Based on an article by Matt Schur, from the 91短视频正版Pulse.
There’s a saying in the Parkinson’s community: Once you’ve met one person with Parkinson’s disease, you’ve met one person with Parkinson’s disease. Meaning, despite popular depictions, Parkinson’s can present much differently from person to person.
This variance, in combination with no known cause, has presented tremendous difficulty in diagnosing the disease, which is the fastest-growing neurological condition in the world. Until now, clinical observation and assessment have driven diagnoses, but that has been prone to error. While reports vary, misdiagnosis can be as high as 25%. Overall, half a million people in the U.S. have been diagnosed with Parkinson’s, but researchers think that number might be twice as much since the disease is so often misdiagnosed or missed.
“The most pressing concern is that, despite all the research, we still do not understand the underlying pathogenesis of Parkinson’s disease,” says Michael S. Okun, MD, Medical Advisor, Parkinson’s Foundation. He is also a Director for the Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida. “To efficiently develop meaningful therapies, we need to invest in unlocking all or most of the steps necessary to convert a normal brain into a Parkinson’s brain.”
There has been a range of new developments, from exercise based behavioral therapies to surgical-based interventions. But the most promising has been the recent advent of tests that confirm whether people have the disease. That might sound mild—but researchers think it could be the beginning of a revolution in Parkinson’s research and clinical trials.
“It is exciting to see a variety of tests emerging that may assist in both the diagnosis and potentially in the monitoring of Parkinson’s symptom progression,” Okun says. “Spinal fluid, blood, imaging, skin and other tissues have been quickly emerging and changing this landscape and will likely drive biological classification and more clinical trials.”
Protein Problem
To be sure, there are common and tell-tale markers of Parkinson’s: tremors, stiffness, balance problems, slowed movements. Researchers have also known that the disease happens when the brain cells responsible for dopamine production, which helps coordinate movement, stop working or die.
But for years, researchers have been unable to pinpoint the disease’s biomarker (biological marker), a medical measure that tracks what is happening in the body, such as blood pressure or cholesterol levels.
Last year, researchers with The Michael J. Fox Foundation for Parkinson’s Research (MJFF) published findings confirming that a test they developed could detect a biomarker, a misfolded protein called Alpha-synuclein. The protein naturally occurs in the body and is responsible for other diseases that often get lumped in—or misdiagnosed—alongside Parkinson’s, such as Lewy body dementia and multiple system atrophy. Until now, confirmation of the presence of Alpha-synuclein only happened posthumously.
“Alpha-synuclein has been sort of a hot biomarker for years and years because it’s the protein that clumps in the brain of almost everybody that has Parkinson’s, based on autopsy data,” says Samantha Hutten, PhD, Director of Translational Research, MJFF. While Parkinson’s is almost always unique to the individual, she says, this is basically “the one thing that is standard. It’s been a target for developing biomarkers for a long time.”
MJFF has been pursuing this biomarker in different studies for decades, finally having success with a spinal tap test called an Alpha-synuclein seeding amplification assay (SAA), which can detect the protein’s pathology of people diagnosed with Parkinson’s and with people who have not been diagnosed yet— even among people who have no symptoms.
“We didn’t have a way to identify people pre-diagnosis, and now we do,” Hutten says. “It’s one of the most exciting things, and one of the things I’m most excited about for the future of diagnosing and treating Parkinson’s, which this test is enabling.”
MJFF isn’t the only group to search for and find a way to identify Parkinson’s. Christopher Gibbons, MD, Neurologist, Beth Israel Deaconess Medical Center, has been working on skin biopsies to look for abnormal proteins in diseases like Parkinson’s for more than a decade.
In March, a research team he led published findings in the Journal of the American Medical Association that showed a Parkinson’s skin test he helped develop was able to pick up the abnormal protein in 95% of cases. “The problem with this misfolded protein is that the body can’t get rid of it, and it starts to pile up,” Gibbons says. He is also a professor of neurology at Harvard. “It takes many years for it to clump up to such a degree that a clinical problem develops.”
The test he developed, he says, is “basically the same skin biopsy as you might get in a dermatologist’s office, like a punch biopsy for a mole. A three-millimeter punch biopsy taken on three different parts of the body.”
The total time, from start to finish for his procedure, takes less than 15 minutes, he says. “It’s a test that we could do in an outpatient office very easily and have a very high sensitivity of picking up this protein that would help confirm a Parkinson’s diagnosis.”
The Biomarker Boost
There are several reasons why researchers are so gung-ho about biomarkers. For starters, “People can go around and around with different doctors, and it can take upwards of five years to get an actual diagnosis,” Hutten says.
For a disease where people are symptomatic in different ways, a lack of disease confirmation can complicate treatments, too. “When people present to a neurologist, sometimes we’re very confident,” Gibbons says. “We give you a medication that’s a dopamine replacement that’s very effective.” However, he says, if somebody has some common Parkinson’s symptoms but is not responding to typical Parkinson’s medication, do you give them more of the drug, potentially causing side effects? Or do you take them off the drug?
It’s partly what makes treatment of conditions around, say, cholesterol, much more effective. “With cholesterol, there are definitive tests to tell us whether we have an issue,” Hutten says. “There are specific levels that we can measure: If you’re below the threshold, you’re good to go. If you’re above, there’s a diagnosis and intervention.”
Before the Alpha-synuclein identification, perhaps the most pressing limitation was the difficulty in establishing effective clinical trials. With current clinician diagnosis rates, if you have a study of, say, 200 people in the disease group, there might be as many as 50 people who don’t have Parkinson’s. “Your trial was not actually powered to answer the question: Is this drug effective for Parkinson’s?” Hutten says.
Gibbons also emphasized how biomarkers are going to play a major role in this idea of trial enrichment. “Selecting the right people for future trials is absolutely critical,” he says.
That’s especially true for people in the disease’s early stages, where misdiagnosis rates can be as high as 50%, Gibbons says. “You want to enroll people with early Parkinson’s disease in a clinical trial because that’s probably the opportunity for the biggest intervention,” he says. “Until now, you were risking them not having the disease. Knowing that they have the Alpha-synuclein protein would really help get the right patient testing the right drug.”
The Limitations of Biomarkers
While the advent of biomarkers signals a shift in research, potentially opening the door for a lot of promise in the future, Hutten does refer to this stage as phase 1.0. “It’s important that patients work with their doctor to understand if the biomarker test is right for them,” Hutten says. “Unlike your cholesterol level, knowing that you’re positive for this test might not change how your clinician treats you.”
In part, that’s because the biomarker tests aren’t fully quantitative yet. “If you think about blood sugar tests, you have a threshold and can benchmark treatment to see if diabetes is improving or not,” Hutten says.
Biomarkers aren’t there yet. Gibbons and his team are working to develop a quantitative skin biopsy test, having presented results of this research in April. “We’re also studying how early you can detect this problem. We know that Alphasynuclein is present in patients that will develop Parkinson’s in the future, and we know it accumulates over many years. We suspect we can eventually identify it 10 to 15 years before the diagnosis of Parkinson’s disease.”
These biomarker advances would unlock what Hutten calls phase 2.0 of Parkinson’s care. “What we’re investing heavily in right now is making the test less invasive, but also quantitative so that we can use it for informing patient care, understanding disease progression and knowing whether drugs are actually having an effect,” Hutten says. On the less-invasive side, that includes blood tests, urine tests and nasal swabs. “That would be huge because that would impact drug approvals and how we design clinical trials.”
While much work remains, Hutten sees this as a time of tremendous potential growth. “Now that we have this biomarker test, we have so many exciting possibilities. We’re collaborating and working together as a field in a way that I’ve never seen before. People are really jazzed to be able to work together, be competitive to develop something and all work together to get to this next phase.”