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International Parkinson and Movement Disorder Society
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Inflammation is an early feature of Parkinson's disease

May 29, 2023
Dr. Michele Matarazzo interviews Dr. Talene Yacoubian on an article recently published on the Movement disorders journal that reveals increased inflammatory markers in recently diagnosed patients with Parkinson's disease without medication, suggesting the important role of inflammation from the early stages of the disease. Furthermore, inflammatory biomarkers are related to cognition.
Journal CME is available until May 22, 2024 Read the article.

[00:00:00] Dr. Michele Matarazzo: Hello and welcome to the MDS Podcast, the podcast channel of the International Parkinson and Movement Disorder Society. I am Michele Matarazzo, the editor-in-chief of the podcast. Today we are discussing an incredibly hot and relevant topic, which is the role of inflammation in Parkinson's disease. More specifically, we are going to talk about an article published on the Movement Disorder Journal, titled Brain and Systemic Inflammation in De Novo Parkinson's Disease.

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Our guest today is the first author of the article, Dr. Talene Yacoubian from the Department of Neurology of the University of Alabama at Birmingham in the United States of America. Hello Talene and welcome to the podcast.

[00:00:42] Dr. Talene A. Yacoubian: Hello. Thanks for having me.

[00:00:44] Dr. Michele Matarazzo: So to briefly summarize your article, you analyze the cohort of de novo PD patients looking at brain and peripheral markers of inflammation. First comparing them with a group of healthy controls, and then looking at association between different markers, and also between [00:01:00] markers and clinical measures. Mainly looking at cognitive measures. I will start by asking what is the previous evidence that inflammation plays a role in Parkinson's disease?

[00:01:09] Dr. Talene A. Yacoubian: So I think there's a lot of bits of data over the past, five, ten years if not more looking both in human subjects and also from animal studies, sort of showing that there does appear to be a role of inflammation in Parkinson's disease. If you look at Pathology of patients who've had Parkinson's disease and looked in the brain. There are signs of microglial activation. If you collect samples like CSF or blood from subjects who have Parkinson's disease, you'll see evidence of cytokines that are elevated. You might see different populations of immune cells that differ between PD patients and controls. There's even epidemiological studies suggesting that maybe things like non-steroidal anti-inflammatories may influence the risk of Parkinson's disease. Patients who had like [00:02:00] inflammatory bowel disease who are treated with anti-TNF biologics, they seem to have reduced risk of Parkinson's disease. So there's been a lot of evidence in the scientific literature that there is probably a role for Parkinson's disease. I think one thing that's not clear from the data is this occurring early in the disease, affecting sort of the ultimate induction or start of the disease? Or is it something that might be a response to the neurodegenerative process? And then that sort of triggers the immune response.

So I think those are one of the critical things that we were hoping to start to answer with our study.

[00:02:37] Dr. Michele Matarazzo: Perfect. So with all this evidence, I think that we can say beyond the reasonable doubt that the inflammation is one of the things that at least happens in PD. So again, going back to your study, why did we need your study? What is the novelty of your approach?

[00:02:53] Dr. Talene A. Yacoubian: So I think the novelty of our approach is that we had a substantial size cohort of PD [00:03:00] subjects who were just newly diagnosed. So a lot of the studies that have looked at inflammatory markers either in CSF or imaging or in the blood have been done in a mix population of PD subjects, people of different severity.

They're on medications, different types of medications. So the actual signal has been hard to interpret what inflammation means. And what we were hoping to do with our study is starting with people who are newly diagnosed. They could not have had diagnosis more than two years. They were not on medication, so they were de novo Parkinson's patients.

And to look with multiple modalities of inflammation. So we looked at cytokines, chemokines in the plasma and in the CSF we did this PET imaging using a TSPO ligand to look at inflammation by imaging modalities. And then we also did a lot of flow measures. From blood samples to sort of look at what inflammatory [00:04:00] changes may be seen before patients are further along in the disease and before they've started on medication to get rid of any sort of medication impacts that there might be on the immune system.

[00:04:11] Dr. Michele Matarazzo: Perfect. So let's talk about the results. What were the main differences between Parkinson's disease and healthy controls in your study?

[00:04:19] Dr. Talene A. Yacoubian: So I think the main difference that we saw, the strongest signal that we saw in terms of the inflammatory measures was in the PET TSPO scanning. So we used what's called DPA-714, which is a second generation TSPO ligand. What TSPO is, it's found enriched in particular immune populations like microglia, but it can also be associated with astrocytes and any peripheral immune cells that might be getting into the brain.

And so the DPA-714 sort of labels these cells and so that signal measures what's going on in the brain at a given [00:05:00] time. And so what we saw is that comparing controls to PD, there was a significant increase in the binding of this TSPO ligand in the PD group as a whole compared to the control subjects.

I think the other interesting finding was that not all the PD had the same amount of signal. The signal really sort of varied. There were some subjects who were pretty comparable to the controls and then some other subjects that had really high levels of this TSPO binding compared to the other groups.

And the signal was not just limited to the nigra, but we saw that in several cortical brain regions in the thalamus and also sort of in striatal regions.

[00:05:43] Dr. Michele Matarazzo: Perfect. And what about the blood and CSF biomarkers?

[00:05:48] Dr. Talene A. Yacoubian: So in terms of the other biomarkers, the main other change that we saw was on some of our flow measures. So we did see a change in certain subsets of T-cell populations. We [00:06:00] saw changes in non-T regulatory cells and T-reg populations. So that it was more in the pro-inflammatory sort of state.

And then the other thing that we saw was that there was an increase in the neutrophil to lymphocyte ratio among the Parkinson's patients. And this can be used as a measure of sort of systemic inflammation. We also looked at cytokines and chemokines and there were a couple changes that were mildly at the border of statistical significance. But we didn't see any dramatic changes in the cytokine chemokine profiles as other people have reported.

[00:06:38] Dr. Michele Matarazzo: And why do you think that happened? Why other people have reported it and why you didn't find it? Maybe is it because it's at the de novo population. It's very early in the disease 

[00:06:48] Dr. Talene A. Yacoubian: I'm not sure. I mean, I think there's a couple different reasons. I mean, some of the other studies have had more of a mixed population of patients. Some of the biggest studies have been done, [00:07:00] like there was one study done in a large LRRK2 population. So that showed sort of changes in like IL1 beta and some other things.

Maybe it's more seen in some of the genetic disorders. But there have been sporadic PD populations where they've seen changes in cytokines and chemokines in the CSF and in the plasma. If you look at all the studies, different people see different cytokines, chemokines. It could be that this is fluctuating with time, might be relevant to what those particular patient populations were exposed to at the time. There are changes like diurnal changes in some of these cytokines and chemokines. So timing of when you measured those samples could have affected the findings in our study. A lot of these studies that have been done have been done in a larger group of people.

So we had 58 and 62 as our breakdown with 58 of them being the PD group. There have been studies that are more like in the order of 200 subjects or more, [00:08:00] so we just may have not had the power to see any dramatic changes. It may also be that our patients were not on medications, whereas in most of these other study there was some potential impact of medications.

[00:08:11] Dr. Michele Matarazzo: And also one other interesting thing of your study was that you looked at the association between the PET and the blood or CSF results. And also you look at association with clinical outcomes such as the cognitive measures. Can you tell me a little bit about these findings?

[00:08:28] Dr. Talene A. Yacoubian: Yeah, so we did sort of a discovery based sort of correlation analysis. And so we sort of looked at the binding potentials in different brain regions from the TSPO PET and then compared it up. First we looked at cognitive outcomes. So we did an extensive sort of neurocognitive battery in our patients.

So all the patients got at least two sort of cognitive tests per sort of cognitive sub-domain. So covering things like executive function, these [00:09:00] geospatial areas, memory, et cetera. Sort of following the level two like MDS sort of criteria for MCI.

And what we found was that the TSPO signal seemed to correlate with several of the cognitive domains.

Particularly what was sort of interesting, and we weren't necessarily predicting it, is that the thalamic signal was the one that most strongly correlated with several different cognitive domains like visual-spatial domain, executive function, and several other domains. So we did see some other associations between the TSPO signal and some of the other brain regions like the striatum and other things that you'd expect some association with.

[00:09:43] Dr. Michele Matarazzo: And did you also look at motor outcomes or you just focused on the cognition?

[00:09:48] Dr. Talene A. Yacoubian: We do have other sort of clinical scales that we measure. So we measure the UPDRS, which since these are baseline not on medications, there isn't any medication effect [00:10:00] to affect that. We didn't see any clear association between the total UPDRS score and what we were seeing on the TSPO PET.

We do the upset smell test. We have the SCOPA-AUT testing. We do the Schwab and England ADLs and a bunch of other scores and most of the other clinical outcomes did not seem to, at least at this point see a correlation. What will be really interesting is with longitudinal follow up, will there be more of a signal as people change over time?

We're predicting that we'll see more of an association with cognition cause as these patients go on medications, that's gonna be the thing that's not really gonna be affected by the addition of levodopa or something like that. Whereas things like the UPDRS won't really. It's hard to use that as a good metric for following longitudinally with patients.

[00:10:54] Dr. Michele Matarazzo: Great. Just to summarize what we've been discussing, what would you say is the key message of the [00:11:00] article? The one most important conclusion.

[00:11:02] Dr. Talene A. Yacoubian: I think the key message of this study is that there is clear evidence of inflammatory changes in de novo patients right at the time of diagnosis. That this is something that's at least happening early on in disease, at least at the stage where a neurologist can make the diagnosis of Parkinson's disease.

And that though all people with PD are not the same, there are varying levels of how much inflammation that we're detecting by this PET scan, among the cohort. I think the important question that remains is that, we're sort of hypothesizing that inflammation at the stage will be bad and that people will do worse clinically in the long run to have more cognitive deficits. But we don't really know that. As far as I know, there hasn't really been any data that's really shown a clear association over time. And so it may be that the people with more [00:12:00] inflammation, maybe they're protected. And that's why these types of studies need to be done for us to understand. Is inflammation a good thing or a bad thing when you see that at this stage of disease

[00:12:10] Dr. Michele Matarazzo: Now talking about that last point at the end of the article, you stated you're going to keep gathering more data on this cohort. So I expect more results and publications in the future. Maybe we will interview again in the next few years. What do you think we need to keep unraveling the role of inflammation in PD. What do you plan to study and what will other people study in the upcoming years?

[00:12:31] Dr. Talene A. Yacoubian: I mean, at least with regard to our immediate project, we have been following these patients on an annual basis, so they undergo all the same clinical scales. We do the blood work, we collect blood for cytokines. We're measuring flow at an annual basis, and then also doing the cognitive measures.

And so we're hoping that over the next few years we'll be able to maybe see if there is any sort of association between those who might have higher [00:13:00] levels of inflammation versus lower, if it's has any predictive value or not. So that's sort of the goal of the next stage of our study. 

If there is an association, then I think becomes a question of can we use this type of imaging to be predictive and give a prognosis for patients. I think another important thing is if we are seeing that inflammation is good or bad, how can we sort of manipulate the immune system to use it as a therapeutic to slow down progression of the disease. I think those are very important questions. There's a lot of animal work where people have done various interventions on different arms of the immune system and shown a protective effect in animal models. Hopefully we can carry that type of research over to humans, and be able to offer our patients more than just replacing and treating the symptoms, but hopefully actually slowing down the neurodegenerative process.

So inflammation could be a key part of that. But, [00:14:00] these types of studies need to happen so we really understand what the immune system's doing.

[00:14:05] Dr. Michele Matarazzo: Sounds great. So a lot of interesting questions, a lot of work to do. Is there anything else that you want to share with our listeners?

[00:14:12] Dr. Talene A. Yacoubian: No, I think you asked a lot of great questions, so.

[00:14:15] Dr. Michele Matarazzo: Perfect. Well, Talene, thank you very much for joining me today. It has been a pleasure to have you.

[00:14:21] Dr. Talene A. Yacoubian: Thank you very much. I enjoyed talking about our study.

[00:14:24] Dr. Michele Matarazzo: We have had Dr. Talene Yacoubian and we have discussed the article, Brain and Systemic Inflammation in De Novo Parkinson's Disease from the Movement Disorders Journal. Download and read the article that is available on the website of the journal. And thank you all for listening. [00:15:00] [00:16:00] 

Special thank you to:

Dr. Talene A. Yacoubian
Professor in the Department of Neurology
University of Alabama at Birmingham

Michele Matarazzo, MD 

Neurologist and clinical researcher HM CINAC

Madrid, Spain

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