28 March 2019

Diagnosing Parkinson's is not easy. In particular in the early stages, it can be difficult to distinguish Parkinson's from a group of other disorders that at first sight look identical. In Annals of Neurology, researchers from Radboud umc and the University of Edinburgh describe a new biomarker that can quickly and reliably indicate whether someone has Parkinson's or not.

In a typical patient with Parkinson's disease, there is usually little doubt about the diagnosis. However, many patients display less typical symptoms. In this group, certainly in the early stages of the disease, it can be difficult to distinguish Parkinson's from a group of other disorders that at first sight look identical. There is a large group of other disorders within the Parkinson's spectrum that have overlapping symptoms, such as progressive supranuclear gaze palsy (PSP), parkinsonism as a result of medication use and vascular parkinsonism. This often leads to years of searching: after twelve years, ten percent of these patients still do not have a clear diagnosis! This leads to a great deal of uncertainty for patients, makes treatment less goal-oriented, and hinders scientific research.

Useful biomarkers

Researchers from Radboud umc and the University of Edinburgh have started looking for useful biomarkers that can shorten this search. Biomarkers are products in the metabolism that are very characteristic of a certain disease. Alpha-synuclein is such a substance. If this protein is folded incorrectly (misfolded), it has a stick-on effect. Other alpha-synucleins stick to it, creating protein cables (fibrils) that are characteristic of Parkinson's disease. These protein cables are absent in many other forms of parkinsonism.
In some people with an unclear form of Parkinson's disease, this misfolded protein can be detected at an early stage. That finding means that a patient almost certainly has Parkinson's.

More clarity

Marcel Verbeek from the Department of Neurology: “We have observed many people within the Parkinson spectrum. We have collected clinical data, DNA, body fluids and all kinds of other data. Together with the researchers from Edinburgh, who came up with the alpha-synuclein test, we checked whether the test worked for more than one hundred patients and fifty control subjects.” The results have now been published in Annals of Neurology. In more than eighty percent of patients with an unclear diagnosis, this test enabled physicians to reliably determine whether or not the patient had Parkinson's. Verbeek: “This test can make a very valuable contribution to the diagnosis of people with an unclear form of Parkinson's disease.”

Lighting up?

The test uses cerebrospinal fluid that is collected from the patient through a spinal puncture. But how can you determine whether this fluid contains misfolded alpha-synucleins? “Because of the extremely low concentration, they are difficult to demonstrate,” says Verbeek. “That's why we add a high concentration of well-folded proteins. This creates a domino effect: if misfolded alpha-synucleins are present in the patient's cerebrospinal fluid, they will also misfold the good proteins. When this happens, they will light up, because this activity activates a fluorescent substance. If light is generated, then there are misfolded alpha-synucleins present in the cerebrospinal fluid, and the patient probably has Parkinson's disease. If the proteins do not light up, the patient doesn't have Parkinson's disease, but another form of parkinsonism.”

Valuable addition

The new test with this biomarker can contribute, at an early stage, to more clarity for the group of patients without a completed diagnosis. “This is very important for patients who are sometimes in the dark about what ails them for ten years or longer,” says Verbeek. “A clear diagnosis also provides more information about the further progression of the disease, and the use of medication. If this test also yields good results in other research groups, it can be a valuable addition to Parkinson's diagnostics.”
 
Publication:
Alpha-synuclein RT-QuIC in the CSF of uncertain cases of parkinsonism
Anouke van Rumund, Alison JE Green, Graham Fairfoul, Rianne AJ Esselink, Bastiaan R Bloem, Marcel M Verbeek.
Annals of Neurology
 
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