By the time someone experiences symptoms of Parkinson’s disease, around 70 to 80 percent of their dopaminergic neurons in the nigrostriatal pathway are dead (1). Unfortunately, without a way to repopulate these neurons, current treatments, such as levodopa, can treat the symptoms but cannot halt progression of the disease.

If you can couple very early diagnosis with a good and safe treatment, you could actually eradicate [Parkinson’s disease]. 
– Claudio Soto, The University of Texas Health Science Center at Houston

“This means we are too late,” said Michael Bartl, a clinical scientist and neurologist who treats patients with Parkinson’s disease at the University Medical Center Goettingen. “Nowadays, we still treat Parkinson's disease patients with symptomatic drugs that just improve overall ability to move and so on. But that is something that we have done [since] 10 years ago, 20 years ago, 30 years ago … there is a huge gap.”

To have any chance of preventing or curing Parkinson’s disease, patients must be identified before symptoms like tremors, slowed movements, and cognitive issues begin. Researchers across the globe are searching for early markers of the disease in blood and cerebrospinal fluid (CSF), with the ultimate goal of diagnosing patients earlier and providing treatments that could prevent brain damage.

“If you can couple very early diagnosis with a good and safe treatment, you could actually eradicate [Parkinson’s disease],” said Claudio Soto, a neurobiologist at The University of Texas Health Science Center at Houston. “This sounds like a dream, but I think it's possible.”

Protein folding gone wrong

To identify Parkinson’s disease and other neurodegenerative diseases earlier, Soto and his colleagues measure the alpha synuclein protein in the brain. When this protein begins to misfold and aggregate to form Lewy bodies inside neurons, studies repeatedly show a strong association with Parkinson’s disease (2). In postmortem studies of Parkinson’s disease patients, researchers found clumps of alpha synuclein in the dopaminergic signaling pathways (3). Yet, scientists don’t know for certain whether this protein buildup directly causes Parkinson’s disease. “We don't have yet the formal proof,” said Soto. “The best formal proof will be to eliminate the protein aggregates, and therefore eliminate the clinical disease.”

Originally, Soto was studying prion diseases, a group of neurodegenerative diseases triggered by prion proteins, which cause other proteins to misfold. In 2001, his team published a method that used cyclic amplification of protein misfolding to detect prions in rat brain samples (4). In 2016, they expanded that work to create one of the first seed amplification assays to detect alpha synuclein protein to diagnose Parkinson’s disease (5). The company that Soto co-founded, Amprion, subsequently developed an alpha synuclein assay called SYNTap to detect multiple kinds of synucleinopathies associated with Parkinson’s disease, Alzheimer’s disease with Lewy bodies, and more.

Several groups worldwide are now further developing this technology with the hope of being able to diagnose Parkinson’s disease in its early stages. But Soto acknowledged that they need to improve the quantitative power of the technology. “So far, most of the experimental studies have been done to say, can we detect, or we don't? So, yes or no,” he said. “The other thing that we would like to do is to be able to say, yes, you have it, and you have this relative quantity of protein aggregates, and try to correlate with perhaps the time that you would need to develop the disease.”

Other scientists are currently working on that goal. David Walt, a chemical biologist at Harvard Medical School, pioneers digital detection methods to isolate individual molecules. His team recently applied this technology to seed amplification assays for alpha synuclein as a way to quantify the amount of individual fibrils that clump together (6). According to Walt, this tool could be used in early screening of Parkinson’s disease to monitor at what point someone needs to go on medication and could also serve as a marker of drug efficacy in clinical trials. “If a patient receives a drug and their fibrils are growing, and then all of a sudden, you give a drug and it slows down, you know that that drug is effective,” he said.

The biggest limitation of most of these assays currently is that they must analyze patient’s CSF, which requires an invasive spinal tap. “The big push, of course, is to go from CSF to some other biological fluids that can be more easy to collect,” said Soto. “It's just like what happened with prions. In prions, we were able to detect in CSF and brain at the beginning, and it took us, I don't know, maybe 10 years to be able to detect in blood, and now it's working super well in blood. … So, we think we're going to get there.”

Once the less invasive tests are available, Soto envisions a future where they become a part of routine clinical tests. “When everybody [turns] 40 or 50, in addition to going for a cholesterol test or glycemia test or colonoscopy, you will also go for testing the presence of your brain health,” he said. In that scenario, depending on whether protein aggregates of alpha synuclein or others are found in a patient, doctors would be in a much better position to offer earlier treatments. Soto added that it’s possible that drugs that have already been tested to treat Parkinson’s disease may have failed not because of the drug itself, but because they were being tested in patients too late.

Probing the proteome

To more easily test for a marker of Parkinson’s disease in the blood, Bartl and his colleagues went searching beyond alpha synuclein. Instead, they looked through the entire proteome (7). Using mass spectrometry, they compared proteins from blood samples in patients with a REM sleep disorder that puts them at risk of developing Parkinson’s disease in the future, patients that were recently diagnosed, and healthy controls. They identified 23 proteins that were differentially expressed in the healthy control groups compared to both patient groups. A machine learning model identified that eight of these proteins were useful in predicting, with 79 percent accuracy, whether patients in the at-risk group would develop Parkinson’s disease — up to seven years before their diagnosis. These eight proteins were especially relevant to processes related to immune system activity, inflammation, survival of dopaminergic neurons, and protein folding responses. 

“There are a lot of things below the surface, a lot of processes already going on before we see something. So, the prediction is … a very important result,” said Bartl. Moving forward, their team is now working to validate their results in independent samples and in patients with other neurodegenerative diseases to see whether the proteins they identified are unique to Parkinson’s disease. 

But even if their blood-based assay could be used today to predict patients who will go on to have Parkinson’s disease, there wouldn’t be any treatments available that could delay onset or reverse the disease. Bartl’s group is interested in collaborating with other research groups to investigate potential new treatments based on their findings. “All these proteins are possible targets for drugs,” he said. “I think this is not far-fetched. It's something that is really feasible.”

Soto agreed. He pointed to other diseases that modern medicine has eradicated that may have seemed impossible at one point. “In 20 years from now, it's like people will say, ‘Oh, a lot of people actually in the past developed Parkinson's, but now we have an early detection, and we can actually apply good treatment, safe treatment, and nobody now develops Parkinson's disease anymore,’” he said. “Imagine a world without Parkinson’s, a world without Alzheimer's. So, our elderly population living good lives until the end. That's a very meaningful achievement.”

References

1. Schapira, A.H.V. Parkinson’s disease. BMJ    318, 311–314 (1999).
2. Stefanis, L. α-Synuclein in Parkinson’s Disease. Cold Spring Harb Perspect Med   2, a009399 (2012).
3. Wills, J. et al. Elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson’s disease brains with and without dementia. Exp Neurol    225, 210–218 (2010).
4. Saborio, G.P., Permanne, B., & Soto, C. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature   411, 810–813 (2001).
5. Shahnawaz, M. et al. Development of a Biochemical Diagnosis of Parkinson Disease by Detection of α-Synuclein Misfolded Aggregates in Cerebrospinal Fluid. JAMA Neurol   74, 163–172 (2017).
6. Gilboa, T. et al. Toward the quantification of α-synuclein aggregates with digital seed amplification assays. Proc Natl Acad Sci USA   121, e2312031121 (2024).
7. Hällqvist, J. et al. Plasma proteomics identify biomarkers predicting Parkinson’s disease up to 7 years before symptom onset. Nat Commun   15, 4759 (2024).