MDJ Research Article of the Year: Microglial activation in isolated REM sleep behavior disorder

This year, the award for the best research article goes to, microglial activation and progression of nigrostriatal dysfunction in isolated REM sleep behavior disorder. The study investigates the role of microglial activation, which is closely linked to the brain's immune response in people with isolated REM sleep behavior disorder, which is a key prodromal stage of synucleinopathies.

I'm delighted to be joined today by the corresponding author, Dr. Victor Hvingelby from the Department of Nuclear Medicine and PET at the Aarhus University Hospital in Denmark. [00:01:00] Victor, congratulations on this recognition and welcome to the podcast.

Dr. Victor Hvingelby: Thank you so much. My pleasure.

Dr. Michele Matarazzo: So before we get into the study itself, let me start with the award, the list of authors on this paper is really impressive.

This was a huge collaborative effort. How did you and your co-authors receive the news? And what does this recognition mean for you and for your work?

Dr. Victor Hvingelby: Of course it is really a recognition of the entire team's efforts. So it's a huge honor, especially, I mean when you work with movement disorders you wanna be recognized by the Movement Disorder Society. That's second only to being recognized by the patients themselves.

I would say so. 

Dr. Michele Matarazzo: Perfect. And now let's dive a little bit into the background of the study. For listeners who might not be so familiar, could you explain what isolating REM sleep behavior disorder or RBD is and why it's such an important condition in the field of movement disorders? 

Dr. Victor Hvingelby: Yeah, so just to explain briefly, isolated REM sleep behavior disorder is, in general when you [00:02:00] go to sleep, there's a disconnection or there's a disassociation of your lower body from your motor system. So you don't move while you sleep. You don't, enact your dreams in isolated REM sleep behavior disorders for reasons that aren't entirely clear yet this shutting down of the body for some reason doesn't work properly.

So we have patients who act out their dreams. If you dream that you're being chased by a dragon, let's say you'll be running around in your living room or your bedroom trying to escape. So, So that's the long and short of the disorder. The reason why it's so important is for Parkinson's disease and other Parkinsonism, is it's been well known for a while that the disease pathophysiological process starts years and even decades before there is a recognition or a diagnosis made. And in many cases this prodromal stage, you might be able to discern it retroactively and so for Parkinson's, it's well known that decades before manifest Parkinson's, a lot of patients will lose their sense of smell and they might not have been aware that this is an early sign.

So [00:03:00] that the important thing about isolated REM sleep behavior disorder is that it is actually a recognizable prodromal syndrome to Parkinson's. So it actually gives us a window into the early or prodromal stages of the disease.

Dr. Michele Matarazzo: Yeah. Perfect. So basically looking into people with isolated REM behavior disorder, we are looking into people that are highly likely to get Parkinson's disease or related disorders in the upcoming years. 

Dr. Victor Hvingelby: Yes.

Dr. Michele Matarazzo: Okay. So definitely it's, it sounds like a very important condition and situation to look at when you want to understand better the pathophysiology of Parkinson's disease, and also some other parkinsonisms as you were mentioning. But why did you decide to focus on microglia activation?

Dr. Victor Hvingelby: Yes. So the reason why microglia are interesting in this regard is that, it's a very hot topic right now. The issue of neuroinflammation in a breadth of disorders, not just in parkinsonisms but in much of neurology actually. And it's an intriguing idea that inflammation of the brain might somehow be related [00:04:00] to the pathophysiology or neurodegeneration that we see in Parkinson's. And for that reason, that's why microglia interesting because they are sort of the, I'm probably gonna anger a few pathologists by saying this, but they are the monocytes of the central nervous system different cell lines, but

Dr. Michele Matarazzo: You're receiving an award. You can you're allowed to get some people angry.

Dr. Victor Hvingelby: Yes. 

Dr. Michele Matarazzo: Now let's talk about the study and let's talk about the design of the study. You used two different PET scans the PK 11195 to measure microglial activation and the F-Dopa to measure the dopaminergic function.

How did the study work? How did you design it?

Dr. Victor Hvingelby: So we had, at the initial stages we had a cohort of iRBD patients who were scanned with PK 11195 and with F dopa. And then we also had a control group. Who are scanned with PK 11195 to get the baseline, because what we're interested in here is essentially the inflammation particularly of the substantial nigra, right?

So we had the control group to have sort of a baseline to compare to in the iRBD cohort. [00:05:00] Then after, three years had passed we re-scanned the iRBD patients with F dopa, the dopaminergic tracer, to see the degree to which the nigro neuroinflammation or microglial activation predicts or correlates with dopaminergic degeneration over time in these patients.

Yeah.

Dr. Michele Matarazzo: And now let's, tell me what were the main findings of the study?

Dr. Victor Hvingelby: Yes. I mean there are several, but I think the most striking or the most important is when looking at the patients who had the highest PK 11195 binding in the substantia nigra at baseline, they had more substantial dopaminergic degeneration over time. And also it appeared to be more widespread.

I mean, the areas of the nigrostriatal system that were affected were larger in these patients compared to those patients with a lower degree of microglial activation at baseline. Yeah, so I think that's the main, the big finding, I would say yes.

Dr. Michele Matarazzo: So we could say that microglial activation could predict the [00:06:00] degree of neurodegeneration from the dopaminergic point of view.

Dr. Victor Hvingelby: That seems to be the case. Yes, a larger degree or a higher degree of neuroinflammation in the nigra predicts, that would be the sort of the weak inference would be that that it predicts higher dopaminergic degeneration over time. I mean, you could phrase it a little bit stronger or you could speculate a little bit stronger and say that there seems to be some correlation between these two and so that obviously raises the question to the extent to which they're causally related.

Dr. Michele Matarazzo: Before we speculate into this, when I was reading a paper, it was interesting to me that there were actually four patients who converted to manifest Parkinsonism during the follow-up. Did their scans provide any extra clues or information?

Dr. Victor Hvingelby: Yeah. So in that sense, I think it's interesting to note that of the four iRBD patients who converted three of them had PK 11195 binding in the substantia nigra that was at least a standard deviation and a half above that of the controls. The fourth [00:07:00] person who converted while they were lower in nigral, PK 111 95 binding in the nigra at at baseline.

They also had one of the lowest, or most widespread dopaminergic degenerations at baseline indicating that they were probably closer to converting anyway, which, it raises a question of if we accept or if we entertain the hypothesis that neuroinflammation is causally related, then it raises some interesting questions about the timeline or the dynamics of inflammation in relation to dopaminergic degeneration in these patients.

Dr. Michele Matarazzo: Perfect. Now related to that, let's speculate a little bit. What do you think these findings tell us about the role of neuroinflammation in the early stages of Parkinson's disease?

Dr. Victor Hvingelby: Yeah. So I think it raises some important questions. When we looked at baseline, it was very clear that patients with iRBD had higher PK 11195 binding compared to healthy controls. And what also seems to be the case of the findings of this paper, it seems to indicate that [00:08:00] higher binding at baseline indicates, a larger relative degree of dopaminergic degeneration over time.

So at the least it indicates that these are correlated. It might be that it's an epiphenomenon, that these are processes that run in parallel. We can't say that based on this paper, but at the very least they seem to be correlated by, you know, it might be by some third, unknown process, or it might be causally related.

Dr. Michele Matarazzo: Perfect. I like that you're cautious about it, that the correlation is not causation. That's classic problem in research, but definitely these findings points at least towards two processes that might be related to each other. And that's something very interesting.

Now in this study you used a TSPO PET tracer, which is one of the main targets for neuroinflammation PET. You think that using a different target, like for example, the imidazole-2 binding site, monoamine oxidase B, or phosphodiesterase 4B, I mean other neuroinflammation PET tracer. Do you think that using an [00:09:00] other tracer might have told us a different part of the story?

Dr. Victor Hvingelby: I mean, certainly it could have told us a different part of the story, but I think what's the general characteristic of any neuroinflammatory tracer is they're comparable in to the extent that they're not able to reliably distinguish between neuroinflammation as a neuroprotective process or as a neurodegenerative process. So I think in that regard, they are they're comparable. And the same goes for a TSPO tracer, I would say. And I think that's actually part of the reason why I think this study is so interesting, because we know that for in some diseases at specific times, even during Parkinsonisms, microglia seemed to exert a neuroprotective effect. And then at some point for reasons we're not quite sure of yet, this changes. So it becomes it turns right? And I think that might be actually part of what we're what we're seeing here.

So I think in that regard choosing a different tracer might have told us a different part of the story, but I think the crucial part of the story is still the temporal dynamics of neuroinflammation [00:10:00] and the dopaminergic degeneration. And I don't, and I think in that sense, yes most tracers are equal in that regard.

It would be nice if we sometime in the future had more targeted neuroinflammatory traces or that we're able to more reliably distinguish between these types of inflammation, protective and degenerative. But we're not quite there yet, unfortunately.

Dr. Michele Matarazzo: Great. Now we are getting close to the end of this interview. What are the next steps for your group? What do you plan to keep studying the role of neuroinflammation in this stage of the disease or in general, in Parkinson's disease or in REM sleep behavior disorder. 

Dr. Victor Hvingelby: I can tell you obviously that my successor in my group he's been working with the same cohort and he's also examining some of these temporal dynamics of neuroinflammation and the dopaminergic degeneration. So there is more to come in this regard. And I think personally, for my own sake, there's still a lot of work to be done regarding neuroinflammation, not just in parkinsonisms, but also in related disorders.

So absolutely.

Dr. Michele Matarazzo: Perfect. Victor, congratulations again to you and to the rest of the team for this outstanding [00:11:00] recognition. And thank you for joining us today,

Dr. Victor Hvingelby: Thank you.

Dr. Michele Matarazzo: And thank you all for listening today. We've been celebrating the article, microglial activation and progression of nigrostriatal dysfunction in isolated REM sleep behavior disorder, awarded best research article of the year by the Movement Disorders Journal. The article was published in the August 2024 issue and is available open access.

Goodbye and see you in the next episode of the MDS Podcast.