylation signature having the strongest association with MSA included SNCA, the gene encoding α- synuclein. Altogether, our results provide the first evidence for DNA methylation changes contributing to the molecular processes altered in MSA, and highlight potential novel routes for diagnosis and therapeutic interventions.

I would also like to highlight several examples of excellent research done by others, including:

PO09 – by Antonio Heras-Garvin et al. (Austria), “HYPOXIA, A POSSIBLE PATHOGENIC FACTOR IN MSA AND PD”, investigating a possible role for hypoxia as a pathogenic factor in MSA and PD. The authors observed a significant accumulation of the hypoxic marker HIF2α in MSA and are pursuing this further with additional investigations.

PO17 – by Miguel Lemos et al. (Austria), “COMBINED ANTI-Α-SYNUCLEIN THERAPY FOR DISEASE MODIFICATION IN MULTIPLE SYSTEM ATROPHY” testing disease modification properties of two compounds in a transgenic mouse model overexpressing α-Synuclein in oligodendrocytes. One of these compounds consist of short immunogenic peptides (AFFITOPEs), carrying a sequence that mimics the original α- Synuclein epitope, and the other (Anle138b) is an aggregation inhibitor. The authors confirmed the efficacy of the single therapy with AFFITOPEs or Anle138b, observing motor improvement, rescue of dopaminergic neurons, reduction in α-Synuclein oligomers, decrease of GCIs density, and decreased levels of microglia activation. The combination of Anle138b+AFFITOPEs has also shown benefits but no cumulative beneficial effects were achieved by combining the two. Interesting results in this mouse model that certainly warrant further investigation.

PO35 – by Violetta Refolo et al. (Austria), “NEUROINFLAMMATORY PATHWAYS INVOLVED IN THE SELECTIVE NEURODEGENERATION OBSERVED IN A TRANSGENIC MOUSE MODEL OF MULTIPLE SYSTEM ATROPHY”, investigating the pathways involved in the neuroinflammatory region-specific events occurring, over the disease course, in a transgenic mouse model of MSA. Their findings suggest an important role of the early, alpha-synuclein-triggered neuroinflammation for the progressive neurodegeneration of the substantia nigra in this mouse model.

PO44 – by Jonas Folke et al. (Denmark), “PERIPHERAL IMMUNE CELLS CORRELATE TO DISEASE PROGRESSION IN MULTIPLE SYSTEM ATROPHY AND PARKINSON’S DISEASE”, evaluating peripheral immune cell changes in MSA and PD in a longitudinal manner, and showing changes in immune cells in both MSA and PD patients.

PO75 – by Vincenzo Donadio et al. (Italy), “INTRANEURAL SKIN NERVE Α-SYNUCLEIN DEPOSITS IN MULTIPLE SYSTEM ATROPHY”, who reports that neuritic inclusions of phosphorylated α-synuclein in somatic skin nerves can represent a sensitive biomarker for MSA.

PO116 – by Teresa Torre-Muruzabal et al. (Belgium), “CHARACTERIZATION OF TWO DISTINCT ALPHA- SYNUCLEIN STRAINS IN A MOUSE MODEL FOR MULTIPLE SYSTEM ATROPHY”, examining whether different α-synuclein strains might exert distinct pathologies in an animal model of MSA. They found distinct histopathological and behavioural phenotypes in vivo.

PO118 – by Ilaria Poggiolini et al. (United Kingdom), “DEVELOPMENT OF ALPHA-SYNUCLEIN SEEDING ASSAY AS AN EARLY, PROGRESSION AND STRATIFYING BIOMARKER FOR SYNUCLEINOPATHIES”, examining aSyn RT-QuIC assay in brain tissue from Multiple System Atrophy (MSA) in parallel to PD patients in order to see if it can stratify between the different synucleinopathies. The authors found substantially different kinetic properties on RT-QuIC in MSA vs. PD, and suggest the aSyn RT-QuIC assay has potential as an early, differential test for prodromal disease.

The Importance of Supporting Young MSA Investigators

The Importance of Supporting Young MSA Investigators

A Report on the Movement Disorder Society Congress in Vancouver

June 4-8, 2017

By Roberto De Marzi

Since I started working as a research fellow in Innsbruck 2 years ago, I focused on new methods for the early diagnosis of Parkinson’s Disease (PD) and Multiple System Atrophy (MSA). In MSA an early diagnosis is of particular interest, since it would enable a more specialised patient’s care and a better selection of patients for clinical trials testing new therapies. Unfortunately the early diagnosis is still a big challenge for the clinicians, since the clinical overlap with PD doesn’t always allow a correct classification.

Roberto DeMarzi, a multiple system atrophy researcher

Roberto De Marzi
2017 MSA Coalition Travel Award Winner

In the project I presented at the Movement Disorders Society Congress in Vancouver, my colleagues and I tried to find early changes in the magnetic resonance imaging (MRI) of MSA patients. We tested six different approaches in selecting the areas of the brain to be analysed with MRI on 115 subjects. 61 PD patients, 24 MSA patients and 30 healthy controls were evaluated, and the regions of the brain to be analyzed had to be manually selected for each of the six approaches. That means that 690 brain scans were manually processed by our team! The results of the study were really interesting, showing that, using 3 of the methods that we tested, we were able to differentiate MSA patients from PD with a very high accuracy. This method could be used in the clinical routine to better individuate patients with MSA even in an early stage.

This study was really time-consuming and it was a great honor and a privilege to be awarded with the travel grant of the MSA Coalition in order to present my project with a poster at the Vancouver MDS Congress. The funding for clinical research in the academic field is often lacking, especially for rare diseases like MSA. Therefore it is a big help for us researchers to have charitable organizations like the MSA coalition providing for additional funding, even more to take part to a congress on the other side of the world.

The MDS congress is the most important congress for researchers in the field of movement disorders. It was only my second participation and on my arrival to the conference hall in Vancouver I was once again amazed by how big the congress is. The movement disorders field is not a big field of research and I work in the university hospital of a medium-sized city, therefore I was also amazed when I saw thousands of other movement disorders specialists taking part to the congress.

On the first day of the congress I attended a very exciting poster session regarding atypical Parkinsonism. It was interesting to see in which directions the researchers are moving. I received a lot of inputs on which topics could be part of my future projects. Especially interesting was a poster by Y. Compta and colleagues, from Barcelona, who detected a decrease in coenzyme Q10 levels in the cerebrospinal fluid of MSA patients. The role of coenzyme Q10 in MSA is still controversial, therefore this study could probably shed some light on the role of coenzyme Q10 in the pathogenesis of MSA or help in the early diagnose of the disease.

The day of my poster presentation was the most exciting. I presented my project in front of the guided poster tour and I received positive feed backs and comments from many experts of the field. There were also some advices on how to better conduct similar studies in the future. I will surely take these advices into account once I further develop my project.

Read Roberto De Marzi’s MDS Poster

I also had the chance to talk to many other young researchers from the entire world (UK, Italy, USA, Germany and many other countries) which are active in the MSA research and who also are investigating MRI in MSA patients. While exchanging ideas and experiences I talked to them about the MSA coalition and its initiatives. We also realized how important it would be to have more networks in the MSA research in order to increase the number of patients studied and to reproduce the findings of our research in different centers. I was really motivated by these talks and we exchanged contacts in order to try to start collaboration within our groups.

During the congress I had the privilege to hear some outstanding lectures by the world’s most renowned experts in the movement disorders field and to personally meet some of them. It was really interesting to finally connect a face to many specialists that I knew because of their scientific publications. Particularly stimulating was a lecture by Prof. Kordower about immunotherapies in PD and MSA. In Innsbruck we conducted a study with one of these therapies and it was an honor to see our study being cited in one of the plenary lectures. The last day I attended a special session about atypical forms of atypical parkinsonism, which saw Prof. Wenning as chairman and presenter. During this lecture many videos of the different clinical presentation of MSA were shown and I learn a great deal about the different phenotype of the disease. It was an exciting presentation and I’m sure it will improve my ability to recognize atypical cases of MSA in the clinical setting.

In summary, attending the MDS congress in Vancouver was a very enriching experience. In a few days I learned a lot of things about the latest discoveries in the field of movement disorders and I had the chance to know famous experts and to network with other young researchers. All these inputs gave me new motivations and ideas to further develop my projects in this field.