2023-04-21 09:25:53
New test detects the nerve disease before it broke out
by Sandra Wilcken
(21.04.2023) For the first time, the misfolded protein alpha-synuclein can be detected in the cerebrospinal fluid of people with Parkinson’s disease, even before the onset of motor symptoms. The new test could enable early and accurate diagnosis and treatment of the condition before the brain is too badly damaged, according to a study published in The Lancet Neurology in May 2023.
“This result of complex methodological developments in recent years is a milestone for Parkinson’s research and a breakthrough in the field of biomarkers and for the development of new therapies,” confirms PD Dr. Kathrin Brockmann, senior physician and head of the Parkinson’s outpatient clinic at the University Hospital in Tübingen and member of the board of the German Society for Parkinson’s and Movement Disorders (DPG).
In Parkinson’s disease, the protein alpha-synuclein clumps together and accumulates in the brain. This leads to malfunction and death of the nerve cells. The new method, known as the Alpha-Synuclein Seed Amplification Assay (SAA), enables the misfolded protein to be detected in the cerebrospinal fluid, which could be an early indication of imminent Parkinson’s disease.
Early detection before the brain is damaged
Research teams from the USA, Israel and Germany (Kassel and Tübingen) were involved in the multi-centre worldwide study, which was funded by the Michael J Fox Foundation (Parkinson’s Progression Markers Initiative (PPMI)). In the study, a total of 1123 people with diagnosed Parkinson’s disease, frequent pre-stages of the disease and healthy people were examined using the new method. Across all groups examined, the test found the misfolded protein in 88 percent. In people with pre-PD, the hit rate depended heavily on the symptoms: the protein was detected in 97 percent of participants with an impaired sense of smell, but only in 63 percent of people with REM dream sleep disorder.
However, in most of the participants with pre-Parkinson’s disease in whom the protein was detected in the cerebrospinal fluid, there was still no evidence of changes in the nerve cells in the substantia nigra. The discovery of misfolded alpha-synucleins in the cerebrospinal fluid could thus indicate the development of Parkinson’s disease very early on – a prerequisite for the use of new modifying therapies in therapy studies.
Differences in people with genetic risk factors
Interestingly, the cerebrospinal fluid in Parkinson’s patients with genetic changes shows very different profiles depending on the affected gene. In a study by the Tübingen research team involved in developing the method, 93 percent of Parkinson’s patients with mutations in the GBA gene had a clear alpha-synuclein profile, while this was found in only 78 percent of patients with a mutation in the LRRK2 gene and patients with two mutations in the genes Parkin or PINK1 had no misfolded alpha-synuclein in the cerebrospinal fluid.
These results from the German study have now been confirmed in the global PPMI study. “The different sensitivities are an indication of the different ways in which the misfolded alpha-synuclein spreads in the nervous system,” explains PD Dr. Catherine Brockman. Thus, the (cerebrospinal fluid) analysis with this new SAA is suitable for identifying patients with misfolded alpha-synuclein. “Since there are actually initial studies with vaccinations against misfolded forms of alpha-synuclein, it is important to predict which patients have misfolded alpha-synuclein, which drives the progression of the disease,” says Dr. Brockman.
Milestone for the development of biomarkers and therapies
So far, the clumped protein could not be detected while alive. Those affected only come to the clinic for the diagnosis when they notice the classic motor symptoms such as slow movement, stiffness and tremors at rest. At this point, the disease process in the brain has been going on for many years.
“So we are actually too late with the diagnosis because many nerve cells have already died,” says Dr. Brockman. “With this test, we can now say directly for each patient individually whether the clumped alpha-synuclein is present. This not only significantly improves the diagnosis, but also the planning of Parkinson’s studies and ultimately the treatment of the patients. The test will definitely be used as a screening test in the future,” she says. The test works best in the cerebrospinal fluid, but less invasive analyzes in blood, skin and mucous membranes are also being examined in studies.
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