Updates in MSA | Congress 2026

Thank you very much for joining us today, Wassilios.

[00:00:41] Wassilios Meissner: Thank you very much, and hello everybody. It's a real pleasure to be with you.

[00:00:44] Eduardo de Pablo Fernandez: First of all, I would like to start with the advances in the pathophysiology of multiple system atrophy. There is growing evidence showing that multiple system atrophy is a strain-specific synucleinopathy. So how has our understanding of the pathophysiology and how the role of synuclein driving the disease progression has changed over the last couple of years?

[00:01:08] Wassilios Meissner: This is really very exciting what we have seen over the last 10 years because 10 years ago we did not really understand what the differences were between the strains of MSA compared to Parkinson's disease. And now, with all these very nice cryo-EM studies, we have seen the different conformation and we know now that the strains, there are probably at least two MSA strains, are looking quite differently from Parkinson's disease. I know we'll talk probably later about that. That may have implications for the diagnosis but also for therapeutic approaches, which may need to specifically target the different strains to see efficacy.

I think the understanding of the underlying synuclein pathology in terms of the structure of alpha-synuclein has really tremendously improved over the last 10 years. One paper published earlier last year, which I found the most exciting paper I've read for years, challenging a little bit this classical view that MSA is a more glial synucleinopathy compared to Parkinson's disease.

Indeed we knew from a long time ago that even in MSA you can see in some patients Lewy bodies and there are neural neurites so there's also neural synucleinopathy, but the idea was that it's predominantly glial. And in fact there was a study with new antibodies that used N-terminal antibodies, and they showed abundant neuronal synucleinopathy in postmortem brains of patients with MSA. And it looked even that these alpha-synuclein species were distinct from those in the glial cells. Because when they did some digestion, there were differences in the signal they could see. And one question now is what are we doing with that neuronal synucleinopathy? And it is not the first paper. There have been other papers, one from a Japanese group a couple of years ago, also showing abundant oligomeric synucleinopathy, especially in regions that are not highly involved in the pathophysiology.

Meaning that maybe these are very early stages and maybe in the regions that are affected also in the early stages, you would see more neural pathologies. So I think there's a lot of challenging and now telling us that maybe this classical view, this very classical view

of specifically glial synucleinopathy is no longer true, but the future will tell us with more data coming out where that goes.

[00:03:17] Eduardo de Pablo Fernandez: Definitely, yeah, we have more information, but more questions

to answer in that regard. Going back to synuclein strains and how to detect synuclein for diagnostic purposes. Obviously, there has been significant advances in the synuclein seeding assays and also different techniques to detect pathogenic synuclein deposition in different tissues, particularly skin.

So where are we at the moment with that, and how is that going to help in the future to diagnose MSA? And, moving forward, is it more like we're going to focus on the CSF? Are we going to focus more on the skin? I would like to hear your thoughts.

[00:03:53] Wassilios Meissner: I think that the CSF assays, they are definitely the most advanced. Cell groups have been working on that for years. The results are quite distinct. Most assays can distinguish between Parkinson's disease and controls and have a rather similar signal for MSA compared to the controls.

And this is probably linked to coming back to the strains and the different conformations that the fluorescence marker which is used in these seeding, which is thioflavin T, seems predominantly to bind to the strains in Parkinson's disease, but not in MSA. And that gives then this difference in the reaction.

And this fluorescence is somehow used by one of the assays, which can somehow distinguish between Parkinson's disease, MSA, and controls based on the intensity of the fluorescence signal. So this is very exciting because it looks good in terms of specificity and sensitivity. So they have in this specific assay, two types have been identified: a type 1 response of fluorescence, which is more likely connected to at least a clinical diagnosis of Parkinson's disease, and then a type 2 response, which is referred to the pattern seen in MSA.

Specificity and sensitivity are very high. The challenge is once we are moving from here, because that was the question also into clinical routine practice, then of course the prevalence has also a role because, just to remind us, there have been recent publications about the prevalence of Parkinson's disease and how it will evolve until 2050.

And in that study, the prevalence of Parkinson's disease worldwide measure average is 130 to 170 out of 100,000 inhabitants, and MSA is 2 to 5 out of 100,000 inhabitants, which means that probably if we are are using it systematically in all patients with parkinsonian disorders, we will get a very high number finally in our clinic setting with a positive type 2 2 response who

have at least a clinical diagnosis of Parkinson's disease.

Of course, it will be very important to continue to

have a postmortem evaluation of these tests to really understand if these are clinical misdiagnosis currently or if the positive predictive value of these tests is not 100%, which will clearly have impact on the way we're using it. If we would have a test, a reliable test, that would probably, to answer another question you had about the early diagnosis, which is really very challenging still in MSA. Of course, we have seen and learned from the PD field, especially with the characterization of RBD cohorts. We know also that 5% to 10% of the patients with RBD have a later diagnosis of MSA, but this is really a very low number.

There has been another entry point, I would say, to the diagnosis based on autonomic dysfunction in patients with pure autonomic failure. There have been a few cohort studies now also identifying factors, predictors for later diagnosis of MSA, and here the number is higher compared to RBD, where the number is lower.

So these are somehow early stages of the disease, but we are absolutely not there compared to Parkinson's disease. But, having a powerful diagnostic test in early disease stages would probably allow at a stage where we as a clinician see a patient first with a parkinsonian syndrome, where we would first suspect Parkinson's disease after a couple of month or years, the full-blown picture of MSA would appear, then revise the diagnosis, that already at that stage we'll be able to make the diagnosis.

I'm not sure that a CSF test would really be facilitating to have a large implementation. In Alzheimer's disease it's working pretty well, but not all patients with a suspicion of Alzheimer's disease are getting a spinal tap. So probably having a bloodborne test, and there have been some attempts and some publications already.

And I remember, I think two or three years ago, there was one of the junior awards going to one of the colleagues from Japan who has published just in "Nature Medicine," a paper on the SAA in blood where they had fair sensitivity and specificity for the distinction between MSA and Parkinson's disease and control.

And I think that is the way we should go. And if we would have that kind of test, that would allow early diagnosis. Of course, then comes the question about the ethics behind as long as we don't have a powerful treatment to offer, does it really matter to push as early for the diagnosis, at least from the perspective of the patient?

I think there are a lot of considerations we have to consider before applying those tests. Of course, a game changer will be if one of the treatments currently in the pipeline will get market approval, and then, of course, we would have an interest to make an diagnosis as early as possible to make benefit the patients from these treatments.

[00:08:27] Eduardo de Pablo Fernandez: So yeah, I think we are still a few steps back from there, but hopefully that will happen one day. But yeah, definitely, there is a lot of ethical considerations in applying this test to a population without symptoms or just making a diagnosis of prodromal MSA at this stage. So you mentioned therapeutics and disease-modifying treatments. There has been recent studies targeting different mechanisms in in terms of iron metabolism or GLP-1 targeting also synuclein. Can you give us a brief summary, a list of the most exciting areas and where do you think the, again, like the field is moving forward?

[00:09:07] Wassilios Meissner: Most of the efforts have been put into trials with compounds targeting alpha-synuclein. So there are currently one phase III and one phase II ongoing, one with a small molecule, one with an antibody targeting alpha-synuclein. The phase III trial is based on results of a phase II trial that have recently been published in "Lancet Neurology," showing a 19% separation of the progression curves between those individuals receiving placebo compared to the IV administration of the antibody every 4 weeks.

And there has been a phase II trial with a compound acting on iron metabolism, but also on alpha-synuclein aggregation, small trial phase II. Because of the action on iron metabolism, the accumulation of iron in the basal ganglia was the primary endpoint of that trial. And there were, of course, as always, secondary endpoints based on clinical assessments.

The UMSARS is the classical scale that is usually used as primary endpoint or a secondary endpoint in that study. Although this trial failed to show significant reductions or differences on iron metabolism based on iron sequences on MRI, there was a signal in favor of both groups on the progression of UMSARS.

And based on that, the company is keen on conducting a phase III trial to confirm the potential efficacy behind. So that is something that is probably in the future.

You mentioned GLP-1 agonists. There has been a small open-label trial showing slower progression in the 25 individuals who received exenatide, one of the GLP-1 agonists, compared to best medical treatment.

Of course, this is an open-label trial. We have to be very cautious, but the results were quite strong in a way that the progression with best medical treatment was, I think, 13 points, which is the classical progression you see with UMSARS on the range of progression, you see with UMSARS over a year, while the treatment group had a progression over 6 points.

So it's really a 6- to 7-point difference. Of course, we have to be very cautious, but I think that warrants also further exploration in a double-blinded trial. And at the French level, we're working on that, and we have requested funding to run a phase II trial to build on that. There are several other trials targeting alpha-synuclein. It's not only about the antibodies, small molecules. There's also an attempt to reduce the genetic expression of alpha-synuclein based on ASO, similar to what we have seen in the Huntington's disease field and in other fields.

So there are phase I trials currently ongoing to generate more data to understand what the potential interest is for MSA before then potentially moving into larger trials. There's also a small trial that has applied neurotrophic factor GDNF, so quite differently a neurosurgical approach, to see if local administration into the putamen may have beneficial effects on the fate of dopamine neurons, but also on non-dopamine neurons in the putamen.

And with that potentially having an impact on progression of motor features. So it's quite a very active field currently. There are really several phase II and phase III trials ongoing every year and more in the pipeline. So I think or I hope that one of these or several of these trials will really lead to demonstrating slowing of disease progression and translating into clinical practice.

[00:12:32] Eduardo de Pablo Fernandez: It's very exciting just to see as well MSA has been always a bit lagging behind Parkinson's disease, so it's exciting to see these promising results and all this ongoing research. Just to end the interview, obviously, this is the first day of the Congress. There is a few interesting talks on MSA. You are also giving a therapeutics symposium tomorrow, where you are going to talk about different aspects of MSA. But would you like to highlight any specific talks that you are looking forward to related to MSA?

[00:13:02] Wassilios Meissner: To build on our discussion, I think this afternoon there will be a nice lecture about the current therapeutics in MSA and also targets, emerging targets, so that will probably expand to our discussion we had. On Tuesday, there is an imaging session where there will be presented also data about alpha-synuclein PET.

So this is another modality that may become relevant, maybe not for diagnostic purposes, but at least for understanding of the progression of the synucleinopathy and potentially in a subset of patients of clinical trials in the future.

[00:13:36] Eduardo de Pablo Fernandez: Excellent. Thank you very much, Wassilios, for joining us today, and I hope the listeners enjoy the podcast today.

Thank you.

[00:13:41] Wassilios Meissner: Thank you.