Dhe detection of a protein in the cerebrospinal fluid enables Parkinson’s to be diagnosed long before the onset of the disease – and even before the onset of brain damage. An international research team writes that the test can significantly improve the development of therapies in the journal The Lancet Neurology. In a “Lancet” comment, Daniela Berg and Christine Klein from the Schleswig-Holstein University Hospital write that the method for detecting the misfolded protein alpha-synuclein is a “game changer” for the diagnosis, research and treatment of Parkinson’s. The President of the German Society of Neurology (DGN), Lars Timmermann, expects the findings to have an impact on new therapies over the next few years.
According to estimates, around 300,000 people live with Parkinson’s disease in Germany, making it the second most common neurodegenerative disease following Alzheimer’s dementia. The treatment of Parkinson’s has so far been subject to a major dilemma: if the disease is diagnosed on the basis of typical movement disorders such as tremors or muscle stiffness, the substantia nigra brain area, which is crucial for the coordination of movements, has been damaged for years.
Genetic risk factors such as the gene variants GBA and LRRK2 increase the risk of disease, as do other influences such as age, exposure to pesticides or brain trauma. The misfolded protein alpha-synuclein (α-synuclein), which occurs in nerve cells, plays a key role. It can clump together and form deposits like the so-called Lewy bodies, which are considered the main feature of the disease in the substantia nigra.
The protein has recently been detected in the cerebrospinal fluid using a new method, the so-called Alpha-Synuclein Seed Amplification Assay (αSyn-SAA). In the current study, the team led by Andrew Siderowf from the University of Pennsylvania in Philadelphia – including researchers from Göttingen and Kassel – evaluated studies on 1123 people. In addition to patients with diagnosed Parkinson’s disease, these included people with two common early stages of the disease – the loss of the sense of smell and dream sleep disorders – as well as healthy people.
Overall, the test found the protein in 88 percent of Parkinson’s patients. In people with the sporadic form of the disease – i.e. without a particular genetic risk factor – the test showed a positive result of 93 percent. In patients with the genetic risk factor GBA it was even 96 percent. In patients with the LRRK2 variant, on the other hand, the proportion was only 68 percent – here studies indicate a possible different mechanism of the disease.
In people with pre-Parkinson’s disease, the hit rate depended heavily on the symptoms: If the sense of smell was impaired, the misfolded protein was detectable in a good 97 percent of the participants. In people with a dream sleep disorder, the proportion was only 63 percent.
Particularly important: In most participants with a pre-Parkinson’s disease in which the protein was present in the cerebrospinal fluid, there was no evidence of changes in the nerve cells in the substantia nigra. From this, the team deduces that alpha-synuclein can be a very early indication of the developing disease.
“The core problem with Parkinson’s is that we are too late with the therapies,” explains Timmermann, Director of the Department of Neurology at the University Hospital in Marburg. “We have to be able to reliably identify patients before the brain is damaged.” The study shows that this is possible with the method being examined.
This is also emphasized by the authors of the study: “Our results indicate that the αSyn-SAA method determines the biomarker for Parkinson’s disease very reliably,” says co-author Luis Concha from the biotechnology company Amprion in a “Lancet”. -Notice quoted. This makes it possible to diagnose the disease in the early stages. Apparently, the misfolded proteins spread before brain damage might be detected.
However, the method proved to be less reliable in people with the LRRK2 gene variant whose sense of smell was not impaired: Here the hit rate was just under 35 percent. For women in this group, it was just under 13 percent – in absolute numbers: 3 out of 24.
This is also an important finding: “The results of our study have direct consequences for the planning of clinical studies,” emphasize the authors. When examining therapies for people with the LRRK2 gene variant, the αSyn-SAA finding must be taken into account. “Similarly, for those therapies that target alpha-synuclein, one should consider the possibility that people without accumulation of the misfolded protein may respond differently to treatment.”
A look at the recent past shows how important this might be: In 2022, two large studies with antibodies once morest alpha-synuclein failed – a major setback for Parkinson’s research. This study data can now be analyzed once more, taking into account the current findings, says Timmermann.
German commentators Berg and Klein stress that we are entering “a new era in the development of biomarkers and therapies for Parkinson’s disease”. The ability to detect misfolded alpha-synuclein is “a groundbreaking development,” they write. However, compared to examining the cerebrospinal fluid (liquor), a less invasive blood test is desirable. A study recently demonstrated that this is fundamentally possible.
DGN President Timmermann can imagine that findings from the study might be reflected in new therapies in regarding five years.
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