Highlights on Parkinson’s Disease | Congress 2022

[00:00:35] Dr. Ron Postuma: A pleasure.

[00:00:36] Dr. Eduardo de Pablo Fernandez: We will start with the advances over the last year, couple of years. Can you summarize, or what are your highlights on PD research?

[00:00:44] Dr. Ron Postuma: I would say the two biggest things to happen in Parkinson's in the last two years, first of all, would be the publication of the New England Journal just last month. Two trials of the antibodies, which were mixed. I wouldn't call them failures. There is some signal, at least in one of the measures. And we do have to ask what one would've expected to find with the passive synuclein antibody in only one year. At least we have safety and tolerability and things are moving forward. We don't really know what they're gonna do, obviously. They're not obviously gonna change things overnight, but I think those are really important advances, because those are the things that we are really looking forward to in the field.

I think the second biggest thing that's changed, I think probably the thing that's gonna change the most, is the diagnosis of Parkinson's disease based on tissue, or fluid or whatever it is. I mean, this is really gonna revolutionize, I think how we do things, maybe not immediately. But the idea that we can make a firm diagnosis of the synucleinopathy in a patient during their life is of some use now. I mean, we still really are struggling sometimes between PSP and PD, and MSA and PD. We don't know what to tell our patients. So I think we will be able to tell our patients something.

But in the future, of course, when we have any sort of therapy based on synuclein or based on the presence of Parkinson's and not another disease, it will have no symptomatic effect. We'll never be able to know if it's doing anything. I would certainly want to know and make sure that my patient had Parkinson's had synucleinopathy before I was gonna commit them to such a therapy for the rest of their lives. So I think this is gonna be a massive advance when disease modifying therapy comes forward.

[00:02:17] Dr. Eduardo de Pablo Fernandez: So, absolutely. I think you said that the best starting point for clinical trials should be a biomarker confirmed, diagnosed in line. So we have had a busy Congress, of research studies and results presented. Has anything caught your eye? Would you like to comment?

[00:02:31] Dr. Ron Postuma: O ne thing that sort of made me write with my pen furiously was a poster from Germany and then a platform presentation of Dr. Hittori, so Daniel Birch's group and Dr. Hittori's group, on the potential of plasma or blood diagnosis of synuclein. The German poster is relatively early and it was 18 patients showing quite good sensitivity and specificity. And I think we'd certainly be interested in exploring that in the prodromal space as well.

And then in Japan where they're getting almost triple digits and getting very high sensitivity and specificity for blood based ynuclein RT-Quic, or PMCA assay, I think its the RT-Quic assays. That is a lot simpler than CSF examination and skin biopsy, which I'm sure will work as well. It's simpler than that, too. So we might be where Alzheimer's is very, very soon.

[00:03:17] Dr. Eduardo de Pablo Fernandez: So you've talked about the work done, but there's still a lot ahead. So what do you think would be the hot topics in the next year on Parkinson's research, and the challenges that we will have to face?

[00:03:28] Dr. Ron Postuma: Yeah. So, I work in prodromal and so I guess I really still feel that we need to start moving our trials earlier. It's not even a question of clinical trial design. I mean, there's major, major advantages going in the program space for clinical trial design. They're not on symptomatic therapy. You don't have to go a long time, but you can go a long time. You can do a five year trial if you wanted to. I wouldn't do it.

But that's also, you know it's biological. So you've got yourself an agent that's working on synuclein. How long does it take synuclein to get into the cell and cause dysfunction? How long does it take to start killing a neuron, nevermind dysfunction? This is probably a process that takes several years. And so really are we just too late? Is anything we try, especially in the synuclein space, especially in the gene therapy, fixing a genetic process that's been going on for 50 years. If we're in that space, can we really do anything if the patient already has lost a large proportion of the dopaminergic system. And so I think we really have to start becoming comfortable with calling the early stages of Parkinson's disease, prodomal Parkinson's, is Parkinson's. It's just a stage, but it's Parkinson's exactly like the Alzheimer's field did 10 years ago, 15 years ago, and with a complete change in the way they do things.

[00:04:44] Dr. Eduardo de Pablo Fernandez: Exactly. I think movement disorder specialists, we have been classically focused on the movement and the motor symptoms. But I think probably, yeah, we need to start calling that.

[00:04:54] Dr. Ron Postuma: Yeah, I mean, MIBG sonography can pick up Parkinson's disease guaranteed in a proportion of people five, 10 years before RBD, of course, everyone knows that. Pure failure is usually Parkinson's not MSA.

[00:05:06] Dr. Eduardo de Pablo Fernandez: Absolutely. There's several sorts of clinical syndromes that are gonna lead to Parkinson's. This is where synucleinopathies come in in a minority of patients. But yeah, I think we need to focus on those populations populations and clinical trials with them, yeah.

Question so you have been involved in many studies with the MDS Task Forces for the definition of the diagnostic criteria. And you're currently involved with the Parkinson's disease subtypes task force. And what are you planning for the next year?

[00:05:36] Dr. Ron Postuma: So this is Connie Marras and Tiago Mestre who are the chairs of this. So I'm just sitting in the room, throwing out comments. It's very interesting because you know, the task force has been struggling a little bit with how reliable subtypes really are. To what degree is Parkinson's subtypeable? And I think one of the insights that's come out of the committee is that subtypes are really a poor proxy for a personalized medicine that is individualized. And so, for example, the idea is that rather than identifying a person in front of you as being in one subtype, you could actually identify what this person most likely resembles at an individual level.

So there's a proposal, for example, that's being run in the Netherlands where they'll do a massive characterization of Parkinson's disease, clinical markers, and I think they should add biomarkers. And then follow that patient over time. And then, when you have a new patient, you can enter as many clinical details as possible and pull out their digital twin, if you will. What does this person most likely resemble? And what's their biomarker status? And what's their MRI like? And what's their clinical course like? And how do they respond to this treatment? This is pipe dream, of course. This is a long way way, but this is really fascinating.

And the other thing that I think that came out of the discussion was that we don't do enough of using what we do know about subtypes now to actually change treatment. I use it in the clinic every day. If I know the patient based on their subtype or based on their characteristics, it's a high risk or low risk of dementia, it completely changes my choice of dopaminergic therapy, my choice of antidepressants, my choice of a whole lot of, of things am I gonna use amantadine or not?

And so if we're able to predict the course of the disease on an individualized basis, particularly with things like dementia and response to levodopa, and these things that we actually already know how to do, I think we have to start learning how to use that and making the treatment choices for the future.

[00:07:24] Dr. Eduardo de Pablo Fernandez: I agree with that, that there is lot of clinical implications from PD subtyping that probably there hasn't been so much emphasis on that, but we should probably be implementing in practice. So exciting times ahead. And hopefully we will have great news to present in the next MDS Congress. So thank you very much for your time.

[00:07:43] Dr. Ron Postuma: It's a pleasure.