This transcript has been edited for clarity.
Indu Subramanian, MD: Welcome, everyone. Thanks so much for joining us. My name is Dr Indu Subramanian. I am a neurologist at UCLA and I'm also the director of the Southwest PADRECC here at the West Los Angeles VA.
Today I'm joined by Professor Michael Okun. He is the director of the Norman Fixel Institute for Neurologic Diseases at the University of Florida. We have a blog together called Parkinson Secrets, and he wrote a beautiful blog about something that was a very hot topic around biomarkers in Parkinson's disease that had been hyped through the media, with attention through many of our support groups. I think people have just been trying to understand a little bit about this biomarker breakthrough, so he wrote a blog called "Quaking Our Way To A Parkinson's Biomarker Breakthrough In 2023?"
Welcome, Mike.
Michael S. Okun, MD: It's great to be with you, and fantastic to try to talk through this really cool and interesting subject.
Subramanian: There was a paper that came out that led to this hype, so maybe you can tell us a little bit about the paper and its findings.
Okun: It actually traces back to a paper that was just published in Lancet Neurology, and it was led by an author named Andy Siderowf, who's a professor of neurology and leads the Parkinson's and movement disorders division at the University of Pennsylvania.
Andy and his colleagues looked into the Michael J. Fox Foundation's treasure trove. They have this awesome study called the Parkinson's Progression Markers Initiative study (PPMI). They had about 1000 patients and collected the spinal fluid, which is a fluid that bathes the brain, and they had all these clinical scores.
They took that spinal fluid, all of the information, including the genetic status of the folks that were in that study, and they performed a test called real-time quaking — some people call it a synuclein seeding assay — where they were able to see whether or not this abnormal protein in Parkinson's, synuclein, was in those spinal fluid samples, and then correlate it to the different disease within these 1000 really super–well-characterized folks.
Andy Siderowf and Claudio Soto, who was really instrumental in developing this technology and this assay over many years, put this together. It was a big wake-up call for the field about what could be done with this type of technology.
RT-QuIC Seeding Assay
Subramanian: Very cool technology indeed. Why do they call it RT-QuIC?
Okun: First, it's not quick. That's the first thing that folks should know. It's actually real-time quaking. Essentially, you have to figure out how to measure that bad Parkinson's protein within that spinal fluid.
They actually used a technique that was invented not for Parkinson's but for prion disease or Creutzfeldt-Jakob disease, which is a rapidly progressing dementia/cognitive dysfunction syndrome. That detail is not super-important.
What is important is that they were able to take protein in that disease and quake it, meaning they shake it. They shake it for hours — sometimes 20 hours or more — and they try to separate out the bad protein from the good protein. They add some recombinant good protein, and the bad protein will bind with that and then they can measure it when it crystallizes, and it changes its configuration of how it folds. It's very cool.
In the old days, when it was used just for prion disease or Creutzfeldt-Jakob, it told you whether you had this really devastating condition. In Parkinson, the way that it's used is they can tell you if you have this abnormal protein configuration; that could be a marker that you have Parkinson's disease. It's kind of a cool and nice way that we see technology, methods, and science from one thing translated to another.
Subramanian: Very cool. It's also called a seeding assay, right? Why is it called that?
Okun: I think the easiest way to think about this is: Let's say you plant a seed in the ground and you're trying to make the plant grow. Now imagine you have this spinal fluid of these folks that may or may not have Parkinson's disease, and it may or may not have this abnormal protein. Let's say it does have the abnormal protein. That's the seed.
You can put that in, combine it with some normal protein, and quake the two together and see if you can make something grow. What's going to happen is you're going to get the growth when the abnormal protein turns the normal bad. When it turns that normal bad, you quake it for 20 or 30 hours or however long your assay runs, and you're going to be able to see that they have that bad Parkinson's protein.
Subramanian: Your criticism of the way that the paper is done and also the technique is that it's really important as to who's looking at this assay and doing the assay. It's very operator dependent, right?
Okun: My criticism isn't necessarily of the paper or of the authors. It's more of a caution than a criticism. It's a cautionary tale. If you look over the past 10 years, people who have used these types of assays where they quake and shake to get the answer, it really depends on how the assay is done, what the ingredients are, the secret sauce, to see if you can get over 90% in terms of the sensitivity of that assay. It is really important how it's done.
One of the things that was nice about this study is that cerebrospinal fluid is a really rich source that may have that Parkinson's protein in it. They used an assay that was developed by Claudio Soto, who was one of the early pioneers of making these assays in prion diseases and quaking proteins, for other reasons. They used a really good assay.
If you look across all the different papers, I just caution people to watch out because some of those assays are down to 50%. As we apply it, we have to remember that it matters how it's done. Hopefully, these will get better and better. We hope that they're going to go to skin and some other body fluids that are easier to get to than spinal fluid.
Some LRRK2-Kinase Missed
Subramanian: Absolutely. I think that is one of the drawbacks. Trying to give a lumbar puncture is not a joke on our patients. For the study, they were able to collect an amazingly rich dataset. Let's get into the nitty gritty of that Lancet study.
Okun: The findings of the study were that they were able to look at folks with and without genetic abnormalities for Parkinson's, so these would be mutations that cause Parkinson. They were able to look at people who are at risk, who might have some prodromal signs like acting out your dreams or loss of smell. Some people use that term, meaning maybe these are symptoms that occur before they have Parkinson's and they might be at risk because they have a gene. They were able to look at all these different populations.
They found that when they did this assay, when they quake this and shake up that CSF, when they get their result out, they do the best when they combine it with someone who they think is going to get Parkinson's or has Parkinson's and also has smell abnormalities, which is very interesting. The smell actually drove up the sensitivity of this way into the high 90s. It can matter when you pair it with the right things. I think using all the data was important.
One of the things that was absolutely critical for people to remember is that the most common genetic abnormality of Parkinson's is called the LRRK2 kinase. It's just a single mutation. That's the most common mutation for Parkinson's disease. It turns out that these types of assays, even when done on this great, enriched study, hits maybe two thirds of the people correctly.
That tells us something about Parkinson's disease, something about these assays, and where we have to be careful. Some folks who are carrying that mutation may come up negative, so there's learning that is still yet to be done. By the way, the findings in this study have been shown by several previous studies, if you look back in the literature. The great thing about this is it's enriched, it's in CSF, it's a large cohort, and the drip, drip, drip of evidence comes together on this paper and shows us things that we knew. We knew that these assays were having trouble with the LRRK2 mutation.
Subramanian: You also mentioned that there were some issues with the gender differences as well, with respect to women. Can you elaborate on that?
Okun: I spoke with the study's senior author, Andy Siderowf, who thought it was actually pretty interesting that there are differences in this assay for picking up Parkinson's, whether you're a man or whether you're a woman. That is something that is a novel finding to the study, but it's very preliminary so I hesitate to go too far with that until we see more data. It's something we're going to have to pay attention to.
I will remind people who are interested in this topic that Parkinson's is much more common in men than in women, but it's going to be important for us to develop an accurate test for women who we're trying to detect whether or not they may have Parkinson's or are going to get Parkinson's.
Practical Implications?
Subramanian: It is absolutely important that women get involved in research in general, because I think we have not seen many women be studied and we haven't really catered many treatments to women.
This is all really interesting, but what does this type of information mean for our general neurologists out there or even our primary care doctors?
Okun: That's so important. I'm so glad you asked that. At the end of the day, what is the take-home message? Everybody sees this and it's up in lights, so we better do something. I would say, not so fast and not necessarily. If you already have Parkinson's, the cat is out of the bag, as they say in the old cliché, and you're not going to get anything more from knowing whether or not you have a synuclein from this assay.
If you don't have Parkinson's, it could be a diagnostic test, but it isn't quite ready for primetime yet. I think we should be careful about using it until we've really brought it forward, we know all the data, and we want to make sure we don't miss some of the mutations and we understand what it means.
Now, if you have dopamine-responsive Parkinson's — meaning, you're taking dopamine medicine for your Parkinson's — and it's doing well, it's very clear, and there's no concern with your doctor because they know you have Parkinson's, the only benefit you get from this is knowing potentially if you have positivity on this assay that might allow you to qualify for a clinical trial or might allow you to get a different treatment in the future, but nothing right now.
Those of you who are enrolling in studies, I totally encourage that. We want to try these assays on as many people as we can, with a number of different techniques, and help to make this better. "Better" means we're going to be able to create classification systems, particularly for regulatory agencies like the FDA, who are going to require that we better classify and also stage disease in order to develop new therapeutics and to drive the next generation of therapies for Parkinson's. I think it's going to be important as you move forward.
New Era of Biomarkers
Subramanian: Outside of this biomarker, Mike, are there other things that you're excited about on the horizon? I know we were just at the AAN and there were some reports of peripheral biopsies of different areas of the body and other biomarkers. What's your take on that?
Okun: We're in a new era of "biomarkers." How can we measure diseases in a more exact way than some of the scales? And then we have to think about diagnosis. It's a difference between diagnosis and then monitoring the disease over time. Once the cat's out of the bag and you know what you have, it's more important to monitor it and to have good accuracy. If you're treating diabetes, you see that the sugar level goes up and down; it's very accurate. We are not that accurate yet in Parkinson's.
I think folks need to understand that the skin biopsies are going to be really interesting; you can do many of these assays on the skin. If the skin can be shown to be as good as the spinal fluid, that's going to be a much easier test for folks. There were also some data presented here recently on submandibular gland biopsies and also getting body fluid from other areas, sweat, and other things.
Thinking through what might be the path forward is going to be exciting, including monitoring diseases and then using that information to be able to measure and reduce the number of folks that we're going to need in clinical trials to drive a new treatment for Parkinson's disease. Once you can biologically diagnose and monitor —and that second part, monitor, is really important — you can reduce the number that you need to test these new drugs and therapies from potentially thousands to hundreds. That's a huge difference.
Subramanian: This is very exciting. Thank you so much for summarizing this so beautifully. I think you really brought it home about how we're not there quite yet, on a clinical level, to use this type of assay to diagnose people. Thanks so much for watching.
Thanks, Mike, for joining us today. We're excited about this new biomarker era.
Okun: It was a pleasure. Thank you for having me.
Follow Indu Subramanian on Twitter @DrISubramanian
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Cite this: What the Parkinson's Disease Biomarker Breakthrough Means in Practice - Medscape - Jun 21, 2023.
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