Special Issue - Biomarker Updates: The immune system in Parkinson’s disease

[00:00:23] Prof. Marina Romero-Ramos: Thank you, Tiago. 

[00:00:24] Prof. Tiago Outeiro: So you just gave a, a beautiful lecture here at the MDS-E S workshop in Padua, and I would like to ask you to briefly summarize your presentation to our listeners. 

[00:00:37] Prof. Marina Romero-Ramos: Yeah. So I have the task in the, in this workshop to actually introduce the concept of, immune or inflammatory biomarkers. And during my talk, my aim was to try to explain how I think we should start using immune cells in blood to try to understand how the disease is progressing [00:01:00] and how they can tell us what is happening in the brain and what is happening clinically to our patients as to move a little bit beyond the cytokine era that we had before.

I think we are ready to go into more immune cellular analysis rather than soluble cytokines and chemokines as we did before. 

[00:01:25] Prof. Tiago Outeiro: Yeah, so this is still a small field, but I think mostly, and you alluded to this, mostly because we are not really immunologists, so we're not used to thinking about Immunology in the context of a neurodegenerative disease like Parkinson's, but It's a very important topic and for a few years we've had some important studies come out on this topic and based on what we know so far What is your view about how immune system alterations should be seen in the context of Parkinson's?

Are they a cause or a [00:02:00] consequence of Parkinson's? 

[00:02:01] Prof. Marina Romero-Ramos: I always say that although my lab is very interested in immunity, I never want to lose the focus of the neuron. I still think that the neuron is central to the disease. However, I may think that in certain, at least in certain cases, patients, maybe events that are happening within neurons that should be handled nicely by immune cells may lead to disease when these immune cells do not, let's say, work properly.

And I think that may be even better. Very relevant for for patients who have maybe mutations in the LRRK2, because as we know, LRRK2 is highly expressing monocytes and in microglia in the humans in the mouse is a little bit different, but in the humans is like that. And maybe also GBA because.

We well know that GBA affects lysosomes and one of [00:03:00] the highly phagocytic cells that we have in the body are immune cells. So I'm not saying everything starts in an immune cell, but I'm saying that maybe things that start in a neuron that should be handled nicely. In these conditions, the failure of the immune system to actually respond nicely, eventually precipitates the disease.

So can we say then that it is due to the immune system? I don't think so because the initial point has to come from the neuron. But, but I think indeed there are cases where, where the immune system will be a major driver of the disease. 

[00:03:38] Prof. Tiago Outeiro: We are in this workshop on diagnostic and progression biomarkers.

So how should we look at the immune system as a possible source for biomarkers for Parkinson's? 

[00:03:52] Prof. Marina Romero-Ramos: Well, I think more, more and more studies are coming out about the expression of certain [00:04:00] proteins in immune cells in the blood that seems to correlate to symptomatic findings in the patients and even imaging findings in the brain.

And I believe that they can be used as process to know what is happening in the brain. So that can be very useful. Another thing that that it has been found is that immune cells present certain pathological cellular process that normally we have associated with neurons, like mitochondrial failure or lysosomal failure.

So we may use those ones as tools to know what are those pathways that are altered within neurons and and therefore that can be really powerful tools that we can use in our everyday lab to learn better what is happening in our patients, maybe even to, jump to this personalized therapies, let's say, to, to learn if I'm going to do a mitochondrial protection, is it [00:05:00] meaningful in this patient years or not?

So, so I, I think they can be used both as process of what is happening in the brain and also as cellular tools to, to test things. 

[00:05:10] Prof. Tiago Outeiro: Yeah. In your presentation, you mentioned your recent work on the transport of immune modulatory information via the vagus nerve, which we know is an important communication highway between the periphery and the brain.

And and you mentioned how this might be used for subtyping PD, especially in the context of the brain first versus body first hypothesis. So can you explain a bit your thoughts about this and maybe whether you think we are getting close to understanding this enough that we can incorporate this level of information for subtyping Parkinson's in the context of a possible biological classification of Parkinson's?

[00:05:56] Prof. Marina Romero-Ramos: Yeah. Well I think the, the fact that that [00:06:00] the vagus nerve is that immune modulatory nerve has been known for very long. Probably this is something that as, as researchers in the field of Parkinson's, we haven't thought very much about it. The truth is that we have really significant data indicating that there is a affection of the vagus nerve, at least in a subgroup.

In our patients, we can refer to, to the, to the hypothesis of the brain, first body first or not. If you are not very fond of that hypothesis, you can just acknowledge that the fact that some patients have a clear vagus affection and others that are not. My hypothesis or the belief in my lab is that maybe that affection of the vagus nerve will actually influence how the immune system will respond to the neuronal process of the disease.

Normally, the vagus nerve is anti inflammatory. It tries to decrease inflammation. And if you vagus nerve doing that, in your patient, the inflammatory component [00:07:00] may be more aggressive and that will lead to a more severe form of the disease. This is still a hypothesis. And my lab and other labs in the world are trying to understand if there is an immune component that can distinguish between the different subtypes of the diseases.

And I believe maybe we're not yet there but I believe it will be used in the future as one tool more to actually characterize what type of Parkinson's disease my patient is presenting. We just mentioned during the workshop the, the urgency that there is about working together with pathologies, with imaging, with a geneticist.

And until now we have been a little bit of a loner, each of us, and we have to work together to really characterize the patient. 

[00:07:53] Prof. Tiago Outeiro: And I was just thinking now about patients that underwent vagotomy [00:08:00] or hemivagotomy. And there are studies, as you know, that suggest that they may be protected. against the spread.

So then how would we incorporate this with this possibility? 

[00:08:13] Prof. Marina Romero-Ramos: Yeah, that's a very good question. I do not doubt that maybe the vagus it may be an entrance to the brain. Obviously, if you close the door, there is no entrance to the brain. So basically, there's no need to respond to anything because there is there's not an origin.

I don't think that that occurring. However, it will be interesting to see, and this is something that has not been done, but I have talked to, to Per Bohammer about that, to see, out of the patients who underwent vagotomy, those who developed Parkinson's disease, did they develop a very aggressive one? That will be interesting to see, because we actually, vagus nerve stimulation is being used nowadays in, as a therapy in brain diseases.

[00:09:00] So it is being proposed to as a therapy for Crohn's disease and other inflammatory diseases. the ability of the vagus nerve to control certain immune environment is known. What we do not know is what happened if you have Parkinson's and you have no vagus nerve. Nobody has checked that.

So that will be another epidemiological study there. 

[00:09:18] Prof. Tiago Outeiro: Yeah. there's a lot to do. And so do you think with the tools that are available today? Especially pharmacological tools. Do you think clinicians should start thinking about using strategies for modulating the immune system in their clinical practice?

Do you think this could make sense as an additional therapeutic option, at least in some forms of Parkinson's. 

[00:09:42] Prof. Marina Romero-Ramos: That's a very good question. I think that there are now many basic research studies suggesting that indeed the immune component, even if we are still unsure if it is at the, at the onset of the disease, it really promotes disease.

So, [00:10:00] so anti inflammatories will make sense, isn't it? But on the other hand, it is true that we are lacking longitudinal studies. I think this is the big problem of the field. We need to have longitudinal studies to truly jump from association to actual happening. This is changing where my patient is going to the next level of, of severity.

So maybe we are not yet there. On the other hand, We should use the enormous amount of drugs that are out there that have been used so far in other diseases. that are very efficiently targeting T cells and monocytes and so forth. And there is a recent paper from Ashley Harms where she actually used a drug that is used already in humans to modulate T cells.

And she shows that it's protective in an animal model. So we [00:11:00] can jump to those drugs that are already approved. Yeah. And that it's very promising, but probably we need a little bit more of a longitudinal studies for that. 

[00:11:07] Prof. Tiago Outeiro: Yeah, I understand. And so just a final question. What do you think will be major advances in the, in this field, in the, in the coming years?

Is there something that you think, "oh, we will get there". We will address this and this will be important? 

[00:11:22] Prof. Marina Romero-Ramos: I think. Again, I will come back to the longitudinal. I think the field is becoming more and more aware of that need in the immune world. And, and I know as the fact that, that the Michael J.

Fox is planning a new PPMI and they have make a very big effort to isolate immune cells properly this time for the PPMI, because in the previous one, it was not in the list of things that they wanted to collect. So, but now they are and they are, they have taken it very seriously. They have they have approached how to, what is the best protocol, what is the best way to, to harmonize these between the [00:12:00] different you know, centers in the world.

So it will come, it will come this longitudinal. It will tell us if the immune component is equally relevant in all our patients. That's another major thing. We, we will in the future say you have an immune driven Parkinson's disease versus a non immune driven Parkinson's disease. And that will help us very much to how to approach therapy, I think.

[00:12:26] Prof. Tiago Outeiro: Wonderful. Marina, thank you so much. It's been a pleasure having you on the podcast. I hope you enjoyed as well. 

[00:12:32] Prof. Marina Romero-Ramos: Thank you so much. 

[00:12:33] Prof. Tiago Outeiro: So we've just interviewed Dr. Marina Romero Ramos on the occasion of the MDS-ES workshop on diagnostic and progression biomarkers in Parkinson's disease and atypical Parkinsonism here in Padua.

And I thank you all for listening. I invite you to listen our upcoming podcasts. Thank you.