Parkinson’s is often misdiagnosed. New tests may change that.

A new wave of biomarker tests could improve diagnostic accuracy in early Parkinson’s disease and even diagnose it before symptoms begin. The tests detect the presence of an abnormal form of a protein called alpha-synuclein in the cerebrospinal fluid, skin or blood. A Parkinson’s diagnosis is typically confirmed by the discovery of abnormal alpha-synuclein in the postmortem brain.

“Initially, the clinical diagnosis of Parkinson’s is wrong, some studies say, up to half of the time. After five years, the accuracy improves, but that’s a long time for patients to wait for the more typical symptoms to arise,” said Andrew Siderowf, director of the Parkinson’s Disease and Movement Disorders Center at the University of Pennsylvania. “So, there’s a need for better diagnosis, and alpha-synuclein testing can help with that.”

Two tests of misfolded proteins

Normally, proteins fold into an ordered three-dimensional structure to become biologically functional. Some proteins fail to achieve this form and can cause neighboring proteins to also misfold, leading to large, toxic aggregates that damage cells, tissues and organs.

In patients with Parkinson’s disease, misfolded alpha-synuclein can often be found throughout the body — not only in the brain, but also in the gut, skin and blood. The misfolding is thought to begin years or even decades before the appearance of motor symptoms, leading to prodromal, or early, symptoms such as loss of sense of smell, constipation and REM sleep behavior disorder.

Two alpha-synuclein tests are commercially available in the United States, though they haven’t yet been approved by the Food and Drug Administration. The Syn-One Test, from CND Life Sciences, detects phosphorylated alpha-synuclein, a form of the protein that causes it to misfold, in skin biopsies. It has been ordered by “over 1,200 neurologists in 46 states to aid the diagnosis of 20,000 patients in the last few years,” CND Life Sciences said in March.

The SAAmplify-ɑSYN Test, from Amprion, directly detects the presence of misfolded alpha-synuclein in cerebrospinal fluid, which requires a spinal tap to retrieve.

“If you want to know if someone has Parkinson’s, the only way to know for sure is, when they die, eventually you look in their brains, and the pathology is the disease,” said Russ Lebovitz, chief executive and co-founder of Amprion. “What we have learned from 10 years of third-party validation studies is that our test literally predicts with incredible accuracy what you would see in the brain.”

A 2023 study of 1,123 participants found that the SAAmplify-ɑSYN Test was able to distinguish individuals with Parkinson’s from healthy controls with a sensitivity of 88 percent and specificity of 96 percent. Interestingly, 86 percent of participants who had not been diagnosed with Parkinson’s but had smell loss or REM sleep behavior disorder had a positive test.

Experts urge caution

However, experts have expressed concern about individuals getting tested with the new technology — particularly, those with no motor symptoms — stressing that more research is needed to understand what a positive or negative test means in terms of clinical practice.

“If a patient came to my clinic having done the test, I’d be a bit wary about knowing how to interpret it and what I would tell the patient on the basis of the result,” said Huw Morris, a professor of neurology and neurogenetics at University College London. “It’s extremely interesting and helpful from a research point of view, but I’m not sure it really changes what we’re doing with patients in the clinic at the moment.”

“People really have to talk to an expert to help guide them and get counseling on whether to get the test since, right now, we don’t have any therapies that can slow the progression of Parkinson’s,” said Ted M. Dawson, Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases at Johns Hopkins University School of Medicine.

Misfolded proteins can signal many different diseases

The main clinical challenge is not in distinguishing Parkinson’s from healthy controls but in differentiating Parkinson’s from diseases with similar features, Morris said. As of now, alpha-synuclein testing may rule out some conditions such as essential tremor, but not others.

Abnormal alpha-synuclein is a hallmark of synucleinopathies, a group of neurodegenerative diseases characterized by aggregates of the protein, of which Parkinson’s is the most common but also includes Lewy body dementia and others. Because of this, both Amprion and CND Life Sciences state on their websites that their tests help diagnose synucleinopathies in general.

“One of the things that’s important is that the tests aren’t really tests to diagnose Parkinson’s disease. The tests identify alpha-synuclein pathology,” Siderowf said. “Those two things are nearly the same, but not exactly the same, and you can still have clinical features of Parkinson’s disease like tremor and not have a positive alpha-synuclein test.”

For reasons not yet fully understood, about 10 percent of patients with Parkinson’s disease meeting clinical criteria have a negative alpha-synuclein result. They may have another disease altogether, such as progressive supranuclear palsy (PSP), a rare neurological disorder with symptoms similar to Parkinson’s. There are also genetic forms of Parkinson’s that result in less alpha-synuclein pathology.

On the other hand, those diagnosed with other diseases can end up with a positive test. A recent study discovered that 38.1 percent of participants with Alzheimer’s disease had a positive alpha-synuclein test. And earlier this year, Morris and his colleagues found that roughly 10 percent of patients with PSP tested positive for misfolded alpha-synuclein.

“That doesn’t mean they’ve got Parkinson’s disease. They’ve still got PSP, and that’s their clinical diagnosis,” Morris said. “What it probably means is they’ve got some synuclein co-pathologies — they’ve got a bit of synuclein their brain as well — but their predominant problem is that they’ve got a PSP condition.”

Biomarker tests could improve accuracy in the future

Despite the caveats for clinical use, experts agree that the effect of alpha-synuclein testing on research studies will be monumental. Having a biomarker test would accelerate research toward a better understanding of Parkinson’s, as well as the development of therapies that can slow or stop disease progression.

In August, the FDA issued a Letter of Support encouraging scientists and drug developers to use alpha-synuclein testing in cerebrospinal fluid to improve the efficiency of clinical trials targeting early intervention for Parkinson’s and similar neurodegenerative disorders.

As the technology is further refined, alpha-synuclein testing could routinely provide a more accurate way to diagnose Parkinson’s and related conditions, years or decades earlier than today’s methods. Research groups are actively working on a blood test, as well as ways to differentiate Parkinson’s from other diseases by how the protein misfolds.

“Cancers are now biologically and molecularly defined, with therapy based upon the type of cancer you have — and eventually, it’s probably going to be the same for Parkinson’s disease,” Dawson said. “We’re not there yet, but that’s where the field is going.”

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