Test of alpha-synuclein protein may help in Parkinson’s diagnosis: Study

AlphaSyn-SAA found to detect protein buildup 10 years before diagnosis

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A scientist used a microscope in a lab alongside a rack of vials and a beaker filled with blood.

A test known as the alpha-synuclein seed amplification assay, or alphaSyn-SAA, was able to measure the accumulation of alpha-synuclein protein in the blood up to 10 years before a clinical diagnosis of Parkinson’s disease, a study reported.

These findings support the use of such a blood test “as a diagnostic biomarker for prodromal [before symptoms appear] PD [Parkinson’s disease] activity,” the researchers wrote.

If further testing validates this method, it could help in “paving the way for early intervention approaches” in treating Parkinson’s, the team noted.

The study, “Detecting Misfolded α-Synuclein in Blood Years before the Diagnosis of Parkinson’s Disease,” was published in the journal Movement Disorders.

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Parkinson’s is characterized by motor symptoms, which are commonly used to reach a clinical diagnosis. Additional tests such as neuroimaging scans, and invasive brain and spinal fluid tests that detect clumps of the alpha-synuclein protein — a disease hallmark — are normally used to confirm a diagnosis.

However, nonmotor symptoms are commonly reported during the so-called prodromal stage of Parkinson’s, before the motor symptoms that define the diagnosis develop. One such early nonmotor symptom is isolated rapid eye movement sleep behavior disorder (iRBD). This condition is marked by acting out vivid and violent dreams while sleeping, during the phase of sleep in which most dreams occur.

Now, mounting evidence suggests that the accumulation of alpha-synuclein protein may occur years before patients show any symptoms, including such nonmotor symptoms.

Researchers in Germany previously have shown that they could identify the disease with 100% accuracy by performing a test called alpha-synuclein seed amplification assay, or alphaSyn-SAA, using blood samples from people with symptomatic Parkinson’s.

Toxic alpha-synuclein spreads in a prion-like fashion, meaning that clumps in one part of the brain can trigger more clumps to form in neighboring areas.

While the original alphaSyn-SAA assay uses spinal fluid — the liquid surrounding the brain and spinal cord — the researchers here used a tweaked version in which they added a seed of clumped alpha-synuclein to a sample of blood, observing whether the clumping spreads in the prion-like manner characteristic of Parkinson’s.

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Now, the same team evaluated whether they could also diagnose Parkinson’s using the same principle in patients at the prodromal phase of the disease.

They retrospectively analyzed blood samples from participants in the TREND study, which enrolled 1,201 participants, ages 50 to 80, without a diagnosis of Parkinson’s. These participants have been examined using several tests since 2009.

At the time of the analysis, in 2022, 20 people had been diagnosed with Parkinson’s based on clinical examination. The team analyzed blood samples from 12 of these patients, who had a mean age of 68. They compared them with blood samples from 13 age- and sex-matched healthy participants, followed for at least nine years, who served as controls. Additionally, samples from 20 patients with iRBD (mean age, 66 years) not included in the TREND study also were analyzed.

From the blood samples, the team isolated extracellular vesicles released by nerve cells, called neuronal extracellular vesicles. Extracellular vesicles are carriers of cargo between cells and are believed to be one of the ways that alpha-synuclein aggregates propagate.

They first confirmed the presence of alpha-synuclein toxic clumps in the neuronal extracellular vesicles from all 12 Parkinson’s patients, tested at least once before their diagnosis, using a technique called immunoblotting. That method separates proteins based on their size, and identifies specific proteins by using antibodies that bind to them. Among the healthy controls, one sample also tested positive.

In the alphaSyn-SAA test, all Parkinson’s patients were positive for the presence of accumulated toxic alpha-synuclein, while all healthy participants were negative. Among the iRBD group, a positive alphaSyn-SAA test was observed in six of the 20 patients (30%).

We believe that this blood-based SAA holds great potential as a future diagnostic biomarker for the prodromal phase of PD [Parkinson’s disease].

When testing patients during their prodromal phase, the results showed that all of them had a positive result in the alphaSyn-SAA assay. The time from a positive test to a clinical Parkinson’s diagnosis varied from one to 10 years.

Among the 12 patients with incident Parkinson’s, 11 of them showed mild motor signs before the diagnosis, as assessed by the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale-Part 3 (MDS-UPDRS-III).

Among nonmotor symptoms, a decreased sense of smell was observed in 10 patients.

“We believe that this blood-based SAA holds great potential as a future diagnostic biomarker for the prodromal phase of PD [Parkinson’s disease],” the study concluded.