Reacción a "Early signs of Parkinson's disease detected for the first time in post mortem brain tissue"

For the first time, an international team of scientists has managed to directly observe and measure the protein aggregates believed to trigger Parkinson's disease (PD). This breakthrough is key to the study of the fastest-growing neurological disease in the world. Using a new microscopy technique called ASA-PD, the researchers were able to identify and compare alpha-synuclein (aS) oligomers in post mortem samples of human brain tissue. They found that in PD patients, these oligomers are larger, brighter, and more abundant than in healthy brains. They also discovered a type of oligomer that only appears in patients with the disease, which could serve as an early marker of the disease. Clinical experts do not have tools at their disposal to efficiently diagnose PD. For these reasons, the finding described in the article is of great value, not only for understanding how the pathology begins, but also for opening up new possibilities for diagnosis and treatments that modify the course of the disease, which are not currently available.

The major breakthrough of the study is the development of a technique called ASA-PD (Advanced Sensing of Aggregates for Parkinson's Disease). This is an ultra-sensitive fluorescence microscopy method that allows the signal from oligomers, very small structures that are difficult to detect in the brain, to be “amplified” and the noise generated by other biological materials that coexist in brain tissue to be reduced. Thanks to this tool, scientists were able to observe and analyse millions of oligomers in human brain tissue samples, something that was previously impossible.

Despite the relevance of the technique and its possible application to other diseases, the greatest limitation we see is the definition of the oligomer. Depending on how broad or specific the definition is, aS oligomers can include many different types of species corresponding to different stages of the disease. While it is true that, in general terms, aS oligomers appear much earlier than Lewy bodies and are more clinically relevant, their definition in the article is broad. Therefore, according to their definition, oligomers could correspond to small fibrillar amyloids, less than 200 nm in size. According to data from our laboratory, toxic oligomers would be much smaller, less than 25 nm in size. In our opinion, it would be more correct to refer to the species detected in the article as prefibrillary species or small aggregates. Even so, we would like to emphasise the importance of the discovery made by the researchers, as the detection of aggregates, protofibrils or oligomers in tissue had only been achieved using indirect amplification methods.

Finally, we believe it is important to highlight the inherent difficulty of transferring scientific discoveries into real technologies in clinical settings. The process is often slow and costly due to technical and regulatory constraints. ASA-PD is applied to post mortem tissue. Therefore, the technology requires overcoming technical obstacles in order to be used in PD patients to study disease progression as a method of early diagnosis. These obstacles can range from increasing the sensitivity of the technique in living tissue to using harmless oligomer markers that can diffuse in the brain and provide an interpretable signal.

The combination of developing a disease-modifying therapy with efficient early diagnosis is the optimal scenario for which the research and clinical community should work. Without a doubt, ASA-PD has the characteristics and potential to become a crucial technique on this path.