What the Parkinsons Disease Biomarker Breakthrough Means in Practice

Neurologists Indu Subramanian and Michael Okun discuss the implications of the alpha-synuclein seed amplification assay for the diagnosis and management of Parkinson's disease.

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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.