Unravelling the progression of tremor in Parkinson's disease

[00:00:46] Dr. Jacopo Pasquini: Hello, Dr. Morales, and thank you for your kind invitation.

[00:00:50] Dr. Hugo Morales: Yes, it's a pleasure to have you here. Now in this paper, you and your colleagues evaluate tremor in Parkinson's disease and its [00:01:00] behavior over time. And I'm looking back in the literature, is something you mentioned in your paper as well, there's not many studies addressing in a very standardized manner tremor over many years. And I found that very interesting and particularly to understand what's happening and answering the question of what's happened with the tremor over time. But tell me how this study was designed and where is the study population that you gathered?

[00:01:28] Dr. Jacopo Pasquini: Yeah, so you're absolutely right. The first catalyzer of our research idea was that although we assume that tremor is a very well established symptom of Parkinson's — it's a cardinal symptom — and we assume that usually is a benign symptom that decreases over time.

 This is the assumption that we all have. It's probably right. It's correct. And it's based on clinical practice. So it must be right. 

However, when we looked in the literature, there weren't many studies that confirmed this assumption. [00:02:00] So being in the evidence based era, we just wanted to verify this hypothesis and see if we could have any more insight.

We know that tremor is still troublesome for many patients with PD. There was a recent survey where people mentioned that tremor was the most troublesome manifestation over the first 10 years of the disease. So we found that very interesting is that we usually see more troublesome PD symptoms like gait symptoms, falls. These are very troublesome manifestations, obviously, where dopaminergic medication is not very effective. But we did find that evidence quite interesting. So we wanted to look at the data. 

So we had A very interesting option to go and look in the PPMI cohort, which was our starting cohort. This is a very large cohort that was recruited in specialized centers. There are almost 400 people with PD that were recruited all over the world. And they were followed up for more than 10 years now. We looked at the first [00:03:00] seven years for our study, because that was what was available when we conducted the study. So that was basically our starting point.

[00:03:09] Dr. Hugo Morales: And from the PPMI cohort, so I understand these patients were treatment naive patients, you give them treatment, and then you did similar examinations yearly. 

[00:03:19] Dr. Jacopo Pasquini: Yeah, exactly. All these participants were drug naive when they entered the study. They had to have a diagnosis for two years or less, so their PD diagnosis was not older than two years, so they were de novo PD patients and untreated. Then they could start medication after the first six months that they enter the study.

And then they just had their usual medication that they were managed as with the usual clinical practice guidelines. Then every year they had an off and on evaluation in clinic. So that was very helpful for our analysis, because that let us explore both the [00:04:00] off trajectory, which is something that is quite interesting because that's not usually available in the literature to see patients that you see the trajectory in the off period. It's something that we don't see anymore, obviously, unless you do a study like the PPMI. And then there was obviously also the on evaluation, which gave us the ability to look at the response of tremor to medication. 

[00:04:27] Dr. Hugo Morales: I think that's a very good point in the design of this study , which allows you to do this very detailed analysis to look for this association or the effects of time and medication effect in the way you model the analysis .

Tell me, what is the tremor in Parkinson's disease in patients in the off state, in the on state, and how it behaves over time? Is there any difference between the rest tremor over time? Is the postural and kinetic [00:05:00] tremor the same over time, although they behave differently, including with the treatment effect?

[00:05:07] Dr. Jacopo Pasquini: There is only one figure that we put in this paper, and I think it's very useful to look at. So you can see that Tremor in the off state, actually, all types of tremor increase over time, and this effect is statistically significant over time. If you see the on state, that follows a, a more linear effect, and it's usually, it looks more flat. So we might say that probably in the on state, tremor is quite stable over time, at least in the cohort.

So at least as a cohort effect, we have to remember that there are more than 300 participants here, a bit decreasing over time, but still more than a hundred at the last follow up. So this is a cohort effect. So it's not the same for everybody. And I think we will talk about this a bit later of, of responsiveness and non [00:06:00] responsiveness.

I think, however, the interesting point is that the rest tremor and to a lesser extent, kinetic and postural tremor, do increase a bit over time in the off stage. So if we do not treat it then it follows an increasing path, which was something that unless you had these data available, you really could not see.

And probably the assumption that we were talking about earlier, that tremor does not worsen over time, maybe actually it improves, is that we always observe patients in clinic in the on state. So we don't really know what happens when they're off. But actually, when people are off, they do tell you that they're slower, they have freezing of gait, but they also say, the tremor comes back. And that's obviously something that we do observe in the clinic every day.

[00:06:51] Dr. Hugo Morales: Can I ask with subtypes of the tremor, w Was there any difference between patients , in terms of the demographics of the cohort?

[00:06:58] Dr. Jacopo Pasquini: There was actually a quite [00:07:00] interesting result in this data. Rest tremor was actually increasing with age as a presentation, meaning that rest tremor was positively correlated with age. So older patients in this cohort tended to have worse rest tremor in the off state. 

But that's something that I cannot really comment more than that on. And I hope that I can provide more data in the future.

[00:07:26] Dr. Hugo Morales: Then you were hinting early to the medication responsiveness of the tremor. So I wonder how much consistent the tremor was responsive to the medication over time? Did you find anything specifically about how many of the patients had actually maintained the response over time? Was it resistant in some way?

[00:07:48] Dr. Jacopo Pasquini: I think there are two sides of this story. Meaning that if you look at the cohort level, so the group of patients, you see that there is a significant improvement over time. [00:08:00] There is a significant improvement at all times, at all observations. It doesn't go to zero like as with any other manifestation, but there is a significant improvement at the cohort level and you can see that statistically.

However, if you look at the individual responses, then you can see that if you look at every observation, we found that about 20% of participants at each follow-up, the rest tremor does not respond to dopaminergic medication. These percentage is about 30% for postural tremor, and about 40% for kinetic tremor. So this is quite interesting because it tells us that at every time point over seven years, there is a significant percentage of patients that does not respond to the medication that we give them, in this case, in clinic.

[00:08:50] Dr. Hugo Morales: And then with this knowledge now that 20 percent of the patients with rest tremor may be resistant in some way to medication. Was [00:09:00] any of the scales in your study addressing patient symptoms perspective, meaning that quality of life, or how they rated the severity of the tremor?

Because I found this may be something maybe impairing quality of life as well.

[00:09:16] Dr. Jacopo Pasquini: Absolutely. We only had in this study an analysis on the UPDRS Part 2. The item on the reported severity of tremor, there was a small increase in that. A statistically significant, but a small effect that increased over time. So at least over the first seven years, there may be a small increase in how bothersome tremor is over the first seven years.

However, we did not have any other patient related scale to assess this. And this is obviously an area for improvement and to study, I think.

[00:09:53] Dr. Hugo Morales: Thank you. Now with all this rich data being part of the PPMI [00:10:00] and with the study you just published, where's the next step to get more knowledge about what's happening with the Parkinson's tremor progression? Is there any plans to do correlations with others signs, symptoms, or is there any other ideas as to how this data can be use exploited?

[00:10:22] Dr. Jacopo Pasquini: Yes, I think that a research paper is a good one when it raises more questions than, than the ones that it answers. And I hope our paper was one of that. There are many open questions. So what happens to tremor after the first seven years? Is it true that it really decreases even for tremulous people?

And this was a first starting point. So, we believe that this was the first step in uh, establishing how is the tremor landscape in tremor. Then, obviously we can build on that. And I think this was useful and this was needed also to catalyze some [00:11:00] change and some clinical trials for PD tremor.

 There have been some recent trials with for example, zonisamide. It failed, but for drug specific for tremor, there is now the non lesional techniques. So I think that An evidence based description was needed. I'm not saying our description is perfect.

There is room for improvement and for other cohorts as well, maybe community cohorts. This is a very well selected cohorts of PD patient from specialized centers, but it may not be the usual community cohort. So yeah, there is much more to build on, I think, for PD tremor.

[00:11:39] Dr. Hugo Morales: Now, thanks again, Dr. Pasquini for sharing your insights and details of your paper as this may help us to understand, actually, PD, tremor progression over time . And I would like to invite our listeners to go and read the paper, "The Clinical Profile of Tremor in Parkinson's Disease," [00:12:00] published in Movement Disorders Clinical Practice.

[00:12:01] Dr. Jacopo Pasquini: Thank you, Dr. Morales. And I would like to thank all my coauthors who helped me build on this nice piece of paper, I think.

[00:12:09] Dr. Hugo Morales: Indeed. Thank you.